Cardiovascular and intestinal responses to oxidative and nitrosative stress during prolonged magnesium deficiency.

PubMed

Weglicki, William B; Chmielinska, Joanna J; Kramer, Jay H; Mak, I Tong

2011-08-01

In rodents with dietary magnesium deficiency (Mg deficiency), hypomagnesemia, occurs leading to a rise in circulating substance P from neuronal tissues to trigger systemic inflammatory stress in cardiac and intestinal tissues. Sustained elevations of substance P may result from impaired neutral endopeptidase (NEP) activity due to reactive oxygen and reactive nitrogen species. Associated increase in intestinal permeability includes infiltration of WBC and endotoxemia, which can further amplify the systemic inflammatory response that leads to impaired contractile function associated with up-regulation of the cardiac CD14 endotoxin receptor. The neurogenic signal transduction pathways that we have identified in the pro-oxidant/pro-inflammatory processes found with prolonged hypomagnesemia are described in this report.

Cyanidin-3-O-glucoside inhibits NF-kB signalling in intestinal epithelial cells exposed to TNF-α and exerts protective effects via Nrf2 pathway activation.

PubMed

Ferrari, Daniela; Speciale, Antonio; Cristani, Mariateresa; Fratantonio, Deborah; Molonia, Maria Sofia; Ranaldi, Giulia; Saija, Antonella; Cimino, Francesco

2016-12-15

Chronic intestinal inflammatory disorders, such as Inflammatory Bowel Diseases (IBDs), are characterized by excessive release of proinflammatory mediators, intestinal barrier dysfunction and excessive activation of NF-kB cascade. Previous studies shown that TNF-α plays a central role in intestinal inflammation of IBDs and supported beneficial effects of flavonoids against chronic inflammatory diseases. In this study, we employed an in vitro model of acute intestinal inflammation using intestinal Caco-2 cells exposed to TNF-α. The protective effects of cyanidin-3-glucoside (C3G), an anthocyanin widely distributed in mediterranean diet, were then evaluated. Caco-2 cells exposure to TNF-α activated NF-kB proinflammatory pathway and induced IL6 and COX-2 expression. Cells pretreatment for 24h with C3G (20-40μM) prevented TNF-α-induced changes, and improved intracellular redox status. Our results demonstrated that C3G, also without any kind of stimulus, increased the translocation of the transcription factor Nrf2 into the nucleus so activating antioxidant and detoxifying genes. In conclusion, C3G exhibited protective effects through the inhibition of NF-kB signalling in Caco-2 cells and these beneficial effects appear to be due to its ability to activate cellular protective responses modulated by Nrf2. These data suggest that anthocyanins could contribute, as complementary or preventive approaches, to the management of chronic inflammatory diseases. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Preventative oral methylthioadenosine is anti-inflammatory and reduces DSS-induced colitis in mice

USDA-ARS?s Scientific Manuscript database

Methylthioadenosine (MTA) is a precursor of the methionine salvage pathway and has been shown to have anti-inflammatory properties in various models of acute and chronic inflammation. However, the anti-inflammatory properties of MTA in models of intestinal inflammation are not defined. We hypothesiz...

Chronic mucosal inflammation/inflammatory bowel disease-like inflammation after intestinal transplantation: where are we now?

PubMed

Matsumoto, Cal S; Zasloff, Michael A; Fishbein, Thomas M

2014-06-01

The purpose of this review is to highlight the similarities between inflammatory bowel disease and the state of the intestine allograft after transplantation. The mutant nucleotide-binding oligomerization protein 2 (NOD2) gene, which encodes for an intracellular protein that serves as an innate immune system microbial sensor in macrophages, dendritic cells, and certain intestinal epithelial cells, has been recognized as a risk factor in Crohn's disease. Similarly, recent studies have also highlighted the contribution the NOD2 mutation may have on intestinal failure itself. More specifically, in intestinal transplant recipients with the NOD2 mutation, the discovery of the reduced ability to prevent bacterial clearance, increased enterocyte stress response, and failure of key downstream expression of important cytokines and growth factors have been implicated as major factors in intestinal transplant outcomes, namely graft loss and septic death. Treatment strategies with anti tumor necrosis factor (TNF) α, similar to inflammatory bowel disease, have been employed in intestinal transplantation with promising results. In intestinal transplantation, there is evidence that the classical alloimmunity pathways that lead toward graft dysfunction and eventual graft loss may, in fact, be working in concert with a disordered innate immune system to produce a state of chronic inflammation not unlike that seen in inflammatory bowel disease.

Olive oil polyphenols reduce oxysterols -induced redox imbalance and pro-inflammatory response in intestinal cells.

PubMed

Serra, Gessica; Incani, Alessandra; Serreli, Gabriele; Porru, Laura; Melis, M Paola; Tuberoso, Carlo I G; Rossin, Daniela; Biasi, Fiorella; Deiana, Monica

2018-05-16

Dietary habits may strongly influence intestinal homeostasis. Oxysterols, the oxidized products of cholesterol present in cholesterol-containing foodstuffs, have been shown to exert pro-oxidant and pro-inflammatory effects, altering intestinal epithelial layer and thus contributing to the pathogenesis of human inflammatory bowel diseases and colon cancer. Extra virgin olive oil polyphenols possess antioxidant and anti-inflammatory properties, and concentrate in the intestinal lumen, where may help in preventing intestinal diseases. In the present study we evaluated the ability of an extra virgin olive oil phenolic extract to counteract the pro-oxidant and pro-inflammatory action of a representative mixture of dietary oxysterols in the human colon adenocarcinoma cell line (Caco-2) undergoing full differentiation into enterocyte-like cells. Oxysterols treatment significantly altered differentiated Caco-2 cells redox status, leading to oxidant species production and a decrease of GSH levels, after 1 h exposure, followed by an increase of cytokines production, IL-6 and IL-8, after 24 h. Oxysterol cell treatment also induced after 48 h an increase of NO release, due to the induction of iNOS. Pretreatment with the phenolic extract counteracted oxysterols effects, at least in part by modulating one of the main pathways activated in the cellular response to the action of oxysterols, the MAPK-NF-kB pathway. We demonstrated the ability of the phenolic extract to directly modulate p38 and JNK1/2 phosphorylation and activation of NF-kB, following its inhibitor IkB phosphorylation. The phenolic extract also inhibited iNOS induction, keeping NO concentration at the control level. Our results suggest a protective effect at intestinal level of extra virgin olive oil polyphenols, able to prevent or limit redox unbalance and the onset and progression of chronic intestinal inflammation. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment

PubMed Central

2012-01-01

Background The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically-related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status. Results Firmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohn's disease was notable for increases in virulence and secretion pathways. Conclusions This inferred functional metagenomic information provides the first insights into community-wide microbial processes and pathways that underpin IBD pathogenesis. PMID:23013615

Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux[S

PubMed Central

Meriwether, David; Sulaiman, Dawoud; Wagner, Alan; Grijalva, Victor; Kaji, Izumi; Williams, Kevin J.; Yu, Liqing; Fogelman, Spencer; Volpe, Carmen; Bensinger, Steven J.; Anantharamaiah, G. M.; Shechter, Ishaiahu; Fogelman, Alan M.; Reddy, Srinivasa T.

2016-01-01

The site and mechanism of action of the apoA-I mimetic peptide 4F are incompletely understood. Transintestinal cholesterol efflux (TICE) is a process involved in the clearance of excess cholesterol from the body. While TICE is responsible for at least 30% of the clearance of neutral sterols from the circulation into the intestinal lumen, few pharmacological agents have been identified that modulate this pathway. We show first that circulating 4F selectively targets the small intestine (SI) and that it is predominantly transported into the intestinal lumen. This transport of 4F into the SI lumen is transintestinal in nature, and it is modulated by TICE. We also show that circulating 4F increases reverse cholesterol transport from macrophages and cholesterol efflux from lipoproteins via the TICE pathway. We identify the cause of this modulation of TICE either as 4F being a cholesterol acceptor with respect to enterocytes, from which 4F enhances cholesterol efflux, or as 4F being an intestinal chaperone with respect to TICE. Our results assign a novel role for 4F as a modulator of the TICE pathway and suggest that the anti-inflammatory functions of 4F may be a partial consequence of the codependent intestinal transport of both 4F and cholesterol. PMID:27199144

Cell-free culture supernatant of Bifidobacterium breve CNCM I-4035 decreases pro-inflammatory cytokines in human dendritic cells challenged with Salmonella typhi through TLR activation.

PubMed

Bermudez-Brito, Miriam; Muñoz-Quezada, Sergio; Gomez-Llorente, Carolina; Matencio, Esther; Bernal, Maria J; Romero, Fernando; Gil, Angel

2013-01-01

Dendritic cells (DCs) constitute the first point of contact between gut commensals and our immune system. Despite growing evidence of the immunomodulatory effects of probiotics, the interactions between the cells of the intestinal immune system and bacteria remain largely unknown. Indeed,, the aim of this work was to determine whether the probiotic Bifidobacterium breve CNCM I-4035 and its cell-free culture supernatant (CFS) have immunomodulatory effects in human intestinal-like dendritic cells (DCs) and how they respond to the pathogenic bacterium Salmonella enterica serovar Typhi, and also to elucidate the molecular mechanisms involved in these interactions. Human DCs were directly challenged with B. breve/CFS, S. typhi or a combination of these stimuli for 4 h. The expression pattern of genes involved in Toll-like receptor (TLR) signaling pathway and cytokine secretion was analyzed. CFS decreased pro-inflammatory cytokines and chemokines in human intestinal DCs challenged with S. typhi. In contrast, the B. breve CNCM I-4035 probiotic strain was a potent inducer of the pro-inflammatory cytokines and chemokines tested, i.e., TNF-α, IL-8 and RANTES, as well as anti-inflammatory cytokines including IL-10. CFS restored TGF-β levels in the presence of Salmonella. Live B.breve and its supernatant enhanced innate immune responses by the activation of TLR signaling pathway. These treatments upregulated TLR9 gene transcription. In addition, CFS was a more potent inducer of TLR9 expression than the probiotic bacteria in the presence of S. typhi. Expression levels of CASP8 and IRAK4 were also increased by CFS, and both treatments induced TOLLIP gene expression. Our results indicate that the probiotic strain B. breve CNCM I-4035 affects the intestinal immune response, whereas its supernatant exerts anti-inflammatory effects mediated by DCs. This supernatant may protect immune system from highly infectious agents such as Salmonella typhi and can down-regulate pro-inflammatory pathways.

Cell-Free Culture Supernatant of Bifidobacterium breve CNCM I-4035 Decreases Pro-Inflammatory Cytokines in Human Dendritic Cells Challenged with Salmonella typhi through TLR Activation

PubMed Central

Bermudez-Brito, Miriam; Muñoz-Quezada, Sergio; Gomez-Llorente, Carolina; Matencio, Esther; Bernal, Maria J.; Romero, Fernando; Gil, Angel

2013-01-01

Dendritic cells (DCs) constitute the first point of contact between gut commensals and our immune system. Despite growing evidence of the immunomodulatory effects of probiotics, the interactions between the cells of the intestinal immune system and bacteria remain largely unknown. Indeed,, the aim of this work was to determine whether the probiotic Bifidobacterium breve CNCM I-4035 and its cell-free culture supernatant (CFS) have immunomodulatory effects in human intestinal-like dendritic cells (DCs) and how they respond to the pathogenic bacterium Salmonella enterica serovar Typhi, and also to elucidate the molecular mechanisms involved in these interactions. Human DCs were directly challenged with B. breve/CFS, S. typhi or a combination of these stimuli for 4 h. The expression pattern of genes involved in Toll-like receptor (TLR) signaling pathway and cytokine secretion was analyzed. CFS decreased pro-inflammatory cytokines and chemokines in human intestinal DCs challenged with S. typhi. In contrast, the B. breve CNCM I-4035 probiotic strain was a potent inducer of the pro-inflammatory cytokines and chemokines tested, i.e., TNF-α, IL-8 and RANTES, as well as anti-inflammatory cytokines including IL-10. CFS restored TGF-β levels in the presence of Salmonella. Live B.breve and its supernatant enhanced innate immune responses by the activation of TLR signaling pathway. These treatments upregulated TLR9 gene transcription. In addition, CFS was a more potent inducer of TLR9 expression than the probiotic bacteria in the presence of S. typhi. Expression levels of CASP8 and IRAK4 were also increased by CFS, and both treatments induced TOLLIP gene expression. Our results indicate that the probiotic strain B. breve CNCM I-4035 affects the intestinal immune response, whereas its supernatant exerts anti-inflammatory effects mediated by DCs. This supernatant may protect immune system from highly infectious agents such as Salmonella typhi and can down-regulate pro-inflammatory pathways. PMID:23555025

TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease

PubMed Central

Yoneno, Kazuaki; Hisamatsu, Tadakazu; Shimamura, Katsuyoshi; Kamada, Nobuhiko; Ichikawa, Riko; Kitazume, Mina T; Mori, Maiko; Uo, Michihide; Namikawa, Yuka; Matsuoka, Katsuyoshi; Sato, Toshiro; Koganei, Kazutaka; Sugita, Akira; Kanai, Takanori; Hibi, Toshifumi

2013-01-01

Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (Mϕs) and dendritic cells. Mϕs differentiated with macrophage colony-stimulating factor and interferon-γ (Mγ-Mϕs), which are similar to the human intestinal lamina propria CD14+ Mϕs that contribute to Crohn's disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated Mϕ and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-α production in Mγ-Mϕs stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5–cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-κB p65 activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with CD. Compared with non-inflammatory bowel disease, inflamed CD LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14+ intestinal Mϕs from patients with CD expressed TGR5. In isolated intestinal CD14+ Mϕs, a TGR5 agonist could inhibit tumour necrosis factor-α production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease. PMID:23566200

Polyphenol supplementation as a complementary medicinal approach to treating inflammatory bowel disease.

PubMed

Biasi, F; Astegiano, M; Maina, M; Leonarduzzi, G; Poli, G

2011-01-01

Inflammatory bowel disease (IBD) comprises a group of idiopathic chronic intestinal inflammation syndromes that are very common in developed countries. It is characterized by intermittent episodes of clinical remission and relapse, with recurrent inflammatory injury that can lead to structural damage of the intestine. The uncontrolled intestinal immune response to bacterial antigens leads to the production of abundant cytokines and chemokines, by activated leukocytes and epithelial cells, which trigger inflammatory and oxidative reactions. The current treatment of IBD consists in long-term anti-inflammatory therapy that, however, does not exclude relapses and side effects, frequently resulting in surgical intervention. Polyphenols have been acknowledged to be anti-oxidant and anti-inflammatory and therefore, have been proposed as an alternative natural approach to prevent or treat chronic inflammatory diseases. Most studies have been in animal models of colitis, using chemical inducers or mice defective in anti-inflammatory mediators and in intestinal cell lines treated with pro-inflammatory cytokines or lipid oxidation products. These studies provide evidence that polyphenols can effectively modulate intestinal inflammation. They exert their effects by modulating cell signaling pathways, mainly activated in response to oxidative and inflammatory stimuli, and NF-kB is the principal downstream effector. Polyphenols may thus be considered able to prevent or delay the progression of IBD, especially because they reach higher concentrations in the gut than in other tissues. However, knowledge of the use of polyphenols in managing human IBD is still scanty, and further clinical studies should afford more solid evidence of their beneficial effects.

Berberine promotes recovery of colitis and inhibits inflammatory responses in colonic macrophages and epithelial cells in DSS-treated mice

PubMed Central

Wang, Lihong; Shi, Yan; Cao, Hanwei; Liu, Liping; Washington, M. Kay; Chaturvedi, Rupesh; Israel, Dawn A.; Cao, Hailong; Wang, Bangmao; Peek, Richard M.; Wilson, Keith T.; Polk, D. Brent

2012-01-01

Inflammatory bowel disease (IBD) results from dysregulation of intestinal mucosal immune responses to microflora in genetically susceptible hosts. A major challenge for IBD research is to develop new strategies for treating this disease. Berberine, an alkaloid derived from plants, is an alternative medicine for treating bacterial diarrhea and intestinal parasite infections. Recent studies suggest that berberine exerts several other beneficial effects, including inducing anti-inflammatory responses. This study determined the effect of berberine on treating dextran sulfate sodium (DSS)-induced intestinal injury and colitis in mice. Berberine was administered through gavage to mice with established DSS-induced intestinal injury and colitis. Clinical parameters, intestinal integrity, proinflammatory cytokine production, and signaling pathways in colonic macrophages and epithelial cells were determined. Berberine ameliorated DSS-induced body weight loss, myeloperoxidase activity, shortening of the colon, injury, and inflammation scores. DSS-upregulated proinflammatory cytokine levels in the colon, including TNF, IFN-γ, KC, and IL-17 were reduced by berberine. Berberine decreased DSS-induced disruption of barrier function and apoptosis in the colon epithelium. Furthermore, berberine inhibited proinflammatory cytokine production in colonic macrophages and epithelial cells in DSS-treated mice and promoted apoptosis of colonic macrophages. Activation of signaling pathways involved in stimulation of proinflammatory cytokine production, including MAPK and NF-κB, in colonic macrophages and epithelial cells from DSS-treated mice was decreased by berberine. In summary, berberine promotes recovery of DSS-induced colitis and exerts inhibitory effects on proinflammatory responses in colonic macrophages and epithelial cells. Thus berberine may represent a new therapeutic approach for treating gastrointestinal inflammatory disorders. PMID:22173918

Lipopolysaccharide regulation of intestinal tight junction permeability is mediated by TLR-4 signal transduction pathway activation of FAK and MyD88

PubMed Central

Guo, Shuhong; Nighot, Meghali; Al-Sadi, Rana; Alhmoud, Tarik; Nighot, Prashant; Ma, Thomas Y.

2015-01-01

Gut-derived bacterial lipopolysaccharides (LPS) play an essential role in inducing intestinal and systemic inflammatory responses and have been implicated as a pathogenic factor of necrotizing enterocolitis (NEC) and inflammatory bowel disease (IBD). The defective intestinal tight junction (TJ) barrier has been shown to be an important factor contributing to the development of intestinal inflammation. LPS, at physiological concentrations, cause an increase in intestinal tight junction permeability (TJP) via a TLR-4 dependent process; however the intracellular mechanisms that mediate LPS regulation of intestinal TJP remain unclear. The aim of this study was to investigate the adaptor proteins and the signaling interactions that mediate LPS modulation of intestinal TJ barrier using an in-vitro and in-vivo model system. LPS caused a TLR-4 dependent activation of membrane-associated adaptor protein FAK in Caco-2 monolayers. LPS caused an activation of both MyD88-dependent and –independent pathways. SiRNA silencing of MyD88 prevented LPS-induced increase in TJP. LPS caused a MyD88-dependent activation of IRAK4. TLR-4, FAK and MyD88 were co-localized. SiRNA silencing of TLR-4 inhibited TLR-4 associated FAK activation; and FAK knockdown prevented MyD88 activation. In-vivo studies also confirmed that LPS-induced increase in mouse intestinal permeability was associated with FAK and MyD88 activation; knockdown of intestinal epithelial FAK prevented LPS-induced increase in intestinal permeability. Additionally, high dose LPS-induced intestinal inflammation was also dependent on TLR-4/FAK/MyD88 signal-transduction axis. Our data show for the first time that LPS-induced increase in intestinal TJP and intestinal inflammation was regulated by TLR-4 dependent activation of FAK-MyD88-IRAK4 signaling pathway. PMID:26466961

Differential Effect of Lactobacillus johnsonii BFE 6128 on Expression of Genes Related to TLR Pathways and Innate Immunity in Intestinal Epithelial Cells.

PubMed

Seifert, Stephanie; Rodriguez Gómez, Manuel; Watzl, Bernhard; Holzapfel, Wilhelm H; Franz, Charles M A P; Vizoso Pinto, María G

2010-12-01

Probiotics have been shown to enhance immune defenses, but their mechanisms of action are only partially understood. We investigated the modulation of signal pathways involved in innate immunity in enterocytes by Lactobacillus johnsonii BFE 6128 isolated from 'Kule naoto', a Maasai traditional fermented milk product. This lactobacillus sensitized HT29 intestinal epithelial cells toward recognition of Salmonella enterica serovar Typhimurium by increasing the IL-8 levels released after challenge with this pathogen and by differentially modulating genes related to toll-like receptor (TLR) pathways and innate immunity. Thus, the modulation of pro-inflammatory mediators and TLR-pathway-related molecules may be an important mechanism contributing to the potential stimulation of innate immunity by lactobacilli at the intestinal epithelial level.

Inhibition of cyclooxygenase-2 alleviates liver cirrhosis via improvement of the dysfunctional gut-liver axis in rats.

PubMed

Gao, Jin-Hang; Wen, Shi-Lei; Tong, Huan; Wang, Chun-Hui; Yang, Wen-Juan; Tang, Shi-Hang; Yan, Zhao-Ping; Tai, Yang; Ye, Cheng; Liu, Rui; Huang, Zhi-Yin; Tang, Ying-Mei; Yang, Jin-Hui; Tang, Cheng-Wei

2016-06-01

Inflammatory transport through the gut-liver axis may facilitate liver cirrhosis. Cyclooxygenase-2 (COX-2) has been considered as one of the important molecules that regulates intestinal epithelial barrier function. This study was aimed to test the hypothesis that inhibition of COX-2 by celecoxib might alleviate liver cirrhosis via reduction of intestinal inflammatory transport in thiacetamide (TAA) rat model. COX-2/prostaglandin E2 (PGE2)/EP-2/p-ERK integrated signal pathways regulated the expressions of intestinal zonula occludens-1 (ZO-1) and E-cadherin, which maintain the function of intestinal epithelial barrier. Celecoxib not only decreased the intestinal permeability to a 4-kDa FITC-dextran but also significantly increased expressions of ZO-1 and E-cadherin. When celecoxib greatly decreased intestinal levels of LPS, TNF-α, and IL-6, it significantly enhanced T cell subsets reduced by TAA. As a result, liver fibrosis induced by TAA was significantly alleviated in the celecoxib group. These data indicated that celecoxib improved the integrity of intestinal epithelial barrier, blocked inflammatory transport through the dysfunctional gut-liver axis, and ameliorated the progress of liver cirrhosis. Copyright © 2016 the American Physiological Society.

Burns, inflammation, and intestinal injury: protective effects of an anti-inflammatory resuscitation strategy.

PubMed

Costantini, Todd W; Peterson, Carrie Y; Kroll, Lauren; Loomis, William H; Putnam, James G; Wolf, Paul; Eliceiri, Brian P; Baird, Andrew; Bansal, Vishal; Coimbra, Raul

2009-12-01

Intestinal barrier breakdown after severe burn can lead to intestinal inflammation, which may act as the source of the systemic inflammatory response. In vitro intestinal cell studies have shown that mitogen-activated protein kinase (MAPK) signaling is an important modulator of intestinal inflammation. We have previously observed that pentoxifylline (PTX) attenuates burn-induced intestinal permeability and tight junction breakdown. We hypothesized that PTX would limit intestinal barrier breakdown and attenuate inflammatory signaling via the MAPK pathway. Male balb/c mice underwent 30% total body surface area full-thickness steam burn. Immediately after burn, animals received an intraperitoneal injection of PTX (12.5 mg/kg) in normal saline or normal saline alone. In vivo intestinal permeability to 4 kDa fluorescein isothiocyanate-dextran was measured. Intestinal extracts were obtained to measure interleukin-6 by enzyme-linked immunosorbent assay, and phosphorylated p38 MAPK, p38 MAPK, phosphorylated extracellular signal-related kinase (1/2) (ERK (1/2)), and ERK (1/2) by immunoblotting. Acute lung injury was assessed by histology at 24 hours after burn. Administration of PTX immediately after injury attenuated burn-induced intestinal permeability. PTX also decreased the burn-induced phosphorylation of p38 MAPK and decreased phosphorylation of ERK (1/2) at 2 hours and 24 hours after injury. Animals given PTX had decreased intestinal interleukin-6 levels. A single dose of PTX also decreased histologic lung injury at 24 hours after burn. PTX attenuates burn-induced intestinal permeability and subsequent intestinal inflammation. Use of PTX after burn was also associated with decreased acute lung injury. Because of its compelling anti-inflammatory effects, PTX may be an ideal candidate for use as an immunomodulatory adjunct to resuscitation fluid.

Inhibitors of apoptosis (IAPs) regulate intestinal immunity and inflammatory bowel disease (IBD) inflammation.

PubMed

Pedersen, Jannie; LaCasse, Eric C; Seidelin, Jakob B; Coskun, Mehmet; Nielsen, Ole H

2014-11-01

The inhibitor of apoptosis (IAP) family members, notably cIAP1, cIAP2, and XIAP, are critical and universal regulators of tumor necrosis factor (TNF) mediated survival, inflammatory, and death signaling pathways. Furthermore, IAPs mediate the signaling of nucleotide-binding oligomerization domain (NOD)1/NOD2 and other intracellular NOD-like receptors in response to bacterial pathogens. These pathways are important to the pathogenesis and treatment of inflammatory bowel disease (IBD). Inactivating mutations in the X-chromosome-linked IAP (XIAP) gene causes an immunodeficiency syndrome, X-linked lymphoproliferative disease type 2 (XLP2), in which 20% of patients develop severe intestinal inflammation. In addition, 4% of males with early-onset IBD also have inactivating mutations in XIAP. Therefore, the IAPs play a greater role in gut homeostasis, immunity and IBD development than previously suspected, and may have therapeutic potential. Copyright © 2014 Elsevier Ltd. All rights reserved.

TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota.

PubMed

Ihara, Sozaburo; Hirata, Yoshihiro; Koike, Kazuhiko

2017-07-01

Inflammatory bowel disease (IBD) is defined as chronic intestinal inflammation, and includes ulcerative colitis and Crohn's disease. Multiple factors are involved in the pathogenesis of IBD, and the condition is characterized by aberrant mucosal immune reactions to intestinal microbes in genetically susceptible hosts. Transforming growth factor-β (TGF-β) is an immune-suppressive cytokine produced by many cell types and activated by integrins. Active TGF-β binds to its receptor and regulates mucosal immune reactions through the TGF-β signaling pathway. Dysregulated TGF-β signaling is observed in the intestines of IBD patients. TGF-β signal impairment in specific cell types, such as T-cells and dendritic cells, results in spontaneous colitis in mouse models. In addition, specific intestinal microbes contribute to immune homeostasis by modulating TGF-β production. In this review, we describe the role of TGF-β in intestinal immunity, focusing on immune cells, epithelium, and intestinal microbes. In addition, we present potential therapeutic strategies for IBD that target TGF-β.

Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice.

PubMed

The, Frans O; Boeckxstaens, Guy E; Snoek, Susanne A; Cash, Jenna L; Bennink, Roel; Larosa, Gregory J; van den Wijngaard, Rene M; Greaves, David R; de Jonge, Wouter J

2007-10-01

We previously showed that intestinal inflammation is reduced by electrical stimulation of the efferent vagus nerve, which prevents postoperative ileus in mice. We propose that this cholinergic anti-inflammatory pathway is mediated via alpha7 nicotinic acetylcholine receptors expressed on macrophages. The aim of this study was to evaluate pharmacologic activation of the cholinergic anti-inflammatory pathway in a mouse model for postoperative ileus using the alpha7 nicotinic acetylcholine receptor-agonist AR-R17779. Mice were pretreated with vehicle, nicotine, or AR-R17779 20 minutes before a laparotomy (L) or intestinal manipulation (IM). Twenty-four hours thereafter gastric emptying was determined using scintigraphy and intestinal muscle inflammation was quantified. Nuclear factor-kappaB transcriptional activity and cytokine production was assayed in peritoneal macrophages. Twenty-four hours after surgery IM led to a delayed gastric emptying compared with L (gastric retention: L(saline) 14% +/- 4% vs IM(saline) 38% +/- 10%, P = .04). Pretreatment with AR-R17779 prevented delayed gastric emptying (IM(AR-R17779) 15% +/- 4%, P = .03). IM elicited inflammatory cell recruitment (L(saline) 50 +/- 8 vs IM(saline) 434 +/- 71 cells/mm(2), P = .001) which was reduced by AR-R17779 pretreatment (IM(AR-R17779) 231 +/- 32 cells/mm(2), P = .04). An equimolar dose of nicotine was not tolerated. Subdiaphragmal vagotomy did not affect the anti-inflammatory properties of AR-R17779. In peritoneal macrophages, both nicotinic agonists reduced nuclear factor kappaB transcriptional activity and proinflammatory cytokine production, with nicotine being more effective than AR-R17779. AR-R17779 treatment potently prevents postoperative ileus, whereas toxicity limits nicotine administration to ineffective doses. Our data further imply that nicotinic inhibition of macrophage activation may involve other receptors in addition to alpha7 nicotinic acetylcholine receptor.

Review article: mitogen-activated protein kinases in chronic intestinal inflammation - targeting ancient pathways to treat modern diseases.

PubMed

Waetzig, G H; Schreiber, S

2003-07-01

Conventional treatment of chronic inflammatory disorders, including inflammatory bowel diseases, employs broad-range anti-inflammatory drugs. In order to reduce the side-effects and increase the efficacy of treatment, several strategies have been developed in the last decade to interfere with intercellular and intracellular inflammatory signalling processes. The highly conserved mitogen-activated protein kinase pathways regulate most cellular processes, particularly defence mechanisms such as stress reactions and inflammation. In this review, we provide an overview of the current knowledge of the specificity and interconnection of mitogen-activated protein kinase pathways, their functions in the gut immune system and published and ongoing studies on the role of mitogen-activated protein kinases in inflammatory bowel disease. The development of mitogen-activated protein kinase inhibitors and their use for the therapy of inflammatory disorders is a paradigm of the successful bridging of the gap between basic research and clinical practice.

Bioactive dietary peptides and amino acids in inflammatory bowel disease.

PubMed

Zhang, Hua; Hu, Chien-An A; Kovacs-Nolan, Jennifer; Mine, Yoshinori

2015-10-01

Inflammatory bowel disease (IBD), most commonly ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammation of the gastrointestinal tract. Patients affected with IBD experience symptoms including abdominal pain, persistent diarrhea, rectal bleeding, and weight loss. There is no cure for IBD; thus treatments typically focus on preventing complications, inducing and maintaining remission, and improving quality of life. During IBD, dysregulation of the intestinal immune system leads to increased production of pro-inflammatory cytokines, such as TNF-α and IL-6, and recruitment of activated immune cells to the intestine, causing tissue damage and perpetuating the inflammatory response. Recent biological therapies targeting specific inflammatory cytokines or pathways, in particular TNF-α, have shown promise, but not all patients respond to treatment, and some individuals become intolerant to treatment over time. Dietary peptides and amino acids (AAs) have been shown to modulate intestinal immune functions and influence inflammatory responses, and may be useful as alternative or ancillary treatments in IBD. This review focuses on dietary interventions for IBD treatment, in particular the role of dietary peptides and AAs in reducing inflammation, oxidative stress, and apoptosis in the gut, as well as recent advances in the cellular mechanisms responsible for their anti-inflammatory activity.

Mechanisms and function of autophagy in intestinal disease.

PubMed

Lassen, Kara G; Xavier, Ramnik J

2018-01-01

The discovery of numerous genetic variants in the human genome that are associated with inflammatory bowel disease (IBD) has revealed critical pathways that play important roles in intestinal homeostasis. These genetic studies have identified a critical role for macroautophagy/autophagy and more recently, lysosomal function, in maintaining the intestinal barrier and mucosal homeostasis. This review highlights recent work on the functional characterization of IBD-associated human genetic variants in cell type-specific functions for autophagy.

Immunobiotic Lactobacillus jensenii Elicits Anti-Inflammatory Activity in Porcine Intestinal Epithelial Cells by Modulating Negative Regulators of the Toll-Like Receptor Signaling Pathway

PubMed Central

Shimazu, Tomoyuki; Villena, Julio; Tohno, Masanori; Fujie, Hitomi; Hosoya, Shoichi; Shimosato, Takeshi; Aso, Hisashi; Suda, Yoshihito; Kawai, Yasushi; Saito, Tadao; Makino, Seiya; Ikegami, Shuji; Itoh, Hiroyuki

2012-01-01

The effect of Lactobacillus jensenii TL2937 on the inflammatory immune response triggered by enterotoxigenic Escherichia coli (ETEC) and lipopolysaccharide (LPS) in a porcine intestinal epitheliocyte cell line (PIE cells) was evaluated. Challenges with ETEC or LPS elicited Toll-like receptor 4 (TLR4)-mediated inflammatory responses in cultured PIE cells, indicating that our cell line may be useful for studying inflammation in the guts of weaning piglets. In addition, we demonstrated that L. jensenii TL2937 attenuated the expression of proinflammatory cytokines and chemokines caused by ETEC or LPS challenge by downregulating TLR4-dependent nuclear factorκB (NF-κB) and mitogen-activated protein kinase (MAPK) activation. Furthermore, we demonstrated that L. jensenii TL2937 stimulation of PIE cells upregulated three negative regulators of TLRs: A20, Bcl-3, and MKP-1, deepening the understanding of an immunobiotic mechanism of action. L. jensenii TL2937-mediated induction of negative regulators of TLRs would have a substantial physiological impact on homeostasis in PIE cells, because excessive TLR inflammatory signaling would be downregulated. These results indicated that PIE cells can be used to study the mechanisms involved in the protective activity of immunobiotics against intestinal inflammatory damage and may provide useful information for the development of new immunologically functional feeds that help to prevent inflammatory intestinal disorders, including weaning-associated intestinal inflammation. PMID:22083706

Intestinal CCL11 and eosinophilic inflammation is regulated by myeloid cell-specific RelA/p65 in mice.

PubMed

Waddell, Amanda; Ahrens, Richard; Tsai, Yi-Ting; Sherrill, Joseph D; Denson, Lee A; Steinbrecher, Kris A; Hogan, Simon P

2013-05-01

In inflammatory bowel diseases (IBDs), particularly ulcerative colitis, intestinal macrophages (MΦs), eosinophils, and the eosinophil-selective chemokine CCL11, have been associated with disease pathogenesis. MΦs, a source of CCL11, have been reported to be of a mixed classical (NF-κB-mediated) and alternatively activated (STAT-6-mediated) phenotype. The importance of NF-κB and STAT-6 pathways to the intestinal MΦ/CCL11 response and eosinophilic inflammation in the histopathology of experimental colitis is not yet understood. Our gene array analyses demonstrated elevated STAT-6- and NF-κB-dependent genes in pediatric ulcerative colitis colonic biopsies. Dextran sodium sulfate (DSS) exposure induced STAT-6 and NF-κB activation in mouse intestinal F4/80(+)CD11b(+)Ly6C(hi) (inflammatory) MΦs. DSS-induced CCL11 expression, eosinophilic inflammation, and histopathology were attenuated in RelA/p65(Δmye) mice, but not in the absence of STAT-6. Deletion of p65 in myeloid cells did not affect inflammatory MΦ recruitment or alter apoptosis, but did attenuate LPS-induced cytokine production (IL-6) and Ccl11 expression in purified F4/80(+)CD11b(+)Ly6C(hi) inflammatory MΦs. Molecular and cellular analyses revealed a link between expression of calprotectin (S100a8/S100a9), Ccl11 expression, and eosinophil numbers in the DSS-treated colon. In vitro studies of bone marrow-derived MΦs showed calprotectin-induced CCL11 production via a p65-dependent mechanism. Our results indicate that myeloid cell-specific NF-κB-dependent pathways play an unexpected role in CCL11 expression and maintenance of eosinophilic inflammation in experimental colitis. These data indicate that targeting myeloid cells and NF-κB-dependent pathways may be of therapeutic benefit for the treatment of eosinophilic inflammation and histopathology in IBD.

Intestinal CCL11 and eosinophilic inflammation is regulated by myeloid cell-specific RelA/p65 in mice

PubMed Central

Waddell, Amanda; Ahrens, Richard; Tsai, Yi Ting; Sherrill, Joseph D.; Denson, Lee A.; Steinbrecher, Kris A.; Hogan, Simon P.

2014-01-01

In inflammatory bowel diseases (IBD), particularly ulcerative colitis (UC), intestinal macrophages (MΦs), eosinophils and the eosinophil-selective chemokine CCL11 have been associated with disease pathogenesis. MΦs, a source of CCL11, have been reported to be of a mixed classical (NF-κB-mediated) and alternatively activated (STAT-6-mediated) phenotype. The importance of NF-κB and STAT-6 pathways to the intestinal MΦ/CCL11 response and eosinophilic inflammation in the histopathology of experimental colitis is not yet understood. Our gene array analyses demonstrated elevated STAT-6- and NF-κB-dependent genes in pediatric UC colonic biopsies. Dextran sodium sulphate (DSS) exposure induced STAT-6 and NF-κB activation in mouse intestinal F4/80+CD11b+Ly6Chi (inflammatory) MΦs. DSS-induced CCL11 expression, eosinophilic inflammation and histopathology were attenuated in RelA/p65Δmye mice but not in the absence of STAT-6. Deletion of p65 in myeloid cells did not affect inflammatory MΦ recruitment or alter apoptosis, but did attenuate lipopolysaccharide-induced cytokine production (IL-6) and Ccl11 expression in purified F4/80+CD11b+Ly6Chi inflammatory MΦs. Molecular and cellular analyses revealed a link between expression of calprotectin (S100a8/S100a9), Ccl11 expression and eosinophil numbers in the DSS-treated colon. In vitro studies of bone marrow-derived MΦs showed calprotectin-induced CCL11 production via a p65-dependent mechanism. Our results indicate that myeloid cell-specific NF-κB-dependent pathways play an unexpected role in CCL11 expression and maintenance of eosinophilic inflammation in experimental colitis. These data indicate that targeting myeloid cells and NF-κB-dependent pathways may be of therapeutic benefit for the treatment of eosinophilic inflammation and histopathology in IBD. PMID:23562811

Intestinal Effector T Cells in Health and Disease

PubMed Central

Maynard, Craig L.; Weaver, Casey T.

2011-01-01

Summary Crohn’s disease and ulcerative colitis are the two major forms of chronic relapsing inflammatory disorders of the human intestines collectively referred to as inflammatory bowel disease (IBD). Though a complex set of autoinflammatory disorders that can be precipitated by diverse genetic and environmental factors, a feature that appears common to IBD pathogenesis is a dysregulated effector T cell response to the commensal microbiota. Due to the heightened effector T cell activity in IBD, developmental and functional pathways that give rise to these cells are potential targets for therapeutic intervention. In this review, we highlight recent advances in our understanding of effector T cell biology in the context of intestinal immune regulation and speculate on their potential clinical significance. PMID:19766082

Vitamin D inhibits lipopolysaccharide-induced inflammatory response potentially through the Toll-like receptor 4 signalling pathway in the intestine and enterocytes of juvenile Jian carp (Cyprinus carpio var. Jian).

PubMed

Jiang, Jun; Shi, Dan; Zhou, Xiao-Qiu; Yin, Long; Feng, Lin; Jiang, Wei-Dan; Liu, Yang; Tang, Ling; Wu, Pei; Zhao, Ye

2015-11-28

The present study was conducted to investigate the anti-inflammatory effect of vitamin D both in juvenile Jian carp (Cyprinus carpio var. Jian) in vivo and in enterocytes in vitro. In primary enterocytes, exposure to 10 mg lipopolysaccharide (LPS)/l increased lactate dehydrogenase activity in the culture medium (P<0·05) and resulted in a significant loss of cell viability (P<0·05). LPS exposure increased (P<0·05) the mRNA expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-8), which was decreased by pre-treatment with 1,25-dihydroxyvitamin D (1,25D3) in a dose-dependent manner (P<0·05). Further results showed that pre-treatment with 1,25D3 down-regulated Toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (Myd88) and NF-κB p65 mRNA expression (P<0·05), suggesting potential mechanisms against LPS-induced inflammatory response. In vivo, intraperitoneal injection of LPS significantly increased TNF-α, IL-1β, IL-6 and IL-8 mRNA expression in the intestine of carp (P<0·05). Pre-treatment of fish with vitamin D3 protected the fish intestine from the LPS-induced increase of TNF-α, IL-1β, IL-6 and IL-8 mainly by downregulating TLR4, Myd88 and NF-κB p65 mRNA expression (P<0·05). These observations suggest that vitamin D could inhibit LPS-induced inflammatory response in juvenile Jian carp in vivo and in enterocytes in vitro. The anti-inflammatory effect of vitamin D is mediated at least in part by TLR4-Myd88 signalling pathways in the intestine and enterocytes of juvenile Jian carp.

Functional macrophages and gastrointestinal disorders.

PubMed

Liu, Yue-Hong; Ding, Yue; Gao, Chen-Chen; Li, Li-Sheng; Wang, Yue-Xiu; Xu, Jing-Dong

2018-03-21

Macrophages (MΦ) differentiate from blood monocytes and participate in innate and adaptive immunity. Because of their abilities to recognize pathogens and activate bactericidal activities, MΦ are always discovered at the site of immune defense. MΦ in the intestine are unique, such that in the healthy intestine, they possess complex mechanisms to protect the gut from inflammation. In these complex mechanisms, they produce anti-inflammatory cytokines, such as interleukin-10 and transforming growth factor-β, and inhibit the inflammatory pathways mediated by Toll-like receptors. It has been demonstrated that resident MΦ play a crucial role in maintaining intestinal homeostasis, and they can be recognized by their unique markers. Nonetheless, in the inflamed intestine, the function of MΦ will change because of environmental variation, which may be one of the mechanisms of inflammatory bowel disease (IBD). We provide further explanation about these mechanisms in our review. In addition, we review recent discoveries that MΦ may be involved in the development of gastrointestinal tumors. We will highlight the possible therapeutic targets for the management of IBD and gastrointestinal tumors, and we also discuss why more details are needed to fully understand all other effects of intestinal MΦ.

[Recent advances in Saccharomyces boulardii research].

PubMed

Im, E; Pothoulakis, C

2010-09-01

This review summarizes the probiotic mechanisms of action of Saccharomyces boulardii (S. boulardii) against inflammatory and non-inflammatory diarrheal conditions. S. boulardii is distributed in lyophilized form in many countries and used for the prevention of diarrhea in children and adults, including Clostridium difficile (C. difficile) associated infection. The main mechanisms of action of S. boulardii include inhibition of activities of bacterial pathogenic products, trophic effects on the intestinal mucosa, as well as modification of host signaling pathways involved in inflammatory and non-inflammatory intestinal diseases. S. boulardii inhibits production of pro-inflammatory cytokines by inhibiting main regulators of inflammation, including nuclear factor κB (NF-κB), and mitogen-activated protein kinases (MAP kinases), ERK1/2 and p38, but stimulates production of anti-inflammatory molecules such as peroxisome proliferator-activated receptor-gamma (PPAR-γ). Moreover, S. boulardii suppresses bacterial infection by inhibiting adhesion and/or overgrowth of bacteria, produces a serine protease that cleaves C. difficile toxin A, and stimulates antibody production against this toxin. Furthermore, S. boulardii may interfere with pathogenesis of Inflammatory Bowel Disease (IBD) by acting on T cells and acts in diarrheal conditions by improving the fecal biostructure in patients with diarrhea. These diverse mechanisms exerted by S. boulardii provide molecular clues for its effectiveness in diarrheal diseases and intestinal inflammatory conditions with an inflammatory component. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Hydrogen peroxide inhibits Ca2+-dependent chloride secretion across colonic epithelial cells via distinct kinase signaling pathways and ion transport proteins

PubMed Central

Chappell, Alfred E.; Bunz, Michael; Smoll, Eric; Dong, Hui; Lytle, Christian; Barrett, Kim E.; McCole, Declan F.

2018-01-01

Reactive oxygen species (ROS) are key mediators in a number of inflammatory conditions, including inflammatory bowel disease (IBD). ROS, including hydrogen peroxide (H2O2), modulate intestinal epithelial ion transport and are believed to contribute to IBD-associated diarrhea. Intestinal crypt fluid secretion, driven by electrogenic Cl− secretion, hydrates and sterilizes the crypt, thus reducing bacterial adherence. Here, we show that pathophysiological concentrations of H2O2 inhibit Ca2+-dependent Cl− secretion across T84 colonic epithelial cells by elevating cytosolic Ca2+, which contributes to activation of two distinct signaling pathways. One involves recruitment of the Ca2+-responsive kinases, Src and Pyk-2, as well as extracellular signal-regulated kinase (ERK). A separate pathway recruits p38 MAP kinase and phosphoinositide 3-kinase (PI3-K) signaling. The ion transport response to Ca2+-dependent stimuli is mediated in part by K+ efflux through basolateral K+ channels and Cl− uptake by the Na+-K+-2Cl− cotransporter, NKCC1. We demonstrate that H2O2 inhibits Ca2+-dependent basolateral K+ efflux and also inhibits NKCC1 activity independently of inhibitory effects on apical Cl− conductance. Thus, we have demonstrated that H2O2 inhibits Ca2+-dependent Cl− secretion through multiple negative regulatory signaling pathways and inhibition of specific ion transporters. These findings increase our understanding of mechanisms by which inflammation disturbs intestinal epithelial function and contributes to intestinal pathophysiology.—Chappell, A. E., Bunz, M., Smoll, E., Dong, H., Lytle, C., Barrett, K. E., McCole, D. F. Hydrogen peroxide inhibits Ca2+-dependent chloride secretion across colonic epithelial cells via distinct kinase signaling pathways and ion transport proteins. FASEB J. 22, 000–000 (2008) PMID:18211955

Catechol Groups Enable Reactive Oxygen Species Scavenging-Mediated Suppression of PKD-NFkappaB-IL-8 Signaling Pathway by Chlorogenic and Caffeic Acids in Human Intestinal Cells.

PubMed

Shin, Hee Soon; Satsu, Hideo; Bae, Min-Jung; Totsuka, Mamoru; Shimizu, Makoto

2017-02-20

Chlorogenic acid (CHA) and caffeic acid (CA) are phenolic compounds found in coffee, which inhibit oxidative stress-induced interleukin (IL)-8 production in intestinal epithelial cells, thereby suppressing serious cellular injury and inflammatory intestinal diseases. Therefore, we investigated the anti-inflammatory mechanism of CHA and CA, both of which inhibited hydrogen peroxide (H₂O₂)-induced IL-8 transcriptional activity. They also significantly suppressed nuclear factor kappa-light-chain-enhancer of activated B cells ( NF-κB ) transcriptional activity, nuclear translocation of the p65 subunit, and phosphorylation of IκB kinase (IKK). Additionally, upstream of IKK, protein kinase D (PKD) was also suppressed. Finally, we found that they scavenged H₂O₂-induced reactive oxygen species (ROS) and the functional moiety responsible for the anti-inflammatory effects of CHA and CA was the catechol group. Therefore, we conclude that the presence of catechol groups in CHA and CA allows scavenging of intracellular ROS, thereby inhibiting H₂O₂-induced IL-8 production via suppression of PKD-NF-κB signaling in human intestinal epithelial cells.

Characterization of intestinal inflammation and identification of related gene expression changes in mdr1a−/− mice

PubMed Central

Dommels, Y. E.M.; Zhu, S.; Davy, M.; Martell, S.; Hedderley, D.; Barnett, M. P.G.; McNabb, W. C.; Roy, N. C.

2007-01-01

Multidrug resistance targeted mutation (mdr1a−/−) mice spontaneously develop intestinal inflammation. The aim of this study was to further characterize the intestinal inflammation in mdr1a−/− mice. Intestinal samples were collected to measure inflammation and gene expression changes over time. The first signs of inflammation occurred around 16 weeks of age and most mdr1a−/− mice developed inflammation between 16 and 27 weeks of age. The total histological injury score was the highest in the colon. The inflammatory lesions were transmural and discontinuous, revealing similarities to human inflammatory bowel diseases (IBD). Genes involved in inflammatory response pathways were up-regulated whereas genes involved in biotransformation and transport were down-regulated in colonic epithelial cell scrapings of inflamed mdra1−/− mice at 25 weeks of age compared to non-inflamed FVB mice. These results show overlap to human IBD and strengthen the use of this in vivo model to study human IBD. The anti-inflammatory regenerating islet-derived genes were expressed at a lower level during inflammation initiation in non-inflamed colonic epithelial cell scrapings of mdr1a−/− mice at 12 weeks of age. This result suggests that an insufficiently suppressed immune response could be crucial to the initiation and development of intestinal inflammation in mdr1a−/− mice. PMID:18850176

TNF-α inhibits SCF, ghrelin, and substance P expressions through the NF-κB pathway activation in interstitial cells of Cajal.

PubMed

Ren, Keyu; Yong, Chunming; Yuan, Hao; Cao, Bin; Zhao, Kun; Wang, Jin

2018-01-01

Ulcerative colitis is a chronic inflammatory disease of the colon where intestinal motility is disturbed. Interstitial cells of Cajal (ICC) are required to maintain normal intestinal motility. In the present study, we assessed the effect of tumor necrosis factor-alpha (TNF-α) on viability and apoptosis of ICC, as well as on the expression of stem cell factor (SCF), ghrelin, and substance P. ICC were derived from the small intestines of Swiss albino mice. Cell viability and apoptosis were measured using CCK-8 assay and flow cytometry, respectively. ELISA was used to measure the concentrations of IL-1β, IL-6, ghrelin, substance P, and endothelin-1. Quantitative RT-PCR was used to measure the expression of SCF. Western blotting was used to measure the expression of apoptosis-related proteins, interleukins, SCF, and NF-κB signaling pathway proteins. TNF-α induced inflammatory injury in ICC by decreasing cell viability and increasing apoptosis and levels of IL-1β and IL-6. TNF-α decreased the levels of SCF, ghrelin, and substance P, but had no effect on endothelin-1. TNF-α down-regulated expressions of SCF, ghrelin, and substance P by activating the NF-κB pathway in ICC. In conclusion, TNF-α down-regulated the expressions of SCF, ghrelin, and substance P via the activation of the NF-κB pathway in ICC.

Cross-modulation of pathogen-specific pathways enhances malnutrition during enteric co-infection with Giardia lamblia and enteroaggregative Escherichia coli

PubMed Central

Bartelt, Luther A.; Bolick, David T.; Zaenker, Edna I.; Donowitz, Jeffery; Thomas-Beckett, Rose Viguna; Rogala, Allison; Carroll, Ian M.; Swann, Jonathan R.; Guerrant, Richard L.

2017-01-01

Diverse enteropathogen exposures associate with childhood malnutrition. To elucidate mechanistic pathways whereby enteric microbes interact during malnutrition, we used protein deficiency in mice to develop a new model of co-enteropathogen enteropathy. Focusing on common enteropathogens in malnourished children, Giardia lamblia and enteroaggregative Escherichia coli (EAEC), we provide new insights into intersecting pathogen-specific mechanisms that enhance malnutrition. We show for the first time that during protein malnutrition, the intestinal microbiota permits persistent Giardia colonization and simultaneously contributes to growth impairment. Despite signals of intestinal injury, such as IL1α, Giardia-infected mice lack pro-inflammatory intestinal responses, similar to endemic pediatric Giardia infections. Rather, Giardia perturbs microbial host co-metabolites of proteolysis during growth impairment, whereas host nicotinamide utilization adaptations that correspond with growth recovery increase. EAEC promotes intestinal inflammation and markers of myeloid cell activation. During co-infection, intestinal inflammatory signaling and cellular recruitment responses to EAEC are preserved together with a Giardia-mediated diminishment in myeloid cell activation. Conversely, EAEC extinguishes markers of host energy expenditure regulatory responses to Giardia, as host metabolic adaptations appear exhausted. Integrating immunologic and metabolic profiles during co-pathogen infection and malnutrition, we develop a working mechanistic model of how cumulative diet-induced and pathogen-triggered microbial perturbations result in an increasingly wasted host. PMID:28750066

Cross-modulation of pathogen-specific pathways enhances malnutrition during enteric co-infection with Giardia lamblia and enteroaggregative Escherichia coli.

PubMed

Bartelt, Luther A; Bolick, David T; Mayneris-Perxachs, Jordi; Kolling, Glynis L; Medlock, Gregory L; Zaenker, Edna I; Donowitz, Jeffery; Thomas-Beckett, Rose Viguna; Rogala, Allison; Carroll, Ian M; Singer, Steven M; Papin, Jason; Swann, Jonathan R; Guerrant, Richard L

2017-07-01

Diverse enteropathogen exposures associate with childhood malnutrition. To elucidate mechanistic pathways whereby enteric microbes interact during malnutrition, we used protein deficiency in mice to develop a new model of co-enteropathogen enteropathy. Focusing on common enteropathogens in malnourished children, Giardia lamblia and enteroaggregative Escherichia coli (EAEC), we provide new insights into intersecting pathogen-specific mechanisms that enhance malnutrition. We show for the first time that during protein malnutrition, the intestinal microbiota permits persistent Giardia colonization and simultaneously contributes to growth impairment. Despite signals of intestinal injury, such as IL1α, Giardia-infected mice lack pro-inflammatory intestinal responses, similar to endemic pediatric Giardia infections. Rather, Giardia perturbs microbial host co-metabolites of proteolysis during growth impairment, whereas host nicotinamide utilization adaptations that correspond with growth recovery increase. EAEC promotes intestinal inflammation and markers of myeloid cell activation. During co-infection, intestinal inflammatory signaling and cellular recruitment responses to EAEC are preserved together with a Giardia-mediated diminishment in myeloid cell activation. Conversely, EAEC extinguishes markers of host energy expenditure regulatory responses to Giardia, as host metabolic adaptations appear exhausted. Integrating immunologic and metabolic profiles during co-pathogen infection and malnutrition, we develop a working mechanistic model of how cumulative diet-induced and pathogen-triggered microbial perturbations result in an increasingly wasted host.

Western diet induces a shift in microbiota composition enhancing susceptibility to Adherent-Invasive E. coli infection and intestinal inflammation.

PubMed

Agus, Allison; Denizot, Jérémy; Thévenot, Jonathan; Martinez-Medina, Margarita; Massier, Sébastien; Sauvanet, Pierre; Bernalier-Donadille, Annick; Denis, Sylvain; Hofman, Paul; Bonnet, Richard; Billard, Elisabeth; Barnich, Nicolas

2016-01-08

Recent advances have shown that the abnormal inflammatory response observed in CD involves an interplay among intestinal microbiota, host genetics and environmental factors. The escalating consumption of fat and sugar in Western countries parallels an increased incidence of CD during the latter 20(th) century. The impact of a HF/HS diet in mice was evaluated for the gut micro-inflammation, intestinal microbiota composition, function and selection of an E. coli population. The HF/HS diet created a specific inflammatory environment in the gut, correlated with intestinal mucosa dysbiosis characterized by an overgrowth of pro-inflammatory Proteobacteria such as E. coli, a decrease in protective bacteria, and a significantly decreased of SCFA concentrations. The expression of GPR43, a SCFA receptor was reduced in mice treated with a HF/HS diet and reduced in CD patients compared with controls. Interestingly, mice treated with an agonist of GPR43 were protected against DSS-induced colitis. Finally, the transplantation of feces from HF/HS treated mice to GF mice increased susceptibility to AIEC infection. Together, our results demonstrate that a Western diet could aggravate the inflammatory process and that the activation of the GPR43 receptor pathway could be used as a new strategy to treat CD patients.

Western diet induces a shift in microbiota composition enhancing susceptibility to Adherent-Invasive E. coli infection and intestinal inflammation.

PubMed Central

Agus, Allison; Denizot, Jérémy; Thévenot, Jonathan; Martinez-Medina, Margarita; Massier, Sébastien; Sauvanet, Pierre; Bernalier-Donadille, Annick; Denis, Sylvain; Hofman, Paul; Bonnet, Richard; Billard, Elisabeth; Barnich, Nicolas

2016-01-01

Recent advances have shown that the abnormal inflammatory response observed in CD involves an interplay among intestinal microbiota, host genetics and environmental factors. The escalating consumption of fat and sugar in Western countries parallels an increased incidence of CD during the latter 20th century. The impact of a HF/HS diet in mice was evaluated for the gut micro-inflammation, intestinal microbiota composition, function and selection of an E. coli population. The HF/HS diet created a specific inflammatory environment in the gut, correlated with intestinal mucosa dysbiosis characterized by an overgrowth of pro-inflammatory Proteobacteria such as E. coli, a decrease in protective bacteria, and a significantly decreased of SCFA concentrations. The expression of GPR43, a SCFA receptor was reduced in mice treated with a HF/HS diet and reduced in CD patients compared with controls. Interestingly, mice treated with an agonist of GPR43 were protected against DSS-induced colitis. Finally, the transplantation of feces from HF/HS treated mice to GF mice increased susceptibility to AIEC infection. Together, our results demonstrate that a Western diet could aggravate the inflammatory process and that the activation of the GPR43 receptor pathway could be used as a new strategy to treat CD patients. PMID:26742586

Immunotherapy in inflammatory bowel disease: Novel and emerging treatments.

PubMed

Catalan-Serra, Ignacio; Brenna, Øystein

2018-04-06

Inflammatory bowel disease (IBD) is a chronic disabling inflammatory process that affects young individuals, with growing incidence. The etiopathogenesis of IBD remains poorly understood. A combination of genetic and environmental factors triggers an inadequate immune response against the commensal intestinal flora in IBD patients. Thus, a better understanding of the immunological mechanisms involved in IBD pathogenesis is central to the development of new therapeutic options. Current pharmacological treatments used in clinical practice like thiopurines or anti-TNF are effective but can produce significant side effects and their efficacy may diminish over time. In fact, up to one third of the patients do not have a satisfactory response to these therapies. Consequently, the search for new therapeutic strategies targeting alternative immunological pathways has intensified. Several new oral and parenteral substances are in the pipeline for IBD. In this review we discuss novel therapies targeting alternative pro-inflammatory pathways like IL-12/23 axis, IL-6 pathway or Janus Kinase inhibitors; as well as others modulating anti-inflammatory signalling pathways like transforming growth factor-β1 (TGF-β1). We also highlight new emerging therapies targeting the adhesion and migration of leukocytes into the inflamed intestinal mucosa by blocking selectively different subunits of α 4 β 7 integrins or binding alternative adhesion molecules like MAdCAM-1. Drugs reducing the circulating lymphocytes by sequestering them in secondary lymphoid organs (sphingosine-1-phosphate (S1P) receptor modulators) are also discussed. Finally, the latest advances in cell therapies using mesenchymal stem cells or engineered T regs are reviewed. In addition, we provide an update on the current status in clinical trials of these new immune-regulating therapies that open a new era in the treatment of IBD.

Cinnamon polyphenols regulate multiple metabolic pathways involved in insulin signaling and intestinal lipoprotein metabolism of small intestinal enterocytes.

PubMed

Qin, Bolin; Dawson, Harry D; Schoene, Norberta W; Polansky, Marilyn M; Anderson, Richard A

2012-01-01

Increasing evidence suggests that dietary factors may affect the expression of multiple genes and signaling pathways, which regulate intestinal lipoprotein metabolism. The small intestine is actively involved in the regulation of dietary lipid absorption, intracellular transport, and metabolism and is closely linked to systemic lipid metabolism. Cinnamon polyphenols have been shown to improve glucose, insulin, and lipid metabolism and improve inflammation in cell culture, animal, and human studies. However, little is known of the effects of an aqueous cinnamon extract (CE) on the regulation of genes and signaling pathways related to intestinal metabolism. The aim of the study was to investigate the effects of a CE on the primary enterocytes of chow-fed rats. Freshly isolated intestinal enterocytes were used to investigate apolipoprotein-B48 secretion by immunoprecipitation; gene expressions by quantitative reverse transcriptase-polymerase chain reaction and the protein and phosphorylation levels were evaluated by western blot and flow cytometric analyses. Ex vivo, the CE significantly decreased the amount of apolipoprotein-B48 secretion into the media, inhibited the mRNA expression of genes of the inflammatory cytokines, interleukin-1β, interleukin-6, and tumor necrosis factor-α, and induced the expression of the anti-inflammatory gene, Zfp36. CE also increased the mRNA expression of genes leading to increased insulin sensitivity, including Ir, Irs1, Irs2, Pi3k, and Akt1, and decreased Pten expression. CE also inhibited genes associated with increased cholesterol, triacylglycerols, and apolipoprotein-B48 levels, including Abcg5, Npc1l1, Cd36, Mttp, and Srebp1c, and facilitated Abca1 expression. CE also stimulated the phospho-p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and extracellular-signal-regulated kinase expressions determined by flow cytometry, with no changes in protein levels. These results demonstrate that the CE regulates genes associated with insulin sensitivity, inflammation, and cholesterol/lipogenesis metabolism and the activity of the mitogen-activated protein kinase signal pathway in intestinal lipoprotein metabolism. Copyright © 2012 Elsevier Inc. All rights reserved.

Lactobacillus amylovorus Inhibits the TLR4 Inflammatory Signaling Triggered by Enterotoxigenic Escherichia coli via Modulation of the Negative Regulators and Involvement of TLR2 in Intestinal Caco-2 Cells and Pig Explants

PubMed Central

Finamore, Alberto; Roselli, Marianna; Imbinto, Ambra; Seeboth, Julie; Oswald, Isabelle P.; Mengheri, Elena

2014-01-01

Inflammation derived from pathogen infection involves the activation of toll-like receptor (TLR) signaling. Despite the established immunomodulatory activities of probiotics, studies relating the ability of such bacteria to inhibit the TLR signaling pathways are limited or controversial. In a previous study we showed that Lactobacillus amylovorus DSM 16698T, a novel lactobacillus isolated from unweaned pigs, protects the intestinal cells from enterotoxigenic Escherichia coli (ETEC) K88 infection through cytokine regulation. In the present study we investigated whether the ability of L. amylovorus to counteract the inflammatory status triggered by ETEC in intestine is elicited through inhibition of the TLR4 signaling pathway. We used the human intestinal Caco-2/TC7 cells and intestinal explants isolated from 5 week-old crossbreed Pietrain/Duroc/Large-White piglets, treated with ETEC, L. amylovorus or L. amylovorus cell free supernatant, either alone or simultaneously with ETEC. Western blot analysis showed that L. amylovorus and its cell free supernatant suppress the activation of the different steps of TLR4 signaling in Caco-2/TC7 cells and pig explants, by inhibiting the ETEC induced increase in the level of TLR4 and MyD88, the phosphorylation of the IKKα, IKKβ, IκBα and NF-κB subunit p65, as well as the over-production of inflammatory cytokines IL-8 and IL-1β. The immunofluorescence analysis confirms the lack of phospho-p65 translocation into the nucleus. These anti-inflammatory effects are achieved through modulation of the negative regulators Tollip and IRAK-M. We also found that L. amylovorus blocks the up-regulation of the extracellular heat shock protein (Hsp)72 and Hsp90, that are critical for TLR4 function. By using anti-TLR2 antibody, we demonstrate that TLR2 is required for the suppression of TLR4 signaling activation. These results may contribute to develop therapeutic interventions using L. amylovorus in intestinal disorders of piglets and humans. PMID:24733511

Pro-Inflammatory Flagellin Proteins of Prevalent Motile Commensal Bacteria Are Variably Abundant in the Intestinal Microbiome of Elderly Humans

PubMed Central

Neville, B. Anne; Sheridan, Paul O.; Harris, Hugh M. B.; Coughlan, Simone; Flint, Harry J.; Duncan, Sylvia H.; Jeffery, Ian B.; Claesson, Marcus J.; Ross, R. Paul; Scott, Karen P.; O'Toole, Paul W.

2013-01-01

Some Eubacterium and Roseburia species are among the most prevalent motile bacteria present in the intestinal microbiota of healthy adults. These flagellate species contribute “cell motility” category genes to the intestinal microbiome and flagellin proteins to the intestinal proteome. We reviewed and revised the annotation of motility genes in the genomes of six Eubacterium and Roseburia species that occur in the human intestinal microbiota and examined their respective locus organization by comparative genomics. Motility gene order was generally conserved across these loci. Five of these species harbored multiple genes for predicted flagellins. Flagellin proteins were isolated from R. inulinivorans strain A2-194 and from E. rectale strains A1-86 and M104/1. The amino-termini sequences of the R. inulinivorans and E. rectale A1-86 proteins were almost identical. These protein preparations stimulated secretion of interleukin-8 (IL-8) from human intestinal epithelial cell lines, suggesting that these flagellins were pro-inflammatory. Flagellins from the other four species were predicted to be pro-inflammatory on the basis of alignment to the consensus sequence of pro-inflammatory flagellins from the β- and γ- proteobacteria. Many fliC genes were deduced to be under the control of σ28. The relative abundance of the target Eubacterium and Roseburia species varied across shotgun metagenomes from 27 elderly individuals. Genes involved in the flagellum biogenesis pathways of these species were variably abundant in these metagenomes, suggesting that the current depth of coverage used for metagenomic sequencing (3.13–4.79 Gb total sequence in our study) insufficiently captures the functional diversity of genomes present at low (≤1%) relative abundance. E. rectale and R. inulinivorans thus appear to synthesize complex flagella composed of flagellin proteins that stimulate IL-8 production. A greater depth of sequencing, improved evenness of sequencing and improved metagenome assembly from short reads will be required to facilitate in silico analyses of complete complex biochemical pathways for low-abundance target species from shotgun metagenomes. PMID:23935906

The Microbiome in Inflammatory Bowel Diseases: Current Status and the Future Ahead

PubMed Central

Kostic, Aleksandar D.; Xavier, Ramnik J.; Gevers, Dirk

2014-01-01

Studies of the roles of microbial communities in the development of inflammatory bowel diseases (IBD) have reached an important milestone. A decade of genome-wide association studies and other genetic analyses have linked IBD with loci that implicate an aberrant immune response to the intestinal microbiota. More recently, profiling studies of the intestinal microbiome have associated pathogenesis of IBD with characteristic shifts in the composition of the intestinal microbiota, reinforcing the view that IBD results from altered interactions between intestinal microbes and the mucosal immune system. Enhanced technologies can increase our understanding of the interactions between the host and its resident microbiota, and their respective roles in IBD, from both a large-scale pathway view and at the metabolic level. We review important microbiome studies of patients with IBD and describe what we have learned about the mechanisms of intestinal microbiota dysfunction. We describe the recent progress in microbiome research from exploratory 16S-based studies, reporting associations of specific organisms with a disease, to more recent studies that have taken a more nuanced view, addressing the function of the microbiota by metagenomic and metabolomic methods. Finally, we propose study designs and methodologies for future investigations of the microbiome in patients with inflammatory gut and autoimmune diseases in general. PMID:24560869

Effects of flavonoids on intestinal inflammation, barrier integrity and changes in gut microbiota during diet-induced obesity.

PubMed

Gil-Cardoso, Katherine; Ginés, Iris; Pinent, Montserrat; Ardévol, Anna; Blay, Mayte; Terra, Ximena

2016-12-01

Diet-induced obesity is associated with low-grade inflammation, which, in most cases, leads to the development of metabolic disorders, primarily insulin resistance and type 2 diabetes. Although prior studies have implicated the adipose tissue as being primarily responsible for obesity-associated inflammation, the latest discoveries have correlated impairments in intestinal immune homeostasis and the mucosal barrier with increased activation of the inflammatory pathways and the development of insulin resistance. Therefore, it is essential to define the mechanisms underlying the obesity-associated gut alterations to develop therapies to prevent and treat obesity and its associated diseases. Flavonoids appear to be promising candidates among the natural preventive treatments that have been identified to date. They have been shown to protect against several diseases, including CVD and various cancers. Furthermore, they have clear anti-inflammatory properties, which have primarily been evaluated in non-intestinal models. At present, a growing body of evidence suggests that flavonoids could exert a protective role against obesity-associated pathologies by modulating inflammatory-related cellular events in the intestine and/or the composition of the microbiota populations. The present paper will review the literature to date that has described the protective effects of flavonoids on intestinal inflammation, barrier integrity and gut microbiota in studies conducted using in vivo and in vitro models.

Helminths as an alternative therapy for intestinal diseases.

PubMed

Sipahi, Aytan Miranda; Baptista, Daniel Machado

2017-09-07

Animal models and clinical studies have shown that helminth infections exert immunomodulatory activity, altering intestinal permeability and providing a potential beneficial action on autoimmune and inflammatory disorders in human beings, such as inflammatory bowel disease (IBD) and celiac disease. This is consistent with the theory that intestinal microbiota is responsible for shaping human immunological responses. With the arrival of the immunobiologic era and the use of antibodies, we propose a distinctive pathway for treating patients with IBD and celiac disease. We have some evidence about the safety and tolerability of helminth use, but evidence about their impact on disease activity is lacking. Using worms to treat diseases could be a possible way to lower treatment costs, since the era of immunobiologic agents is responsible for a significant rise in expenses. Some questions remain to be investigated regarding the use of helminths in intestinal disease, such as the importance of the specific species of helminths used, appropriate dosing regimens, optimal timing of treatment, the role of host genetics, diet, environment, and the elucidation of the exact mechanisms of action. One promising approach is the use of helminth-derived anti-inflammatory molecules as drugs. Yet there are still many challenges with this method, especially with regard to safety. Studies on intestinal permeability point to Strongyloides stercoralis as a useful nematode for these purposes.

Microbiota-Dependent Priming of Antiviral Intestinal Immunity in Drosophila.

PubMed

Sansone, Christine L; Cohen, Jonathan; Yasunaga, Ari; Xu, Jie; Osborn, Greg; Subramanian, Harry; Gold, Beth; Buchon, Nicolas; Cherry, Sara

2015-11-11

Enteric pathogens must overcome intestinal defenses to establish infection. In Drosophila, the ERK signaling pathway inhibits enteric virus infection. The intestinal microflora also impacts immunity but its role in enteric viral infection is unknown. Here we show that two signals are required to activate antiviral ERK signaling in the intestinal epithelium. One signal depends on recognition of peptidoglycan from the microbiota, particularly from the commensal Acetobacter pomorum, which primes the NF-kB-dependent induction of a secreted factor, Pvf2. However, the microbiota is not sufficient to induce this pathway; a second virus-initiated signaling event involving release of transcriptional paused genes mediated by the kinase Cdk9 is also required for Pvf2 production. Pvf2 stimulates antiviral immunity by binding to the receptor tyrosine kinase PVR, which is necessary and sufficient for intestinal ERK responses. These findings demonstrate that sensing of specific commensals primes inflammatory signaling required for epithelial responses that restrict enteric viral infections. Copyright © 2015 Elsevier Inc. All rights reserved.

Intestinal CCL25 expression is increased in colitis and correlates with inflammatory activity

PubMed Central

Trivedi, Palak J.; Bruns, Tony; Ward, Stephen; Mai, Martina; Schmidt, Carsten; Hirschfield, Gideon M.; Weston, Chris J.; Adams, David H.

2016-01-01

CCL25-mediated activation of CCR9 is critical for mucosal lymphocyte recruitment to the intestine. In immune-mediated liver injury complicating inflammatory bowel disease, intrahepatic activation of this pathway allows mucosal lymphocytes to be recruited to the liver, driving hepatobiliary destruction in primary sclerosing cholangitis (PSC). However, in mice and healthy humans CCL25 expression is restricted to the small bowel, whereas few data exist on activation of this pathway in the inflamed colon despite the vast majority of PSC patients having ulcerative colitis. Herein, we show that colonic CCL25 expression is not only upregulated in patients with active colitis, but strongly correlates with endoscopic Mayo score and mucosal TNFα expression. Moreover, approximately 90% (CD4+) and 30% (CD8+) of tissue-infiltrating T-cells in colitis were identified as CCR9+ effector lymphocytes, compared to <10% of T-cells being CCR9+ in normal colon. Sorted CCR9+ lymphocytes also demonstrated enhanced cellular adhesion to stimulated hepatic sinusoidal endothelium compared with their CCR9– counterparts when under flow. Collectively, these results suggest that CCR9/CCL25 interactions are not only involved in colitis pathogenesis but also correlate with colonic inflammatory burden; further supporting the existence of overlapping mucosal lymphocyte recruitment pathways between the inflamed colon and liver. PMID:26873648

Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease.

PubMed

Giles, E M; Sanders, T J; McCarthy, N E; Lung, J; Pathak, M; MacDonald, T T; Lindsay, J O; Stagg, A J

2017-01-01

Type 1 interferon (IFN-1) promotes regulatory T-cell function to suppress inflammation in the mouse intestine, but little is known about IFN-1 in the human gut. We therefore assessed the influence of IFN-1 on CD4+ T-cells isolated from human colon tissue obtained from healthy controls or patients with inflammatory bowel disease (IBD). Immunofluorescent imaging revealed constitutive expression of IFNβ in human intestinal tissue, and colonic T-cells were responsive to exogenous IFN-1 as assessed by phosphorylation of signal transduction and activator of transcription 1 (pSTAT1) and induction of interferon stimulated genes (ISGs). Unlike their blood counterparts, intestinal T-cells from non-inflamed regions of IBD colon displayed enhanced responsiveness to IFN-1, increased frequency of pSTAT1+ cells, and greater induction of ISGs upon IFN-1 exposure in vitro. In healthy tissue, antibody neutralization of IFNβ selectively reduced T-cell production of the pro-regulatory cytokine interleukin-10 (IL-10) and increased IFNγ synthesis. In contrast, neutralization of IFNβ in IBD tissue cultures increased the frequency of T-cells producing inflammatory cytokines but did not alter IL-10 expression. These data support a role for endogenous IFN-1 as a context-dependent modulator of T-cell function that promotes regulatory activity in healthy human intestine, but indicate that the IFN-1/STAT1 pathway is dysregulated in inflammatory bowel disease.

Catechol Groups Enable Reactive Oxygen Species Scavenging-Mediated Suppression of PKD-NFkappaB-IL-8 Signaling Pathway by Chlorogenic and Caffeic Acids in Human Intestinal Cells

PubMed Central

Shin, Hee Soon; Satsu, Hideo; Bae, Min-Jung; Totsuka, Mamoru; Shimizu, Makoto

2017-01-01

Chlorogenic acid (CHA) and caffeic acid (CA) are phenolic compounds found in coffee, which inhibit oxidative stress-induced interleukin (IL)-8 production in intestinal epithelial cells, thereby suppressing serious cellular injury and inflammatory intestinal diseases. Therefore, we investigated the anti-inflammatory mechanism of CHA and CA, both of which inhibited hydrogen peroxide (H2O2)-induced IL-8 transcriptional activity. They also significantly suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcriptional activity, nuclear translocation of the p65 subunit, and phosphorylation of IκB kinase (IKK). Additionally, upstream of IKK, protein kinase D (PKD) was also suppressed. Finally, we found that they scavenged H2O2-induced reactive oxygen species (ROS) and the functional moiety responsible for the anti-inflammatory effects of CHA and CA was the catechol group. Therefore, we conclude that the presence of catechol groups in CHA and CA allows scavenging of intracellular ROS, thereby inhibiting H2O2-induced IL-8 production via suppression of PKD-NF-κB signaling in human intestinal epithelial cells. PMID:28230729

Hyperforin, the active component of St. John's wort, induces IL-8 expression in human intestinal epithelial cells via a MAPK-dependent, NF-kappaB-independent pathway.

PubMed

Zhou, Changcheng; Tabb, Michelle M; Sadatrafiei, Asal; Grün, Felix; Sun, Aixu; Blumberg, Bruce

2004-11-01

St. John's wort is widely used as an herbal antidepressant and is among the top-selling botanical products in the United States. Although St. John's wort has been reported to have minimal side effects compared with other antidepressants, here we show that hyperforin, the active component of St. John's wort, can stimulate interleukin-8 (IL-8) expression in human intestinal epithelia cells (IEC) and primary hepatocytes. Hyperforin is also able to induce expression of mRNA, encoding another major inflammatory mediator--intercellular adhesion molecule-1 (ICAM-1). IEC participate in the intestinal inflammatory process and serve as a first line of defense through bidirectional communication between host and infectious pathogens. Although hyperforin is a potent ligand for the steroid and xenobiotic receptor (SXR), we found that hyperforin induced IL-8 mRNA through an SXR-independent transcriptional activation pathway. IL-8 induction by hyperforin required the activation of AP-1 but not the NF-kappaB transcription factor, thereby distinguishing it from the NF-kappaB-dependent IL-8 induction mediated by tumor necrosis factor alpha (TNFalpha). Further study revealed that extracellular signal-regulated kinase 1 and 2 (ERK1/2) were required for the hyperforin-induced expression of IL-8. Our results suggest a previously unsuspected effect of St. John's wort in modulating the immune and inflammatory responses.

Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses.

PubMed

Iyer, Shankar S; Gensollen, Thomas; Gandhi, Amit; Oh, Sungwhan F; Neves, Joana F; Collin, Frederic; Lavin, Richard; Serra, Carme; Glickman, Jonathan; de Silva, Punyanganie S A; Sartor, R Balfour; Besra, Gurdyal; Hauser, Russell; Maxwell, Anthony; Llebaria, Amadeu; Blumberg, Richard S

2018-05-17

Genome-wide association studies have identified risk loci associated with the development of inflammatory bowel disease, while epidemiological studies have emphasized that pathogenesis likely involves host interactions with environmental elements whose source and structure need to be defined. Here, we identify a class of compounds derived from dietary, microbial, and industrial sources that are characterized by the presence of a five-membered oxazole ring and induce CD1d-dependent intestinal inflammation. We observe that minimal oxazole structures modulate natural killer T cell-dependent inflammation by regulating lipid antigen presentation by CD1d on intestinal epithelial cells (IECs). CD1d-restricted production of interleukin 10 by IECs is limited through activity of the aryl hydrocarbon receptor (AhR) pathway in response to oxazole induction of tryptophan metabolites. As such, the depletion of the AhR in the intestinal epithelium abrogates oxazole-induced inflammation. In summary, we identify environmentally derived oxazoles as triggers of CD1d-dependent intestinal inflammatory responses that occur via activation of the AhR in the intestinal epithelium. Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.

The Effect of DA-6034 on Intestinal Permeability in an Indomethacin-Induced Small Intestinal Injury Model.

PubMed

Kwak, Dong Shin; Lee, Oh Young; Lee, Kang Nyeong; Jun, Dae Won; Lee, Hang Lak; Yoon, Byung Chul; Choi, Ho Soon

2016-05-23

DA-6034 has anti-inflammatory activities and exhibits cytoprotective effects in acute gastric injury models. However, explanations for the protective effects of DA-6034 on intestinal permeability are limited. This study sought to investigate the effect of DA-6034 on intestinal permeability in an indomethacin-induced small intestinal injury model and its protective effect against small intestinal injury. Rats in the treatment group received DA-6034 from days 0 to 2 and indomethacin from days 1 to 2. Rats in the control group received indomethacin from days 1 to 2. On the fourth day, the small intestines were examined to compare the severity of inflammation. Intestinal permeability was evaluated by using fluorescein isothiocyanate-labeled dextran. Western blotting was performed to confirm the association between DA-6034 and the extracellular signal-regulated kinase (ERK) pathway. The inflammation scores in the treatment group were lower than those in the control group, but the difference was statistically insignificant. Hemorrhagic lesions in the treatment group were broader than those in the control group, but the difference was statistically insignificant. Intestinal permeability was lower in the treatment group than in the control group. DA-6034 enhanced extracellular signal-regulated kinase expression, and intestinal permeability was negatively correlated with ERK expression. DA-6034 may decrease intestinal permeability in an indomethacin-induced intestinal injury model via the ERK pathway.

Non-digestible oligosaccharides directly regulate host kinome to modulate host inflammatory responses without alterations in the gut microbiota.

PubMed

Wu, Richard Y; Määttänen, Pekka; Napper, Scott; Scruten, Erin; Li, Bo; Koike, Yuhki; Johnson-Henry, Kathene C; Pierro, Agostino; Rossi, Laura; Botts, Steven R; Surette, Michael G; Sherman, Philip M

2017-10-10

Prebiotics are non-digestible food ingredients that enhance the growth of certain microbes within the gut microbiota. Prebiotic consumption generates immune-modulatory effects that are traditionally thought to reflect microbial interactions within the gut. However, recent evidence suggests they may also impart direct microbe-independent effects on the host, though the mechanisms of which are currently unclear. Kinome arrays were used to profile the host intestinal signaling responses to prebiotic exposures in the absence of microbes. Identified pathways were functionally validated in Caco-2Bbe1 intestinal cell line and in vivo model of murine endotoxemia. We found that prebiotics directly regulate host mucosal signaling to alter response to bacterial infection. Intestinal epithelial cells (IECs) exposed to prebiotics are hyporesponsive to pathogen-induced mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) activations, and have a kinome profile distinct from non-treated cells pertaining to multiple innate immune signaling pathways. Consistent with this finding, mice orally gavaged with prebiotics showed dampened inflammatory response to lipopolysaccharide (LPS) without alterations in the gut microbiota. These findings provide molecular mechanisms of direct host-prebiotic interactions to support prebiotics as potent modulators of host inflammation.

Saccharomyces cerevisiae Modulates Immune Gene Expressions and Inhibits ETEC-Mediated ERK1/2 and p38 Signaling Pathways in Intestinal Epithelial Cells

PubMed Central

Zanello, Galliano; Berri, Mustapha; Dupont, Joëlle; Sizaret, Pierre-Yves; D'Inca, Romain

2011-01-01

Background Enterotoxigenic Escherichia coli (ETEC) infections result in large economic losses in the swine industry worldwide. ETEC infections cause pro-inflammatory responses in intestinal epithelial cells and subsequent diarrhea in pigs, leading to reduced growth rate and mortality. Administration of probiotics as feed additives displayed health benefits against intestinal infections. Saccharomyces cerevisiae (Sc) is non-commensal and non-pathogenic yeast used as probiotic in gastrointestinal diseases. However, the immuno-modulatory effects of Sc in differentiated porcine intestinal epithelial cells exposed to ETEC were not investigated. Methodology/Principal Findings We reported that the yeast Sc (strain CNCM I-3856) modulates transcript and protein expressions involved in inflammation, recruitment and activation of immune cells in differentiated porcine intestinal epithelial IPEC-1 cells. We demonstrated that viable Sc inhibits the ETEC-induced expression of pro-inflammatory transcripts (IL-6, IL-8, CCL20, CXCL2, CXCL10) and proteins (IL-6, IL-8). This inhibition was associated to a decrease of ERK1/2 and p38 MAPK phosphorylation, an agglutination of ETEC by Sc and an increase of the anti-inflammatory PPAR-γ nuclear receptor mRNA level. In addition, Sc up-regulates the mRNA levels of both IL-12p35 and CCL25. However, measurement of transepithelial electrical resistance displayed that Sc failed to maintain the barrier integrity in monolayer exposed to ETEC suggesting that Sc does not inhibit ETEC enterotoxin activity. Conclusions Sc (strain CNCM I-3856) displays multiple immuno-modulatory effects at the molecular level in IPEC-1 cells suggesting that Sc may influence intestinal inflammatory reaction. PMID:21483702

Titanium dioxide nanoparticles activate IL8-related inflammatory pathways in human colonic epithelial Caco-2 cells

NASA Astrophysics Data System (ADS)

Krüger, Kristin; Cossais, François; Neve, Horst; Klempt, Martin

2014-05-01

Nanosized titanium dioxide (TiO2) particles are widely used as food additive or coating material in products of the food and pharmaceutical industry. Studies on various cell lines have shown that TiO2 nanoparticles (NPs) induced the inflammatory response and cytotoxicity. However, the influences of TiO2 NPs' exposure on inflammatory pathways in intestinal epithelial cells and their differentiation have not been investigated so far. This study demonstrates that TiO2 NPs with particle sizes ranging between 5 and 10 nm do not affect enterocyte differentiation but cause an activation of inflammatory pathways in the human colon adenocarcinoma cell line Caco-2. 5 and 10 nm NPs' exposures transiently induce the expression of ICAM1, CCL20, COX2 and IL8, as determined by quantitative PCR, whereas larger particles (490 nm) do not. Further, using nuclear factor (NF)-κB reporter gene assays, we show that NP-induced IL8 mRNA expression occurs, in part, through activation of NF-κB and p38 mitogen-activated protein kinase pathways.

Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases

PubMed Central

Abraham, Clara; Dulai, Parambir S.; Vermeire, Séverine; Sandborn, William J.

2016-01-01

Insights into the pathogenesis of inflammatory bowel diseases (IBD) have provided important information for the development of therapeutics. Levels of interleukin 23 (IL23) and T-helper (Th) 17 cell pathway molecules are elevated in inflamed intestinal tissues of patients with IBD. Loss of function variants of the interleukin 23 receptor gene (IL23R) protect against IBD, and in animals, blocking IL23 reduces severity of colitis. These findings indicated that the IL23 and Th17 cell pathways might be promising targets for treatment of IBD. Clinical trials have investigated the effects of agents designed to target distinct levels of the IL23 and Th17 cell pathways, and the results are providing insights into IBD pathogenesis and additional strategies for modulating these pathways. Strategies to reduce levels of proinflammatory cytokines more broadly and increase anti-inflammatory mechanisms are also emerging for treatment of IBD. The results from trials targeting these immune system pathways have provided important lessons for future trials. Findings indicate the importance of improving approaches to integrate patient features and biomarkers of response with selection of therapeutics. PMID:27780712

Exercising the hepatobiliary-gut axis. The impact of physical activity performance.

PubMed

Molina-Molina, Emilio; Lunardi Baccetto, Raquel; Wang, David Q-H; de Bari, Ornella; Krawczyk, Marcin; Portincasa, Piero

2018-05-24

Physical inactivity puts the populations at risk of several health problems, while regular physical activity brings beneficial effects on cardiovascular disease, mortality and other health outcomes, including obesity, glycaemic control and insulin resistance. The hepatobiliary tract is greatly involved in several metabolic aspects which include digestion and absorption of nutrients in concert with intestinal motility, bile acid secretion and flow across the enterohepatic circulation and intestinal microbiota. Several metabolic abnormalities, including nonalcoholic fatty liver as well as cholesterol cholelithiasis, represent two conditions explained by changes of the aforementioned pathways. This review defines different training modalities and discusses the effects of physical activity in two metabolic disorders, that is nonalcoholic fatty liver disease (NAFLD) and cholelithiasis. Emphasis is given to pathogenic mechanisms involving intestinal bile acids, microbiota and inflammatory status. A full definition of physical activity includes the knowledge of aerobic and endurance exercise, metabolic equivalent tasks, duration, frequency and intensity, beneficial and harmful effects. Physical activity influences the hepatobiliary-gut axis at different levels and brings benefits to fat distribution, liver fat and gallbladder disease while interacting with bile acids as signalling molecules, intestinal microbiota and inflammatory changes in the body. Several beneficial effects of physical activity are anticipated on metabolic disorders linking liver steatosis, gallstone disease, gut motility, enterohepatic circulation of signalling bile acids in relation to intestinal microbiota and inflammatory changes. © 2018 Stichting European Society for Clinical Investigation Journal Foundation.

The microbiome in inflammatory bowel disease: current status and the future ahead.

PubMed

Kostic, Aleksandar D; Xavier, Ramnik J; Gevers, Dirk

2014-05-01

Studies of the roles of microbial communities in the development of inflammatory bowel disease (IBD) have reached an important milestone. A decade of genome-wide association studies and other genetic analyses have linked IBD with loci that implicate an aberrant immune response to the intestinal microbiota. More recently, profiling studies of the intestinal microbiome have associated the pathogenesis of IBD with characteristic shifts in the composition of the intestinal microbiota, reinforcing the view that IBD results from altered interactions between intestinal microbes and the mucosal immune system. Enhanced technologies can increase our understanding of the interactions between the host and its resident microbiota and their respective roles in IBD from both a large-scale pathway view and at the metabolic level. We review important microbiome studies of patients with IBD and describe what we have learned about the mechanisms of intestinal microbiota dysfunction. We describe the recent progress in microbiome research from exploratory 16S-based studies, reporting associations of specific organisms with a disease, to more recent studies that have taken a more nuanced view, addressing the function of the microbiota by metagenomic and metabolomic methods. Finally, we propose study designs and methodologies for future investigations of the microbiome in patients with inflammatory gut and autoimmune diseases in general. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Crosstalk between the gut and the liver via susceptibility loci: Novel advances in inflammatory bowel disease and autoimmune liver disease.

PubMed

Li, Xinyang; Shen, Jun; Ran, Zhihua

2017-02-01

Inflammatory bowel disease (IBD) is an autoimmune disorder characterized by chronic, relapsing intestinal inflammation. Autoimmune liver disease (AILD) may be involved in IBD as an extra-intestinal manifestation (EIM). Epidemiologic and anatomic evidence have demonstrated an intimate crosstalk between the gut and the liver. In this review, we briefly introduced nine groups of susceptibility loci shared by inflammatory bowel and autoimmune liver disease for the first time. The genome-wide association studies (GWAS) evidence of pathways involving crosstalk between the gut and the liver is clarified and explained. It has been found that HNF4-α, GPR35, MST1R, CARD9, IL2/IL21/IL2R, BACH2, TNFRSF14, MAdCAM-1, and FUT2 are the genes involved in tight junction formation, macrophage function, T helper cell or T reg cell cycle and function, TNF secretion, lymphocyte homing or intestinal dysbiosis, respectively. The intimate crosstalk between the gut and liver in immunity is also highlighted and discussed in this review. Copyright © 2016 Elsevier Inc. All rights reserved.

Maternal Obesity Induces Sustained Inflammation in Both Fetal and Offspring Large Intestine of Sheep

PubMed Central

Yan, Xu; Huang, Yan; Wang, Hui; Du, Min; Hess, Bret W.; Ford, Stephen P.; Nathanielsz, Peter W.; Zhu, Mei-Jun

2010-01-01

Background Both maternal obesity and inflammatory bowel diseases (IBDs) are increasing. It was hypothesized that maternal obesity induces an inflammatory response in the fetal large intestine, predisposing offspring to IBDs. Methods Nonpregnant ewes were assigned to a control (Con, 100% of National Research Council [NRC] recommendations) or obesogenic (OB, 150% of NRC) diet from 60 days before conception. The large intestine was sampled from fetuses at 135 days (term 150 days) after conception and from offspring lambs at 22.5 ± 0.5 months of age. Results Maternal obesity enhanced mRNA expression tumor necrosis factor (TNF)α, interleukin (IL)1α, IL1β, IL6, IL8, and monocyte/macrophage chemotactic protein-1 (MCP1), as well as macrophage markers, CD11b, CD14, and CD68 in fetal gut. mRNA expression of Toll-like receptor (TLR) 2 and TLR4 was increased in OB versus Con fetuses; correspondingly, inflammatory NF-κB and JNK signaling pathways were also upregulated. Both mRNA expression and protein content of transforming growth factor (TGF) β was increased. The IL-17A mRNA expression and protein content was higher in OB compared to Con samples, which was associated with fibrosis in the large intestine of OB fetuses. Similar inflammatory responses and enhanced fibrosis were detected in OB compared to Con offspring. Conclusions Maternal obesity induced inflammation and enhanced expression of proinflammatory cytokines in fetal and offspring large intestine, which correlated with increased TGFβ and IL17 expression. These data show that maternal obesity may predispose offspring gut to IBDs. PMID:21674707

Intestinal anti-inflammatory effects of goat whey on DNBS-induced colitis in mice

PubMed Central

Araújo, Daline F. S.; Guerra, Gerlane C. B.; Pintado, Maria Manuela E.; Sousa, Yasmim R. F.; Algieri, Francesca; Rodriguez-Nogales, Alba; Araújo, Raimundo F.; Gálvez, Julio; Queiroga, Rita de Cássia R. E.; Rodriguez-Cabezas, Maria Elena

2017-01-01

This study evaluated the intestinal anti-inflammatory effects of goat whey in a mouse model of colitis induced by 2,4-dinitrobenzenesulfonic acid that resembles human IBD. At a concentration of 4 g/kg/day, the goat whey improved the symptoms of intestinal inflammation, namely by decreasing the disease activity index, colonic weight/length, and leukocyte infiltration. Moreover, goat whey inhibited NF-κB p65 and p38 MAPK signaling pathways and consequently down-regulated the gene expression of various proinflammatory markers such as IL-1β, IL-6, IL-17, TNF-α, iNOS, MMP-9, ICAM-1. Also, goat whey increased the expression of proteins such as mucins, occludin proteins and cytokine signalling suppressors. The immunomodulatory properties of goat whey were also evaluated in vitro using the murine macrophage cell line Raw 264 and CMT-93 cells derived from mouse rectum carcinomas. The results revealed the ability of goat whey to inhibit the production of NO and reduce IL-6 production in LPS-stimulated cells. In conclusion, goat whey exhibited anti-inflammatory effects in the DNBS model of intestinal inflammation, and these observations were confirmed by its immunomodulatory properties in vitro. Together, our results indicate that goat whey could have applications for the treatment of IBD. PMID:28957373

Intestinal anti-inflammatory effects of goat whey on DNBS-induced colitis in mice.

PubMed

Araújo, Daline F S; Guerra, Gerlane C B; Pintado, Maria Manuela E; Sousa, Yasmim R F; Algieri, Francesca; Rodriguez-Nogales, Alba; Araújo, Raimundo F; Gálvez, Julio; Queiroga, Rita de Cássia R E; Rodriguez-Cabezas, Maria Elena

2017-01-01

This study evaluated the intestinal anti-inflammatory effects of goat whey in a mouse model of colitis induced by 2,4-dinitrobenzenesulfonic acid that resembles human IBD. At a concentration of 4 g/kg/day, the goat whey improved the symptoms of intestinal inflammation, namely by decreasing the disease activity index, colonic weight/length, and leukocyte infiltration. Moreover, goat whey inhibited NF-κB p65 and p38 MAPK signaling pathways and consequently down-regulated the gene expression of various proinflammatory markers such as IL-1β, IL-6, IL-17, TNF-α, iNOS, MMP-9, ICAM-1. Also, goat whey increased the expression of proteins such as mucins, occludin proteins and cytokine signalling suppressors. The immunomodulatory properties of goat whey were also evaluated in vitro using the murine macrophage cell line Raw 264 and CMT-93 cells derived from mouse rectum carcinomas. The results revealed the ability of goat whey to inhibit the production of NO and reduce IL-6 production in LPS-stimulated cells. In conclusion, goat whey exhibited anti-inflammatory effects in the DNBS model of intestinal inflammation, and these observations were confirmed by its immunomodulatory properties in vitro. Together, our results indicate that goat whey could have applications for the treatment of IBD.

Extrinsic control of Wnt signaling in the intestine.

PubMed

Koch, Stefan

The canonical Wnt/β-catenin signaling pathway is a central regulator of development and tissue homeostasis. In the intestine, Wnt signaling is primarily known as the principal organizer of epithelial stem cell identity and proliferation. Within the last decade, numerous scientific breakthroughs have shed light on epithelial self-organization in the gut, and organoids are now routinely used to study stem cell biology and intestinal pathophysiology. The contribution of non-epithelial cells to Wnt signaling in the gut has received less attention. However, there is mounting evidence that stromal cells are a rich source of Wnt pathway activators and inhibitors, which can dynamically shape Wnt signaling to control epithelial proliferation and restitution. Elucidating the extent and mechanisms of paracrine Wnt signaling in the intestine has the potential to broaden our understanding of epithelial homeostasis, and may be of particular relevance for disorders such as inflammatory bowel diseases and colitis-associated cancers. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Sphingosine-1-Phosphate Metabolism and Its Role in the Development of Inflammatory Bowel Disease

PubMed Central

Wollny, Tomasz; Wątek, Marzena; Durnaś, Bonita; Niemirowicz, Katarzyna; Piktel, Ewelina; Żendzian-Piotrowska, Małgorzata; Góźdź, Stanisław; Bucki, Robert

2017-01-01

Beyond their role as structural molecules, sphingolipids are involved in many important cellular processes including cell proliferation, apoptosis, inflammation, and migration. Altered sphingolipid metabolism is observed in many pathological conditions including gastrointestinal diseases. Inflammatory bowel disease (IBD) represents a state of complex, unpredictable, and destructive inflammation of unknown origin within the gastrointestinal tract. The mechanisms explaining the pathophysiology of IBD involve signal transduction pathways regulating gastro-intestinal system’s immunity. Progressive intestinal tissue destruction observed in chronic inflammation may be associated with an increased risk of colon cancer. Sphingosine-1-phosphate (S1P), a sphingolipid metabolite, functions as a cofactor in inflammatory signaling and becomes a target in the treatment of IBD, which might prevent its conversion to cancer. This paper summarizes new findings indicating the impact of (S1P) on IBD development and IBD-associated carcinogenesis. PMID:28362332

Soluble Proteins Produced by Probiotic Bacteria Regulate Intestinal Epithelial Cell Survival and Growth

PubMed Central

YAN, FANG; CAO, HANWEI; COVER, TIMOTHY L.; WHITEHEAD, ROBERT; WASHINGTON, M. KAY; POLK, D. BRENT

2011-01-01

Background & Aims Increased inflammatory cytokine levels and intestinal epithelial cell apoptosis leading to disruption of epithelial integrity are major pathologic factors in inflammatory bowel diseases. The probiotic bacterium Lactobacillus rhamnosus GG (LGG) and factors recovered from LGG broth culture supernatant (LGG-s) prevent cytokine-induced apoptosis in human and mouse intestinal epithelial cells by regulating signaling pathways. Here, we purify and characterize 2 secreted LGG proteins that regulate intestinal epithelial cell antiapoptotic and proliferation responses. Methods LGG proteins were purified from LGG-s, analyzed, and used to generate polyclonal antibodies for immunodepletion of respective proteins from LGG-conditioned cell culture media (CM). Mouse colon epithelial cells and cultured colon explants were treated with purified proteins in the absence or presence of tumor necrosis factor (TNF). Akt activation, proliferation, tissue injury, apoptosis, and caspase-3 activation were determined. Results We purified 2 novel proteins, p75 (75 kilodaltons) and p40 (40 kilodaltons), from LGG-s. Each of these purified protein preparations activated Akt, inhibited cytokine-induced epithelial cell apoptosis, and promoted cell growth in human and mouse colon epithelial cells and cultured mouse colon explants. TNF-induced colon epithelial damage was significantly reduced by p75 and p40. Immunodepletion of p75 and p40 from LGG-CM reversed LGG-CM activation of Akt and its inhibitory effects on cytokine-induced apoptosis and loss of intestinal epithelial cells. Conclusions p75 and p40 are the first probiotic bacterial proteins demonstrated to promote intestinal epithelial homeostasis through specific signaling pathways. These findings suggest that probiotic bacterial components may be useful for preventing cytokine-mediated gastrointestinal diseases. PMID:17258729

The Role of the Noncanonical NF-KappaB Pathway in Colon Cancer

DTIC Science & Technology

2016-08-01

AWARD NUMBER: W81XWH-13-1-0321 TITLE: The Role of the Noncanonical NF -KappaB Pathway in Colon Cancer PRINCIPAL INVESTIGATOR: Yatrik Shah...2013 - 29 May 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-13-1-0321 The Role of the Noncanonical NF -KappaB Pathway in Colon Cancer 5b...inflammatory bowel disease samples that the non-canonical NF -κB2 signaling cascade is highly activated in intestinal epithelial cells compared to normal

Intestinal Epithelial Cell Response to Clostridium difficile Flagella.

PubMed

Batah, Jameel; Kansau, Imad

2016-01-01

Clostridium difficile is the bacterium responsible for most antibiotic-associated diarrhea in North America and Europe. This bacterium, which colonizes the gut of humans and animals, produces toxins that are known to contribute directly to damage of the gut. It is known that bacterial flagella are involved in intestinal lesions through the inflammatory host response. The C. difficile flagellin recognizes TLR5 and consequently activates the NF-κB and the MAPK signaling pathways which elicit the synthesis of pro-inflammatory cytokines. Increasing interest on the role of C. difficile flagella in eliciting this cell response was recently developed and the development of tools to study cell response triggered by C. difficile flagella will improve our understanding of the pathogenesis of C. difficile.

Saccharomyces cerevisiae Boulardii Reduces the Deoxynivalenol-Induced Alteration of the Intestinal Transcriptome.

PubMed

Alassane-Kpembi, Imourana; Pinton, Philippe; Hupé, Jean-François; Neves, Manon; Lippi, Yannick; Combes, Sylvie; Castex, Mathieu; Oswald, Isabelle P

2018-05-15

Type B trichothecene mycotoxin deoxynivalenol (DON) is one of the most frequently occurring food contaminants. By inducing trans-activation of a number of pro-inflammatory cytokines and increasing the stability of their mRNA, trichothecene can impair intestinal health. Several yeast products, especially Saccharomyces cerevisiae , have the potential for improving the enteric health of piglets, but little is known about the mechanisms by which the administration of yeast counteracts the DON-induced intestinal alterations. Using a pig jejunum explant model, a whole-transcriptome analysis was performed to decipher the early response of the small intestine to the deleterious effects of DON after administration of S. cerevisiae boulardii strain CNCM I-1079. Compared to the control condition, no differentially expressed gene (DE) was observed after treatment by yeast only. By contrast, 3619 probes-corresponding to 2771 genes-were differentially expressed following exposure to DON, and 32 signaling pathways were identified from the IPA software functional analysis of the set of DE genes. When the intestinal explants were treated with S. cerevisiae boulardii prior to DON exposure, the number of DE genes decreased by half (1718 probes corresponding to 1384 genes). Prototypical inflammation signaling pathways triggered by DON, including NF-κB and p38 MAPK, were reversed, although the yeast demonstrated limited efficacy toward some other pathways. S. cerevisiae boulardii also restored the lipid metabolism signaling pathway, and reversed the down-regulation of the antioxidant action of vitamin C signaling pathway. The latter effect could reduce the burden of DON-induced oxidative stress. Altogether, the results show that S. cerevisiae boulardii reduces the DON-induced alteration of intestinal transcriptome, and point to new mechanisms for the healing of tissue injury by yeast.

Saccharomyces cerevisiae boulardii Reduces the Deoxynivalenol-Induced Alteration of the Intestinal Transcriptome

PubMed Central

Alassane-Kpembi, Imourana; Hupé, Jean-François; Neves, Manon; Lippi, Yannick; Combes, Sylvie; Castex, Mathieu

2018-01-01

Type B trichothecene mycotoxin deoxynivalenol (DON) is one of the most frequently occurring food contaminants. By inducing trans-activation of a number of pro-inflammatory cytokines and increasing the stability of their mRNA, trichothecene can impair intestinal health. Several yeast products, especially Saccharomyces cerevisiae, have the potential for improving the enteric health of piglets, but little is known about the mechanisms by which the administration of yeast counteracts the DON-induced intestinal alterations. Using a pig jejunum explant model, a whole-transcriptome analysis was performed to decipher the early response of the small intestine to the deleterious effects of DON after administration of S. cerevisiae boulardii strain CNCM I-1079. Compared to the control condition, no differentially expressed gene (DE) was observed after treatment by yeast only. By contrast, 3619 probes—corresponding to 2771 genes—were differentially expressed following exposure to DON, and 32 signaling pathways were identified from the IPA software functional analysis of the set of DE genes. When the intestinal explants were treated with S. cerevisiae boulardii prior to DON exposure, the number of DE genes decreased by half (1718 probes corresponding to 1384 genes). Prototypical inflammation signaling pathways triggered by DON, including NF-κB and p38 MAPK, were reversed, although the yeast demonstrated limited efficacy toward some other pathways. S. cerevisiae boulardii also restored the lipid metabolism signaling pathway, and reversed the down-regulation of the antioxidant action of vitamin C signaling pathway. The latter effect could reduce the burden of DON-induced oxidative stress. Altogether, the results show that S. cerevisiae boulardii reduces the DON-induced alteration of intestinal transcriptome, and point to new mechanisms for the healing of tissue injury by yeast. PMID:29762474

Toll-like receptor signaling and its relevance to intestinal inflammation.

PubMed

Cario, Elke; Podolsky, Daniel K

2006-08-01

This review discusses the current progress in the understanding of how commensal-mediated activation of toll-like receptors (TLRs) may be involved in the regulation of physiological and pathophysiological processes of the intestinal mucosa including tissue regeneration and inflammation. While regulation of TLRs and their downstream signaling mediators might be used to prevent and treat inflammatory bowel diseases, paradoxically, at this time, it remains uncertain whether this would be more effectively accomplished by enhancing or inhibiting these pathways.

Metabolic phenotyping of an adoptive transfer mouse model of experimental colitis and impact of dietary fish oil intake.

PubMed

Martin, Francois-Pierre J; Lichti, Pia; Bosco, Nabil; Brahmbhatt, Viral; Oliveira, Manuel; Haller, Dirk; Benyacoub, Jalil

2015-04-03

Inflammatory bowel diseases are acute and chronic disabling inflammatory disorders with multiple complex etiologies that are not well-defined. Chronic intestinal inflammation has been linked to an energy-deficient state of gut epithelium with alterations in oxidative metabolism. Plasma-, urine-, stool-, and liver-specific metabonomic analyses are reported in a naïve T cell adoptive transfer (AT) experimental model of colitis, which evaluated the impact of long-chain n-3 polyunsaturated fatty acid (PUFA)-enriched diet. Metabolic profiles of AT animals and their controls under chow diet or fish oil supplementation were compared to describe the (i) consequences of inflammatory processes and (ii) the differential impact of n-3 fatty acids. Inflammation was associated with higher glycoprotein levels (related to acute-phase response) and remodeling of PUFAs. Low triglyceride levels and enhanced PUFA levels in the liver suggest activation of lipolytic pathways that could lead to the observed increase of phospholipids in the liver (including plasmalogens and sphingomyelins). In parallel, the increase in stool excretion of most amino acids may indicate a protein-losing enteropathy. Fecal content of glutamine was lower in AT mice, a feature exacerbated under fish oil intervention that may reflect a functional relationship between intestinal inflammatory status and glutamine metabolism. The decrease in Krebs cycle intermediates in urine (succinate, α-ketoglutarate) also suggests a reduction in the glutaminolytic pathway at a systemic level. Our data indicate that inflammatory status is related to this overall loss of energy homeostasis.

Naringin attenuates MLC phosphorylation and NF-κB activation to protect sepsis-induced intestinal injury via RhoA/ROCK pathway.

PubMed

Li, Zhiling; Gao, Ming; Yang, Bingchang; Zhang, Huali; Wang, Kangkai; Liu, Zuoliang; Xiao, Xianzhong; Yang, Mingshi

2018-07-01

Sepsis is commonly associated with excessive stimulation of host immune system and result in multi-organ failure dysfunction. Naringin has been reported to exhibit a variety of biological effects. The present study aimed to investigate the protective effect of naringin on sepsis-induced injury of intestinal barrier function in vivo and in vitro. Mice were randomly divided into 4 groups named sham (n = 20), CLP + vehicle (n = 20), CLP + NG (30 mg/kg) (n = 20) and CLP + NG (60 mg/kg) (n = 20) groups. Sepsis was induced by cecal ligation and puncture (CLP). H&E staining and transmission electron microscopy (TEM) were performed to observe intestinal mucosal morphology. ELISA was used to determine the intestinal permeability and inflammatory response in vivo and in vitro. Western blot and RhoA activity assay were performed to determine the levels of tight junction proteins and the activation of indicated signaling pathways. MTT assay was used to determine cell viability. Naringin improved survival rate of CLP mice and alleviated sepsis-induced intestinal mucosal injury. Furthermore, naringin improved impaired intestinal permeability and inhibited the release of TNF-α and IL-6, while increased IL-10 level in CLP mice and lipopolysaccharide (LPS)-stimulated MODE-K cells in a dose-dependent manner. Naringin increased the expression of tight junction proteins ZO-1 and claudin-1 via RhoA/ROCK/NF-κB/MLCK/MLC signaling pathway in vivo and in vitro. Naringin improved sepsis-induced intestinal injury via RhoA/ROCK/NF-κB/MLCK/MLC signaling pathway in vivo and in vitro. Copyright © 2018. Published by Elsevier Masson SAS.

Dietary feeding of freeze-dried whole cranberry inhibits intestinal tumor development in Apcmin/+ mice

PubMed Central

Dong, Wenxiao; Zhang, Yujie; Wang, Sinan; Xie, Runxiang; Wang, Bangmao; Cao, Hailong

2017-01-01

It is increasingly perceived that dietary components have been linked with the prevention of intestinal cancer. Cranberry is a rich source of phenolic constituents and non-digestible fermentable dietary fiber, which shows anti-proliferation effect in colorectal cancer cells. Herein, we investigated the efficacy of long-term cranberry diet on intestinal adenoma formation in Apcmin/+ mice. Apcmin/+ mice were fed a basal diet or a diet containing 20% (w/w) freeze-dried whole cranberry powder for 12 weeks, and the number and size of tumors were recorded after sacrifice. Our results showed that cranberry strongly prevented the growth of intestinal tumors by 33.1%. Decreased cell proliferation and increased apoptosis were observed in tumors of cranberry-fed mice. Cranberry diet reduced the expression profile of colonic inflammatory cytokines (IFN-γ, IL-1β and TNF-α) accompanied with increased levels of anti-inflammatory cytokines (IL-4 and IL-10). Moreover, the number of colonic goblet cells and MUC2 production were increased, and the intestinal barrier function was also improved. In addition, cranberry diet increased caecal short chain fatty acids concentrations, and down-regulated epidermal growth factor receptor signaling pathway. These data firstly show the efficacy and associated mechanisms of cranberry diet on intestinal tumor growth in Apcmin/+ mice, suggesting its chemopreventive potential against intestinal cancer. PMID:29228651

Maternal obesity induces sustained inflammation in both fetal and offspring large intestine of sheep.

PubMed

Yan, Xu; Huang, Yan; Wang, Hui; Du, Min; Hess, Bret W; Ford, Stephen P; Nathanielsz, Peter W; Zhu, Mei-Jun

2011-07-01

Both maternal obesity and inflammatory bowel diseases (IBDs) are increasing. It was hypothesized that maternal obesity induces an inflammatory response in the fetal large intestine, predisposing offspring to IBDs. Nonpregnant ewes were assigned to a control (Con, 100% of National Research Council [NRC] recommendations) or obesogenic (OB, 150% of NRC) diet from 60 days before conception. The large intestine was sampled from fetuses at 135 days (term 150 days) after conception and from offspring lambs at 22.5 ± 0.5 months of age. Maternal obesity enhanced mRNA expression tumor necrosis factor (TNF)α, interleukin (IL)1α, IL1β, IL6, IL8, and monocyte/macrophage chemotactic protein-1 (MCP1), as well as macrophage markers, CD11b, CD14, and CD68 in fetal gut. mRNA expression of Toll-like receptor (TLR) 2 and TLR4 was increased in OB versus Con fetuses; correspondingly, inflammatory NF-κB and JNK signaling pathways were also upregulated. Both mRNA expression and protein content of transforming growth factor (TGF) β was increased. The IL-17A mRNA expression and protein content was higher in OB compared to Con samples, which was associated with fibrosis in the large intestine of OB fetuses. Similar inflammatory responses and enhanced fibrosis were detected in OB compared to Con offspring. Maternal obesity induced inflammation and enhanced expression of proinflammatory cytokines in fetal and offspring large intestine, which correlated with increased TGFβ and IL17 expression. These data show that maternal obesity may predispose offspring gut to IBDs. Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.

Orexigenic Hormone Ghrelin Attenuates Local and Remote Organ Injury after Intestinal Ischemia-Reperfusion

PubMed Central

Wu, Rongqian; Dong, Weifeng; Ji, Youxin; Zhou, Mian; Marini, Corrado P.; Ravikumar, Thanjavur S.; Wang, Ping

2008-01-01

Background Gut ischemia/reperfusion (I/R) injury is a serious condition in intensive care patients. Activation of immune cells adjacent to the huge endothelial cell surface area of the intestinal microvasculature produces initially local and then systemic inflammatory responses. Stimulation of the vagus nerve can rapidly attenuate systemic inflammatory responses through inhibiting the activation of macrophages and endothelial cells. Ghrelin, a novel orexigenic hormone, is produced predominately in the gastrointestinal system. Ghrelin receptors are expressed at a high density in the dorsal vagal complex of the brain stem. In this study, we investigated the regulation of the cholinergic anti-inflammatory pathway by the novel gastrointestinal hormone, ghrelin, after gut I/R. Methods and Findings Gut ischemia was induced by placing a microvascular clip across the superior mesenteric artery for 90 min in male adult rats. Our results showed that ghrelin levels were significantly reduced after gut I/R and that ghrelin administration inhibited pro-inflammatory cytokine release, reduced neutrophil infiltration, ameliorated intestinal barrier dysfunction, attenuated organ injury, and improved survival after gut I/R. Administration of a specific ghrelin receptor antagonist worsened gut I/R-induced organ injury and mortality. To determine whether ghrelin's beneficial effects after gut I/R require the intact vagus nerve, vagotomy was performed in sham and gut I/R animals immediately prior to the induction of gut ischemia. Our result showed that vagotomy completely eliminated ghrelin's beneficial effect after gut I/R. To further confirm that ghrelin's beneficial effects after gut I/R are mediated through the central nervous system, intracerebroventricular administration of ghrelin was performed at the beginning of reperfusion after 90-min gut ischemia. Our result showed that intracerebroventricular injection of ghrelin also protected the rats from gut I/R injury. Conclusions These findings suggest that ghrelin attenuates excessive inflammation and reduces organ injury after gut I/R through activation of the cholinergic anti-inflammatory pathway. PMID:18431503

Tissue damage-induced intestinal stem cell division in Drosophila

PubMed Central

Amcheslavsky, Alla; Jiang, Jin; Ip, Y. Tony

2009-01-01

SUMMARY Stem cell division is essential for tissue integrity during growth, aging, and pathogenic assaults. Adult gastrointestinal tract encounters numerous stimulations and impaired tissue regeneration may lead to inflammatory diseases and cancer. Intestinal stem cells in adult Drosophila have recently been identified and shown to replenish the various cell types within the midgut. However, it is not known whether these intestinal stem cells can respond to environmental challenges. By feeding dextran sulfate sodium and bleomycin to flies and by expressing apoptotic proteins, we show that Drosophila intestinal stem cells can increase the rate of division in response to tissue damage. Moreover, if tissue damage results in epithelial cell loss, the newly formed enteroblasts can differentiate into mature epithelial cells. By using this newly established system of intestinal stem cell proliferation and tissue regeneration, we find that the insulin receptor signaling pathway is required for intestinal stem cell division. PMID:19128792

Lactobacillus delbrueckii TUA4408L and its extracellular polysaccharides attenuate enterotoxigenic Escherichia coli-induced inflammatory response in porcine intestinal epitheliocytes via Toll-like receptor-2 and 4.

PubMed

Wachi, Satoshi; Kanmani, Paulraj; Tomosada, Yohsuke; Kobayashi, Hisakazu; Yuri, Toshihito; Egusa, Shintaro; Shimazu, Tomoyuki; Suda, Yoshihito; Aso, Hisashi; Sugawara, Makoto; Saito, Tadao; Mishima, Takashi; Villena, Julio; Kitazawa, Haruki

2014-10-01

Immunobiotics are known to modulate intestinal immune responses by regulating Toll-like receptor (TLR) signaling pathways, which are responsible for the induction of cytokines and chemokines in response to microbial-associated molecular patterns. However, little is known about the immunomodulatory activity of compounds or molecules from immunobiotics. We evaluated whether Lactobacillus delbrueckii subsp. delbrueckii TUA4408L (Ld) or its extracellular polysaccharide (EPS): acidic EPS (APS) and neutral EPS (NPS), modulated the response of porcine intestinal epitheliocyte (PIE) cells against Enterotoxigenic Escherichia coli (ETEC) 987P. The roles of TLR2, TLR4, and TLR negative regulators in the immunoregulatory effects were also studied. ETEC-induced inflammatory cytokines were downregulated when PIE cells were prestimulated with both Ld or EPSs. Ld, APS, and NPS inhibited ETEC mediated mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) activation by upregulating TLR negative regulators. The capability of Ld to suppress inflammatory cytokines was diminished when PIE cells were blocked with anti-TLR2 antibody, while APS failed to suppress inflammatory cytokines when cells were treated with anti-TLR4 antibody. Induction of Ca²⁺ fluxes in TLR knockdown cells confirmed that TLR2 plays a principal role in the immunomodulatory action of Ld, while the activity of APS is mediated by TLR4. In addition, NPS activity depends on both TLR4 and TLR2. Ld and its EPS have the potential to be used for the development of anti-inflammatory functional foods to prevent intestinal diseases in both humans and animals. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Saccharomyces boulardii Inhibits EGF Receptor Signaling and Intestinal Tumor Growth in Apcmin Mice

PubMed Central

Chen, Xinhua; Fruehauf, Johannes; Goldsmith, Jeffrey D.; Xu, Hua; Katchar, Kianoosh K; Koon, Hon-Wai; Zhao, Dezheng; Kokkotou, Efi G.; Pothoulakis, Charalabos; Kelly, Ciarán P.

2009-01-01

Saccharomyces boulardii (Sb) is a probiotic yeast with anti-inflammatory and antimicrobial activities and has been used for decades in the prevention and treatment of a variety of human gastrointestinal disorders. We reported previously that Sb modulates host inflammatory responses through down regulation of Erk1/2 MAP kinase activities both in vitro and in vivo. The aim of this study was to identify upstream mediators responsible for Erk1/2 inactivation and to examine the effects of Sb on tumor development in ApcMin mice. We found that the EGF receptor was deactivated upon exposure to Sb leading to inactivation of both the EGFR-Erk and EGFR-Akt pathways. In human colonic cancer cells, Sb prevented EGF induced proliferation, reduced cell colony formation and promoted apoptosis. HER-2, HER-3 and IGF-1R were also found to be inactivated by Sb. Oral intake of Sb reduced intestinal tumor growth and dysplasia in C57BL/6J Min/+ (ApcMin) mice. Thus, in addition to its anti-inflammatory effects, S. boulardii inhibits EGFR and other receptor tyrosine kinase signaling and thereby may also serve a novel therapeutic or prophylactic role in intestinal neoplasia. PMID:19482027

Establishment of immortalized mouse intestinal epithelial cells line and study of effects of Arg-Arg on inflammatory response.

PubMed

Zhan, Kang; Jiang, Maocheng; Sui, Yannan; Yan, Kang; Lin, Miao; Zhao, Guoqi

2017-06-01

Primary mouse intestinal epithelial cells (MIEs) are not ideal models for long-term culture in vitro and a limited amount of approximate three generations. In addition, the mechanism that arginine-arginine dipeptide (Arg-Arg) regulates mouse intestinal inflammatory response remains unknown. Therefore, the aim of this study was to establish immortal MIEs and study the effects of Arg-Arg on inflammatory response after challenging the MIEs with lipopolysaccharide (LPS) or staphylococcal enterotoxin C (rSEC). Our data showed that immortalized MIEs could be cultured over 100 generations. The immortalized MIEs showed positive reaction against cytokeratine 18 antigen, E-cadherin, and peptide transporters (Pept1) using indirect immunofluorescence. Cytokeratine 18 and Pept1 can be expressed in immortalized MIEs by immunoblotting. Fatty acid-binding proteins (FABPs) and villin known as intestinal epithelial cell functional protein were constitutively expressed in immortalized MIEs. For inflammatory response, these results showed that Arg-Arg can decrease the LPS-induced expression of IL-1β and the rSEC-induced expression of TNF-α; however, it can upregulate the LPS-induced expression of IL-6 and TNF-α and the rSEC-induced expression level of IL-1β. In addition, in the MAPK signaling pathway, pSAPK/JNK and p-Erk1/2 in LPS with Arg-Arg treatment were upregulated than that in LPS treatment. p-p38 in LPS with Arg-Arg treatment was attenuated than that in LPS treatment. pSAPK/JNK and p-p38 in rSEC with Arg-Arg treatment were enhanced than that in rSEC treatment. Conversely, p-Erk1/2 in rSEC with Arg-Arg treatment was attenuated than that in rSEC treatment. These novel findings suggest that Arg-Arg dipeptide plays an important role for regulation of the immunologic balance in mouse intestinal inflammatory response.

Comparative Effects of Triflusal, S-Adenosylmethionine, and Dextromethorphan over Intestinal Ischemia/Reperfusion Injury

PubMed Central

Cámara-Lemarroy, Carlos R.; Guzmán-de la Garza, Francisco J.; Cordero-Pérez, Paula; Alarcón-Galván, Gabriela; Torres-Gonzalez, Liliana; Muñoz-Espinosa, Linda E.; Fernández-Garza, Nancy E.

2011-01-01

Ischemia/reperfusion (I/R) is a condition that stimulates an intense inflammatory response. No ideal treatment exists. Triflusal is an antiplatelet salicylate derivative with anti-inflammatory effects. S-adenosylmethionine is a metabolic precursor for glutathione, an endogenous antioxidant. Dextromethorphan is a low-affinity N-methyl-D-aspartate receptor inhibitor. There is evidence that these agents modulate some of the pathways involved in I/R physiopathology. Intestinal I/R was induced in rats by clamping the superior mesenteric artery for 60 minutes, followed by 60 minutes of reperfusion. Rats either received saline or the drugs studied. At the end of the procedure, serum concentrations of tumor necrosis factor-alpha (TNF-alpha), malonaldehyde (MDA), and total antioxidant capacity (TAC) were determined and intestinal morphology analyzed. I/R resulted in tissue damage, serum TNF-alpha and MDA elevations, and depletion of TAC. All drugs showed tissue protection. Only triflusal reduced TNF-alpha levels. All drugs lowered MDA levels, but only triflusal and S-adenosylmethionine maintained the serum TAC. PMID:22125445

Protectin D1n-3 DPA and resolvin D5n-3 DPA are effectors of intestinal protection

PubMed Central

Gobbetti, Thomas; Dalli, Jesmond; Colas, Romain A.; Federici Canova, Donata; Aursnes, Marius; Bonnet, Delphine; Alric, Laurent; Vergnolle, Nathalie; Deraison, Celine; Hansen, Trond V.; Serhan, Charles N.

2017-01-01

The resolution of inflammation is an active process orchestrated by specialized proresolving lipid mediators (SPM) that limit the host response within the affected tissue; failure of effective resolution may lead to tissue injury. Because persistence of inflammatory signals is a main feature of chronic inflammatory conditions, including inflammatory bowel diseases (IBDs), herein we investigate expression and functions of SPM in intestinal inflammation. Targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics was used to identify SPMs from n-3 polyunsaturated fatty acids in human IBD colon biopsies, quantifying a significant up-regulation of the resolvin and protectin pathway compared with normal gut tissue. Systemic treatment with protectin (PD)1n-3 DPA or resolvin (Rv)D5n-3 DPA protected against colitis and intestinal ischemia/reperfusion-induced inflammation in mice. Inhibition of 15-lipoxygenase activity reduced PD1n-3 DPA and augmented intestinal inflammation in experimental colitis. Intravital microscopy of mouse mesenteric venules demonstrated that PD1n-3 DPA and RvD5n-3 DPA decreased the extent of leukocyte adhesion and emigration following ischemia-reperfusion. These data were translated by assessing human neutrophil–endothelial interactions under flow: PD1n-3 DPA and RvD5n-3 DPA reduced cell adhesion onto TNF-α–activated human endothelial monolayers. In conclusion, we propose that innovative therapies based on n-3 DPA-derived mediators could be developed to enable antiinflammatory and tissue protective effects in inflammatory pathologies of the gut. PMID:28356517

Preinduction of heat shock protein 70 protects mice against post-infection irritable bowel syndrome via NF-κB and NOS/NO signaling pathways.

PubMed

Zhou, Xuchun; Dong, Liwei; Yang, Bo; He, Zhoutao; Chen, Yiyao; Deng, Taozhi; Huang, Baili; Lan, Cheng

2015-12-01

This study aimed to investigate the protective effects of preinduction of heat shock protein 70 (HSP70) on Trichinella spiralis infection-induced post-infectious irritable bowel syndrome (PI-IBS) in mice. Trichinella spiralis infection significantly reduced HSP70 abundance, ileal villus height and crypt depth, expression of tight junctions, serum lysine and arginine concentrations, and ileal SCL7A6 and SCL7A7 mRNA levels, induced inflammatory response, and activated NF-κB signaling pathway. Meanwhile, the heat treatment upregulated HSP70 expression, and then reversed intestinal dysfunction and inflammatory response. Preinduction of HSP70 enhanced serum arginine and intestinal SCL7A7 expression and inhibited NF-κB activation compared with PI-IBS model. Treatment with pyrrolidine dithiocarbamate (PDTC, an NF-κB inhibitor) and N-nitro-L-arginine methyl ester hydrochloride (L-NAME, a nitric oxide synthase inhibitor, NOS) further demonstrated that preinduction of HSP70 might inhibit NF-κB and activated NOS/nitric oxide (NO) signaling pathways. In conclusion, preinduction of HSP70 by heat treatment may confer beneficial effects on Trichinella spiralis infection-induced PI-IBS in mice, and the protective effect of HSP70 may be associated with inhibition of NF-κB and stimulation of NOS/NO signaling pathways.

Expression of the aryl hydrocarbon receptor contributes to the establishment of intestinal microbial community structure in mice

PubMed Central

Murray, Iain A.; Nichols, Robert G.; Zhang, Limin; Patterson, Andrew D.; Perdew, Gary H.

2016-01-01

Environmental and genetic factors represent key components in the establishment/maintenance of the intestinal microbiota. The aryl hydrocarbon receptor (AHR) is emerging as a pleiotropic factor, modulating pathways beyond its established role as a xenobiotic sensor. The AHR is known to regulate immune surveillance within the intestine through retention of intraepithelial lymphocytes, functional redistribution of Th17/Treg balance. Consequently, environmental/genetic manipulation of AHR activity likely influences host-microbe homeostasis. Utilizing C57BL6/J Ahr−/+ and Ahr−/− co-housed littermates followed by 18 days of genotypic segregation, we examined the influence of AHR expression upon intestinal microbe composition/functionality and host physiology. 16S sequencing/quantitative PCR (qPCR) revealed significant changes in phyla abundance, particularly Verrucomicrobia together with segmented filamentous bacteria, and an increase in species diversity in Ahr−/− mice following genotypic segregation. Metagenomics/metabolomics indicate microbial composition is associated with functional shifts in bacterial metabolism. Analysis identified Ahr−/−-dependent increases in ileal gene expression, indicating increased inflammatory tone. Transfer of Ahr−/− microbiota to wild-type germ-free mice recapitulated the increase Verrucomicrobia and inflammatory tone, indicating Ahr−/−-microbial dependence. These data suggest a role for the AHR in influencing the community structure of the intestinal microbiota. PMID:27659481

Role of interleukin-22 in inflammatory bowel disease.

PubMed

Li, Lin-Jing; Gong, Chen; Zhao, Mei-Hua; Feng, Bai-Sui

2014-12-28

Inflammatory bowel disease (IBD) is a chronic inflammatory disease thought to be mediated by the microbiota of the intestinal lumen and inappropriate immune responses. Aberrant immune responses can cause secretion of harmful cytokines that destroy the epithelium of the gastrointestinal tract, leading to further inflammation. Interleukin (IL)-22 is a member of the IL-10 family of cytokines that was recently discovered to be mainly produced by both adaptive and innate immune cells. Several cytokines and many of the transcriptional factors and T regulatory cells are known to regulate IL-22 expression through activation of signal transducer and activator of transcription 3 signaling cascades. This cytokine induces antimicrobial molecules and proliferative and antiapoptotic pathways, which help prevent tissue damage and aid in its repair. All of these processes play a beneficial role in IBD by enhancing intestinal barrier integrity and epithelial innate immunity. In this review, we discuss recent progress in the involvement of IL-22 in the pathogenesis of IBD, as well as its therapeutic potential.

Disruption of the Gut Ecosystem by Antibiotics

PubMed Central

2018-01-01

The intestinal microbiota is a complex ecosystem consisting of various microorganisms that expands human genetic repertoire and therefore affects human health and disease. The metabolic processes and signal transduction pathways of the host and intestinal microorganisms are intimately linked, and abnormal progression of each process leads to changes in the intestinal environment. Alterations in microbial communities lead to changes in functional structures based on the metabolites produced in the gut, and these environmental changes result in various bacterial infections and chronic enteric inflammatory diseases. Here, we illustrate how antibiotics are associated with an increased risk of antibiotic-associated diseases by driving intestinal environment changes that favor the proliferation and virulence of pathogens. Understanding the pathogenesis caused by antibiotics would be a crucial key to the treatment of antibiotic-associated diseases by mitigating changes in the intestinal environment and restoring it to its original state. PMID:29214770

Enteroaggregative Escherichia coli Promotes Transepithelial Migration of Neutrophils Through a Conserved 12-Lipoxygenase Pathway

PubMed Central

Boll, Erik J.; Struve, Carsten; Sander, Anja; Demma, Zachary; Krogfelt, Karen A.; McCormick, Beth A.

2014-01-01

Summary Enteroaggregative Escherichia coli (EAEC) induces release of pro-inflammatory markers and disruption of intestinal epithelial barriers in vitro suggesting an inflammatory aspect to EAEC infection. However, the mechanisms underlying EAEC-induced mucosal inflammatory responses and the extent to which these events contribute to pathogenesis is not well characterized. Employing an established in vitro model we demonstrated that EAEC prototype strain 042 induces migration of polymorphonuclear neutrophils (PMNs) across polarized T84 cell monolayers. This event was mediated through a conserved host cell signaling cascade involving the 12/15-LOX pathway and led to apical secretion of an arachidonic acid-derived lipid PMN chemoattractant, guiding PMNs across the epithelia to the site of infection. Moreover, supporting the hypothesis that inflammatory responses may contribute to EAEC pathogenesis, we found that PMN transepithelial migration promoted enhanced attachment of EAEC 042 to T84 cells. These findings suggest that EAEC-induced PMN infiltration may favor colonization and thus pathogenesis of EAEC. PMID:21951973

Microbiota signalling through MyD88 is necessary for a systemic neutrophilic inflammatory response

PubMed Central

Karmarkar, Dipti; Rock, Kenneth L

2013-01-01

In the present study, we have found that intestinal flora strongly influence peritoneal neutrophilic inflammatory responses to diverse stimuli, including pathogen-derived particles like zymosan and sterile irritant particles like crystals. When germ-free and flora-deficient (antibiotic-treated) mice are challenged with zymosan intraperitoneally, neutrophils are markedly impaired in their ability to extravasate from blood into the peritoneum. In contrast, in these animals, neutrophils can extravasate in response to an intraperitoneal injection of the chemokine, macrophage inflammatory protein 2. Neutrophil recruitment upon inflammatory challenge requires stimulation by microbiota through a myeloid differentiation primary response gene (88) (MyD88) -dependent pathway. MyD88 signalling is crucial during the development of the immune system but depending upon the ligand it may be dispensable at the time of the actual inflammatory challenge. Furthermore, pre-treatment of flora-deficient mice with a purified MyD88-pathway agonist is sufficient to restore neutrophil migration. In summary, this study provides insight into the role of gut microbiota in influencing acute inflammation at sites outside the gastrointestinal tract. PMID:23909393

Lactobacillus acidophilus attenuates Salmonella-induced intestinal inflammation via TGF-β signaling.

PubMed

Huang, I-Fei; Lin, I-Chun; Liu, Pei-Feng; Cheng, Ming-Fang; Liu, Yen-Chen; Hsieh, Yao-Dung; Chen, Jih-Jung; Chen, Chun-Lin; Chang, Hsueh-Wei; Shu, Chih-Wen

2015-10-07

Salmonella is a common intestinal pathogen that causes acute and chronic inflammatory response. Probiotics reduce inflammatory cytokine production and serve as beneficial commensal microorganisms in the human gastrointestinal tract. TGF-β (transforming growth factor β)/SMAD and NF-κB signaling play important roles in inflammation in intestinal cells. However, the involvement of the signaling in regulating inflammation between Salmonella and probiotics is not fully understood. L. acidophilus and prebiotic inulin were used to treat human intestinal Caco-2 cells prior to infection with Salmonella. The cells were harvested to examine the cytokines and MIR21 expression with immunoblotting and real-time PCR. NF-κB and SMAD3/4 reporter vectors were transfected into cells to monitor inflammation and TGF-β1 signaling, respectively. In this study, we showed that the probiotic L. acidophilus decreased Salmonella-induced NF-κB activation in human intestinal Caco-2 cells. Expression of the inflammatory cytokines, TNF-α and IL-8, in L. acidophilus-pretreated cells was also significantly lower than that in cells infected with Salmonella alone. Moreover, TGF-β1 and MIR21 expression was elevated in cells pretreated with L. acidophilus or synbiotic, a combination of inulin and L. acidophilus, compared to that in untreated cells or cells infected with S. typhimurium alone. By contrast, expression of SMAD7, a target of MIR21, was accordingly reduced in cells treated with L. acidophilus or synbiotics. Consistent with TGF-β1/MIR21 and SMAD7 expression, SMAD3/4 transcriptional activity was significantly higher in the cells treated with L. acidophilus or synbiotics. Furthermore, TGF-β1 antibody antagonized the SMAD3/4 and NF-κB transcriptional activity modulated by L. acidophilus in intestinal cells. Our results suggest that the TGF-β1/MIR21 signaling pathway may be involved in the suppressive effects of L. acidophilus on inflammation caused by S. typhimurium in intestinal Caco-2 cells.

Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells.

PubMed

Pietz, Grzegorz; De, Rituparna; Hedberg, Maria; Sjöberg, Veronika; Sandström, Olof; Hernell, Olle; Hammarström, Sten; Hammarström, Marie-Louise

2017-01-01

Celiac disease is a chronic inflammatory disease of the small intestine mucosa due to permanent intolerance to dietary gluten. The aim was to elucidate the role of small intestinal epithelial cells in the immunopathology of celiac disease in particular the influence of celiac disease-associated bacteria. Duodenal biopsies were collected from children with active celiac disease, treated celiac disease, and clinical controls. Intestinal epithelial cells were purified and analyzed for gene expression changes at the mRNA and protein levels. Two in vitro models for human intestinal epithelium, small intestinal enteroids and polarized tight monolayers, were utilized to assess how interferon-γ, interleukin-17A, celiac disease-associated bacteria and gluten influence intestinal epithelial cells. More than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1, were significantly upregulated in intestinal epithelial cells at active celiac disease. Of these genes, 70% were upregulated by interferon-γ via the IRF1 pathway. Most interestingly, IRF1 was also upregulated by celiac disease-associated bacteria. The NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin-18, which induces interferon-γ in intraepithelial lymphocytes, was expressed in intestinal epithelial cells. A key factor in the epithelial reaction in celiac disease appears to be over-expression of IRF1 that could be inherent and/or due to presence of undesirable microbes that act directly on IRF1. Dual activation of IRF1 and IRF1-regulated genes, both directly and via the interleukin-18 dependent inflammasome would drastically enhance the inflammatory response and lead to the pathological situation seen in active celiac disease.

Immunopathology of childhood celiac disease—Key role of intestinal epithelial cells

PubMed Central

Hedberg, Maria; Sjöberg, Veronika; Sandström, Olof; Hernell, Olle; Hammarström, Sten

2017-01-01

Background & Aims Celiac disease is a chronic inflammatory disease of the small intestine mucosa due to permanent intolerance to dietary gluten. The aim was to elucidate the role of small intestinal epithelial cells in the immunopathology of celiac disease in particular the influence of celiac disease-associated bacteria. Methods Duodenal biopsies were collected from children with active celiac disease, treated celiac disease, and clinical controls. Intestinal epithelial cells were purified and analyzed for gene expression changes at the mRNA and protein levels. Two in vitro models for human intestinal epithelium, small intestinal enteroids and polarized tight monolayers, were utilized to assess how interferon-γ, interleukin-17A, celiac disease-associated bacteria and gluten influence intestinal epithelial cells. Results More than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1, were significantly upregulated in intestinal epithelial cells at active celiac disease. Of these genes, 70% were upregulated by interferon-γ via the IRF1 pathway. Most interestingly, IRF1 was also upregulated by celiac disease-associated bacteria. The NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin-18, which induces interferon-γ in intraepithelial lymphocytes, was expressed in intestinal epithelial cells. Conclusion A key factor in the epithelial reaction in celiac disease appears to be over-expression of IRF1 that could be inherent and/or due to presence of undesirable microbes that act directly on IRF1. Dual activation of IRF1 and IRF1-regulated genes, both directly and via the interleukin-18 dependent inflammasome would drastically enhance the inflammatory response and lead to the pathological situation seen in active celiac disease. PMID:28934294

Frontiers in Drug Research and Development for Inflammatory Bowel Disease

PubMed Central

Currò, Diego; Pugliese, Daniela; Armuzzi, Alessandro

2017-01-01

Inflammatory bowel disease (IBD) is idiopathic, lifelong, immune-mediated diseases, for which curative therapies are not yet available. In the last 15 years, the introduction of monoclonal antibodies targeting tumor necrosis factor-α, a cytokine playing a key role in bowel inflammation, has revolutionized treatment paradigms for IBD. Despite their proven long-term efficacy, however, many patients do not respond or progressively lose response to these drugs. Major advances of knowledge in immunology and pathophysiology of intestinal inflammatory processes have made possible the identification of new molecular targets for drugs, thus opening several new potential therapeutic opportunities for IBD. The abnormal response of intestinal immunity to unknown antigens leads to the activation of T helper lymphocytes and triggers the inflammatory cascade. Sphingosine 1-phosphate receptor agonists negatively modulate the egress of lymphocytes, inducted by antigen-presenting cells, from secondary lymphoid tissues to intestinal wall. Leukocyte adhesion inhibitors (both anti-integrin and anti-Mucosal Vascular Addressin Cell Adhesion Molecule 1) interfere with the tissue homing processes. Activated T helper lymphocytes increase the levels of pro-inflammatory cytokines, such as interleukin 12, 23, and 6, offering several potential pharmacological interventions. The Janus kinases, intracellular enzymes mediating the transduction of several cytokine signals, are other explored targets for treating immune-mediated diseases. Finally, the impact of modulating Smad7 pathway, which is responsible for the down-regulation of the immunosuppressive cytokine transforming growth factor-β signaling, is currently under investigation. The purpose of this review is to discuss the most promising molecules in late-stage clinical development, with a special emphasis on pharmacological properties. PMID:28690543

Microbiota-specific Th17 Cells: Yin and Yang in Regulation of Inflammatory Bowel Disease.

PubMed

Wu, Wei; Chen, Feidi; Liu, Zhanju; Cong, Yingzi

2016-06-01

Multiple mechanisms are involved in regulation of host response to microbiota to maintain the intestinal homeostasis. Th17 cells are enriched in the intestinal lamina propria under steady conditions. Many studies have demonstrated that microbiota-reactive Th17 cells in the intestines mediate the pathogenesis of inflammatory bowel diseases. However, clinical trials of anti-interleukin-17A or anti-interleukin-17RA antibodies in patients with Crohn's Disease show no improvement or even exacerbation of disease. Accumulating data has also indicated that Th17 cells may provide a protective effect as well to the intestines from inflammatory insults under homeostasis regulation, even under inflammatory conditions. Thus both proinflammatory and anti-inflammatory functions of intestinal Th17 cells have emerged under various conditions. In this review article, we will summarize recent progresses of Th17 cells in regulation of intestinal homeostasis and in the pathogenesis of inflammatory bowel diseases.

Human colonic myocytes are involved in postischemic inflammation through ADAM17-dependent TNFα production

PubMed Central

Jarry, Anne; Bach-Ngohou, Kalyane; Masson, Damien; Dejoie, Thomas; Lehur, Paul-Antoine; Mosnier, Jean-François; Denis, Marc G; Laboisse, Christian L

2005-01-01

The aim of this study was to identify human colonic resident cells able to initiate an inflammatory response in postischemic injury. Postischemic colonic injury, a condition relevant to various clinical settings, involves an inflammatory cascade in intestinal tissues through the recruitment of circulating inflammatory cells. However, there is no information on the nature of resident cells of the different intestinal layers able to initiate a postischemic inflammatory response. It is however an important issue in the context of a pharmacological approach of the early phase of intestinal ischemia. We reasoned that maintaining the different colonic layers as explant cultures in an oxygenated medium immediately after colonic resection, that is, after an ischemic period, would allow one to identify the resident cells able to initiate an inflammatory cascade, without interference of recruited inflammatory/immune cells. To this end, we designed an explant culture system that operationally defines three compartments in surgical specimens of the human colon, based on the microdissected layers, that is, mucosa, submucosa (containing muscularis mucosae) and muscularis propria. To validate the results obtained in explant cultures in the clinical setting of ischemic colitis, eight cases of sigmoid volvulus were examined. Only the myocytes-containing explants produced tumor necrosis factor alpha (TNFα), via an ADAM17 (a disintegrin and metalloproteinase-17)-dependent pathway, as shown by the abrogation of TNFα production by the inhibitor Tapi-2. Immunofluorescence studies identified nonvascular and vascular myocytes as resident cells coexpressing TNFα and ADAM17, both in our postischemic explant system and in surgical specimens from ischemic colitis patients. Finally, time-course experiments on explanted tissues showed that TNFα production by myocytes was an early event triggered by a postischemic oxidative stress involving nuclear factor kappa B (NF-κB). In conclusion, this study identifies human intestinal myocytes as resident cells able to initiate an inflammatory reaction through TNFα production in postischemic conditions, and delineates two points of control in TNFα production, NF-κB and ADAM17, which can be targeted by pharmacological manipulation. PMID:16273118

Microbiota-specific Th17 cells: Yin and Yang in regulation of inflammatory bowel disease

PubMed Central

Wei, Wu; Feidi, Chen; Zhanju, Liu; Yingzi, Cong

2016-01-01

Multiple mechanisms are involved in regulation of host response to microbiota to maintain the intestinal homeostasis. Th17 cells are enriched in the intestinal lamina propria (LP) under steady conditions. Many studies have demonstrated that microbiota reactive Th17 cells in the intestines mediate the pathogenesis of inflammatory bowel diseases. However, clinical trials of anti-IL-17A or anti-IL-17RA antibodies in patients with Crohn’s Disease show no improvement or even exacerbation of disease. Accumulating data has also indicated that Th17 cells may provide a protective effect as well to the intestines from inflammatory insults under homeostasis regulation, even under inflammatory conditions. Thus both pro-inflammatory and anti-inflammatory functions of intestinal Th17 cells have emerged under various conditions. In this review article, we will summarize recent progresses of Th17 cells in regulation of intestinal homeostasis as well as in the pathogenesis of inflammatory bowel diseases. PMID:27057688

Irinotecan-induced mucositis: the interactions and potential role of GLP-2 analogues.

PubMed

Mayo, Bronwen J; Stringer, Andrea M; Bowen, Joanne M; Bateman, Emma H; Keefe, Dorothy M

2017-02-01

A common side effect of irinotecan administration is gastrointestinal mucositis, often manifesting as severe diarrhoea. The damage to the structure and function of the gastrointestinal tract caused by this cytotoxic agent is debilitating and often leads to alterations in patients' regimens, hospitalisation or stoppage of treatment. The purpose of this review is to identify mechanisms of irinotecan-induced intestinal damage and a potential role for GLP-2 analogues for intervention. This is a review of current literature on irinotecan-induced mucositis and GLP-2 analogues mechanisms of action. Recent studies have found alterations that appear to be crucial in the development of severe intestinal mucositis, including early apoptosis, alterations in proliferation and cell survival pathways, as well as induction of inflammatory cascades. Several studies have indicated a possible role for glucagon-like peptide-2 analogues in treating this toxicity, due to its proven intestinotrophic, anti-apoptotic and anti-inflammatory effects in other models of gastrointestinal disease. This review provides evidence as to why and how this treatment may improve mucositis through the possible molecular crosstalk that may be occurring in models of severe intestinal mucositis.

Adenine Inhibits TNF-α Signaling in Intestinal Epithelial Cells and Reduces Mucosal Inflammation in a Dextran Sodium Sulfate-Induced Colitis Mouse Model.

PubMed

Fukuda, Toshihiko; Majumder, Kaustav; Zhang, Hua; Turner, Patricia V; Matsui, Toshiro; Mine, Yoshinori

2016-06-01

Adenine (6-amino-6H-purine), found in molokheiya (Corchorus olitorius L.), has exerted vasorelaxation effects in the thoracic aorta. However, the mode of action of the anti-inflammatory effect of adenine is unclear. Thus, we investigated to clarify the effect of adenine on chronic inflammation of the gastrointestinal tract. In intestinal epithelial cells, adenine significantly inhibited tumor necrosis factor-α-induced interleukin-8 secretion. The inhibition of adenine was abolished under the treatment of inhibitors of adenyl cyclase (AC) and protein kinase A (PKA), indicating the effect of adenine was mediated through the AC/PKA pathway. Adenine (5, 10, and 50 mg/kg BW/day) was administered orally for 14 days to female BALB/c mice, and then 5% dextran sodium sulfate (DSS) was given to induce colitis. Adenine (5 mg/kg BW/day) significantly prevented DSS-induced colon shortening, expression of pro-inflammatory cytokines, and histological damage in the colon. These results suggest that adenine can be a promising nutraceutical for the prevention of intestinal inflammation.

Anti-inflammatory protection afforded by cyanidin-3-glucoside and resveratrol in human intestinal cells via Nrf2 and PPAR-γ: Comparison with 5-aminosalicylic acid.

PubMed

Serra, Diana; Almeida, Leonor M; Dinis, Teresa C P

2016-12-25

This study investigated the involvement of nuclear factor erythroid 2 (Nrf2) and peroxisome proliferator-activated receptor-gamma (PPAR-γ) pathways in the protection afforded by two polyphenols abundant in diet, cyanidin-3-glucoside and resveratrol, against cytokine-induced inflammation and oxidative insult in HT-29 intestinal cells, in comparison with the drug 5-aminosalicylic acid (5-ASA). Our data show for the first time that in cytokine-challenged cells, cyanidin-3-glucoside and resveratrol induced Nrf2 activation, increased hemoxygenase-1 and glutamate cysteine ligase mRNA expression, enhanced reduced glutathione to oxidized glutathione ratio and inhibited reactive species production, at much lower concentrations than 5-ASA. Unlike cyanidin-3-glucoside, resveratrol and 5-ASA also increased nuclear levels of PPAR-γ in cytokine-stimulated cells. In conclusion, both polyphenols might be interesting as nutraceuticals, giving complementary benefits to conventional drugs against intestinal inflammation, typically present in patients with inflammatory bowel disease. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Flavonoids from Engineered Tomatoes Inhibit Gut Barrier Pro-inflammatory Cytokines and Chemokines, via SAPK/JNK and p38 MAPK Pathways.

PubMed

Tomlinson, Matthew L; Butelli, Eugenio; Martin, Cathie; Carding, Simon R

2017-01-01

Flavonoids are a diverse group of plant secondary metabolites, known to reduce inflammatory bowel disease symptoms. How they achieve this is largely unknown. Our study focuses on the gut epithelium as it receives high topological doses of dietary constituents, maintains gut homeostasis, and orchestrates gut immunity. Dysregulation leads to chronic gut inflammation, via dendritic cell (DC)-driven immune responses. Tomatoes engineered for enriched sets of flavonoids (anthocyanins or flavonols) provided a unique and complex naturally consumed food matrix to study the effect of diet on chronic inflammation. Primary murine colonic epithelial cell-based inflammation assays consist of chemokine induction, apoptosis and proliferation, and effects on kinase pathways. Primary murine leukocytes and DCs were used to assay effects on transmigration. A murine intestinal cell line was used to assay wound healing. Engineered tomato extracts (enriched in anthocyanins or flavonols) showed strong and specific inhibitory effects on a set of key epithelial pro-inflammatory cytokines and chemokines. Chemotaxis assays showed a resulting reduction in the migration of primary leukocytes and DCs. Activation of epithelial cell SAPK/JNK and p38 MAPK signaling pathways were specifically inhibited. The epithelial wound healing-associated STAT3 pathway was unaffected. Cellular migration, proliferation, and apoptosis assays confirmed that wound healing processes were not affected by flavonoids. We show flavonoids target epithelial pro-inflammatory kinase pathways, inhibiting chemotactic signals resulting in reduced leukocyte and DC chemotaxis. Thus, both anthocyanins and flavonols modulate epithelial cells to become hyporesponsive to bacterial stimulation. Our results identify a viable mechanism to explain the in vivo anti-inflammatory effects of flavonoids.

Overexpression of GRß in colonic mucosal cell line partly reflects altered gene expression in colonic mucosa of patients with inflammatory bowel disease.

PubMed

Nagy, Zsolt; Acs, Bence; Butz, Henriett; Feldman, Karolina; Marta, Alexa; Szabo, Peter M; Baghy, Kornelia; Pazmany, Tamas; Racz, Karoly; Liko, Istvan; Patocs, Attila

2016-01-01

The glucocorticoid receptor (GR) plays a crucial role in inflammatory responses. GR has several isoforms, of which the most deeply studied are the GRα and GRß. Recently it has been suggested that in addition to its negative dominant effect on GRα, the GRß may have a GRα-independent transcriptional activity. The GRß isoform was found to be frequently overexpressed in various autoimmune diseases, including inflammatory bowel disease (IBD). In this study, we wished to test whether the gene expression profile found in a GRß overexpressing intestinal cell line (Caco-2GRß) might mimic the gene expression alterations found in patients with IBD. Whole genome microarray analysis was performed in both normal and GRß overexpressing Caco-2 cell lines with and without dexamethasone treatment. IBD-related genes were identified from a meta-analysis of 245 microarrays available in online microarray deposits performed on intestinal mucosa samples from patients with IBD and healthy individuals. The differentially expressed genes were further studied using in silico pathway analysis. Overexpression of GRß altered a large proportion of genes that were not regulated by dexamethasone suggesting that GRß may have a GRα-independent role in the regulation of gene expression. About 10% of genes differentially expressed in colonic mucosa samples from IBD patients compared to normal subjects were also detected in Caco-2 GRß intestinal cell line. Common genes are involved in cell adhesion and cell proliferation. Overexpression of GRß in intestinal cells may affect appropriate mucosal repair and intact barrier function. The proposed novel role of GRß in intestinal epithelium warrants further studies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells

PubMed Central

Hepworth, Matthew R.; Fung, Thomas C.; Masur, Samuel H.; Kelsen, Judith R.; McConnell, Fiona M.; Dubrot, Juan; Withers, David R.; Hugues, Stephanie; Farrar, Michael A.; Reith, Walter; Eberl, Gerard; Baldassano, Robert N.; Laufer, Terri M.; Elson, Charles O.; Sonnenberg, Gregory F.

2015-01-01

Inflammatory CD4+ T cell responses to self or commensal bacteria underlie the pathogenesis of autoimmunity and inflammatory bowel disease (IBD), respectively. While selection of self-specific T cells in the thymus limits responses to tissue antigens, the mechanisms that control selection of commensal bacteria-specific T cells remain poorly understood. Here we demonstrate that group 3 innate lymphoid cell (ILC3)-intrinsic expression of major histocompatibility complex class II (MHCII) is regulated similarly to thymic epithelial cells, and that MHCII+ ILC3s directly induce cell death of activated commensal bacteria-specific T cells. Further, MHCII on human colonic ILC3s was reduced in pediatric IBD patients. Collectively, these results define a selection pathway for commensal bacteria-specific CD4+ T cells in the intestine, and suggest that this process is dysregulated in human IBD. PMID:25908663

Emerging Mechanisms of Innate Immunity and Their Translational Potential in Inflammatory Bowel Disease

PubMed Central

Corridoni, Daniele; Chapman, Thomas; Ambrose, Tim; Simmons, Alison

2018-01-01

Activation of the innate immune system through pattern-recognition receptor (PRR) signaling plays a pivotal role in the early induction of host defense following exposure to pathogens. Loss of intestinal innate immune regulation leading aberrant immune responses has been implicated in the pathogenesis of inflammatory bowel disease (IBD). The precise role of PRRs in gut inflammation is not well understood, but considering their role as bacterial sensors and their genetic association with IBD, they likely contribute to dysregulated immune responses to the commensal microbiota. The purpose of this review is to evaluate the emerging functions of PRRs including their functional cross-talk, how they respond to mitochondrial damage, induce mitophagy or autophagy, and influence adaptive immune responses by interacting with the antigen presentation machinery. The review also summarizes some of the recent attempts to harness these pathways for therapeutic approaches in intestinal inflammation. PMID:29515999

Western diet enhances intestinal tumorigenesis in Min/+ mice, associating with mucosal metabolic and inflammatory stress and loss of Apc heterozygosity.

PubMed

Niku, Mikael; Pajari, Anne-Maria; Sarantaus, Laura; Päivärinta, Essi; Storvik, Markus; Heiman-Lindh, Anu; Suokas, Santeri; Nyström, Minna; Mutanen, Marja

2017-01-01

Western-type diet (WD) is a risk factor for colorectal cancer, but the underlying mechanisms are poorly understood. We investigated the interaction of WD and heterozygous mutation in the Apc gene on adenoma formation and metabolic and immunological changes in the histologically normal intestinal mucosa of Apc Min/+ (Min/+) mice. The diet used was high in saturated fat and low in calcium, vitamin D, fiber and folate. The number of adenomas was twofold higher in the WD mice compared to controls, but adenoma size, proliferation or apoptosis did not differ. The ratio of the Min to wild-type allele was higher in the WD mice, indicating accelerated loss of Apc heterozygosity (LOH). Densities of intraepithelial CD3ε + T lymphocytes and of mucosal FoxP3 + regulatory T cells were higher in the WD mice, implying inflammatory changes. Western blot analyses from the mucosa of the WD mice showed suppressed activation of the ERK and AKT pathways and a tendency for reduced activation of the mTOR pathway as measured in phosphoS6/S6 levels. The expression of pyruvate dehydrogenase kinase 4 was up-regulated in both mRNA and protein levels. Gene expression analyses showed changes in oxidation/reduction, fatty acid and monosaccharide metabolic pathways, tissue organization, cell fate and regulation of apoptosis. Together, our results suggest that the high-risk Western diet primes the intestine to tumorigenesis through synergistic effects in energy metabolism, inflammation and oxidative stress, which culminate in the acceleration of LOH of the Apc gene. Copyright © 2016 Elsevier Inc. All rights reserved.

MicroRNA-146a constrains multiple parameters of intestinal immunity and increases susceptibility to DSS colitis.

PubMed

Runtsch, Marah C; Hu, Ruozhen; Alexander, Margaret; Wallace, Jared; Kagele, Dominique; Petersen, Charisse; Valentine, John F; Welker, Noah C; Bronner, Mary P; Chen, Xinjian; Smith, Daniel P; Ajami, Nadim J; Petrosino, Joseph F; Round, June L; O'Connell, Ryan M

2015-10-06

Host-microbial interactions within the mammalian intestines must be properly regulated in order to promote host health and limit disease. Because the microbiota provide constant immunological signals to intestinal tissues, a variety of regulatory mechanisms have evolved to ensure proper immune responses to maintain homeostasis. However, many of the genes that comprise these regulatory pathways, including immune-modulating microRNAs (miRNAs), have not yet been identified or studied in the context of intestinal homeostasis. Here, we investigated the role of microRNA-146a (miR-146a) in regulating intestinal immunity and barrier function and found that this miRNA is expressed in a variety of gut tissues in adult mice. By comparing intestinal gene expression in WT and miR-146a-/- mice, we demonstrate that miR-146a represses a subset of gut barrier and inflammatory genes all within a network of immune-related signaling pathways. We also found that miR-146a restricts the expansion of intestinal T cell populations, including Th17, Tregs, and Tfh cells. GC B cells, Tfh ICOS expression, and the production of luminal IgA were also reduced by miR-146a in the gut. Consistent with an enhanced intestinal barrier, we found that miR-146a-/- mice are resistant to DSS-induced colitis, a model of Ulcerative Colitis (UC), and this correlated with elevated colonic miR-146a expression in human UC patients. Taken together, our data describe a role for miR-146a in constraining intestinal barrier function, a process that alters gut homeostasis and enhances at least some forms of intestinal disease in mice.

MicroRNA-146a constrains multiple parameters of intestinal immunity and increases susceptibility to DSS colitis

PubMed Central

Runtsch, Marah C.; Hu, Ruozhen; Alexander, Margaret; Wallace, Jared; Kagele, Dominique; Petersen, Charisse; Valentine, John F.; Welker, Noah C.; Bronner, Mary P.; Chen, Xinjian; Smith, Daniel P.; Ajami, Nadim J.; Petrosino, Joseph F.; Round, June L.; O'Connell, Ryan M.

2015-01-01

Host-microbial interactions within the mammalian intestines must be properly regulated in order to promote host health and limit disease. Because the microbiota provide constant immunological signals to intestinal tissues, a variety of regulatory mechanisms have evolved to ensure proper immune responses to maintain homeostasis. However, many of the genes that comprise these regulatory pathways, including immune-modulating microRNAs (miRNAs), have not yet been identified or studied in the context of intestinal homeostasis. Here, we investigated the role of microRNA-146a (miR-146a) in regulating intestinal immunity and barrier function and found that this miRNA is expressed in a variety of gut tissues in adult mice. By comparing intestinal gene expression in WT and miR-146a−/− mice, we demonstrate that miR-146a represses a subset of gut barrier and inflammatory genes all within a network of immune-related signaling pathways. We also found that miR-146a restricts the expansion of intestinal T cell populations, including Th17, Tregs, and Tfh cells. GC B cells, Tfh ICOS expression, and the production of luminal IgA were also reduced by miR-146a in the gut. Consistent with an enhanced intestinal barrier, we found that miR-146a−/− mice are resistant to DSS-induced colitis, a model of Ulcerative Colitis (UC), and this correlated with elevated colonic miR-146a expression in human UC patients. Taken together, our data describe a role for miR-146a in constraining intestinal barrier function, a process that alters gut homeostasis and enhances at least some forms of intestinal disease in mice. PMID:26456940

Cocoa and Dark Chocolate Polyphenols: From Biology to Clinical Applications

PubMed Central

Magrone, Thea; Russo, Matteo Antonio; Jirillo, Emilio

2017-01-01

It is well known that cocoa and dark chocolate possess polyphenols as major constituents whose dietary consumption has been associated to beneficial effects. In fact, cocoa and dark chocolate polyphenols exert antioxidant and anti-inflammatory activities switching on some important signaling pathways such as toll-like receptor 4/nuclear factor κB/signal transducer and activator of transcription. In particular, cocoa polyphenols induce release of nitric oxide (NO) through activation of endothelial NO synthase which, in turn, accounts for vasodilation and cardioprotective effects. In the light of the above described properties, a number of clinical trials based on the consumption of cocoa and dark chocolate have been conducted in healthy subjects as well as in different categories of patients, such as those affected by cardiovascular, neurological, intestinal, and metabolic pathologies. Even if data are not always concordant, modifications of biomarkers of disease are frequently associated to improvement of clinical manifestations. Quite interestingly, following cocoa and dark chocolate ingestion, cocoa polyphenols also modulate intestinal microbiota, thus leading to the growth of bacteria that trigger a tolerogenic anti-inflammatory pathway in the host. Finally, many evidences encourage the consumption of cocoa and dark chocolate by aged people for the recovery of the neurovascular unit. PMID:28649251

Cocoa and Dark Chocolate Polyphenols: From Biology to Clinical Applications.

PubMed

Magrone, Thea; Russo, Matteo Antonio; Jirillo, Emilio

2017-01-01

It is well known that cocoa and dark chocolate possess polyphenols as major constituents whose dietary consumption has been associated to beneficial effects. In fact, cocoa and dark chocolate polyphenols exert antioxidant and anti-inflammatory activities switching on some important signaling pathways such as toll-like receptor 4/nuclear factor κB/signal transducer and activator of transcription. In particular, cocoa polyphenols induce release of nitric oxide (NO) through activation of endothelial NO synthase which, in turn, accounts for vasodilation and cardioprotective effects. In the light of the above described properties, a number of clinical trials based on the consumption of cocoa and dark chocolate have been conducted in healthy subjects as well as in different categories of patients, such as those affected by cardiovascular, neurological, intestinal, and metabolic pathologies. Even if data are not always concordant, modifications of biomarkers of disease are frequently associated to improvement of clinical manifestations. Quite interestingly, following cocoa and dark chocolate ingestion, cocoa polyphenols also modulate intestinal microbiota, thus leading to the growth of bacteria that trigger a tolerogenic anti-inflammatory pathway in the host. Finally, many evidences encourage the consumption of cocoa and dark chocolate by aged people for the recovery of the neurovascular unit.

Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis.

PubMed

Czaja, Albert J

2016-11-14

The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune responses, indicate how these responses contribute to the development of systemic immune-mediated diseases, and encourage investigations that improve the understanding and management of autoimmune hepatitis. Alterations in the composition of the intestinal microflora (dysbiosis) can disrupt intestinal and systemic immune tolerances for commensal bacteria. Toll-like receptors within the intestine can recognize microbe-associated molecular patterns and shape subsets of T helper lymphocytes that may cross-react with host antigens (molecular mimicry). Activated gut-derived lymphocytes can migrate to lymph nodes, and gut-derived microbial antigens can translocate to extra-intestinal sites. Inflammasomes can form within hepatocytes and hepatic stellate cells, and they can drive the pro-inflammatory, immune-mediated, and fibrotic responses. Diet, designer probiotics, vitamin supplements, re-colonization methods, antibiotics, drugs that decrease intestinal permeability, and molecular interventions that block signaling pathways may emerge as adjunctive regimens that complement conventional immunosuppressive management. In conclusion, investigations of the intestinal microbiome are warranted in autoimmune hepatitis and promise to clarify pathogenic mechanisms and suggest alternative management strategies.

Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis

PubMed Central

Czaja, Albert J

2016-01-01

The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune responses, indicate how these responses contribute to the development of systemic immune-mediated diseases, and encourage investigations that improve the understanding and management of autoimmune hepatitis. Alterations in the composition of the intestinal microflora (dysbiosis) can disrupt intestinal and systemic immune tolerances for commensal bacteria. Toll-like receptors within the intestine can recognize microbe-associated molecular patterns and shape subsets of T helper lymphocytes that may cross-react with host antigens (molecular mimicry). Activated gut-derived lymphocytes can migrate to lymph nodes, and gut-derived microbial antigens can translocate to extra-intestinal sites. Inflammasomes can form within hepatocytes and hepatic stellate cells, and they can drive the pro-inflammatory, immune-mediated, and fibrotic responses. Diet, designer probiotics, vitamin supplements, re-colonization methods, antibiotics, drugs that decrease intestinal permeability, and molecular interventions that block signaling pathways may emerge as adjunctive regimens that complement conventional immunosuppressive management. In conclusion, investigations of the intestinal microbiome are warranted in autoimmune hepatitis and promise to clarify pathogenic mechanisms and suggest alternative management strategies. PMID:27895415

Low-Dose Intestinal Trichuris muris Infection Alters the Lung Immune Microenvironment and Can Suppress Allergic Airway Inflammation.

PubMed

Chenery, Alistair L; Antignano, Frann; Burrows, Kyle; Scheer, Sebastian; Perona-Wright, Georgia; Zaph, Colby

2016-02-01

Immunological cross talk between mucosal tissues such as the intestine and the lung is poorly defined during homeostasis and disease. Here, we show that a low-dose infection with the intestinally restricted helminth parasite Trichuris muris results in the production of Th1 cell-dependent gamma interferon (IFN-γ) and myeloid cell-derived interleukin-10 (IL-10) in the lung without causing overt airway pathology. This cross-mucosal immune response in the lung inhibits the development of papain-induced allergic airway inflammation, an innate cell-mediated type 2 airway inflammatory disease. Thus, we identify convergent and nonredundant roles of adaptive and innate immunity in mediating cross-mucosal suppression of type 2 airway inflammation during low-dose helminth-induced intestinal inflammation. These results provide further insight in identifying novel intersecting immune pathways elicited by gut-to-lung mucosal cross talk. Copyright © 2016 Chenery et al.

Anthocyanins as inflammatory modulators and the role of the gut microbiota.

PubMed

Morais, Carina Almeida; de Rosso, Veridiana Vera; Estadella, Débora; Pisani, Luciana Pellegrini

2016-07-01

The health benefits of consuming fruits that are rich in polyphenols, especially anthocyanins, have been the focus of recent in vitro and in vivo investigations. Thus, greater attention is being directed to the reduction of the inflammatory process associated with the intestinal microbiota and the mechanism underlying these effects because the microbiota has been closely associated with the metabolism of these compounds in the gastrointestinal tract. Further interest lies in the ability of these metabolites to modulate the growth of specific intestinal bacteria. Thus, this review examines studies involving the action of the anthocyanins that are present in many fruits and their effect in the modulating the inflammatory process associated with the interaction between the host and the gut microbiota. The findings of both in vitro and in vivo studies suggest a potential antiinflammatory effect of these compounds, which seem to inhibit activation of the signaling pathway mediated by the transcription factor NFκB. This effect is associated with modulation of a beneficial gut microbiota, particularly an increase in Bifidobacterium strains. Copyright © 2015 Elsevier Inc. All rights reserved.

Pregnane X receptor agonists enhance intestinal epithelial wound healing and repair of the intestinal barrier following the induction of experimental colitis.

PubMed

Terc, Joshua; Hansen, Ashleigh; Alston, Laurie; Hirota, Simon A

2014-05-13

The intestinal epithelial barrier plays a key role in the maintenance of homeostasis within the gastrointestinal tract. Barrier dysfunction leading to increased epithelial permeability is associated with a number of gastrointestinal disorders including the inflammatory bowel diseases (IBD) - Crohn's disease and ulcerative colitis. It is thought that the increased permeability in patients with IBD may be driven by alterations in the epithelial wound healing response. To this end considerable study has been undertaken to identify signaling pathways that may accelerate intestinal epithelial wound healing and normalize the barrier dysfunction observed in IBD. In the current study we examined the role of the pregnane X receptor (PXR) in modulating the intestinal epithelial wound healing response. Mutations and reduced mucosal expression of the PXR are associated with IBD, and others have reported that PXR agonists can dampen intestinal inflammation. Furthermore, stimulation of the PXR has been associated with increased cell migration and proliferation, two of the key processes involved in wound healing. We hypothesized that PXR agonists would enhance intestinal epithelial repair. Stimulation of Caco-2 intestinal epithelial cells with rifaximin, rifampicin and SR12813, all potent agonists of the PXR, significantly increased wound closure. This effect was driven by p38 MAP kinase-dependent cell migration, and occurred in the absence of cell proliferation. Treating mice with a rodent specific PXR agonist, pregnenolone 16α-carbonitrile (PCN), attenuated the intestinal barrier dysfunction observed in the dextran sulphate sodium (DSS) model of experimental colitis, an effect that occurred independent of the known anti-inflammatory effects of PCN. Taken together our data indicate that the activation of the PXR can enhance intestinal epithelial repair and suggest that targeting the PXR may help to normalize intestinal barrier dysfunction observed in patients with IBD. Furthermore, our data provide additional insight into the potential mechanisms through which rifaximin elicits its clinical efficacy in the treatment of IBD. Copyright © 2014 Elsevier B.V. All rights reserved.

The cholinergic anti-inflammatory pathway revisited.

PubMed

Murray, K; Reardon, C

2018-03-01

Inflammatory bowel disease negatively affects the quality of life of millions of patients around the world. Although the precise etiology of the disease remains elusive, aberrant immune system activation is an underlying cause. As such, therapies that selectively inhibit immune cell activation without broad immunosuppression are desired. Inhibition of immune cell activation preventing pro-inflammatory cytokine production through neural stimulation has emerged as one such treatment. These therapeutics are based on the discovery of the cholinergic anti-inflammatory pathway, a reflex arc that induces efferent vagal nerve signaling to reduce immune cell activation and consequently mortality during septic shock. Despite the success of preclinical and clinical trials, the neural circuitry and mechanisms of action of these immune-regulatory circuits are controversial. At the heart of this controversy is the protective effect of vagal nerve stimulation despite an apparent lack of neuroanatomical connections between the vagus and target organs. Additional studies have further emphasized the importance of sympathetic innervation of these organs, and that alternative neural circuits could be involved in neural regulation of the immune system. Such controversies also extend to the regulation of intestinal inflammation, with the importance of efferent vagus nerve signals in question. Experiments that better characterize these pathways have now been performed by Willemze et al. in this issue of Neurogastroenterology & Motility. These continued efforts will be critical to the development of better neurostimulator based therapeutics for inflammatory bowel disease. © 2018 John Wiley & Sons Ltd.

Cinnamon extract attenuates TNF-alpha-induced intestinal lipoprotein ApoB48 overproduction by regulating inflammatory, insulin, and lipoprotein pathways in enterocytes

USDA-ARS?s Scientific Manuscript database

We evaluated whether a water extract of cinnamon (CE = Cinnulin PF®) attenuates the dyslipidemia induced by TNF-alpha in Triton WR-1339-treated hamsters, and whether CE inhibited the over-secretion of apoB48-induced by TNF-alpha in enterocytes in a 35S-labelling study. In vivo, oral treatment with C...

Elucidating pathways of Toxoplasma gondii invasion in the gastrointestinal tract: involvement of the tight junction protein occludin.

PubMed

Weight, Caroline M; Jones, Emily J; Horn, Nikki; Wellner, Nikolaus; Carding, Simon R

2015-10-01

Toxoplasma gondii is an obligate intracellular parasite infecting one third of the world's population. The small intestine is the parasite's primary route of infection, although the pathway of epithelium transmigration remains unclear. Using an in vitro invasion assay and live imaging we showed that T. gondii (RH) tachyzoites infect and transmigrate between adjacent intestinal epithelial cells in polarized monolayers without altering barrier integrity, despite eliciting the production of specific inflammatory mediators and chemokines. During invasion, T. gondii co-localized with occludin. Reducing the levels of endogenous cellular occludin with specific small interfering RNAs significantly reduced the ability of T. gondii to penetrate between and infect epithelial cells. Furthermore, an in vitro invasion and binding assays using recombinant occludin fragments established the capacity of the parasite to bind occludin and in particular to the extracellular loops of the protein. These findings provide evidence for occludin playing a role in the invasion of T. gondii in small intestinal epithelial cells. Copyright © 2015 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Flavonoids from Engineered Tomatoes Inhibit Gut Barrier Pro-inflammatory Cytokines and Chemokines, via SAPK/JNK and p38 MAPK Pathways

PubMed Central

Tomlinson, Matthew L.; Butelli, Eugenio; Martin, Cathie; Carding, Simon R.

2017-01-01

Flavonoids are a diverse group of plant secondary metabolites, known to reduce inflammatory bowel disease symptoms. How they achieve this is largely unknown. Our study focuses on the gut epithelium as it receives high topological doses of dietary constituents, maintains gut homeostasis, and orchestrates gut immunity. Dysregulation leads to chronic gut inflammation, via dendritic cell (DC)-driven immune responses. Tomatoes engineered for enriched sets of flavonoids (anthocyanins or flavonols) provided a unique and complex naturally consumed food matrix to study the effect of diet on chronic inflammation. Primary murine colonic epithelial cell-based inflammation assays consist of chemokine induction, apoptosis and proliferation, and effects on kinase pathways. Primary murine leukocytes and DCs were used to assay effects on transmigration. A murine intestinal cell line was used to assay wound healing. Engineered tomato extracts (enriched in anthocyanins or flavonols) showed strong and specific inhibitory effects on a set of key epithelial pro-inflammatory cytokines and chemokines. Chemotaxis assays showed a resulting reduction in the migration of primary leukocytes and DCs. Activation of epithelial cell SAPK/JNK and p38 MAPK signaling pathways were specifically inhibited. The epithelial wound healing-associated STAT3 pathway was unaffected. Cellular migration, proliferation, and apoptosis assays confirmed that wound healing processes were not affected by flavonoids. We show flavonoids target epithelial pro-inflammatory kinase pathways, inhibiting chemotactic signals resulting in reduced leukocyte and DC chemotaxis. Thus, both anthocyanins and flavonols modulate epithelial cells to become hyporesponsive to bacterial stimulation. Our results identify a viable mechanism to explain the in vivo anti-inflammatory effects of flavonoids. PMID:29326940

Effects of quercetin and menadione on intestinal calcium absorption and the underlying mechanisms.

PubMed

Marchionatti, Ana M; Pacciaroni, Adriana; Tolosa de Talamoni, Nori G

2013-01-01

Quercetin (QT) could be considered as a potential therapeutic agent for different diseases due to its antioxidant, anti-inflammatory, antiviral and anticancer properties. This study was designed to investigate the ability of QT to protect the chick intestine against menadione (MEN) induced injury in vivo and in vitro. Four-week old chicks (Gallus gallus) were treated i.p. with 2.5μmol of MEN/kg b.w. or with i.l. 50μM QT or both. QT protected the intestinal Ca(2+) absorption against the inhibition caused by MEN, but QT alone did not modify. Glutathione (GSH) depletion provoked by MEN in chick enterocytes was abolished by QT treatment, whereas QT alone did not modify the intestinal GSH content. The enhancement of GSH peroxidase activity produced by MEN was blocked by QT treatment. In contrast, superoxide dismutase activity remained high after simultaneous treatment of enterocytes with MEN and QT. The flavonol also avoided changes in the mitochondrial membrane permeability (swelling) produced by MEN. The FasL/Fas/caspase-3 pathway was activated by MEN, effect that was abrogated by QT. In conclusion, QT may be useful in preventing inhibition of chick intestinal Ca(2+) absorption caused by MEN or other substances that deplete GSH, by blocking the oxidative stress and the FasL/Fas/caspase-3 pathway activation. Copyright © 2012 Elsevier Inc. All rights reserved.

Pathogenic role of inflammatory response during Shiga toxin-associated hemolytic uremic syndrome (HUS).

PubMed

Exeni, Ramon Alfonso; Fernandez-Brando, Romina Jimena; Santiago, Adriana Patricia; Fiorentino, Gabriela Alejandra; Exeni, Andrea Mariana; Ramos, Maria Victoria; Palermo, Marina Sandra

2018-01-25

Hemolytic uremic syndrome (HUS) is defined as a triad of noninmune microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The most frequent presentation is secondary to Shiga toxin (Stx)-producing Escherichia coli (STEC) infections, which is termed postdiarrheal, epidemiologic or Stx-HUS, considering that Stx is the necessary etiological factor. After ingestion, STEC colonize the intestine and produce Stx, which translocates across the intestinal epithelium. Once Stx enters the bloodstream, it interacts with renal endothelial and epithelial cells, and leukocytes. This review summarizes the current evidence about the involvement of inflammatory components as central pathogenic factors that could determine outcome of STEC infections. Intestinal inflammation may favor epithelial leakage and subsequent passage of Stx to the systemic circulation. Vascular damage triggered by Stx promotes not only release of thrombin and increased fibrin concentration but also production of cytokines and chemokines by endothelial cells. Recent evidence from animal models and patients strongly indicate that several immune cells types may participate in HUS physiopathology: neutrophils, through release of proteases and reactive oxygen species (ROS); monocytes/macrophages through secretion of cytokines and chemokines. In addition, high levels of Bb factor and soluble C5b-9 (sC5b-9) in plasma as well as complement factors adhered to platelet-leukocyte complexes, microparticles and microvesicles, suggest activation of the alternative pathway of complement. Thus, acute immune response secondary to STEC infection, the Stx stimulatory effect on different immune cells, and inflammatory stimulus secondary to endothelial damage all together converge to define a strong inflammatory status that worsens Stx toxicity and disease.

Inflammatory pathways of importance for management of inflammatory bowel disease.

PubMed

Pedersen, Jannie; Coskun, Mehmet; Soendergaard, Christoffer; Salem, Mohammad; Nielsen, Ole Haagen

2014-01-07

Inflammatory bowel disease (IBD) is a group of chronic disorders of the gastrointestinal tract comprising Crohn's disease (CD) and ulcerative colitis (UC). Their etiologies are unknown, but they are characterised by an imbalanced production of pro-inflammatory mediators, e.g., tumor necrosis factor (TNF)-α, as well as increased recruitment of leukocytes to the site of inflammation. Advantages in understanding the role of the inflammatory pathways in IBD and an inadequate response to conventional therapy in a large portion of patients, has over the last two decades lead to new therapies which includes the TNF inhibitors (TNFi), designed to target and neutralise the effect of TNF-α. TNFi have shown to be efficient in treating moderate to severe CD and UC. However, convenient alternative therapeutics targeting other immune pathways are needed for patients with IBD refractory to conventional therapy including TNFi. Indeed, several therapeutics are currently under development, and have shown success in clinical trials. These include antibodies targeting and neutralising interleukin-12/23, small pharmacologic Janus kinase inhibitors designed to block intracellular signaling of several pro-inflammatory cytokines, antibodies targeting integrins, and small anti-adhesion molecules that block adhesion between leukocytes and the intestinal vascular endothelium, reducing their infiltration into the inflamed mucosa. In this review we have elucidated the major signaling pathways of clinical importance for IBD therapy and highlighted the new promising therapies available. As stated in this paper several new treatment options are under development for the treatment of CD and UC, however, no drug fits all patients. Hence, optimisations of treatment regimens are warranted for the benefit of the patients either through biomarker establishment or other rationales to maximise the effect of the broad range of mode-of-actions of the present and future drugs in IBD.

Methylation-Dependent Activation of CDX1 through NF-κB

PubMed Central

Rau, Tilman T.; Rogler, Anja; Frischauf, Myrjam; Jung, Andreas; Konturek, Peter C.; Dimmler, Arno; Faller, Gerhard; Sehnert, Bettina; El-Rifai, Wael; Hartmann, Arndt; Voll, Reinhard E.; Schneider-Stock, Regine

2013-01-01

The caudal homeobox factor 1 (CDX1) is an essential transcription factor for intestinal differentiation. Its aberrant expression in intestinal metaplasia of the upper gastrointestinal tract is a hallmark within the gastritis-metaplasia-carcinoma sequence. CDX1 expression is influenced by certain pathways, such as Wnt, Ras, or NF-κB signaling; however, these pathways alone cannot explain the transient expression of CDX1 in intestinal metaplasia or the molecular inactivation mechanism of its loss in cases of advanced gastric cancer. In this study, we investigated the epigenetic inactivation of CDX1 by promoter methylation, as well as the functional link of CDX1 promoter methylation to the inflammatory NF-κB signaling pathway. We identified methylation-dependent NF-κB binding to the CDX1 promoter and quantified it using competitive electrophoretic mobility shift assays and chromatin immunoprecipitation. A methylated CDX1 promoter was associated with closed chromatin structure, reduced NF-κB binding, and transcriptional silencing. Along the gastritis-metaplasia-carcinoma sequence, we observed a biphasic pattern of tumor necrosis factor-α (TNF-α) protein expression and an inverse biphasic pattern of CDX1 promoter methylation; both are highly consistent with CDX1 protein expression. The stages of hyper-, hypo-, and hyper-methylation patterns of the CDX1 promoter were inversely correlated with the NF-κB signaling activity along this sequence. In conclusion, these functionally interacting events drive CDX1 expression and contribute to intestinal metaplasia, epithelial dedifferentiation, and carcinogenesis in the human stomach. PMID:22749770

Protection against early intestinal compromise by lipid-rich enteral nutrition through cholecystokinin receptors.

PubMed

de Haan, Jacco J; Thuijls, Geertje; Lubbers, Tim; Hadfoune, M'hamed; Reisinger, Kostan; Heineman, Erik; Greve, Jan-Willem M; Buurman, Wim A

2010-07-01

Early gut wall integrity loss and local intestinal inflammation are associated with the development of inflammatory complications in surgical and trauma patients. Prevention of these intestinal events is a potential target for therapies aimed to control systemic inflammation. Previously, we demonstrated in a rodent shock model that lipid-rich enteral nutrition attenuated systemic inflammation and prevented organ damage through a cholecystokinin receptor-dependent vagal pathway. The influence of lipid-rich nutrition on very early intestinal compromise as seen after shock is investigated. Next, the involvement of cholecystokinin receptors on the nutritional modulation of immediate gut integrity loss and intestinal inflammation is studied. Randomized controlled in vivo study. University research unit. Male Sprague-Dawley rats. Liquid lipid-rich nutrition or control low-lipid feeding was administered per gavage before hemorrhagic shock. Cholecystokinin receptor antagonists were used to investigate involvement of the vagal antiinflammatory pathway. Gut permeability to horseradish peroxidase increased as soon as 30 mins postshock and was prevented by lipid-rich nutrition compared with low-lipid (p<.01) and fasted controls (p<.001). Furthermore, lipid-rich nutrition reduced plasma levels of enterocyte damage marker ileal lipid binding protein at 60 mins (p<.05). Early gut barrier dysfunction correlated with rat mast cell protease plasma concentrations at 30 mins (rs=0.67; p<.001) and intestinal myeloperoxidase levels at 60 mins (rs=0.58; p<.05). Lipid-rich nutrition significantly reduced plasma rat mast cell protease (p<.01) and myeloperoxidase (p<.05) before systemic inflammation was detectable. Protective effects of lipid-rich nutrition were abrogated by cholecystokinin receptor antagonists (horseradish peroxidase; p<.05 and rat mast cell protease; p<.05). Lipid-rich enteral nutrition prevents early gut barrier loss, enterocyte damage, and local intestinal inflammation before systemic inflammation develops in a cholecystokinin receptor-dependent manner. This study identifies activation of the vagal antiinflammatory pathway with lipid-rich nutrition as a potential therapy in patients prone to develop a compromised gut.

Anti-inflammatory Effects of Fungal Metabolites in Mouse Intestine as Revealed by In vitro Models

PubMed Central

Schreiber, Dominik; Marx, Lisa; Felix, Silke; Clasohm, Jasmin; Weyland, Maximilian; Schäfer, Maximilian; Klotz, Markus; Lilischkis, Rainer; Erkel, Gerhard; Schäfer, Karl-Herbert

2017-01-01

Inflammatory bowel diseases (IBD), which include Crohn's disease and ulcerative colitis, are chronic inflammatory disorders that can affect the whole gastrointestinal tract or the colonic mucosal layer. Current therapies aiming to suppress the exaggerated immune response in IBD largely rely on compounds with non-satisfying effects or side-effects. Therefore, new therapeutical options are needed. In the present study, we investigated the anti-inflammatory effects of the fungal metabolites, galiellalactone, and dehydrocurvularin in both an in vitro intestinal inflammation model, as well as in isolated myenteric plexus and enterocyte cells. Administration of a pro-inflammatory cytokine mix through the mesenteric artery of intestinal segments caused an up-regulation of inflammatory marker genes. Treatment of the murine intestinal segments with galiellalactone or dehydrocurvularin by application through the mesenteric artery significantly prevented the expression of pro-inflammatory marker genes on the mRNA and the protein level. Comparable to the results in the perfused intestine model, treatment of primary enteric nervous system (ENS) cells from the murine intestine with the fungal compounds reduced expression of cytokines such as IL-6, TNF-α, IL-1β, and inflammatory enzymes such as COX-2 and iNOS on mRNA and protein levels. Similar anti-inflammatory effects of the fungal metabolites were observed in the human colorectal adenocarcinoma cell line DLD-1 after stimulation with IFN-γ (10 ng/ml), TNF-α (10 ng/ml), and IL-1β (5 ng/ml). Our results show that the mesenterially perfused intestine model provides a reliable tool for the screening of new therapeutics with limited amounts of test compounds. Furthermore, we could characterize the anti-inflammatory effects of two novel active compounds, galiellalactone, and dehydrocurvularin which are interesting candidates for studies with chronic animal models of IBD. PMID:28824460

HMGB1 exacerbates experimental mouse colitis by enhancing innate lymphoid cells 3 inflammatory responses via promoted IL-23 production.

PubMed

Chen, Xiangyu; Li, Lingyun; Khan, Muhammad Noman; Shi, Lifeng; Wang, Zhongyan; Zheng, Fang; Gong, Feili; Fang, Min

2016-11-01

In inflammatory bowel diseases (IBD), high mobility group box 1 (HMGB1), as an endogenous inflammatory molecule, can promote inflammatory cytokines secretion by acting on TLR2/4 resulting in tissue damage. The underlying mechanisms remain unclear. Here we report a novel role of HMGB1 in controlling the maintenance and function of intestine-resident group-3 innate lymphoid cells (ILC3s) that are important innate effector cells implicated in mucosal homeostasis and IBD pathogenesis. We showed that mice treated with anti-HMGB1 Ab, or genetically deficient for TLR2 -/- or TLR4 -/- mice, displayed reduced intestinal inflammation. In these mice, the numbers of colonic ILC3s were significantly reduced, and the levels of IL-17 and IL-22 that can be secreted by ILC3s were also decreased in the colon tissues. Furthermore, HMGB1 promoted DCs via TLR2/4 signaling to produce IL-23, activating ILC3s to produce IL-17 and IL-22. Our data thus indicated that the HMGB1-TLR2/4-DCs-IL-23 cascade pathway enhances the functions of ILC3s to produce IL-17 and IL-22, and this signal way might play a vital role in the development of IBD.

Intestinal Behçet's Disease: A True Inflammatory Bowel Disease or Merely an Intestinal Complication of Systemic Vasculitis?

PubMed Central

Kim, Duk Hwan

2016-01-01

Behçet's disease (BD) is a multi-systemic inflammatory disorder of an unknown etiology and shows a chronic recurrent clinical course. When the disease involves the alimentary tract, it is called intestinal BD because of its clinical importance. Intestinal BD is more frequently reported in East Asian countries than in Western or Middle Eastern countries. While any part of the gastrointestinal tract can be involved, the most common location of intestinal BD is the ileocecal area. A few, large, deep ulcerations with discrete border are characteristic endoscopic findings of intestinal BD. Currently, there is no single gold standard test or pathognomonic finding of intestinal BD. However, recently developed novel diagnostic criteria and a disease activity index have helped in assessing intestinal BD. As intestinal BD shares a lot of characteristics with inflammatory bowel disease, including genetic background, clinical manifestations, and therapeutic strategies, distinguishing between the two diseases in clinical practice is quite difficult. However, biologic agents such as anti-tumor necrosis factor α antibody shows a considerable efficacy similar to inflammatory bowel disease cases. It is important to distinguish and treat those two disease entities separately from the standpoint of precise medicine. Clinicians should require comprehensive knowledge regarding the similarities and differences between intestinal BD and inflammatory bowel disease for making an accurate clinical decision. PMID:26632379

Vinpocetine Ameliorates Acetic Acid-Induced Colitis by Inhibiting NF-κB Activation in Mice.

PubMed

Colombo, Bárbara B; Fattori, Victor; Guazelli, Carla F S; Zaninelli, Tiago H; Carvalho, Thacyana T; Ferraz, Camila R; Bussmann, Allan J C; Ruiz-Miyazawa, Kenji W; Baracat, Marcela M; Casagrande, Rúbia; Verri, Waldiceu A

2018-04-10

The idiopathic inflammatory bowel diseases (IBD) comprise two types of chronic intestinal disorders: Crohn's disease and ulcerative colitis. Recruited neutrophils and macrophages contribute to intestinal tissue damage via production of ROS and NF-κB-dependent pro-inflammatory cytokines. The introduction of anti-TNF-α therapies in the treatment of IBD patients was a seminal advance. This therapy is often limited by a loss of efficacy due to the development of adaptive immune response, underscoring the need for novel therapies targeting similar pathways. Vinpocetine is a nootropic drug and in addition to its antioxidant effect, it is known to have anti-inflammatory and analgesic properties, partly by inhibition of NF-κB and downstream cytokines. Therefore, the present study evaluated the effect of the vinpocetine in a model of acid acetic-induced colitis in mice. Treatment with vinpocetine reduced edema, MPO activity, microscopic score and macroscopic damage, and visceral mechanical hyperalgesia. Vinpocetine prevented the reduction of colonic levels of GSH, ABTS radical scavenging ability, and normalized levels of anti-inflammatory cytokine IL-10. Moreover, vinpocetine reduced NF-κB activation and thereby NF-κB-dependent pro-inflammatory cytokines IL-1β, TNF-α, and IL-33 in the colon. Thus, we demonstrate for the first time that vinpocetine has anti-inflammatory, antioxidant, and analgesic effects in a model of acid acetic-induced colitis in mice and deserves further screening to address its suitability as an approach for the treatment of IBD.

Chemoprevention of intestinal tumorigenesis by the natural dietary flavonoid myricetin in APCMin/+ mice

PubMed Central

Sun, Shi-Yue; Shi, Wen-Na; Song, Zhi-Yu; Wang, Shu-Qing; Yu, Xin-Feng; Gao, Zu-Hua; Qu, Xian-Jun

2016-01-01

Myricetin is a natural dietary flavonoid compound. We evaluated the efficacy of myricetin against intestinal tumorigenesis in adenomatous polyposis coli multiple intestinal neoplasia (APCMin/+) mice. Myricetin was given orally once a day for 12 consecutive weeks. APCMin/+ mice fed with myricetin developed fewer and smaller polyps without any adverse effects. Histopathological analysis showed a decreased number of dysplastic cells and degree of dysplasia in each polyp. Immunohistochemical and western blot analysis revealed that myricetin selectively inhibits cell proliferation and induces apoptosis in adenomatous polyps. The effects of myricetin were associated with a modulation the GSK-3β and Wnt/β-catenin pathways. ELISA analysis showed a reduced concentration of pro-inflammatory cytokines IL-6 and PGE2 in blood, which were elevated in APCMin/+ mice. The effect of myricetin treatment was more prominent in the adenomatous polyps originating in the colon. Further studies showed that myricetin downregulates the phosphorylated p38 MAPK/Akt/mTOR signaling pathways, which may be the mechanisms for the inhibition of adenomatous polyps by myricetin. Taken together, our data show that myricetin inhibits intestinal tumorigenesis through a collection of biological activities. Given these results, we suggest that myricetin could be used preventatively to reduce the risk of developing colon cancers. PMID:27507058

Chemoprevention of intestinal tumorigenesis by the natural dietary flavonoid myricetin in APCMin/+ mice.

PubMed

Li, Ye; Cui, Shu-Xiang; Sun, Shi-Yue; Shi, Wen-Na; Song, Zhi-Yu; Wang, Shu-Qing; Yu, Xin-Feng; Gao, Zu-Hua; Qu, Xian-Jun

2016-09-13

Myricetin is a natural dietary flavonoid compound. We evaluated the efficacy of myricetin against intestinal tumorigenesis in adenomatous polyposis coli multiple intestinal neoplasia (APCMin/+) mice. Myricetin was given orally once a day for 12 consecutive weeks. APCMin/+ mice fed with myricetin developed fewer and smaller polyps without any adverse effects. Histopathological analysis showed a decreased number of dysplastic cells and degree of dysplasia in each polyp. Immunohistochemical and western blot analysis revealed that myricetin selectively inhibits cell proliferation and induces apoptosis in adenomatous polyps. The effects of myricetin were associated with a modulation the GSK-3β and Wnt/β-catenin pathways. ELISA analysis showed a reduced concentration of pro-inflammatory cytokines IL-6 and PGE2 in blood, which were elevated in APCMin/+ mice. The effect of myricetin treatment was more prominent in the adenomatous polyps originating in the colon. Further studies showed that myricetin downregulates the phosphorylated p38 MAPK/Akt/mTOR signaling pathways, which may be the mechanisms for the inhibition of adenomatous polyps by myricetin. Taken together, our data show that myricetin inhibits intestinal tumorigenesis through a collection of biological activities. Given these results, we suggest that myricetin could be used preventatively to reduce the risk of developing colon cancers.

Culturing human intestinal stem cells for regenerative applications in the treatment of inflammatory bowel disease.

PubMed

Holmberg, Fredrik Eo; Seidelin, Jakob B; Yin, Xiaolei; Mead, Benjamin E; Tong, Zhixiang; Li, Yuan; Karp, Jeffrey M; Nielsen, Ole H

2017-05-01

Both the incidence and prevalence of inflammatory bowel disease (IBD) is increasing globally; in the industrialized world up to 0.5% of the population are affected and around 4.2 million individuals suffer from IBD in Europe and North America combined. Successful engraftment in experimental colitis models suggests that intestinal stem cell transplantation could constitute a novel treatment strategy to re-establish mucosal barrier function in patients with severe disease. Intestinal stem cells can be grown in vitro in organoid structures, though only a fraction of the cells contained are stem cells with regenerative capabilities. Hence, techniques to enrich stem cell populations are being pursued through the development of multiple two-dimensional and three-dimensional culture protocols, as well as co-culture techniques and multiple growth medium compositions. Moreover, research in support matrices allowing for efficient clinical application is in progress. In vitro culture is accomplished by modulating the signaling pathways fundamental for the stem cell niche with a suitable culture matrix to provide additional contact-dependent stimuli and structural support. The aim of this review was to discuss medium compositions and support matrices for optimal intestinal stem cell culture, as well as potential modifications to advance clinical use in IBD. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Upregulation of P-glycoprotein by probiotics in intestinal epithelial cells and in the dextran sulfate sodium model of colitis in mice

PubMed Central

Goyal, Sonia; Raheja, Geetu; Singh, Varsha; Akhtar, Maria; Nazir, Talat M.; Alrefai, Waddah A.; Gill, Ravinder K.; Dudeja, Pradeep K.

2011-01-01

P-glycoprotein (P-gp) mediates efflux of xenobiotics and bacterial toxins from the intestinal mucosa into the lumen. Dysregulation of P-gp has been implicated in inflammatory bowel disease. Certain probiotics have been shown to be effective in treating inflammatory bowel disease. However, direct effects of probiotics on P-gp are not known. Current studies examined the effects of Lactobacilli on P-gp function and expression in intestinal epithelial cells. Caco-2 monolayers and a mouse model of dextran sulfate sodium-induced colitis were utilized. P-gp activity was measured as verapamil-sensitive [3H]digoxin transepithelial flux. Multidrug resistant 1 (MDR1)/P-gp expression was measured by real-time quantitative PCR and immunoblotting. Culture supernatant (CS; 1:10 or 1:50, 24 h) of Lactobacillus acidophilus or Lactobacillus rhamnosus treatment of differentiated Caco-2 monolayers (21 days postplating) increased (∼3-fold) MDR1/P-gp mRNA and protein levels. L. acidophilus or L. rhamnosus CS stimulated P-gp activity (∼2-fold, P < 0.05) via phosphoinositide 3-kinase and ERK1/2 MAPK pathways. In mice, L. acidophilus or L. rhamnosus treatment (3 × 109 colony-forming units) increased mdr1a/P-gp mRNA and protein expression in the ileum and colon (2- to 3-fold). In the dextran sulfate sodium (DSS)-induced colitis model (3% DSS in drinking water for 7 days), the degree of colitis as judged by histological damage and myeloperoxidase activity was reduced by L. acidophilus. L. acidophilus treatment to DSS-treated mice blocked the reduced expression of mdr1a/P-gp mRNA and protein in the distal colon. These findings suggest that Lactobacilli or their soluble factors stimulate P-gp expression and function under normal and inflammatory conditions. These data provide insights into a novel mechanism involving P-gp upregulation in beneficial effects of probiotics in intestinal inflammatory disorders. PMID:21350189

Anti-inflammatory intestinal activity of Combretum duarteanum Cambess. in trinitrobenzene sulfonic acid colitis model

PubMed Central

de Morais Lima, Gedson Rodrigues; Machado, Flavia Danniele Frota; Périco, Larissa Lucena; de Faria, Felipe Meira; Luiz-Ferreira, Anderson; Souza Brito, Alba Regina Monteiro; Pellizzon, Cláudia Helena; Hiruma-Lima, Clélia Akiko; Tavares, Josean Fechine; Barbosa Filho, José Maria; Batista, Leônia Maria

2017-01-01

AIM To evaluate the anti-inflammatory intestinal effect of the ethanolic extract (EtOHE) and hexane phase (HexP) obtained from the leaves of Combretum duarteanum (Cd). METHODS Inflammatory bowel disease was induced using trinitrobenzenesulfonic acid in acute and relapsed ulcerative colitis in rat models. Damage scores, and biochemical, histological and immunohistochemical parameters were evaluated. RESULTS Both Cd-EtOHE and Cd-HexP caused significant reductions in macroscopic lesion scores and ulcerative lesion areas. The vegetable samples inhibited myeloperoxidase increase, as well as pro-inflammatory cytokines TNF-α and IL-1β. Anti-inflammatory cytokine IL-10 also increased in animals treated with the tested plant samples. The anti-inflammatory intestinal effect is related to decreased expression of cyclooxygenase-2, proliferating cell nuclear antigen, and an increase in superoxide dismutase. CONCLUSION The data indicate anti-inflammatory intestinal activity. The effects may also involve participation of the antioxidant system and principal cytokines relating to inflammatory bowel disease. PMID:28293082

Protein tyrosine phosphatase non-receptor type 2 and inflammatory bowel disease.

PubMed

Spalinger, Marianne R; McCole, Declan F; Rogler, Gerhard; Scharl, Michael

2016-01-21

Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) with the onset of inflammatory bowel disease (IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.

Influence of adhesion and bacteriocin production by Lactobacillus salivarius on the intestinal epithelial cell transcriptional response.

PubMed

O'Callaghan, John; Buttó, Ludovica F; MacSharry, John; Nally, Kenneth; O'Toole, Paul W

2012-08-01

Lactobacillus salivarius strain UCC118 is a human intestinal isolate that has been extensively studied for its potential probiotic effects in human and animal models. The objective of this study was to determine the effect of L. salivarius UCC118 on gene expression responses in the Caco-2 cell line to improve understanding of how the strain might modulate intestinal epithelial cell phenotypes. Exposure of Caco-2 cells to UCC118 led to the induction of several human genes (TNFAIP3, NFKBIA, and BIRC3) that are negative regulators of inflammatory signaling pathways. Induction of chemokines (CCL20, CXCL-1, and CXCL-2) with antimicrobial functions was also observed. Disruption of the UCC118 sortase gene srtA causes reduced bacterial adhesion to epithelial cells. Transcription of three mucin genes was reduced significantly when Caco-2 cells were stimulated with the ΔsrtA derivative of UCC118 compared to cells stimulated with the wild type, but there was no significant change in the transcription levels of the anti-inflammatory genes. UCC118 genes that were significantly upregulated upon exposure to Caco-2 cells were identified by bacterial genome microarray and consisted primarily of two groups of genes connected with purine metabolism and the operon for synthesis of the Abp118 bacteriocin. Following incubation with Caco-2 cells, the bacteriocin synthesis genes were transcribed at higher levels in the wild type than in the ΔsrtA derivative. These data indicate that L. salivarius UCC118 influences epithelial cells both through modulation of the inflammatory response and by modulation of intestinal cell mucin production. Sortase-anchored cell surface proteins of L. salivarius UCC118 have a central role in promoting the interaction between the bacterium and epithelial cells.

Melatonin prevents secondary intra-abdominal hypertension in rats possibly through inhibition of the p38 MAPK pathway.

PubMed

Chang, Mingtao; Li, Yang; Liu, Dong; Zhang, Lianyang; Zhang, Hongguang; Tang, Hao; Zhang, Huayu

2016-08-01

Exogenous administration of melatonin has been demonstrated to down-regulate inflammatory responses and attenuate organ damage in various models. However, the salutary effect of melatonin against secondary intra-abdominal hypertension (IAH) remains unclear. This study sought to test the influence of melatonin on secondary IAH in a pathophysiological rat model and the underlying mechanisms involved. Before resuscitation, male rats underwent a combination of induced portal hypertension, applying an abdominal restraint device, and hemorrhaging to mean arterial pressure (MAP) of 40mmHg for 2h. After blood reinfusion, the rats were treated with lactated Ringer solution (LR) (30mL/h), melatonin (50mg/kg) +LR, and SB-203580 (10μmol/kg)+LR. LR was continuously infused for 6h. MAP, the inferior vena cava pressure and urine output were monitored. Histopathological examination, immunofluorescence of tight junction proteins, and transmission electron microscopy were administered. Intestinal permeability, myeloperoxidase activity, malondialdehyde, glutathione peroxidase, and levels of TNF-a, IL-2, and IL-6, were assessed. The expression of extracellular signal-regulated kinase, p38, c-Jun NH2-terminal kinase, translocation of nuclear factor kappa B subunit, signal transducers and activators of transcription and tight junction proteins were detected by Western blot. We found that melatonin inhibited the inflammatory responses, decreased expression of p38 MAPK, attenuated intestinal injury, and prevented secondary IAH. Moreover, administration of SB203580 abolished the increase in p38 MAPK and also attenuated intestinal injury. These data indicate that melatonin exerts a protective effect in intestine in secondary IAH primarily by attenuating the inflammatory responses which are in part attributable to p38 MAPK inhibition. Copyright © 2016 Elsevier Inc. All rights reserved.

Protein hydrolysate from canned sardine and brewing by-products improves TNF-α-induced inflammation in an intestinal-endothelial co-culture cell model.

PubMed

Vieira, Elsa F; Van Camp, John; Ferreira, Isabel M P L V O; Grootaert, Charlotte

2017-07-17

The anti-inflammatory activity of sardine protein hydrolysates (SPH) obtained by hydrolysis with proteases from brewing yeast surplus was ascertained. For this purpose, a digested and desalted SPH fraction with molecular weight lower than 10 kDa was investigated using an endothelial cell line (EA.hy926) as such and in a co-culture model with an intestinal cell line (Caco-2). Effects of SPH <10 kDa on nitric oxide (NO) production, reactive oxygen species (ROS) inhibition and secretion of monocyte chemoattractant protein 1 (MCP-1), vascular endothelial growth factor (VEGF), chemokine IL-8 (IL-8) and intercellular adhesion molecule-1 (ICAM-1) were evaluated in TNF-α-treated and untreated cells. Upon TNF-α treatment, levels of NO, MCP-1, VEGF, IL-8, ICAM-1 and endothelial ROS were significantly increased in both mono- and co-culture models. Treatment with SPH <10 kDa (2.0 mg peptides/mL) significantly decreased all the inflammation markers when compared to TNF-α-treated control. This protective effect was more pronounced in the co-culture model, suggesting that SPH <10 kDa Caco-2 cells metabolites produced in the course of intestinal absorption may provide a more relevant protective effect against endothelial dysfunction. Additionally, indirect cross-talk between two cell types was established, suggesting that SPH <10 kDa may also bind to receptors on the Caco-2 cells, thereby triggering a pathway to secrete the pro-inflammatory compounds. Overall, these in vitro screening results, in which intestinal digestion, absorption and endothelial bioactivity are simulated, show the potential of SPH to be used as a functional food with anti-inflammatory properties.

Modulation of immunity and inflammatory gene expression in the gut, in inflammatory diseases of the gut and in the liver by probiotics

PubMed Central

Plaza-Diaz, Julio; Gomez-Llorente, Carolina; Fontana, Luis; Gil, Angel

2014-01-01

The potential for the positive manipulation of the gut microbiome through the introduction of beneficial microbes, as also known as probiotics, is currently an active area of investigation. The FAO/WHO define probiotics as live microorganisms that confer a health benefit to the host when administered in adequate amounts. However, dead bacteria and bacterial molecular components may also exhibit probiotic properties. The results of clinical studies have demonstrated the clinical potential of probiotics in many pathologies, such as allergic diseases, diarrhea, inflammatory bowel disease and viral infection. Several mechanisms have been proposed to explain the beneficial effects of probiotics, most of which involve gene expression regulation in specific tissues, particularly the intestine and liver. Therefore, the modulation of gene expression mediated by probiotics is an important issue that warrants further investigation. In the present paper, we performed a systematic review of the probiotic-mediated modulation of gene expression that is associated with the immune system and inflammation. Between January 1990 to February 2014, PubMed was searched for articles that were published in English using the MeSH terms “probiotics" and "gene expression" combined with “intestines", "liver", "enterocytes", "antigen-presenting cells", "dendritic cells", "immune system", and "inflammation". Two hundred and five original articles matching these criteria were initially selected, although only those articles that included specific gene expression results (77) were later considered for this review and separated into three major topics: the regulation of immunity and inflammatory gene expression in the gut, in inflammatory diseases of the gut and in the liver. Particular strains of Bifidobacteria, Lactobacilli, Escherichia coli, Propionibacterium, Bacillus and Saccharomyces influence the gene expression of mucins, Toll-like receptors, caspases, nuclear factor-κB, and interleukins and lead mainly to an anti-inflammatory response in cultured enterocytes. In addition, the interaction of commensal bacteria and probiotics with the surface of antigen-presenting cells in vitro results in the downregulation of pro-inflammatory genes that are linked to inflammatory signaling pathways, whereas other anti-inflammatory genes are upregulated. The effects of probiotics have been extensively investigated in animal models ranging from fish to mice, rats and piglets. These bacteria induce a tolerogenic and hyporesponsive immune response in which many genes that are related to the immune system, in particular those genes expressing anti-inflammatory cytokines, are upregulated. By contrast, information related to gene expression in human intestinal cells mediated by the action of probiotics is scarce. There is a need for further clinical studies that evaluate the mechanism of action of probiotics both in healthy humans and in patients with chronic diseases. These types of clinical studies are necessary for addressing the influence of these microorganisms in gene expression for different pathways, particularly those that are associated with the immune response, and to better understand the role that probiotics might have in the prevention and treatment of disease. PMID:25400447

Inhibition of Na+/H+ exchanger 1 by cariporide reduces burn-induced intestinal barrier breakdown.

PubMed

Yang, Xuekang; Chen, Ji; Bai, Hua; Tao, Ke; Zhou, Qin; Hou, Hongyi; Hu, Dahai

2013-12-01

Severe burns initiate an inflammatory cascade within the gut, which leads to intestinal mucosal injury. Although Na(+)/H(+) exchanger 1 (NHE1) is recognised as a pivotal player in several inflammatory processes, its role in burn-induced intestinal injury is relatively unknown. We hypothesised that NHE1 might be involved in the increased intestinal permeability and barrier breakdown after severe burns. Thus, we here investigate whether the inhibition of NHE1 has a protective effect on burn-induced intestinal injury. Mice were subjected to a 30% total body surface area (TBSA) full-thickness steam burn. Cariporide was used to assess the function of NHE1 in mice with burn-induced intestinal injury by fluorescence spectrophotometry, Western blotting and enzyme linked immunosorbent assay (ELISA). We found that severe burn increased intestinal permeability, associated with the up-regulation of NHE1 and raised inflammatory cytokine levels. Mice treated with the NHE1 inhibitor cariporide had significantly attenuated burn-induced intestinal permeability and a reduced inflammatory response. NHE1 inhibition also reduced nuclear factor-κB (NF-κB) activation and attenuated p38 mitogen-activated protein kinase (MAPK) phosphorylation. Our study suggests that NHE1 plays an important role in burn-induced intestinal permeability through the regulation of the inflammatory response. Inhibition of NHE1 may be adopted as a potential therapeutic strategy for attenuating intestinal barrier breakdown. Copyright © 2013 Elsevier Ltd and ISBI. All rights reserved.

Understanding Luminal Microorganisms and their Potential Effectiveness in Treating Intestinal Inflammation

PubMed Central

Ince, M. Nedim; Blazar, Bruce R.; Edmond, Michael B.; Tricot, Guido; Wannemuehler, Michael J.

2015-01-01

The human intestine contains 1014 bacteria, which outnumber the mammalian cells 10-fold. Certain other commensal or infectious agents, like helminthic parasites become members of this microbial ecosystem, especially in populations living under less hygienic conditions. Intestinal microbes, also called the microbiome or microbiota, shape the host immune reactivity to self and nonself throughout life. Changes in microbiome composition may impair the maturation of immune regulatory pathways and predispose the host to develop various forms of inflammatory disorders, like Crohn's disease or ulcerative colitis. The microbiome is also critical to successful transplantation of organs or grafts. After allogeneic hematopoietic stem cell transplantation (HSCT), when the new donor cells, such as T lymphocytes learn to discriminate “the new-self from nonself” in the transplant recipient, they need healthy microbiota-derived signals to preserve the immune homeostasis. Restoring microbiota via intestinal delivery of bacterial strains, helminths, fecal microbiota transplantation or stool substitutes have the potential to improve and correct aberrant immune reactivity in various disorders. PMID:26457381

Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner.

PubMed

Drummond, Coyne G; Bolock, Alexa M; Ma, Congrong; Luke, Cliff J; Good, Misty; Coyne, Carolyn B

2017-02-14

Enteroviruses are among the most common viral infectious agents of humans and are primarily transmitted by the fecal-oral route. However, the events associated with enterovirus infections of the human gastrointestinal tract remain largely unknown. Here, we used stem cell-derived enteroids from human small intestines to study enterovirus infections of the intestinal epithelium. We found that enteroids were susceptible to infection by diverse enteroviruses, including echovirus 11 (E11), coxsackievirus B (CVB), and enterovirus 71 (EV71), and that contrary to an immortalized intestinal cell line, enteroids induced antiviral and inflammatory signaling pathways in response to infection in a virus-specific manner. Furthermore, using the Notch inhibitor dibenzazepine (DBZ) to drive cellular differentiation into secretory cell lineages, we show that although goblet cells resist E11 infection, enteroendocrine cells are permissive, suggesting that enteroviruses infect specific cell populations in the human intestine. Taken together, our studies provide insights into enterovirus infections of the human intestine, which could lead to the identification of novel therapeutic targets and/or strategies to prevent or treat infections by these highly clinically relevant viruses.

Deoxynivalenol as a New Factor in the Persistence of Intestinal Inflammatory Diseases: An Emerging Hypothesis through Possible Modulation of Th17-Mediated Response

PubMed Central

Meurens, François; Cognie, Juliette; Abrami, Roberta; Oswald, Isabelle P.; Guzylack-Piriou, Laurence

2013-01-01

Background/Aims Deoxynivalenol (DON) is a mycotoxin produced by Fusarium species which is commonly found in temperate regions worldwide as a natural contaminant of cereals. It is of great concern not only in terms of economic losses but also in terms of animal and public health. The digestive tract is the first and main target of this food contaminant and it represents a major site of immune tolerance. A finely tuned cross-talk between the innate and the adaptive immune systems ensures the homeostatic equilibrium between the mucosal immune system and commensal microorganisms. The aim of this study was to analyze the impact of DON on the intestinal immune response. Methodology Non-transformed intestinal porcine epithelial cells IPEC-1 and porcine jejunal explants were used to investigate the effect of DON on the intestinal immune response and the modulation of naive T cells differentiation. Transcriptomic proteomic and flow cytometry analysis were performed. Results DON induced a pro-inflammatory response with a significant increase of expression of mRNA encoding for IL-8, IL-1α and IL-1β, TNF-α in all used models. Additionally, DON significantly induced the expression of genes involved in the differentiation of Th17 cells (STAT3, IL–17A, IL-6, IL-1β) at the expenses of the pathway of regulatory T cells (Treg) (FoxP3, RALDH1). DON also induced genes related to the pathogenic Th17 cells subset such as IL–23A, IL-22 and IL-21 and not genes related to the regulatory Th17 cells (rTh17) such as TGF-β and IL-10. Conclusion DON triggered multiple immune modulatory effects which could be associated with an increased susceptibility to intestinal inflammatory diseases. PMID:23326479

Increase in substance P precursor mRNA in noninflamed small-bowel sections in patients with Crohn's disease.

PubMed

Michalski, Christoph W; Autschbach, Frank; Selvaggi, Federico; Shi, Xin; Di Mola, Fabio Francesco; Roggo, Antoine; Müller, Michael W; Di Sebastiano, Pierluigi; Büchler, Markus W; Giese, Thomas; Friess, Helmut

2007-04-01

Neuropeptides, such as substance P (SP), are mediators of neurogenic inflammation and play an important role in inflammatory disorders. To further investigate the role of the SP pathway in inflammatory bowel disease (IBD), we analyzed the following in normal intestinal tissue specimens and in tissue specimens from patients with Crohn's disease (CD) and ulcerative colitis (UC): neurokinin receptor-1 (NK-1R); its isoforms (NK-1R-L and NK-1R-S); its ligand SP, encoded by preprotachykinin-A (PPT-A); and the SP-degradation enzyme, neutral endopeptidase (NEP). Real-time quantitative reverse transcription-polymerase chain reaction was used to simultaneously determine the expression of NK-1R-L, NK-1R-S, and PPT-A. Protein levels of NK-1R and NEP were determined by immunoblot analysis. In noninflamed small-bowel tissue samples of CD patients, PPT-A mRNA expression was significantly increased, whereas there was no difference between inflamed or noninflamed UC and normal intestinal tissue samples. Examining subgroups of diverse intestinal segments from CD and UC samples with various levels of inflammation revealed no differences in NK-1R-L and NK-1R-S mRNA expression, whereas there was a tendency toward overall lower NK-1R-S mRNA copy numbers. Immunoblot analysis showed upregulation of NK-1R protein levels in cases of IBD, with more pronounced enhancement in cases of CD than in UC. For NEP, there were no differences in protein levels in normal, CD, and UC intestinal tissues. These observations suggest a contribution of SP and its receptor, NK-1R, in the local inflammatory reaction in IBD and particularly in ileal CD. Moreover, significant upregulation of PPT-A mRNA in the noninflamed ileum of these patients suggests an influence of inflamed intestines on their healthy counterparts.

Potential Use of Food Protein-Derived Peptides in the Treatment of Inflammatory Diseases.

PubMed

Santiago-Lopez, Lourdes; Gonzalez-Cordova, Aaron F; Hernandez-Mendoza, Adrian; Vallejo-Cordoba, Belinda

2017-01-01

In recent years, major developments in the field of inflammatory pathophysiology have clearly shown that arthritis, diabetes, intestinal bowel diseases, and obesity, which affect many people around the world, are essentially inflammatory in nature. Different anti-inflammatory drugs have been used to treat these conditions. Some people are able to take these drugs without difficulty, yet others experience negative side effects. Hence, the search for new, natural anti-inflammatory alternatives has rapidly increased in recent years. Evidence has shown that food protein-derived peptides may be one alternative for treating inflammatory diseases. Peptides are encrypted in food proteins, can be released under hydrolysis conditions, and do not cause adverse effects. Despite limited information on the mechanism of action of peptides, in vitro and animal model studies have demonstrated their potential anti-inflammatory activity. Several in vitro studies have demonstrated that peptides can inhibit different pathways of inflammation processes such as that of the nuclear factor kappalight- chain of activated B cells (NF-κB). They can also induce the production of nitric oxide synthase (iNOs) and c-Jun N-terminal kinases (JNK) as well as influence PepT1 and CaRS, the transporters of peptides to the gastrointestinal tract that are responsible for the absorption of dietary peptides in the intestine. However, contradictory evidence has been reported in clinical assays. Hence, in this review, we present the latest research on the anti-inflammatory activity of food protein-derived peptides and provide future perspectives on the use of peptides as potential natural sources of therapeutic treatments. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The mitochondrially targeted antioxidant MitoQ protects the intestinal barrier by ameliorating mitochondrial DNA damage via the Nrf2/ARE signaling pathway.

PubMed

Hu, Qiongyuan; Ren, Jianan; Li, Guanwei; Wu, Jie; Wu, Xiuwen; Wang, Gefei; Gu, Guosheng; Ren, Huajian; Hong, Zhiwu; Li, Jieshou

2018-03-14

Disruption of the mucosal barrier following intestinal ischemia reperfusion (I/R) is life threatening in clinical practice. Mitochondrial dysfunction and oxidative stress significantly contribute to the early phase of I/R injury and amplify the inflammatory response. MitoQ is a mitochondrially targeted antioxidant that exerts protective effects following I/R injury. In the present study, we aimed to determine whether and how MitoQ protects intestinal epithelial cells (IECs) from I/R injury. In both in vivo and in vitro studies, we found that MitoQ pretreatment downregulated I/R-induced oxidative stress and stabilized the intestinal barrier, as evidenced by MitoQ-treated I/R mice exhibiting attenuated intestinal hyperpermeability, inflammatory response, epithelial apoptosis, and tight junction damage compared to controls. Mechanistically, I/R elevated mitochondrial 8-hydroxyguanine content, reduced mitochondrial DNA (mtDNA) copy number and mRNA transcription levels, and induced mitochondrial disruption in IECs. However, MitoQ pretreatment dramatically inhibited these deleterious effects. mtDNA depletion alone was sufficient to induce apoptosis and mitochondrial dysfunction of IECs. Mitochondrial transcription factor A (TFAM), a key activator of mitochondrial transcription, was significantly reduced during I/R injury, a phenomenon that was prevented by MitoQ treatment. Furthermore, we observed that thee protective properties of MitoQ were affected by upregulation of cellular antioxidant genes, including HO-1, NQO-1, and γ-GCLC. Transfection with Nrf2 siRNA in IECs exposed to hypoxia/reperfusion conditions partially blocked the effects of MitoQ on mtDNA damage and mitochondrial oxidative stress. In conclusion, our data suggest that MitoQ exerts protective effect on I/R-induced intestinal barrier dysfunction.

B Lymphocyte intestinal homing in inflammatory bowel disease

PubMed Central

2011-01-01

Background Inflammatory bowel disease (IBD) is thought to be due to an abnormal interaction between the host immune system and commensal microflora. Within the intestinal immune system, B cells produce physiologically natural antibodies but pathologically atypical anti-neutrophil antibodies (xANCAs) are frequently observed in patients with IBD. The objective is to investigate the localisation of immunoglobulin-producing cells (IPCs) in samples of inflamed intestinal tissue taken from patients with IBD, and their possible relationship with clinical features. Methods The IPCs in small intestinal, colonic and rectal biopsy specimens of patients with IBD were analysed by means of immunofluorescence using polyclonal rabbit anti-human Ig and goat anti-human IgM. The B cell phenotype of the IPC-positive samples was assessed using monoclonal antibodies specific for CD79, CD20, CD23, CD21, CD5, λ and κ chains. Statistical correlations were sought between the histological findings and clinical expression. Results The study involved 96 patients (64 with ulcerative colitis and 32 with Crohn's disease). Two different patterns of B lymphocyte infiltrates were found in the intestinal tissue: one was characterised by a strong to moderate stromal localisation of small IgM+/CD79+/CD20-/CD21-/CD23-/CD5± IPCs (42.7% of cases); in the other (57.3%) no such small IPCs were detected in stromal or epithelial tissues. IPCs were significantly less frequent in the patients with Crohn's disease than in those with ulcerative colitis (p = 0.004). Conclusion Our findings suggest that different immunopathogenetic pathways underlie chronic intestinal inflammation with different clinical expressions. The presence of small B lymphocytes resembling B-1 cells also seemed to be negatively associated with Crohn's disease. It can therefore be inferred that the gut contains an alternative population of B cells that have a regulatory function. PMID:22208453

Depletion of enteric bacteria diminishes leukocyte infiltration following doxorubicin-induced small intestinal damage in mice.

PubMed

Carr, Jacquelyn S; King, Stephanie; Dekaney, Christopher M

2017-01-01

While enteric bacteria have been shown to play a critical role in other forms of intestinal damage, their role in mediating the response to the chemotherapeutic drug Doxorubicin (Doxo) is unclear. In this study, we used a mouse model of intestinal bacterial depletion to evaluate the role enteric bacteria play in mediating Doxo-induced small intestinal damage and, more specifically, in mediating chemokine expression and leukocyte infiltration following Doxo treatment. An understanding of this pathway may allow for development of intervention strategies to reduce chemotherapy-induced small intestinal damage. Mice were treated with (Abx) or without (NoAbx) oral antibiotics in drinking water for four weeks and then with Doxo. Jejunal tissues were collected at various time points following Doxo treatment and stained and analyzed for apoptosis, crypt damage and restitution, and macrophage and neutrophil number. In addition, RNA expression of inflammatory markers (TNFα, IL1-β, IL-10) and cytokines (CCL2, CC7, KC) was assessed by qRT-PCR. In NoAbx mice Doxo-induced damage was associated with rapid induction of apoptosis in jejunal crypt epithelium and an increase weight loss and crypt loss. In addition, we observed an increase in immune-modulating chemokines CCL2, CCL7 and KC and infiltration of macrophages and neutrophils. In contrast, while still positive for induction of apoptosis following Doxo treatment, Abx mice showed neither the overall weight loss nor crypt loss seen in NoAbx mice nor the increased chemokine expression and leukocyte infiltration. Enteric bacteria play a critical role in Doxo-induced small intestinal damage and are associated with an increase in immune-modulating chemokines and cells. Manipulation of enteric bacteria or the damage pathway may allow for prevention or treatment of chemotherapy-induced small intestinal damage.

Regulatory immune cells in regulation of intestinal inflammatory response to microbiota

PubMed Central

Cong, Y; Liu, Z

2015-01-01

The intestinal lumen harbors nearly 100 trillion commensal bacteria that exert crucial function for health. An elaborate balance between immune responses and tolerance to intestinal microbiota is required to maintain intestinal homeostasis. This process depends on diverse regulatory mechanisms, including both innate and adaptive immunity. Dysregulation of the homeostasis between intestinal immune systems and microbiota has been shown to be associated with the development of inflammatory bowel diseases (IBD) in genetically susceptible populations. In this review, we discuss the recent progress reported in studies of distinct types of regulatory immune cells in the gut, including intestinal intraepithelial lymphocytes, Foxp3+ regulatory T cells, regulatory B cells, alternatively activated macrophages, dendritic cells, and innate lymphoid cells, and how dysfunction of this immune regulatory system contributes to intestinal diseases such as IBD. Moreover, we discuss the manipulation of these regulatory immune cells as a potential therapeutic method for management of intestinal inflammatory disorders. PMID:26080708

Regulatory immune cells in regulation of intestinal inflammatory response to microbiota.

PubMed

Sun, M; He, C; Cong, Y; Liu, Z

2015-09-01

The intestinal lumen harbors nearly 100 trillion commensal bacteria that exert crucial function for health. An elaborate balance between immune responses and tolerance to intestinal microbiota is required to maintain intestinal homeostasis. This process depends on diverse regulatory mechanisms, including both innate and adaptive immunity. Dysregulation of the homeostasis between intestinal immune systems and microbiota has been shown to be associated with the development of inflammatory bowel diseases (IBD) in genetically susceptible populations. In this review, we discuss the recent progress reported in studies of distinct types of regulatory immune cells in the gut, including intestinal intraepithelial lymphocytes, Foxp3(+) regulatory T cells, regulatory B cells, alternatively activated macrophages, dendritic cells, and innate lymphoid cells, and how dysfunction of this immune regulatory system contributes to intestinal diseases such as IBD. Moreover, we discuss the manipulation of these regulatory immune cells as a potential therapeutic method for management of intestinal inflammatory disorders.

Lymphatic deletion of calcitonin receptor–like receptor exacerbates intestinal inflammation

PubMed Central

Davis, Reema B.; Kechele, Daniel O.; Blakeney, Elizabeth S.; Pawlak, John B.

2017-01-01

Lymphatics play a critical role in maintaining gastrointestinal homeostasis and in the absorption of dietary lipids, yet their roles in intestinal inflammation remain elusive. Given the increasing prevalence of inflammatory bowel disease, we investigated whether lymphatic vessels contribute to, or may be causative of, disease progression. We generated a mouse model with temporal and spatial deletion of the key lymphangiogenic receptor for the adrenomedullin peptide, calcitonin receptor–like receptor (Calcrl), and found that the loss of lymphatic Calcrl was sufficient to induce intestinal lymphangiectasia, characterized by dilated lacteals and protein-losing enteropathy. Upon indomethacin challenge, Calcrlfl/fl/Prox1-CreERT2 mice demonstrated persistent inflammation and failure to recover and thrive. The epithelium and crypts of Calcrlfl/fl/Prox1-CreERT2 mice exhibited exacerbated hallmarks of disease progression, and the lacteals demonstrated an inability to absorb lipids. Furthermore, we identified Calcrl/adrenomedullin signaling as an essential upstream regulator of the Notch pathway, previously shown to be critical for intestinal lacteal maintenance and junctional integrity. In conclusion, lymphatic insufficiency and lymphangiectasia caused by loss of lymphatic Calcrl exacerbates intestinal recovery following mucosal injury and underscores the importance of lymphatic function in promoting recovery from intestinal inflammation. PMID:28352669

Transglutaminase 2 expression is enhanced synergistically by interferon-γ and tumour necrosis factor-α in human small intestine

PubMed Central

Bayardo, M; Punzi, F; Bondar, C; Chopita, N; Chirdo, F

2012-01-01

Transglutaminase 2 (TG2) is expressed ubiquitously, has multiple physiological functions and has also been associated with inflammatory diseases, neurodegenerative disorders, autoimmunity and cancer. In particular, TG2 is expressed in small intestine mucosa where it is up-regulated in active coeliac disease (CD). The aim of this work was to investigate the induction of TG2 expression by proinflammatory cytokines [interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-α, interferon (IFN)-γ and IL-15] and the signalling pathways involved, in human epithelial and monocytic cells and in intestinal tissue from controls and untreated CD patients. Here we report that IFN-γ was the most potent inducer of TG2 expression in the small intestinal mucosa and in four [Caco-2, HT-29, Calu-6 and human acute monocytic leukaemia cell line (THP-1)] of five cell lines tested. The combination of TNF-α and IFN-γ produced a strong synergistic effect. The use of selective inhibitors of signalling pathways revealed that induction of TG2 by IFN-γ was mediated by phosphoinositide 3-kinase (PI3K), while c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) were required for TNF-α activation. Quantitative polymerase chain reaction (PCR), flow cytometry and Western blot analysis showed that TG2 expression was blocked completely when stimulation by either TNF-α or IFN-γ was performed in the presence of nuclear factor (NF)-κB inhibitors (sulphasalazine and BAY-117082). TG2 was up-regulated substantially by TNF-α and IFN-γ in intestinal mucosa in untreated CD compared with controls. This study shows that IFN-γ, a dominant cytokine in intestinal mucosa in active CD, is the most potent inducer of TG2, and synergism with TNF-α may contribute to exacerbate the pathogenic mechanism of CD. Selective inhibition of signalling pathways may be of therapeutic benefit. PMID:22385244

Systems Biology Analysis of Gene Expression during In Vivo Mycobacterium avium paratuberculosis Enteric Colonization Reveals Role for Immune Tolerance

PubMed Central

Khare, Sangeeta; Lawhon, Sara D.; Drake, Kenneth L.; Nunes, Jairo E. S.; Figueiredo, Josely F.; Rossetti, Carlos A.; Gull, Tamara; Everts, Robin E.; Lewin, Harris A.; Galindo, Cristi L.; Garner, Harold R.; Adams, Leslie Garry

2012-01-01

Survival and persistence of Mycobacterium avium subsp. paratuberculosis (MAP) in the intestinal mucosa is associated with host immune tolerance. However, the initial events during MAP interaction with its host that lead to pathogen survival, granulomatous inflammation, and clinical disease progression are poorly defined. We hypothesize that immune tolerance is initiated upon initial contact of MAP with the intestinal Peyer's patch. To test our hypothesis, ligated ileal loops in neonatal calves were infected with MAP. Intestinal tissue RNAs were collected (0.5, 1, 2, 4, 8 and 12 hrs post-infection), processed, and hybridized to bovine gene expression microarrays. By comparing the gene transcription responses of calves infected with the MAP, informative complex patterns of expression were clearly visible. To interpret these complex data, changes in the gene expression were further analyzed by dynamic Bayesian analysis, and genes were grouped into the specific pathways and gene ontology categories to create a holistic model. This model revealed three different phases of responses: i) early (30 min and 1 hr post-infection), ii) intermediate (2, 4 and 8 hrs post-infection), and iii) late (12 hrs post-infection). We describe here the data that include expression profiles for perturbed pathways, as well as, mechanistic genes (genes predicted to have regulatory influence) that are associated with immune tolerance. In the Early Phase of MAP infection, multiple pathways were initiated in response to MAP invasion via receptor mediated endocytosis and changes in intestinal permeability. During the Intermediate Phase, perturbed pathways involved the inflammatory responses, cytokine-cytokine receptor interaction, and cell-cell signaling. During the Late Phase of infection, gene responses associated with immune tolerance were initiated at the level of T-cell signaling. Our study provides evidence that MAP infection resulted in differentially regulated genes, perturbed pathways and specifically modified mechanistic genes contributing to the colonization of Peyer's patch. PMID:22912686

KH-type splicing regulatory protein is regulated by nuclear factor-κB signaling to mediate innate immunity in Caco-2 cells infected by Salmonella enteritidis.

PubMed

Nie, Yuanyang; Cao, Mei; Wu, Daoyan; Li, Ningzhe; Peng, Jingshan; Yi, Sijun; Yang, Xiaofan; Zhang, Mao; Hu, Guoku; Zhao, Jian

2018-05-04

Salmonella enteritidis infection occurs in enterogenous diseases, such as gastroenteritis and parenteral focal infection, which often involve inflammation of intestinal epithelial cells. The nuclear factor kappa B (NF-κB) pathway participates in the innate immune response to many gram-negative pathogenic bacteria and initiates inflammation in epithelial cells. KH-type splicing regulatory protein (KSRP) is a multi-domain RNA-binding protein that recruits the exosome-containing mRNA degradation complex to mRNAs coding for inflammatory response factors. However, it remains unclear whether KSRP is regulated by NF-κB signaling pathway in response to S. enteritidis infection and affects the development of inflammation. Accordingly, in this study, we investigated the role of KSRP in mediating the response to S. enteritidis in Caco-2 cells. The data revealed that S. enteritidis infection decreased KSRP expression, which was suppressed by blocking the NF-κB pathway. Additionally, S. enteritidis infection significantly increased the expression of inducible nitric oxide synthase and cyclooxygenase-2. Overexpression of KSRP reduced the expression levels of inflammatory factors in Caco-2 cells. KSRP was regulated by the NF-κB signaling pathway and participated in mediating the innate immune response to S. enteritidis infection in Caco-2 cells, and KSRP acted as a negative regulator of inflammatory gene expression.

Gut Microbiota as a Driver of Inflammation in Nonalcoholic Fatty Liver Disease

PubMed Central

Ianiro, Gianluca; Simonelli, Claudia; Newton, Estelle E.

2018-01-01

The prevalence of nonalcoholic fatty liver disease and the consequent burden of metabolic syndrome have increased in recent years. Although the pathogenesis of nonalcoholic fatty liver disease is not completely understood, it is thought to be the hepatic manifestation of the dysregulation of insulin-dependent pathways leading to insulin resistance and adipose tissue accumulation in the liver. Recently, the gut-liver axis has been proposed as a key player in the pathogenesis of NAFLD, as the passage of bacteria-derived products into the portal circulation could lead to a trigger of innate immunity, which in turn leads to liver inflammation. Additionally, higher prevalence of intestinal dysbiosis, larger production of endogenous ethanol, and higher prevalence of increased intestinal permeability and bacterial translocation were found in patients with liver injury. In this review, we describe the role of intestinal dysbiosis in the activation of the inflammatory cascade in NAFLD. PMID:29563854

Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation.

PubMed

Porras, David; Nistal, Esther; Martínez-Flórez, Susana; Pisonero-Vaquero, Sandra; Olcoz, José Luis; Jover, Ramiro; González-Gallego, Javier; García-Mediavilla, María Victoria; Sánchez-Campos, Sonia

2017-01-01

Gut microbiota is involved in obesity, metabolic syndrome and the progression of nonalcoholic fatty liver disease (NAFLD). It has been recently suggested that the flavonoid quercetin may have the ability to modulate the intestinal microbiota composition, suggesting a prebiotic capacity which highlights a great therapeutic potential in NAFLD. The present study aims to investigate benefits of experimental treatment with quercetin on gut microbial balance and related gut-liver axis activation in a nutritional animal model of NAFLD associated to obesity. C57BL/6J mice were challenged with high fat diet (HFD) supplemented or not with quercetin for 16 weeks. HFD induced obesity, metabolic syndrome and the development of hepatic steatosis as main hepatic histological finding. Increased accumulation of intrahepatic lipids was associated with altered gene expression related to lipid metabolism, as a result of deregulation of their major modulators. Quercetin supplementation decreased insulin resistance and NAFLD activity score, by reducing the intrahepatic lipid accumulation through its ability to modulate lipid metabolism gene expression, cytochrome P450 2E1 (CYP2E1)-dependent lipoperoxidation and related lipotoxicity. Microbiota composition was determined via 16S ribosomal RNA Illumina next-generation sequencing. Metagenomic studies revealed HFD-dependent differences at phylum, class and genus levels leading to dysbiosis, characterized by an increase in Firmicutes/Bacteroidetes ratio and in Gram-negative bacteria, and a dramatically increased detection of Helicobacter genus. Dysbiosis was accompanied by endotoxemia, intestinal barrier dysfunction and gut-liver axis alteration and subsequent inflammatory gene overexpression. Dysbiosis-mediated toll-like receptor 4 (TLR-4)-NF-κB signaling pathway activation was associated with inflammasome initiation response and reticulum stress pathway induction. Quercetin reverted gut microbiota imbalance and related endotoxemia-mediated TLR-4 pathway induction, with subsequent inhibition of inflammasome response and reticulum stress pathway activation, leading to the blockage of lipid metabolism gene expression deregulation. Our results support the suitability of quercetin as a therapeutic approach for obesity-associated NAFLD via its anti-inflammatory, antioxidant and prebiotic integrative response. Copyright © 2016 Elsevier Inc. All rights reserved.

Perna canaliculus and the Intestinal Microbiome.

PubMed

Saltzman, Emma Tali; Thomsen, Michael; Hall, Sean; Vitetta, Luis

2017-06-30

Natural medicines are often an attractive option for patients diagnosed with chronic conditions. Three main classes of bioactives that have been reported from marine mussel extracts include proteins, lipids and carbohydrates. Commercially, the most relevant species of marine mollusks belong to two genera, Perna and Mytilus. Specifically, the Perna canaliculus species has been repeatedly demonstrated to harbor anti-inflammatory compounds such as omega-3 polyunsaturated fatty acids ( ω -3 PUFAs) that can ameliorate pro-inflammatory conditions, or proteins that can promote thrombin inhibitory activity. Recent clinical studies have posited that extracts from green-lipped mussels may lead to prebiotic activity in the intestinal microbiome that in turn has been reported to improve symptoms of osteoarthritis of the knee. Prebiotics have been reported to favorably interact with the intestinal microbiome through the proliferation of beneficial bacteria in the gut, suppressing exogenous and endogenous intestinal infections and promoting homeostasis by balancing local pro- and anti-inflammatory actions. Bioactive compounds from Perna canaliculus are functional foods and, in this regard, may positively interact with the intestinal microbiome and provide novel therapeutic solutions for intra-intestinal and extra-intestinal inflammatory conditions.

HORSE SPECIES SYMPOSIUM: Canine intestinal microbiology and metagenomics: From phylogeny to function.

PubMed

Guard, B C; Suchodolski, J S

2016-06-01

Recent molecular studies have revealed a complex microbiota in the dog intestine. Convincing evidence has been reported linking changes in microbial communities to acute and chronic gastrointestinal inflammation, especially in canine inflammatory bowel disease (IBD). The most common microbial changes observed in intestinal inflammation are decreases in the bacterial phyla Firmicutes (i.e., Lachnospiraceae, Ruminococcaceae, and ) and Bacteroidetes, with concurrent increases in Proteobacteria (i.e., ). Due to the important role of microbial-derived metabolites for host health, it is important to elucidate the metabolic consequences of gastrointestinal dysbiosis and physiological pathways implicated in specific disease phenotypes. Metagenomic studies have used shotgun sequencing of DNA as well as phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) to characterize functional changes in the bacterial metagenome in gastrointestinal disease. Furthermore, wide-scale and untargeted measurements of metabolic products derived by the host and the microbiota in intestinal samples allow a better understanding of the functional alterations that occur in gastrointestinal disease. For example, changes in bile acid metabolism and tryptophan catabolism recently have been reported in humans and dogs. Also, metabolites associated with the pentose phosphate pathway were significantly altered in chronic gastrointestinal inflammation and indicate the presence of oxidative stress in dogs with IBD. This review focuses on the advancements made in canine metagenomics and metabolomics and their implications in understanding gastrointestinal disease as well as the development of better treatment approaches.

Enteric bacterial proteases in inflammatory bowel disease- pathophysiology and clinical implications

PubMed Central

Carroll, Ian M; Maharshak, Nitsan

2013-01-01

Numerous reports have identified a dysbiosis in the intestinal microbiota in patients suffering from inflammatory bowel diseases (IBD), yet the mechanism(s) in which this complex microbial community initiates or perpetuates inflammation remains unclear. The purpose of this review is to present evidence for one such mechanism that implicates enteric microbial derived proteases in the pathogenesis of IBD. We highlight and discuss studies demonstrating that proteases and protease receptors are abundant in the digestive system. Additionally, we investigate studies demonstrating an association between increased luminal protease activity and activation of protease receptors, ultimately resulting in increased intestinal permeability and exacerbation of colitis in animal models as well as in human IBD. Proteases are essential for the normal functioning of bacteria and in some cases can serve as virulence factors for pathogenic bacteria. Although not classified as traditional virulence factors, proteases originating from commensal enteric bacteria also have a potential association with intestinal inflammation via increased enteric permeability. Reports of increased protease activity in stools from IBD patients support a possible mechanism for a dysbiotic enteric microbiota in IBD. A better understanding of these pathways and characterization of the enteric bacteria involved, their proteases, and protease receptors may pave the way for new therapeutic approaches for these diseases. PMID:24431894

An intestinal Trojan horse for gene delivery

NASA Astrophysics Data System (ADS)

Peng, Haisheng; Wang, Chao; Xu, Xiaoyang; Yu, Chenxu; Wang, Qun

2015-02-01

The intestinal epithelium forms an essential element of the mucosal barrier and plays a critical role in the pathophysiological response to different enteric disorders and diseases. As a major enteric dysfunction of the intestinal tract, inflammatory bowel disease is a genetic disease which results from the inappropriate and exaggerated mucosal immune response to the normal constituents in the mucosal microbiota environment. An intestine targeted drug delivery system has unique advantages in the treatment of inflammatory bowel disease. As a new concept in drug delivery, the Trojan horse system with the synergy of nanotechnology and host cells can achieve better therapeutic efficacy in specific diseases. Here, we demonstrated the feasibility of encapsulating DNA-functionalized gold nanoparticles into primary isolated intestinal stem cells to form an intestinal Trojan horse for gene regulation therapy of inflammatory bowel disease. This proof-of-concept intestinal Trojan horse will have a wide variety of applications in the diagnosis and therapy of enteric disorders and diseases.

An intestinal Trojan horse for gene delivery.

PubMed

Peng, Haisheng; Wang, Chao; Xu, Xiaoyang; Yu, Chenxu; Wang, Qun

2015-03-14

The intestinal epithelium forms an essential element of the mucosal barrier and plays a critical role in the pathophysiological response to different enteric disorders and diseases. As a major enteric dysfunction of the intestinal tract, inflammatory bowel disease is a genetic disease which results from the inappropriate and exaggerated mucosal immune response to the normal constituents in the mucosal microbiota environment. An intestine targeted drug delivery system has unique advantages in the treatment of inflammatory bowel disease. As a new concept in drug delivery, the Trojan horse system with the synergy of nanotechnology and host cells can achieve better therapeutic efficacy in specific diseases. Here, we demonstrated the feasibility of encapsulating DNA-functionalized gold nanoparticles into primary isolated intestinal stem cells to form an intestinal Trojan horse for gene regulation therapy of inflammatory bowel disease. This proof-of-concept intestinal Trojan horse will have a wide variety of applications in the diagnosis and therapy of enteric disorders and diseases.

CPT-11 activates NLRP3 inflammasome through JNK and NF-κB signalings

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Qian; Zhang, Xiong; Wang, Weicheng

CPT-11 is widely used for cancer therapy as a chemotherapeutic agent. Despite its good efficacy, a large number of side effects appeared during decades of clinical application. Delayed diarrhea, at dose limiting toxicity, happens after 24 h of treatment and the rate of occurrence is up to 90%. Although many investments have been made on this negative impact, the real molecular mechanism of delayed diarrhea is poorly understood. In this study, we have discovered that CPT-11 promotes macrophage infiltration into intestinal tissues and activates the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, resulting in a robust IL-1β responsemore » and colonic inflammation similar to DSS (dextran sodium sulfate) induced experimental colitis. CPT-11 plus LPS primed mouse bone marrow-derived macrophages (BMDMs) and human acute monocytic leukemia cells (THP-1 cells) staying in a highly activated status, showing increased caspase-1 activity and releasing great amounts of IL-1β and IL-18 as detected by ELISA and western blot. A further mechanism showed that JNK and NF-κB signaling pathways participated in inflammatory responses activated by CPT-11. These results prompted us to suggest that the NLRP3-IL-1β signaling pathway might play an important role in CPT11-induced colitis. Our findings provide a basis for developing novel strategies that improve clinical implications of CPT-11. - Highlights: • CPT-11 induced experimental colitis in vivo. • CPT-11 induced intestine injury and macrophage infiltration. • CPT-11 significantly elevated levels of macrophage derived inflammatory cytokines in mice intestines. • CPT-11 activated NLRP3 inflammasome in vitro and in vivo. • CPT-11 activated JNK and NF-κB signalings in THP-1 and BMDMs.« less

Review of sn-2 palmitate oil implications for infant health.

PubMed

Bar-Yoseph, Fabiana; Lifshitz, Yael; Cohen, Tzafra

2013-09-01

Human milk provides the optimal balanced nutrition for the growing infant in the first months after birth. The human mammary gland has evolved with unusual pathways, resulting in a specific positioning of fatty acids at the outer sn-1 and sn-3, and center sn-2 of the triacylglyceride, which is different from the triglycerides in other human tissues and plasma. The development of structured triglycerides enables mimicking the composition as well as structure of human milk fat in infant formulas. Studies conducted two decades ago, together with very recent studies, have provided increasing evidence that this unusual positioning of 16:0 in human milk triglycerides has a significant role for infant health in different directions, such as fat and calcium absorption, bone health, intestinal flora and infant comfort. This review aims to unravel the relevance of human milk triglyceride sn-2 16:0 for intestinal health and inflammatory pathways and for other post-absorption effects. Copyright © 2013 Elsevier Ltd. All rights reserved.

Normal human gingival fibroblasts undergo cytostasis and apoptosis after long-term exposure to butyric acid.

PubMed

Shirasugi, Michihiro; Nishioka, Keisuke; Yamamoto, Toshiro; Nakaya, Takaaki; Kanamura, Narisato

2017-01-22

The causes of periodontal disease are complex. Butyric acid, a metabolite of periodontopathic bacteria such as Porphyromonas gingivalis, acts as a histone deacetylase inhibitor that has a direct effect on mRNA expression. Butyric acid produced by Clostridium butyricum in the intestinal tract induces differentiation of regulatory T cells, thereby suppressing inflammation in the gut. Mice lacking Clostridium butyricum in the intestinal tract suffer from colitis. By contrast, butyric acid in the oral cavity worsens periodontal disease. Periodontal disease is a chronic condition in which periodontal tissue is exposed to virulence factors (such as butyric acid); however, no study has examined the effects of long-term exposure to butyric acid. The present study demonstrated that long-term exposure of human gingival fibroblasts (HGFs) to butyric acid induced cytostasis and apoptosis via the intrinsic and extrinsic pathways. Butyric acid inhibited the division of HGFs by altering expression of mRNAs encoding cyclins. Butyric acid induced apoptosis in HGFs via the intrinsic pathway, followed by activation of caspase 9; there was no DNA damage or p53 activation. Butyric acid also upregulated expression of TNF-α mRNA and protein by HGFs. Furthermore TNF-α induced apoptosis by activating caspase 8 (the extrinsic pathway) and by inducing production of pro-inflammatory cytokines. Taken together, the results show that butyric acid induced cytostasis and apoptosis in HGFs, accompanied by production of pro-inflammatory cytokines. It thus acts as a death ligand and plays a critical role as a prophlogistic substance. Copyright © 2016 Elsevier Inc. All rights reserved.

Resveratrol and inflammatory bowel disease: the evidence so far.

PubMed

Nunes, Sandra; Danesi, Francesca; Del Rio, Daniele; Silva, Paula

2018-06-01

Despite the fact that inflammatory bowel disease (IBD) has still no recognised therapy, treatments which have proven at least mildly successful in improving IBD symptoms include anti-inflammatory drugs and monoclonal antibodies targeting pro-inflammatory cytokines. Resveratrol, a natural (poly)phenol found in grapes, red wine, grape juice and several species of berries, has been shown to prevent and ameliorate intestinal inflammation. Here, we discuss the role of resveratrol in the improvement of inflammatory disorders involving the intestinal mucosa. The present review covers three specific aspects of resveratrol in the framework of inflammation: (i) its content in food; (ii) its intestinal absorption and metabolism; and (iii) its anti-inflammatory effects in the intestinal mucosa in vitro and in the very few in vivo studies present to date. Actually, if several studies have shown that resveratrol may down-regulate mediators of intestinal immunity in rodent models, only two groups have performed intervention studies in human subjects using resveratrol as an agent to improve IBD conditions. The effects of resveratrol should be further investigated by conducting well-designed clinical trials, also taking into account different formulations for the delivery of the bioactive compound.

Toll-like receptor activation by helminths or helminth products to alleviate inflammatory bowel disease.

PubMed

Sun, ShuMin; Wang, XueLin; Wu, XiuPing; Zhao, Ying; Wang, Feng; Liu, XiaoLei; Song, Yanxia; Wu, ZhiLiang; Liu, MingYuan

2011-09-27

Helminth infection may modulate the expression of Toll like receptors (TLR) in dendritic cells (DCs) and modify the responsiveness of DCs to TLR ligands. This may regulate aberrant intestinal inflammation in humans with helminthes and may thus help alleviate inflammation associated with human inflammatory bowel disease (IBD). Epidemiological and experimental data provide further evidence that reducing helminth infections increases the incidence rate of such autoimmune diseases. Fine control of inflammation in the TLR pathway is highly desirable for effective host defense. Thus, the use of antagonists of TLR-signaling and agonists of their negative regulators from helminths or helminth products should be considered for the treatment of IBD.

Toll-like receptor activation by helminths or helminth products to alleviate inflammatory bowel disease

PubMed Central

2011-01-01

Helminth infection may modulate the expression of Toll like receptors (TLR) in dendritic cells (DCs) and modify the responsiveness of DCs to TLR ligands. This may regulate aberrant intestinal inflammation in humans with helminthes and may thus help alleviate inflammation associated with human inflammatory bowel disease (IBD). Epidemiological and experimental data provide further evidence that reducing helminth infections increases the incidence rate of such autoimmune diseases. Fine control of inflammation in the TLR pathway is highly desirable for effective host defense. Thus, the use of antagonists of TLR-signaling and agonists of their negative regulators from helminths or helminth products should be considered for the treatment of IBD. PMID:21943110

St. John's wort attenuates irinotecan-induced diarrhea via down-regulation of intestinal pro-inflammatory cytokines and inhibition of intestinal epithelial apoptosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu Zeping; Yang Xiaoxia; Chan Suiyung

Diarrhea is a common dose-limiting toxicity associated with cancer chemotherapy, in particular for drugs such as irinotecan (CPT-11), 5-fluouracil, oxaliplatin, capecitabine and raltitrexed. St. John's wort (Hypericum perforatum, SJW) has anti-inflammatory activity, and our preliminary study in the rat and a pilot study in cancer patients found that treatment of SJW alleviated irinotecan-induced diarrhea. In the present study, we investigated whether SJW modulated various pro-inflammatory cytokines including interleukins (IL-1{beta}, IL-2, IL-6), interferon (IFN-{gamma}) and tumor necrosis factor-{alpha} (TNF-{alpha}) and intestinal epithelium apoptosis in rats. The rats were treated with irinotecan at 60 mg/kg for 4 days in combination with oralmore » SJW or SJW-free control vehicle at 400 mg/kg for 8 days. Diarrhea, tissue damage, body weight loss, various cytokines including IL-1{beta}, IL-2, IL-6, IFN-{gamma} and TNF-{alpha} and intestinal epithelial apoptosis were monitored over 11 days. Our studies demonstrated that combined SJW markedly reduced CPT-11-induced diarrhea and intestinal lesions. The production of pro-inflammatory cytokines such as IL-1{beta}, IFN-{gamma} and TNF-{alpha} was significantly up-regulated in intestine. In the mean time, combined SJW significantly suppressed the intestinal epithelial apoptosis induced by CPT-11 over days 5-11. In particular, combination of SJW significantly inhibited the expression of TNF-{alpha} mRNA in the intestine over days 5-11. In conclusion, inhibition of pro-inflammatory cytokines and intestinal epithelium apoptosis partly explained the protective effect of SJW against the intestinal toxicities induced by irinotecan. Further studies are warranted to explore the potential for STW as an agent in combination with chemotherapeutic drugs to lower their dose-limiting toxicities.« less

Resveratrol reduces senescence-associated secretory phenotype by SIRT1/NF-κB pathway in gut of the annual fish Nothobranchius guentheri.

PubMed

Liu, Shan; Zheng, Zhaodi; Ji, Shuhua; Liu, Tingting; Hou, Yanhan; Li, Shasha; Li, Guorong

2018-06-13

Senescent cells display a senescence-associated secretory phenotype (SASP), which contributes to aging. Resveratrol, an activator of SIRT1, has anti-aging, anti-inflammatory, anti-oxidant, anti-free radical and other pharmacological effects. The genus of the annual fish Nothobranchius has become an emerging animal model for studying aging. However, the underlying mechanism for resveratrol to delay aging by SASP regulation has not been elucidated in vertebrates. In this study, the annual fish N. guentheri were fed with resveratrol for long-term treatment. The results showed that resveratrol reversed intensive senescence-associated β-galactosidase activity with aging process, down-regulated levels of SASP-associated proinflammatory cytokines IL-8 and TNFα, and up-regulated expression of anti-inflammatory cytokine IL-10 in gut of the fish. Resveratrol increased SIRT1 expression, and inhibited NF-κB by decreasing RelA/p65, Ac-RelA/p65 and p-IκBα levels and by increasing the interaction between SIRT1 and RelA/p65. Moreover, resveratrol reversed the decline of intestinal epithelial cells (IECs) and intestinal stem cells (ISCs) caused by aging in gut of the fish. Together, our results implied that resveratrol inhibited SASP through SIRT1/NF-κB signaling pathway and delayed aging of the annual fish N. guentheri. Copyright © 2018. Published by Elsevier Ltd.

Gut Microbiota in Cardiovascular Health and Disease

PubMed Central

Tang, W.H. Wilson; Kitai, Takeshi; Hazen, Stanley L

2017-01-01

Significant interest in recent years has focused on gut microbiota-host interaction because accumulating evidence has revealed that intestinal microbiota play an important role in human health and disease, including cardiovascular diseases. Changes in the composition of gut microbiota associated with disease, referred to as dysbiosis, have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity and type 2 diabetes mellitus. In addition to alterations in gut microbiota composition, the metabolic potential of gut microbiota has been identified as a contributing factor in the development of diseases. Recent studies revealed that gut microbiota can elicit a variety of effects on the host. Indeed, the gut microbiome functions like an endocrine organ, generating bioactive metabolites, that can impact host physiology. Microbiota interact with the host through a number of pathways, including the trimethylamine (TMA)/ trimethylamine N-oxide (TMAO) pathway, short-chain fatty acids pathway, and primary and secondary bile acids pathways. In addition to these “metabolism dependent” pathways, metabolism independent processes are suggested to also potentially contribute to CVD pathogenesis. For example, heart failure associated splanchnic circulation congestion, bowel wall edema and impaired intestinal barrier function are thought to result in bacterial translocation, the presence of bacterial products in the systemic circulation and heightened inflammatory state. These are believed to also contribute to further progression of heart failure and atherosclerosis. The purpose of the current review is to highlight the complex interplay between microbiota, their metabolites and the development and progression of cardiovascular diseases. We will also discuss the roles of gut microbiota in normal physiology and the potential of modulating intestinal microbial inhabitants as novel therapeutic targets. PMID:28360349

Gut Microbiota in Cardiovascular Health and Disease.

PubMed

Tang, W H Wilson; Kitai, Takeshi; Hazen, Stanley L

2017-03-31

Significant interest in recent years has focused on gut microbiota-host interaction because accumulating evidence has revealed that intestinal microbiota play an important role in human health and disease, including cardiovascular diseases. Changes in the composition of gut microbiota associated with disease, referred to as dysbiosis, have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. In addition to alterations in gut microbiota composition, the metabolic potential of gut microbiota has been identified as a contributing factor in the development of diseases. Recent studies revealed that gut microbiota can elicit a variety of effects on the host. Indeed, the gut microbiome functions like an endocrine organ, generating bioactive metabolites, that can impact host physiology. Microbiota interact with the host through many pathways, including the trimethylamine/trimethylamine N -oxide pathway, short-chain fatty acids pathway, and primary and secondary bile acids pathways. In addition to these metabolism-dependent pathways, metabolism-independent processes are suggested to also potentially contribute to cardiovascular disease pathogenesis. For example, heart failure-associated splanchnic circulation congestion, bowel wall edema, and impaired intestinal barrier function are thought to result in bacterial translocation, the presence of bacterial products in the systemic circulation and heightened inflammatory state. These are thought to also contribute to further progression of heart failure and atherosclerosis. The purpose of the current review is to highlight the complex interplay between microbiota, their metabolites, and the development and progression of cardiovascular diseases. We will also discuss the roles of gut microbiota in normal physiology and the potential of modulating intestinal microbial inhabitants as novel therapeutic targets. © 2017 American Heart Association, Inc.

Pathogenesis of human diffusely adhering Escherichia coli expressing Afa/Dr adhesins (Afa/Dr DAEC): current insights and future challenges.

PubMed

Servin, Alain L

2014-10-01

The pathogenicity and clinical pertinence of diffusely adhering Escherichia coli expressing the Afa/Dr adhesins (Afa/Dr DAEC) in urinary tract infections (UTIs) and pregnancy complications are well established. In contrast, the implication of intestinal Afa/Dr DAEC in diarrhea is still under debate. These strains are age dependently involved in diarrhea in children, are apparently not involved in diarrhea in adults, and can also be asymptomatic intestinal microbiota strains in children and adult. This comprehensive review analyzes the epidemiology and diagnosis and highlights recent progress which has improved the understanding of Afa/Dr DAEC pathogenesis. Here, I summarize the roles of Afa/Dr DAEC virulence factors, including Afa/Dr adhesins, flagella, Sat toxin, and pks island products, in the development of specific mechanisms of pathogenicity. In intestinal epithelial polarized cells, the Afa/Dr adhesins trigger cell membrane receptor clustering and activation of the linked cell signaling pathways, promote structural and functional cell lesions and injuries in intestinal barrier, induce proinflammatory responses, create angiogenesis, instigate epithelial-mesenchymal transition-like events, and lead to pks-dependent DNA damage. UTI-associated Afa/Dr DAEC strains, following adhesin-membrane receptor cell interactions and activation of associated lipid raft-dependent cell signaling pathways, internalize in a microtubule-dependent manner within urinary tract epithelial cells, develop a particular intracellular lifestyle, and trigger a toxin-dependent cell detachment. In response to Afa/Dr DAEC infection, the host epithelial cells generate antibacterial defense responses. Finally, I discuss a hypothetical role of intestinal Afa/Dr DAEC strains that can act as "silent pathogens" with the capacity to emerge as "pathobionts" for the development of inflammatory bowel disease and intestinal carcinogenesis. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Intestinal exposure to PCB 153 induces inflammation via the ATM/NEMO pathway.

PubMed

Phillips, Matthew C; Dheer, Rishu; Santaolalla, Rebeca; Davies, Julie M; Burgueño, Juan; Lang, Jessica K; Toborek, Michal; Abreu, Maria T

2018-01-15

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that adversely affect human health. PCBs bio-accumulate in organisms important for human consumption. PCBs accumulation in the body leads to activation of the transcription factor NF-κB, a major driver of inflammation. Despite dietary exposure being one of the main routes of exposure to PCBs, the gut has been widely ignored when studying the effects of PCBs. We investigated the effects of PCB 153 on the intestine and addressed whether PCB 153 affected intestinal permeability or inflammation and the mechanism by which this occurred. Mice were orally exposed to PCB 153 and gut permeability was assessed. Intestinal epithelial cells (IECs) were collected and evaluated for evidence of genotoxicity and inflammation. A human IEC line (SW480) was used to examine the direct effects of PCB 153 on epithelial function. NF-кB activation was measured using a reporter assay, DNA damage was assessed, and cytokine expression was ascertained with real-time PCR. Mice orally exposed to PCB 153 had an increase in intestinal permeability and inflammatory cytokine expression in their IECs; inhibition of NF-кB ameliorated both these effects. This inflammation was associated with genotoxic damage and NF-кB activation. Exposure of SW480 cells to PCB 153 led to similar effects as seen in vivo. We found that activation of the ATM/NEMO pathway by genotoxic stress was upstream of NF-kB activation. These results demonstrate that oral exposure to PCB 153 is genotoxic to IECs and induces downstream inflammation and barrier dysfunction in the intestinal epithelium. Copyright © 2017 Elsevier Inc. All rights reserved.

Pathogenesis of Human Diffusely Adhering Escherichia coli Expressing Afa/Dr Adhesins (Afa/Dr DAEC): Current Insights and Future Challenges

PubMed Central

2014-01-01

SUMMARY The pathogenicity and clinical pertinence of diffusely adhering Escherichia coli expressing the Afa/Dr adhesins (Afa/Dr DAEC) in urinary tract infections (UTIs) and pregnancy complications are well established. In contrast, the implication of intestinal Afa/Dr DAEC in diarrhea is still under debate. These strains are age dependently involved in diarrhea in children, are apparently not involved in diarrhea in adults, and can also be asymptomatic intestinal microbiota strains in children and adult. This comprehensive review analyzes the epidemiology and diagnosis and highlights recent progress which has improved the understanding of Afa/Dr DAEC pathogenesis. Here, I summarize the roles of Afa/Dr DAEC virulence factors, including Afa/Dr adhesins, flagella, Sat toxin, and pks island products, in the development of specific mechanisms of pathogenicity. In intestinal epithelial polarized cells, the Afa/Dr adhesins trigger cell membrane receptor clustering and activation of the linked cell signaling pathways, promote structural and functional cell lesions and injuries in intestinal barrier, induce proinflammatory responses, create angiogenesis, instigate epithelial-mesenchymal transition-like events, and lead to pks-dependent DNA damage. UTI-associated Afa/Dr DAEC strains, following adhesin-membrane receptor cell interactions and activation of associated lipid raft-dependent cell signaling pathways, internalize in a microtubule-dependent manner within urinary tract epithelial cells, develop a particular intracellular lifestyle, and trigger a toxin-dependent cell detachment. In response to Afa/Dr DAEC infection, the host epithelial cells generate antibacterial defense responses. Finally, I discuss a hypothetical role of intestinal Afa/Dr DAEC strains that can act as “silent pathogens” with the capacity to emerge as “pathobionts” for the development of inflammatory bowel disease and intestinal carcinogenesis. PMID:25278576

6-Gingerol protects intestinal barrier from ischemia/reperfusion-induced damage via inhibition of p38 MAPK to NF-κB signalling.

PubMed

Li, Yanli; Xu, Bin; Xu, Ming; Chen, Dapeng; Xiong, Yongjian; Lian, Mengqiao; Sun, Yuchao; Tang, Zeyao; Wang, Li; Jiang, Chunling; Lin, Yuan

2017-05-01

Intestinal ischemia reperfusion (I/R) injury caused by severe trauma, intestinal obstruction, and operation is one of the tough challenges in clinic. 6-Gingerol (6G), a main active ingredient of ginger, is found to have anti-microbial, anti-inflammatory, anti-oxidative, and anti-cancer activities. The present study was designed to characterize the potential protective effects of 6G on rat intestinal I/R injury and reveal the correlated mechanisms. Rat intestinal I/R model was established with clamping the superior mesenteric artery (SMA) and 6G was intragastrically administered for three consecutive days before I/R injury. Caco-2 and IEC-6 cells were incubated under hypoxia/reoxygenation (H/R) conditions to simulate I/R injury in vitro. The results showed that 6G significantly alleviated intestinal injury in I/R injured rats by reducing the generation of oxidative stress and inhibiting p38 MAPK signaling pathway. 6G significantly reduced MDA level and increased the levels of SOD, GSH, and GSH-Px in I/R injured intestinal tissues. 6G significantly decreased the production of proinflammatory cytokines including TNF-α, IL-1β, and IL-6, and inhibited the expression of inflammatory mediators iNOS/NO in I/R injured intestinal tissues. The impaired intestinal barrier function was restored by using 6G in I/R injured rats and in both Caco-2 and IEC-6 cells characterized by inhibiting p38 MAPK phosphorylation, nuclear translocation of NF-κB, and expression of myosin light chain kinase (MLCK) protein. 6G also reduced the generation of reactive oxygen species (ROS) in both Caco-2 and IEC-6 cells. In vitro transfection of p38 MAPK siRNA mitigated the impact of 6G on NF-κB and MLCK expression, and the results further corroborated the protective effects of 6G on intestinal I/R injury by repressing p38 MAPK signaling. In conclusion, the present study suggests that 6G exerts protective effects against I/R-induced intestinal mucosa injury by inhibiting the formation of ROS and p38 MAPK activation, providing novel insights into the mechanisms of this therapeutic candidate for the treatment of intestinal injury. Copyright © 2017 Elsevier Ltd. All rights reserved.

The relationship between intestinal parasites and some immune-mediated intestinal conditions

PubMed Central

Mohammadi, Rasoul; Hosseini-Safa, Ahmad; Ehsani Ardakani, Mohammad Javad; Rostami-Nejad, Mohammad

2015-01-01

Over the last decades, the incidence of infestation by minor parasites has decreased in developed countries. Infectious agents can also suppress autoimmune and allergic disorders. Some investigations show that various protozoa and helminthes are connected with the main immune-mediated intestinal conditions including celiac disease (CD), inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS). Celiac disease is a digestive and autoimmune disorder that can damage the small intestine and characterized by a multitude gastrointestinal (GI) and extra GI symptoms. IBD (including ulcerative colitis and Crohn’s disease) is a group of inflammatory conditions of the small intestine and colon. The etiology of IBD is unknown, but it may be related to instability in the intestinal microflora that leading to an immoderate inflammatory response to commensal microbiota. Irritable bowel syndrome (IBS) is a common, long-term condition of the digestive system. Bloating, diarrhoea and/or constipation are nonspecific symptoms of IBS. Various studies have shown that some intestinal parasites can effect on immune system of infected hosts and in some cases, they are able to modify and change the host’s immune responses, particularly in autoimmune disorders like celiac disease and IBD. The main objective of this review is to investigate the relationship between intestinal parasites and different inflammatory bowel disorders. PMID:25926937

Innate sensors of pathogen and stress: linking inflammation to obesity.

PubMed

Jin, Chengcheng; Flavell, Richard A

2013-08-01

Pathogen and nutrient response pathways are evolutionarily conserved and highly integrated to regulate metabolic and immune homeostasis. Excessive nutrients can be sensed by innate pattern recognition receptors as danger signals either directly or through production of endogenous ligands or modulation of intestinal microbiota. This triggers the activation of downstream inflammatory cascades involving nuclear factor κB and mitogen-activated protein kinase and ultimately induces the production of inflammatory cytokines and immune cell infiltration in various metabolic tissues. The chronic low-grade inflammation in the brain, islet, liver, muscle, and adipose tissue further promotes insulin resistance, energy imbalance, and impaired glucose/lipid metabolism, contributing to the metabolic complications of obesity, such as diabetes and atherosclerosis. In addition, innate pathogen receptors have now emerged as a critical link between the intestinal microbiota and host metabolism. In this review we summarize recent studies demonstrating the important roles of innate pathogen receptors, including Toll-like receptors, nucleotide oligomerization domain containing proteins, and inflammasomes in mediating the inflammatory response to metabolic stress in different tissues and highlight the interaction of innate pattern recognition receptors, gut microbiota, and nutrients during the development of obesity and related metabolic disorders. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Immunomodulating effects of antibiotics used in the prophylaxis of bacterial infections in advanced cirrhosis

PubMed Central

Zapater, Pedro; González-Navajas, José Manuel; Such, José; Francés, Rubén

2015-01-01

The use of norfloxacin either as primary or secondary prophylaxis of bacterial infections in advanced cirrhosis has improved patient’s survival. This may be explained not only due to a significant decrease in the number of infections, but also because of a direct immunomodulatory effect. Selective intestinal decontamination with norfloxacin reduces translocation of either viable bacteria or bacteria-driven products from the intestinal lumen. In addition, norfloxacin directly modulates the systemic inflammatory response. The pro-inflammatory cytokine profile secreted by neutrophils from these patients shows a close, significant, and inverse correlation with serum norfloxacin levels. Similar effects have been described with other quinolones in different clinical conditions. Although the underlying mechanisms are not well defined for most of the antibiotics, the pathways triggered for norfloxacin to induce such immunomodulatory effects involve the down-regulation of pro-inflammatory inducible nitric oxide synthase, cyclooxygenase-2, and NF-κB and the up-regulation of heme-oxygenase 1 and IL-10 expression. The knowledge of these immunomodulatory effects, additional to their bactericidal role, improves our comprehension of the interaction between antibiotics and the cellular host response and offer new possibilities for the development of new therapeutic strategies to manage and prevent bacterial infections in cirrhosis. PMID:26556982

Doxycycline Promotes Carcinogenesis & Metastasis via Chronic Inflammatory Pathway: An In Vivo Approach

PubMed Central

Nanda, Neha; Dhawan, Devinder K.; Bhatia, Alka; Mahmood, Akhtar; Mahmood, Safrun

2016-01-01

Background Doxycycline (DOX) exhibits anti-inflammatory, anti-tumor, and pro-apoptotic activity and is being tested in clinical trials as a chemotherapeutic agent for several cancers, including colon cancer. Materials & Methods In the current study, the chemotherapeutic activity of doxycycline was tested in a rat model of colon carcinogenesis, induced by colon specific cancer promoter, 1,2, dimethylhydrazine (DMH) as well as study the effect of DOX-alone on a separate group of rats. Results Doxycycline administration in DMH-treated rats (DMH-DOX) unexpectedly increased tumor multiplicity, stimulated progression of colonic tumor growth from adenomas to carcinomas and revealed metastasis in small intestine as determined by macroscopic and histopathological analysis. DOX-alone treatment showed markedly enhanced chronic inflammation and reactive hyperplasia, which was dependent upon the dose of doxycycline administered. Moreover, immunohistochemical analysis revealed evidence of inflammation and anti-apoptotic action of DOX by deregulation of various biomarkers. Conclusion These results suggest that doxycycline caused chronic inflammation in colon, small intestine injury, enhanced the efficacy of DMH in tumor progression and provided a mechanistic link between doxycycline-induced chronic inflammation and tumorigenesis. Ongoing studies thus may need to focus on the molecular mechanisms of doxycycline action, which lead to its inflammatory and tumorigenic effects. PMID:26998758

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moon, Yuseok; Yang, Hyun; Kim, Yung Bu

Non-steroidal anti-inflammatory drugs (NSAIDs) are used to relieve pain and inflammation and have also received considerable attention because of their preventive effects against human cancer. However, the drug application is sometimes limited by the severe gastrointestinal ulcers and mucosal complications. In the present study, NSAID sulindac sulfide was investigated for the cytotoxic injury in the intestinal epithelial cells in association with an immediate inducible factor, early growth response gene 1 (EGR-1). Previously we reported that sulindac sulfide can suppress tumor cell invasion by inducing EGR-1. Extending the previous study, EGR-1 induction by sulindac sulfide was observed both in the non-transformedmore » and transformed human intestinal epithelial cell lines. In terms of signaling pathway, ERK1/2 MAP kinases and its substrate Elk-1 transcription factor were involved in the sulindac sulfide-induced EGR-1 gene expression. Moreover, sulindac sulfide stimulated the nuclear translocation of the transcription factor EGR-1, which was also mediated by ERK1/2 signaling pathway. The roles of EGR-1 signals in the apoptotic cell death were assessed in the intestinal epithelial cells. Suppression of EGR-1 expression retarded cellular growth and colony forming activity in the intestinal epithelial cells. Moreover, induced EGR-1 ameliorated sulindac sulfide-mediated apoptotic cell death and enhanced the cellular survival. Taken all together, sulindac sulfide activated ERK1/2 MAP kinases which then mediated EGR-1 induction and nuclear translocation, all of which played important roles in the cellular survival from NSAID-mediated cytotoxicity in the human intestinal epithelial cells, implicating the protective roles of EGR-1 in the NSAID-mediated mucosal injuries.« less

Bovine Intestinal Alkaline Phosphatase Reduces Inflammation After Induction of Acute Myocardial Infarction in Mice.

PubMed

Fiechter, Danielle; Kats, Suzanne; Brands, Ruud; van Middelaar, Ben; Pasterkamp, Gerard; de Kleijn, Dominique; Seinen, Willem

2011-10-01

There has been increasing evidence suggesting that lipopolysaccharide or endotoxin may be an important activator of the innate immune system after acute myocardial infarction. Bovine intestinal alkaline phosphatase reduces inflammation in several endotoxin mediated diseases by dephosphorylation of the lipid A moiety of lipopolysaccharide. The aim of this study was to investigate the effect of bovine intestinal alkaline phosphatase on reducing inflammation after acute myocardial infarction. Just before permanent ligation of the left anterior descending coronary (LAD) artery to induce acute myocardial infarction in Balb/c mice, bovine intestinal alkaline phosphatase (bIAP) was administrated intravenously. After 4 hours, mice were sacrificed and the inflammatory response was assessed. Acute myocardial infarction induced the production of different cytokines, which were measured in blood. Treatment with bovine intestinal alkaline phosphatase resulted in a significant reduction of the pro-inflammatory cytokines IL-6, IL-1β and the chymase mouse mast cell protease-1. No difference in the production of the anti-inflammatory cytokine IL-10 was observed between the control group and the bovine intestinal alkaline phosphatase treated group. In a mouse model of permanent LAD coronary artery ligation, bIAP diminishes the pro-inflammatory responses but does not have an effect on the anti-inflammatory response in the acute phase after acute myocardial infarction.

An adapted in vitro assay to assess Campylobacter jejuni interaction with intestinal epithelial cells: Taking into stimulation with TNFα.

PubMed

Rodrigues, Ramila Cristiane; Pocheron, Anne-Lise; Cappelier, Jean-Michel; Tresse, Odile; Haddad, Nabila

2018-06-01

Campylobacter jejuni is the most prevalent foodborne bacterial infection agent. This pathogen seems also involved in inflammatory bowel diseases in which pro-inflammatory cytokines, such as tumor necrosis factor α (TNFα), play a major role. C. jejuni pathogenicity has been extensively studied using in vitro cell culture methods, and more precisely "healthy" cells. In fact, no information is available regarding the behavior of C. jejuni in contact with TNFα-stimulated cells. Therefore, this research was designed to investigate the effect of TNFα on C. jejuni interaction with human intestinal epithelial cells (HT29 and HT29-MTX). To ensure IL-8 production induced by TNFα, human rtTNFα was added to HT29 and HT29-MTX before adhesion and invasion assays. About 10 8 CFU bacteria of C. jejuni strains cells were added to measure their adherence and invasion abilities using TNFα-stimulated cells versus non stimulated cells. Exposure to TNFα results in IL-8 overproduction by intestinal epithelial cells. In addition, the effect of TNFα pre-treatment on C. jejuni adhesion and internalization into eukaryotic cells is strain-dependent. Indeed, the adhesion/invasion process is affected in <50% of the strains tested when TNFα is added to the intestinal cells. Interestingly, TNFα affects more strains in their ability to adhere to and invade the mucus-secreting HT29-MTX cells. Among the 10 strains tested, the aero-tolerant C. jejuni Bf strain is one of the most virulent. These results suggest that the TNFα signalling pathway could participate in the internalization of C. jejuni in human intestinal cells and can help in understanding the pathogenicity of this microorganism in contact with TNFα-stimulated cells. Copyright © 2018. Published by Elsevier B.V.

The role of monogenic disease in children with very early onset inflammatory bowel disease.

PubMed

Kelsen, Judith R; Baldassano, Robert N

2017-10-01

Inflammatory bowel disease (IBD) is a multifactorial disease caused by dysregulated immune responses to commensal or pathogenic intestinal microbes, resulting in chronic intestinal inflammation. Patients diagnosed with IBD occurring before the age of 5 are a unique population, known as very early onset (VEO)-IBD and can be phenotypically and genetically distinct from older-onset IBD. We aim to review the clinical presentation of children with VEO-IBD and recent discoveries that point to genomic drivers of disease that may impact our therapeutic decisions. VEO-IBD is increasing in incidence and is associated with more severe disease, aggressive progression and poor response to most conventional therapies. This article will review the advances in sequencing technology that have led to identification of novel gene variants associated with disease and potentially new targeted therapeutic options. Children with VEO-IBD may present with a different phenotype and more severe disease than older children and adults. Identification of the causal gene or pathways, these children may allow for true precision medicine with targeted therapy and improved disease course.

Tanshinone IIA Sodium Sulfonate Attenuates LPS-Induced Intestinal Injury in Mice

PubMed Central

Yang, Xin-Jing; Qian, Jin-Xian; Wei, Yao; Guo, Qiang; Jin, Jun; Sun, Xue; Liu, Sheng-Lan

2018-01-01

Background Tanshinone IIA sodium sulfonate (TSS) is known to possess anti-inflammatory effects and has exhibited protective effects in various inflammatory conditions; however, its role in lipopolysaccharide- (LPS-) induced intestinal injury is still unknown. Objective The present study is designed to explore the role and possible mechanism of TSS in LPS-induced intestinal injury. Methods Male C57BL/6J mice, challenged with intraperitoneal LPS injection, were treated with or without TSS 0.5 h prior to LPS exposure. At 1, 6, and 12 h after LPS injection, mice were sacrificed, and the small intestine was excised. The intestinal tissue injury was analyzed by HE staining. Inflammatory factors (TNF-α, IL-1β, and IL-6) in the intestinal tissue were examined by ELISA and RT-PCR. In addition, expressions of autophagy markers (microtubule-associated light chain 3 (LC3) and Beclin-1) were detected by western blot and RT-PCR. A number of autophagosomes were also observed under electron microscopy. Results TSS treatment significantly attenuated small intestinal epithelium injury induced by LPS. LPS-induced release of inflammatory mediators, including TNF-α, IL-1β, and IL-6, were markedly inhibited by TSS. Furthermore, TSS treatment could effectively upregulate LPS-induced decrease of autophagy levels, as evidenced by the increased expression of LC3 and Beclin-1, and more autophagosomes. Conclusion The protective effect of TSS on LPS-induced small intestinal injury may be attributed to the inhibition of inflammatory factors and promotion of autophagy levels. The present study may provide novel insight into the molecular mechanisms of TSS on the treatment of intestinal injury. PMID:29706995

Both direct and indirect effects account for the pro-inflammatory activity of enteropathogenic mycotoxins on the human intestinal epithelium: Stimulation of interleukin-8 secretion, potentiation of interleukin-1{beta} effect and increase in the transepithelial passage of commensal bacteria

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maresca, Marc; Yahi, Nouara; Younes-Sakr, Lama

Mycotoxins are fungal secondary metabolites responsible of food-mediated intoxication in animals and humans. Deoxynivalenol, ochratoxin A and patulin are the best known enteropathogenic mycotoxins able to alter intestinal functions resulting in malnutrition, diarrhea, vomiting and intestinal inflammation in vivo. Although their effects on intestinal barrier and transport activities have been extensively characterized, the mechanisms responsible for their pro-inflammatory effect are still poorly understood. Here we investigated if mycotoxin-induced intestinal inflammation results from a direct and/or indirect pro-inflammatory activity of these mycotoxins on human intestinal epithelial cells, using differentiated Caco-2 cells as model and interleukin 8 (IL-8) as an indicator ofmore » intestinal inflammation. Deoxynivalenol was the only mycotoxin able to directly increase IL-8 secretion (10- to 15-fold increase). We also investigated if these mycotoxins could indirectly stimulate IL-8 secretion through: (i) a modulation of the action of pro-inflammatory molecules such as the interleukin-1beta (IL-1{beta}), and/or (ii) an increase in the transepithelial passage of non-invasive commensal Escherichia coli. We found that deoxynivalenol, ochratoxin A and patulin all potentiated the effect of IL-1{beta} on IL-8 secretion (ranging from 35% to 138% increase) and increased the transepithelial passage of commensal bacteria (ranging from 12- to 1544-fold increase). In addition to potentially exacerbate established intestinal inflammation, these mycotoxins may thus participate in the induction of sepsis and intestinal inflammation in vivo. Taken together, our results suggest that the pro-inflammatory activity of enteropathogenic mycotoxins is mediated by both direct and indirect effects.« less

Chemokine CXCL11 links microbial stimuli to intestinal inflammation

PubMed Central

Liu, Z; Chen, X; Wang, X; Chen, X; Song, C-H; Du, Y; Su, J; Yaseen, S A; Yang, P-C

2011-01-01

Interleukin (IL)-17 plays an important role in the pathogenesis in a number of immune inflammatory disorders. This study aims to investigate the mechanism by which microbial product flagellin is involved in the development of T helper type (Th)17 cells. Serum levels of IL-17 and CXCL9-11 in patients with ulcerative colitis (UC) were evaluated. The source and mechanism of CXC11 release in intestinal mucosa were examined with colonic biopsies from UC patients and a colitis mouse model. The role of flagellin in the development of Th17 cells was studied with a cell co-culture system. High serum levels of CXCL11 and IL-17 were observed in UC. Flagellin could induce the production of CXCL11 in CD14+ cells that facilitated the development of Th17 cells. In a skewed Th1 response environment flagellin induces intestinal inflammation, with IL-17 expression predominant. CXCR3/CXCL11 pathway is involved in microbial product flagellin-induced intestinal inflammation in which the Th17 response plays an important role. PMID:21438871

Intestinal alkaline phosphatase inhibits the proinflammatory nucleotide uridine diphosphate.

PubMed

Moss, Angela K; Hamarneh, Sulaiman R; Mohamed, Mussa M Rafat; Ramasamy, Sundaram; Yammine, Halim; Patel, Palak; Kaliannan, Kanakaraju; Alam, Sayeda N; Muhammad, Nur; Moaven, Omeed; Teshager, Abeba; Malo, Nondita S; Narisawa, Sonoko; Millán, José Luis; Warren, H Shaw; Hohmann, Elizabeth; Malo, Madhu S; Hodin, Richard A

2013-03-15

Uridine diphosphate (UDP) is a proinflammatory nucleotide implicated in inflammatory bowel disease. Intestinal alkaline phosphatase (IAP) is a gut mucosal defense factor capable of inhibiting intestinal inflammation. We used the malachite green assay to show that IAP dephosphorylates UDP. To study the anti-inflammatory effect of IAP, UDP or other proinflammatory ligands (LPS, flagellin, Pam3Cys, or TNF-α) in the presence or absence of IAP were applied to cell cultures, and IL-8 was measured. UDP caused dose-dependent increase in IL-8 release by immune cells and two gut epithelial cell lines, and IAP treatment abrogated IL-8 release. Costimulation with UDP and other inflammatory ligands resulted in a synergistic increase in IL-8 release, which was prevented by IAP treatment. In vivo, UDP in the presence or absence of IAP was instilled into a small intestinal loop model in wild-type and IAP-knockout mice. Luminal contents were applied to cell culture, and cytokine levels were measured in culture supernatant and intestinal tissue. UDP-treated luminal contents induced more inflammation on target cells, with a greater inflammatory response to contents from IAP-KO mice treated with UDP than from WT mice. Additionally, UDP treatment increased TNF-α levels in intestinal tissue of IAP-KO mice, and cotreatment with IAP reduced inflammation to control levels. Taken together, these studies show that IAP prevents inflammation caused by UDP alone and in combination with other ligands, and the anti-inflammatory effect of IAP against UDP persists in mouse small intestine. The benefits of IAP in intestinal disease may be partly due to inhibition of the proinflammatory activity of UDP.

Antioxidant and intestinal anti-inflammatory effects of plant-derived coumarin derivatives.

PubMed

Witaicenis, Aline; Seito, Leonardo Noboru; da Silveira Chagas, Alexandre; de Almeida, Luiz Domingues; Luchini, Ana Carolina; Rodrigues-Orsi, Patrícia; Cestari, Silvia Helena; Di Stasi, Luiz Claudio

2014-02-15

Coumarins, also known as benzopyrones, are plant-derived products with several pharmacological properties, including antioxidant and anti-inflammatory activities. Based on the wide distribution of coumarin derivatives in plant-based foods and beverages in the human diet, our objective was to evaluate both the antioxidant and intestinal anti-inflammatory activities of six coumarin derivatives of plant origin (scopoletin, scoparone, fraxetin, 4-methyl-umbeliferone, esculin and daphnetin) to verify if potential intestinal anti-inflammatory activity was related to antioxidant properties. Intestinal inflammation was induced by intracolonic instillation of TNBS in rats. The animals were treated with coumarins by oral route. The animals were killed 48 h after colitis induction. The colonic segments were obtained after laparotomy and macroscopic and biochemical parameters (determination of glutathione level and myeloperoxidase and alkaline phosphatase activities) were evaluated. The antioxidant properties of these coumarins were examined by lipid peroxidation and DPPH assays. Treatment with esculin, scoparone and daphnetin produced the best protective effects. All coumarin derivatives showed antioxidant activity in the DPPH assay, while daphnetin and fraxetin also showed antioxidant activity by inhibiting lipid peroxidation. Coumarins, except 4-methyl-umbeliferone, also showed antioxidant activity through the counteraction of glutathione levels or through the inhibition of myeloperoxidase activity. The intestinal anti-inflammatory activity of coumarin derivatives were related to their antioxidant properties, suggesting that consumption of coumarins and/or foods rich in coumarin derivatives, particularly daphnetin, esculin and scoparone, could prevent intestinal inflammatory disease. Copyright © 2013 Elsevier GmbH. All rights reserved.

Cannabinoid-induced autophagy regulates suppressor of cytokine signaling-3 in intestinal epithelium

PubMed Central

Koay, Luan C.; Rigby, Rachael J.

2014-01-01

Autophagy is a catabolic process involved in homeostatic and regulated cellular protein recycling and degradation via the lysosomal degradation pathway. Emerging data associate impaired autophagy, increased activity in the endocannabinoid system, and upregulation of suppressor of cytokine signaling-3 (SOCS3) protein expression during intestinal inflammation. We have investigated whether these three processes are linked. By assessing the impact of the phytocannabinoid cannabidiol (CBD), the synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA), and the endocannabinoid N-arachidonoylethanolamine (AEA) on autophagosome formation, we explored whether these actions were responsible for cyclic SOCS3 protein levels. Our findings show that all three cannabinoids induce autophagy in a dose-dependent manner in fully differentiated Caco-2 cells, a model of mature intestinal epithelium. ACEA and AEA induced canonical autophagy, which was cannabinoid type 1 receptor-mediated. In contrast, CBD was able to bypass the cannabinoid type 1 receptor and the canonical pathway to induce autophagy, albeit to a lesser extent. Functionally, all three cannabinoids reduced SOCS3 protein expression, which was reversed by blocking early and late autophagy. In conclusion, the regulatory protein SOCS3 is regulated by autophagy, and cannabinoids play a role in this process, which could be important when therapeutic applications for the cannabinoids in inflammatory conditions are considered. PMID:24833710

GPR81, a Cell-Surface Receptor for Lactate, Regulates Intestinal Homeostasis and Protects Mice from Experimental Colitis.

PubMed

Ranganathan, Punithavathi; Shanmugam, Arulkumaran; Swafford, Daniel; Suryawanshi, Amol; Bhattacharjee, Pushpak; Hussein, Mohamed S; Koni, Pandelakis A; Prasad, Puttur D; Kurago, Zoya B; Thangaraju, Muthusamy; Ganapathy, Vadivel; Manicassamy, Santhakumar

2018-03-01

At mucosal sites such as the intestine, the immune system launches robust immunity against invading pathogens while maintaining a state of tolerance to commensal flora and ingested food Ags. The molecular mechanisms underlying this phenomenon remain poorly understood. In this study, we report that signaling by GPR81, a receptor for lactate, in colonic dendritic cells and macrophages plays an important role in suppressing colonic inflammation and restoring colonic homeostasis. Genetic deletion of GPR81 in mice led to increased Th1/Th17 cell differentiation and reduced regulatory T cell differentiation, resulting in enhanced susceptibility to colonic inflammation. This was due to increased production of proinflammatory cytokines (IL-6, IL-1β, and TNF-α) and decreased expression of immune regulatory factors (IL-10, retinoic acid, and IDO) by intestinal APCs lacking GPR81. Consistent with these findings, pharmacological activation of GPR81 decreased inflammatory cytokine expression and ameliorated colonic inflammation. Taken together, these findings identify a new and important role for the GPR81 signaling pathway in regulating immune tolerance and colonic inflammation. Thus, manipulation of the GPR81 pathway could provide novel opportunities for enhancing regulatory responses and treating colonic inflammation. Copyright © 2018 by The American Association of Immunologists, Inc.

Polysaccharides derived from Ganoderma lucidum fungus mycelia ameliorate indomethacin-induced small intestinal injury via induction of GM-CSF from macrophages.

PubMed

Nagai, Kenta; Ueno, Yoshitaka; Tanaka, Shinji; Hayashi, Ryohei; Shinagawa, Kei; Chayama, Kazuaki

2017-10-01

Non-steroidal anti-inflammatory drugs often cause ulcers in the human small intestine, but few effective agents exist to treat such injury. Ganoderma lucidum Karst, also known as "Reishi" or "Lingzhi", is a mushroom. We previously reported that a water-soluble extract from G. lucidum fungus mycelia (MAK) has anti-inflammatory effects in murine colitis induced by trinitrobenzene sulfonic acid, and induction of granulocyte macrophage colony-stimulating factor (GM-CSF) by MAK may provide anti-inflammatory effects. However, its effects on indomethacin-induced small intestinal injuries are unknown. The present study investigated the preventative effects of MAK via immunological function and the polysaccharides from MAK on indomethacin-induced ileitis in mice. Peritoneal macrophages (PMs) were stimulated in vitro with MAK and adoptively transferred to C57BL/6 mice intraperitoneally, which were then given indomethacin. Intestinal inflammation was evaluated after 24h. We performed in vivo antibody blockade to investigate the preventive role of GM-CSF, which derived from PMs stimulated with MAK. We then used PMs stimulated with MAK pre-treated by pectinase in an adoptive transfer assay to determine the preventive role of polysaccharides. Indomethacin-induced small intestinal injury was inhibited by adoptive transfer of PMs stimulated in vitro with MAK. In this transfer model, pre-treatment with anti-GM-CSF antibody but not with control antibody reversed the improvement of small intestinal inflammation by indomethacin. Pectinase pretreatment impaired the anti-inflammatory effect of MAK. PMs stimulated by MAK appear to contribute to the anti-inflammatory response through GM-CSF in small intestinal injury induced by indomethacin. The polysaccharides may be the components that elicit the anti-inflammatory effect. Copyright © 2017 Elsevier Inc. All rights reserved.

Colonic eosinophilic inflammation in experimental colitis is mediated by Ly6Chigh CCR2+ inflammatory monocyte/macrophage-derived CCL11

PubMed Central

Waddell, Amanda; Ahrens, Richard; Steinbrecher, Kris; Donovan, Burke; Rothenberg, Marc E.; Munitz, Ariel; Hogan, Simon P.

2011-01-01

Recent genome-wide association studies of pediatric IBD have implicated the 17q12 loci, which contains the eosinophil specific chemokine gene CCL11, with early-onset IBD susceptibility. In the present study, we employed a murine model of experimental colitis to define the molecular pathways that regulate CCL11 expression in the chronic intestinal inflammation and pathophysiology of experimental colitis. Bone marrow chimera experiments showed that hematopoietic cell-derived CCL11 is sufficient for CCL11-mediated colonic eosinophilic inflammation. We show that DSS treatment promotes the recruitment of F4/80+CD11b+CCR2+Ly6Chigh inflammatory monocytes into the colon. F4/80+CD11b+CCR2+Ly6Chigh monocytes express CCL11, and their recruitment positively correlated with colonic eosinophilic inflammation. Phenotypic analysis of purified Ly6Chigh intestinal inflammatory MΦs revealed that these cells express both M1- and M2-associated genes, including Il6, Ccl4 and Cxcl2, and Arg1, Chi3l3, Ccl11 and IL-10, respectively. Attenuation of DSS-induced F4/80+CD11b+CCR2+Ly6Chigh monocyte recruitment to the colon in CCR2−/− mice was associated with decreased colonic CCL11 expression, eosinophilic inflammation and DSS-induced histopathology. These studies identify a mechanism for DSS-induced colonic eosinophilia mediated by Ly6ChighCCR2+ inflammatory monocyte/MΦ-derived CCL11. PMID:21498668

Understanding How Commensal Obligate Anaerobic Bacteria Regulate Immune Functions in the Large Intestine

PubMed Central

Maier, Eva; Anderson, Rachel C.; Roy, Nicole C.

2014-01-01

The human gastrointestinal tract is colonised by trillions of commensal bacteria, most of which are obligate anaerobes residing in the large intestine. Appropriate bacterial colonisation is generally known to be critical for human health. In particular, the development and function of the immune system depends on microbial colonisation, and a regulated cross-talk between commensal bacteria, intestinal epithelial cells and immune cells is required to maintain mucosal immune homeostasis. This homeostasis is disturbed in various inflammatory disorders, such as inflammatory bowel diseases. Several in vitro and in vivo studies indicate a role for Faecalibacterium prausnitzii, Bacteroides thetaiotaomicron, Bacteroides fragilis, Akkermansia muciniphila and segmented filamentous bacteria in maintaining intestinal immune homeostasis. These obligate anaerobes are abundant in the healthy intestine but reduced in several inflammatory diseases, suggesting an association with protective effects on human health. However, knowledge of the mechanisms underlying the effects of obligate anaerobic intestinal bacteria remains limited, in part due to the difficulty of co-culturing obligate anaerobes together with oxygen-requiring human epithelial cells. By using novel dual-environment co-culture models, it will be possible to investigate the effects of the unstudied majority of intestinal microorganisms on the human epithelia. This knowledge will provide opportunities for improving human health and reducing the risk of inflammatory diseases. PMID:25545102

Understanding how commensal obligate anaerobic bacteria regulate immune functions in the large intestine.

PubMed

Maier, Eva; Anderson, Rachel C; Roy, Nicole C

2014-12-24

The human gastrointestinal tract is colonised by trillions of commensal bacteria, most of which are obligate anaerobes residing in the large intestine. Appropriate bacterial colonisation is generally known to be critical for human health. In particular, the development and function of the immune system depends on microbial colonisation, and a regulated cross-talk between commensal bacteria, intestinal epithelial cells and immune cells is required to maintain mucosal immune homeostasis. This homeostasis is disturbed in various inflammatory disorders, such as inflammatory bowel diseases. Several in vitro and in vivo studies indicate a role for Faecalibacterium prausnitzii, Bacteroides thetaiotaomicron, Bacteroides fragilis, Akkermansia muciniphila and segmented filamentous bacteria in maintaining intestinal immune homeostasis. These obligate anaerobes are abundant in the healthy intestine but reduced in several inflammatory diseases, suggesting an association with protective effects on human health. However, knowledge of the mechanisms underlying the effects of obligate anaerobic intestinal bacteria remains limited, in part due to the difficulty of co-culturing obligate anaerobes together with oxygen-requiring human epithelial cells. By using novel dual-environment co-culture models, it will be possible to investigate the effects of the unstudied majority of intestinal microorganisms on the human epithelia. This knowledge will provide opportunities for improving human health and reducing the risk of inflammatory diseases.

Ascorbic acid suppresses endotoxemia and NF-κB signaling cascade in alcoholic liver fibrosis in guinea pigs: A mechanistic approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abhilash, P.A.; Harikrishnan, R.; Indira, M., E-mail: indiramadambath@gmail.com

Alcohol consumption increases the small intestinal bacterial overgrowth (SIBO) and intestinal permeability of endotoxin. The endotoxin mediated inflammatory signaling plays a major role in alcoholic liver fibrosis. We evaluated the effect of ascorbic acid (AA), silymarin and alcohol abstention on the alcohol induced endotoxemia and NF-κB activation cascade pathway in guinea pigs (Cavia porcellus). Guinea pigs were administered ethanol at a daily dose of 4 g/kg b.wt for 90 days. After 90 days, ethanol administration was stopped. The ethanol treated animals were divided into abstention, silymarin (250 mg/kg b.wt) and AA (250 mg/kg b.wt) supplemented groups and maintained for 30more » days. The SIBO, intestinal permeability and endotoxin were significantly increased in the ethanol group. The mRNA expressions of intestinal proteins claudin, occludin and zona occludens-1 were significantly decreased in ethanol group. The mRNA levels of inflammatory receptors, activity of IKKβ and the protein expressions of phospho-IκBα, NF-κB, TNF-α, TGF-β{sub 1} and IL-6 were also altered in ethanol group. The expressions of fibrosis markers α-SMA, α{sub 1} (I) collagen and sirius red staining in the liver revealed the induction of fibrosis. But the supplementation of AA could induce greater reduction of ethanol induced SIBO, intestinal barrier defects, NF-κB activation and liver fibrosis than silymarin. The possible mechanism may be the inhibitory effect of AA on SIBO, intestinal barrier defect and IKKβ, which decreased the activation of NF-κB and synthesis of cytokines. This might have led to suppression of HSCs activation and liver fibrosis. - Highlights: • Alcohol increases intestinal bacterial overgrowth and permeability of endotoxin. • Endotoxin mediated inflammation plays a major role in alcoholic liver fibrosis. • Ascorbic acid reduces endotoxemia, NF-κB activation and proinflammatory cytokines. • AA's action is by inhibition of SIBO, IKKβ and alteration of intestinal permeability. • This might have led to suppression of HSCs activation and liver fibrosis.« less

A new therapeutic association to manage relapsing experimental colitis: Doxycycline plus Saccharomyces boulardii.

PubMed

Garrido-Mesa, José; Algieri, Francesca; Rodriguez-Nogales, Alba; Utrilla, Maria Pilar; Rodriguez-Cabezas, Maria Elena; Zarzuelo, Antonio; Ocete, Maria Angeles; Garrido-Mesa, Natividad; Galvez, Julio

2015-07-01

Immunomodulatory antibiotics have been proposed for the treatment of multifactorial conditions such as inflammatory bowel disease. Probiotics are able to attenuate intestinal inflammation, being considered as safe when chronically administered. The aim of the study was to evaluate the anti-inflammatory effects of doxycycline, a tetracycline with immunomodulatory properties, alone and in association with the probiotic Saccharomyces boulardii CNCMI-745. Doxycycline was assayed both in vitro (Caco-2 epithelial cells and RAW 264.7 macrophages) and in vivo, in the trinitrobenzenesulfonic acid (TNBS) model of rat colitis and the dextran sodium sulfate (DSS) model of mouse colitis. In addition, the anti-inflammatory effect of the association of doxycycline and the probiotic was evaluated in vitro and in vivo in a DSS model of reactivated colitis in mice. Doxycycline displayed immunomodulatory activity in vitro, reducing IL-8 production by intestinal epithelial cells and nitric oxide by macrophages. Doxycycline administration to TNBS-colitic rats (5, 10 and 25 mg/kg) ameliorated the intestinal inflammatory process, being its efficacy comparable to that previously showed by minocycline. Doxycycline treatment was also effective in reducing acute intestinal inflammation in the DSS model of mouse colitis. The association of doxycycline and S. boulardii helped managing colitis in a reactivated model of colitis, by reducing intestinal inflammation and accelerating the recovery and attenuating the relapse. This was evidenced by a reduced disease activity index, colonic tissue damage and expression of inflammatory mediators. This study confirms the intestinal anti-inflammatory activity of doxycycline and supports the potential use of its therapeutic association with S. boulardii for the treatment of inflammatory bowel diseases, in which doxycycline is used to induce remission and long term probiotic administration helps to prevent the relapses. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pituitary adenylate cyclase-activating polypeptide ameliorates experimental acute ileitis and extra-intestinal sequelae.

PubMed

Heimesaat, Markus M; Dunay, Ildiko R; Schulze, Silvia; Fischer, André; Grundmann, Ursula; Alutis, Marie; Kühl, Anja A; Tamas, Andrea; Toth, Gabor; Dunay, Miklos P; Göbel, Ulf B; Reglodi, Dora; Bereswill, Stefan

2014-01-01

The neuropeptide Pituitary adenylate cyclase-activating polypeptide (PACAP) plays pivotal roles in immunity and inflammation. So far, potential immune-modulatory properties of PACAP have not been investigated in experimental ileitis. Mice were perorally infected with Toxoplasma (T.) gondii to induce acute ileitis (day 0) and treated daily with synthetic PACAP38 from day 1 to 6 post infection (p.i.; prophylaxis) or from day 4 to 6 p.i. (therapy). Whereas placebo-treated control mice suffered from acute ileitis at day 7 p.i. and succumbed to infection, intestinal immunopathology was ameliorated following PACAP prophylaxis. PACAP-treated mice exhibited increased abundance of small intestinal FOXP3+ cells, but lower numbers of ileal T lymphocytes, neutrophils, monocytes and macrophages, which was accompanied by less ileal expression of pro-inflammatory cytokines such as IL-23p19, IL-22, IFN-γ, and MCP-1. Furthermore, PACAP-treated mice displayed higher anti-inflammatory IL-4 concentrations in mesenteric lymph nodes and liver and higher systemic anti-inflammatory IL-10 levels in spleen and serum as compared to control animals at day 7 p.i. Remarkably, PACAP-mediated anti-inflammatory effects could also be observed in extra-intestinal compartments as indicated by reduced pro-inflammatory mediator levels in spleen (TNF-α, nitric oxide) and liver (TNF-α, IFN-γ, MCP-1, IL-6) and less severe histopathological sequelae in lungs and kidneys following prophylactic PACAP treatment. Strikingly, PACAP prolonged survival of T. gondii infected mice in a time-of-treatment dependent manner. Synthetic PACAP ameliorates acute small intestinal inflammation and extra-intestinal sequelae by down-regulating Th1-type immunopathology, reducing oxidative stress and up-regulating anti-inflammatory cytokine responses. These findings provide novel potential treatment options of inflammatory bowel diseases.

Effect of Wild-Type Shigella Species and Attenuated Shigella Vaccine Candidates on Small Intestinal Barrier Function, Antigen Trafficking, and Cytokine Release

PubMed Central

Fiorentino, Maria; Levine, Myron M.

2014-01-01

Bacterial dysentery due to Shigella species is a major cause of morbidity and mortality worldwide. The pathogenesis of Shigella is based on the bacteria's ability to invade and replicate within the colonic epithelium, resulting in severe intestinal inflammatory response and epithelial destruction. Although the mechanisms of pathogenesis of Shigella in the colon have been extensively studied, little is known on the effect of wild-type Shigella on the small intestine and the role of the host response in the development of the disease. Moreover, to the best of our knowledge no studies have described the effects of apically administered Shigella flexneri 2a and S. dysenteriae 1 vaccine strains on human small intestinal enterocytes. The aim of this study was to assess the coordinated functional and immunological human epithelial responses evoked by strains of Shigella and candidate vaccines on small intestinal enterocytes. To model the interactions of Shigella with the intestinal mucosa, we apically exposed monolayers of human intestinal Caco2 cells to increasing bacterial inocula. We monitored changes in paracellular permeability, examined the organization of tight-junctions and the pro-inflammatory response of epithelial cells. Shigella infection of Caco2 monolayers caused severe mucosal damage, apparent as a drastic increase in paracellular permeability and disruption of tight junctions at the cell-cell boundary. Secretion of pro-inflammatory IL-8 was independent of epithelial barrier dysfunction. Shigella vaccine strains elicited a pro-inflammatory response without affecting the intestinal barrier integrity. Our data show that wild-type Shigella infection causes a severe alteration of the barrier function of a small intestinal cell monolayer (a proxy for mucosa) and might contribute (along with enterotoxins) to the induction of watery diarrhea. Diarrhea may be a mechanism by which the host attempts to eliminate harmful bacteria and transport them from the small to the large intestine where they invade colonocytes inducing a strong inflammatory response. PMID:24416363

Functional relevance of intestinal epithelial cells in inflammatory bowel disease.

PubMed

Okamoto, Ryuichi; Watanabe, Mamoru

2016-01-01

The intestinal epithelium constitutes a physical barrier between inner and outer side of our body. It also functions as a "hub" which connects factors that determine the development of inflammatory bowel disease, such as microbiota, susceptibility genes, and host immune response. Accordingly, recent studies have implicated and further featured the role of intestinal epithelial cell dysfunction in the pathophysiology of inflammatory bowel disease. For example, mucin producing goblet cells are usually "depleted" in ulcerative colitis patients. Studies have shown that those goblet cells exhibit various immune-regulatory functions in addition to mucin production, such as antigen presentation or cytokine production. Paneth cells are another key cell lineage that has been deeply implicated in the pathophysiology of Crohn's disease. Several susceptibility genes for Crohn's disease may lead to impairment of anti-bacterial peptide production and secretion by Paneth cells. Also, other susceptibility genes may determine the survival of Paneth cells, which leads to reduced Paneth cell function in the patient small intestinal mucosa. Further studies may reveal other unexpected roles of the intestinal epithelium in the pathophysiology of inflammatory bowel disease, and may help to develop alternative therapies targeted to intestinal epithelial cell functions.

In vitro and in vivo protective effect of arginine against lipopolysaccharide induced inflammatory response in the intestine of juvenile Jian carp (Cyprinus carpio var. Jian).

PubMed

Jiang, Jun; Shi, Dan; Zhou, Xiao-Qiu; Hu, Yi; Feng, Lin; Liu, Yang; Jiang, Wei-Dan; Zhao, Ye

2015-02-01

The present study was designed to assess the possible protective effects of arginine (Arg) against lipopolysaccharide (LPS) induced inflammatory response in juvenile Jian carp (Cyprinus carpio var. Jian) in vivo and in enterocytes in vitro. Firstly, inflammatory response was established by exposing enterocytes to different concentrations of LPS for 24 h. Secondly, the protective effects of Arg against subsequent LPS exposure were studied in enterocytes. Finally, we investigated whether dietary Arg supplementation could attenuate immune challenge induced by LPS in vivo. The result indicated that 10 mg/L LPS could induced inflammatory response in enterocytes. Cells exposed to LPS (10-30 mg/L) alone for 24 h resulted in a significant increase in lactate dehydrogenase release (LDH) (P < 0.05). The cell viability, protein content, alkaline phosphatase activity were decreased by LPS (P < 0.05). Moreover, LPS exposure significantly increased TNF-α, IL-1β, and IL-6 mRNA expression in vitro (P < 0.05). However, pre-treatment with Arg remarkably prevented the increase of TNF-α, IL-1β, and IL-6 by inhibiting the excessive activation of TLR4-Myd88 signaling pathway through down-regulating TLR4, Myd88, NFκB p65, and MAPK p38 mRNA expression (P < 0.05). Interestingly, the experiment in vivo showed that Arg pre-supplementation could attenuate immune challenge induced by LPS via TLR4-Myd88 signaling pathway, and thus protect fish against LPS-induced inflammatory response. In conclusion, all of these results indicated pre-supplementation with Arg decreased LPS induced immune damage and regulated TLR4-Myd88 signaling pathway in juvenile Jian carp in vivo and in enterocytes in vitro. Copyright © 2014 Elsevier Ltd. All rights reserved.

Fecal Microbiota and Metabolome in a Mouse Model of Spontaneous Chronic Colitis: Relevance to Human Inflammatory Bowel Disease.

PubMed

Robinson, Ainsley M; Gondalia, Shakuntla V; Karpe, Avinash V; Eri, Rajaraman; Beale, David J; Morrison, Paul D; Palombo, Enzo A; Nurgali, Kulmira

2016-12-01

Dysbiosis of the gut microbiota may be involved in the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms underlying the role of the intestinal microbiome and metabolome in IBD onset and its alteration during active treatment and recovery remain unknown. Animal models of chronic intestinal inflammation with similar microbial and metabolomic profiles would enable investigation of these mechanisms and development of more effective treatments. Recently, the Winnie mouse model of colitis closely representing the clinical symptoms and characteristics of human IBD has been developed. In this study, we have analyzed fecal microbial and metabolomic profiles in Winnie mice and discussed their relevance to human IBD. The 16S rRNA gene was sequenced from fecal DNA of Winnie and C57BL/6 mice to define operational taxonomic units at ≥97% similarity threshold. Metabolomic profiling of the same fecal samples was performed by gas chromatography-mass spectrometry. Composition of the dominant microbiota was disturbed, and prominent differences were evident at all levels of the intestinal microbiome in fecal samples from Winnie mice, similar to observations in patients with IBD. Metabolomic profiling revealed that chronic colitis in Winnie mice upregulated production of metabolites and altered several metabolic pathways, mostly affecting amino acid synthesis and breakdown of monosaccharides to short chain fatty acids. Significant dysbiosis in the Winnie mouse gut replicates many changes observed in patients with IBD. These results provide justification for the suitability of this model to investigate mechanisms underlying the role of intestinal microbiota and metabolome in the pathophysiology of IBD.

Resiniferatoxin lowers TNF-α, NO and PGE2 in the intestinal phase and the parasite burden in the muscular phase of Trichinella spiralis infection.

PubMed

Muñoz-Carrillo, J L; Muñoz-Escobedo, J J; Maldonado-Tapia, C H; Chávez-Ruvalcaba, F; Moreno-García, M A

2017-01-01

During the course of infection with Trichinella spiralis, an inflammatory response is triggered at the intestinal level in the host, playing a crucial role in the expulsion and elimination of the parasite. However, several studies have demonstrated that this inflammatory response is harmful to the host; hence, the importance of studying molecules with therapeutic potential like resiniferatoxin, which is known to have an anti-inflammatory effect both in vitro and in vivo. In this article, we evaluated the anti-inflammatory activity of resiniferatoxin during the intestinal phase of T. spiralis infection by quantitatively determining the levels of TNF-α, NO and PGE 2 as well as the percentage of eosinophils in the blood and intestinal pathology. In addition, parasite burden was determined during the muscle infection. Our results show that resiniferatoxin lowered the serum levels of TNF-α, NO and PGE 2 , as well as the percentage of eosinophils in the blood and intestinal pathology during the intestinal infection. Moreover, resiniferatoxin also lowered the parasite burden in muscle, resulting in a reduction of the humoral response (IgG) associated to treatment with resiniferatoxin. These findings suggest a potential therapeutic use of the anti-inflammatory effect of resiniferatoxin, which also contributes to host defence against the challenge of T. spiralis infection. © 2016 John Wiley & Sons Ltd.

Bovine Intestinal Alkaline Phosphatase Reduces Inflammation After Induction of Acute Myocardial Infarction in Mice

PubMed Central

Fiechter, Danielle; Kats, Suzanne; Brands, Ruud; van Middelaar, Ben; Pasterkamp, Gerard; de Kleijn, Dominique; Seinen, Willem

2011-01-01

Background There has been increasing evidence suggesting that lipopolysaccharide or endotoxin may be an important activator of the innate immune system after acute myocardial infarction. Bovine intestinal alkaline phosphatase reduces inflammation in several endotoxin mediated diseases by dephosphorylation of the lipid A moiety of lipopolysaccharide. The aim of this study was to investigate the effect of bovine intestinal alkaline phosphatase on reducing inflammation after acute myocardial infarction. Methods Just before permanent ligation of the left anterior descending coronary (LAD) artery to induce acute myocardial infarction in Balb/c mice, bovine intestinal alkaline phosphatase (bIAP) was administrated intravenously. After 4 hours, mice were sacrificed and the inflammatory response was assessed. Acute myocardial infarction induced the production of different cytokines, which were measured in blood. Results Treatment with bovine intestinal alkaline phosphatase resulted in a significant reduction of the pro-inflammatory cytokines IL-6, IL-1β and the chymase mouse mast cell protease-1. No difference in the production of the anti-inflammatory cytokine IL-10 was observed between the control group and the bovine intestinal alkaline phosphatase treated group. Conclusion In a mouse model of permanent LAD coronary artery ligation, bIAP diminishes the pro-inflammatory responses but does not have an effect on the anti-inflammatory response in the acute phase after acute myocardial infarction. PMID:28357012

Chemical Composition and Immuno-Modulatory Effects of Urtica dioica L. (Stinging Nettle) Extracts.

PubMed

Francišković, Marina; Gonzalez-Pérez, Raquel; Orčić, Dejan; Sánchez de Medina, Fermín; Martínez-Augustin, Olga; Svirčev, Emilija; Simin, Nataša; Mimica-Dukić, Neda

2017-08-01

The purpose of this work was to determine the chemical profile of stinging nettle and to provide an insight into the mechanisms by which it ameliorates the immune response. Qualitative and quantitative liquid chromatography tandem mass spectrometry analyses indicated that phenolic acids (5-O-caffeoylquinic acid as dominant) and flavonol glycosides (rutin, isoquercitrin, and kaempferol 3-O-glucoside) are present in the aerial parts, while lignans (secoisolariciresinol, 9,9'-bisacetyl-neo-olivil and their glucosides) were detected in the root. Herb and root extracts expressed selective inhibition toward cyclooxygenase and lipoxygenase branches in human platelets: root extracts were better at inhibiting thromboxane production, while herb extracts were more specific toward inhibition of 12-lipoxygenase pathway. Stinging nettle extracts mildly increased monocyte chemoattractant protein-1 and growth-related oncogene release from nonstimulated intestinal epithelial cells, stimulating MyD88/NF-κB/p38 signaling, hence preserving the epithelial integrity and enhancing intestinal steady-state defense. Additionally, root extract reduced lipopolysaccharide-induced monocyte chemoattractant protein-1/growth-related oncogene secretion and cyclooxygenase-2 expression in intestinal epithelial cells, thus showing the potential protective effect against tissue damage caused by inflammation processes. These observations suggest that stinging nettle is an interesting candidate for the development of phytopharmaceuticals or dietary supplements for cotreatment of various inflammatory diseases, particularly inflammatory bowel diseases. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Transglutaminase 2 expression is enhanced synergistically by interferon-γ and tumour necrosis factor-α in human small intestine.

PubMed

Bayardo, M; Punzi, F; Bondar, C; Chopita, N; Chirdo, F

2012-04-01

Transglutaminase 2 (TG2) is expressed ubiquitously, has multiple physiological functions and has also been associated with inflammatory diseases, neurodegenerative disorders, autoimmunity and cancer. In particular, TG2 is expressed in small intestine mucosa where it is up-regulated in active coeliac disease (CD). The aim of this work was to investigate the induction of TG2 expression by proinflammatory cytokines [interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-α, interferon (IFN)-γ and IL-15] and the signalling pathways involved, in human epithelial and monocytic cells and in intestinal tissue from controls and untreated CD patients. Here we report that IFN-γ was the most potent inducer of TG2 expression in the small intestinal mucosa and in four [Caco-2, HT-29, Calu-6 and human acute monocytic leukaemia cell line (THP-1)] of five cell lines tested. The combination of TNF-α and IFN-γ produced a strong synergistic effect. The use of selective inhibitors of signalling pathways revealed that induction of TG2 by IFN-γ was mediated by phosphoinositide 3-kinase (PI3K), while c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) were required for TNF-α activation. Quantitative polymerase chain reaction (PCR), flow cytometry and Western blot analysis showed that TG2 expression was blocked completely when stimulation by either TNF-α or IFN-γ was performed in the presence of nuclear factor (NF)-κB inhibitors (sulphasalazine and BAY-117082). TG2 was up-regulated substantially by TNF-α and IFN-γ in intestinal mucosa in untreated CD compared with controls. This study shows that IFN-γ, a dominant cytokine in intestinal mucosa in active CD, is the most potent inducer of TG2, and synergism with TNF-α may contribute to exacerbate the pathogenic mechanism of CD. Selective inhibition of signalling pathways may be of therapeutic benefit. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.

Postinflammatory visceral sensitivity and pain mechanisms.

PubMed

Vergnolle, N

2008-05-01

The inflammatory reaction is normally tightly regulated, and as soon as the original insult has been cleared, a resolution phase starts that aims at leading the tissues back to a normal physiological state. However, after intestinal inflammation, a number of patients develop postinflammatory hypersensitivity symptoms, which can be defined as an excessive sensitivity to gut nociceptive stimulation. The pain experienced by those patients has been largely studied in the context of postinfectious intestinal diseases. The mechanisms of postinflammatory persistent visceral pain involve peripheral and central neuroplastic changes, low-grade chronic inflammation that sensitizes visceral afferent pathways and sensitization of non-neuronal resident cells of the gut. Several molecular determinants such as neurokinins, serotonin, proteases and voltage-gated ion channels seem to play a significant role in the control of postinflammatory visceral sensation. This review tries to give insights into the mechanisms of persistent visceral pain following the resolution of intestinal inflammation and tries to identify what needs to be done to further advance the field of postinflammatory hypersensitivity clinical management.

Intestinal alkaline phosphatase inhibits the proinflammatory nucleotide uridine diphosphate

PubMed Central

Hamarneh, Sulaiman R.; Mohamed, Mussa M. Rafat; Ramasamy, Sundaram; Yammine, Halim; Patel, Palak; Kaliannan, Kanakaraju; Alam, Sayeda N.; Muhammad, Nur; Moaven, Omeed; Teshager, Abeba; Malo, Nondita S.; Narisawa, Sonoko; Millán, José Luis; Warren, H. Shaw; Hohmann, Elizabeth; Malo, Madhu S.; Hodin, Richard A.

2013-01-01

Uridine diphosphate (UDP) is a proinflammatory nucleotide implicated in inflammatory bowel disease. Intestinal alkaline phosphatase (IAP) is a gut mucosal defense factor capable of inhibiting intestinal inflammation. We used the malachite green assay to show that IAP dephosphorylates UDP. To study the anti-inflammatory effect of IAP, UDP or other proinflammatory ligands (LPS, flagellin, Pam3Cys, or TNF-α) in the presence or absence of IAP were applied to cell cultures, and IL-8 was measured. UDP caused dose-dependent increase in IL-8 release by immune cells and two gut epithelial cell lines, and IAP treatment abrogated IL-8 release. Costimulation with UDP and other inflammatory ligands resulted in a synergistic increase in IL-8 release, which was prevented by IAP treatment. In vivo, UDP in the presence or absence of IAP was instilled into a small intestinal loop model in wild-type and IAP-knockout mice. Luminal contents were applied to cell culture, and cytokine levels were measured in culture supernatant and intestinal tissue. UDP-treated luminal contents induced more inflammation on target cells, with a greater inflammatory response to contents from IAP-KO mice treated with UDP than from WT mice. Additionally, UDP treatment increased TNF-α levels in intestinal tissue of IAP-KO mice, and cotreatment with IAP reduced inflammation to control levels. Taken together, these studies show that IAP prevents inflammation caused by UDP alone and in combination with other ligands, and the anti-inflammatory effect of IAP against UDP persists in mouse small intestine. The benefits of IAP in intestinal disease may be partly due to inhibition of the proinflammatory activity of UDP. PMID:23306083

Substance-P alleviates dextran sulfate sodium-induced intestinal damage by suppressing inflammation through enrichment of M2 macrophages and regulatory T cells.

PubMed

Hong, Hyun Sook; Hwang, Dae Yeon; Park, Ju Hyeong; Kim, Suna; Seo, Eun Jung; Son, Youngsook

2017-02-01

Intestinal inflammation alters immune responses in the mucosa and destroys colon architecture, leading to serious diseases such as inflammatory bowel disease (IBD). Thus, regulation of inflammation is regarded as the ultimate therapy for intestinal disease. Substance-P (SP) is known to mediate proliferation, migration, and cellular senescence in a variety of cells. SP was found to mobilize stem cells from bone marrow to the site of injury and to suppress inflammatory responses by inducing regulatory T cells (Tregs) and M2 macrophages. In this study, we explored the effects of SP in a dextran sodium sulfate (DSS)-induced intestine damage model. The effects of SP were evaluated by analyzing crypt structures, proliferating cells within the colon, cytokine secretion profiles, and immune cells population in the spleen/mesenteric lymph nodes in vivo. DSS treatment provoked an inflammatory response with loss of crypts in the intestines of experimental mice. This response was associated with high levels of inflammatory cytokines such as TNF-α and IL-17, and low levels of Tregs and M2 macrophages, leading to severely damaged tissue structure. However, SP treatment inhibited inflammatory responses by modulating cytokine production as well as the balance of Tregs/Th 17 cells and the M1/M2 transition in lymphoid organs, leading to accelerated tissue repair. Collectively, our data indicate that SP can promote the regeneration of tissue following damage by DSS treatment, possibly by modulating immune response. Our results propose SP as a candidate therapeutic for intestine-related inflammatory diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Interplay between inflammation, immune system and neuronal pathways: Effect on gastrointestinal motility

PubMed Central

De Winter, Benedicte Y; De Man, Joris G

2010-01-01

Sepsis is a systemic inflammatory response representing the leading cause of death in critically ill patients, mostly due to multiple organ failure. The gastrointestinal tract plays a pivotal role in the pathogenesis of sepsis-induced multiple organ failure through intestinal barrier dysfunction, bacterial translocation and ileus. In this review we address the role of the gastrointestinal tract, the mediators, cell types and transduction pathways involved, based on experimental data obtained from models of inflammation-induced ileus and (preliminary) clinical data. The complex interplay within the gastrointestinal wall between mast cells, residential macrophages and glial cells on the one hand, and neurons and smooth muscle cells on the other hand, involves intracellular signaling pathways, Toll-like receptors and a plethora of neuroactive substances such as nitric oxide, prostaglandins, cytokines, chemokines, growth factors, tryptases and hormones. Multidirectional signaling between the different components in the gastrointestinal wall, the spinal cord and central nervous system impacts inflammation and its consequences. We propose that novel therapeutic strategies should target inflammation on the one hand and gastrointestinal motility, gastrointestinal sensitivity and even pain signaling on the other hand, for instance by impeding afferent neuronal signaling, by activation of the vagal anti-inflammatory pathway or by the use of pharmacological agents such as ghrelin and ghrelin agonists or drugs interfering with the endocannabinoid system. PMID:21105185

Extracellular nucleotides inhibit oxalate transport by human intestinal Caco-2-BBe cells through PKC-δ activation

PubMed Central

Amin, Ruhul; Sharma, Sapna; Ratakonda, Sireesha

2013-01-01

Nephrolithiasis remains a major health problem in Western countries. Seventy to 80% of kidney stones are composed of calcium oxalate, and small changes in urinary oxalate affect risk of kidney stone formation. Intestinal oxalate secretion mediated by the anion exchanger SLC26A6 plays an essential role in preventing hyperoxaluria and calcium oxalate nephrolithiasis, indicating that understanding the mechanisms regulating intestinal oxalate transport is critical for management of hyperoxaluria. Purinergic signaling modulates several intestinal processes through pathways including PKC activation, which we previously found to inhibit Slc26a6 activity in mouse duodenal tissue. We therefore examined whether purinergic stimulation with ATP and UTP affects oxalate transport by human intestinal Caco-2-BBe (C2) cells. We measured [14C]oxalate uptake in the presence of an outward Cl− gradient as an assay of Cl−/oxalate exchange activity, ≥50% of which is mediated by SLC26A6. We found that ATP and UTP significantly inhibited oxalate transport by C2 cells, an effect blocked by the PKC inhibitor Gö-6983. Utilizing pharmacological agonists and antagonists, as well as PKC-δ knockdown studies, we observed that ATP inhibits oxalate transport through the P2Y2 receptor, PLC, and PKC-δ. Biotinylation studies showed that ATP inhibits oxalate transport by lowering SLC26A6 surface expression. These findings are of potential relevance to pathophysiology of inflammatory bowel disease-associated hyperoxaluria, where supraphysiological levels of ATP/UTP are expected and overexpression of the P2Y2 receptor has been reported. We conclude that ATP and UTP inhibit oxalate transport by lowering SLC26A6 surface expression in C2 cells through signaling pathways including the P2Y2 purinergic receptor, PLC, and PKC-δ. PMID:23596171

The Interplay Between Fiber and the Intestinal Microbiome in the Inflammatory Response12

PubMed Central

Kuo, Shiu-Ming

2013-01-01

Fiber intake is critical for optimal health. This review covers the anti-inflammatory roles of fibers using results from human epidemiological observations, clinical trials, and animal studies. Fiber has body weight–related anti-inflammatory activity. With its lower energy density, a diet high in fiber has been linked to lower body weight, alleviating obesity-induced chronic inflammation evidenced by reduced amounts of inflammatory markers in human and animal studies. Body weight–unrelated anti-inflammatory activity of fiber has also been extensively studied in animal models in which the type and amount of fiber intake can be closely monitored. Fermentable fructose-, glucose-, and galactose-based fibers as well as mixed fibers have shown systemic and local intestinal anti-inflammatory activities when plasma inflammatory markers and tissue inflammation were examined. Similar anti-inflammatory activities have also been demonstrated in some human studies that controlled total fiber intake. The anti-inflammatory activities of synbiotics (probiotics plus fiber) were reviewed as well, but there was no convincing evidence indicating higher efficacy of synbiotics compared with that of fiber alone. Adverse effects have not been observed with the amount of fiber intake or supplementation used in studies, although patients with Crohn’s disease may be more sensitive to inulin intake. Several possible mechanisms that may mediate the body weight–unrelated anti-inflammatory activity of fibers are discussed based on the in vitro and in vivo evidence. Fermentable fibers are known to affect the intestinal microbiome. The immunomodulatory role of the intestinal microbiome and/or microbial metabolites could contribute to the systemic and local anti-inflammatory activities of fibers. PMID:23319119

Breast Milk and Solid Food Shaping Intestinal Immunity

PubMed Central

Parigi, Sara M.; Eldh, Maria; Larssen, Pia; Gabrielsson, Susanne; Villablanca, Eduardo J.

2015-01-01

After birth, the intestinal immune system enters a critical developmental stage, in which tolerogenic and pro-inflammatory cells emerge to contribute to the overall health of the host. The neonatal health is continuously challenged by microbial colonization and food intake, first in the form of breast milk or formula and later in the form of solid food. The microbiota and dietary compounds shape the newborn immune system, which acquires the ability to induce tolerance against innocuous antigens or induce pro-inflammatory immune responses against pathogens. Disruption of these homeostatic mechanisms might lead to undesired immune reactions, such as food allergies and inflammatory bowel disease. Hence, a proper education and maturation of the intestinal immune system is likely important to maintain life-long intestinal homeostasis. In this review, the most recent literature regarding the effects of dietary compounds in the development of the intestinal immune system are discussed. PMID:26347740

Indole compounds may be promising medicines for ulcerative colitis.

PubMed

Sugimoto, Shinya; Naganuma, Makoto; Kanai, Takanori

2016-09-01

Indole compounds are extracted from indigo plants and have been used as blue or purple dyes for hundreds of years. In traditional Chinese medicine, herbal agents in combination with Qing-Dai (also known as indigo naturalis) have been used to treat patients with ulcerative colitis (UC) and to remedy inflammatory conditions. Recent studies have noted that indole compounds can be biosynthesized from tryptophan metabolites produced by various enzymes derived from intestinal microbiota. In addition to their action on indole compounds, the intestinal microbiota produce various tryptophan metabolites that mediate critical functions through distinct pathways and enzymes. Furthermore, some indole compounds, such as indigo and indirubin, act as ligands for the aryl hydrocarbon receptor. This signaling pathway stimulates mucosal type 3 innate lymphoid cells to produce interleukin-22, which induces antimicrobial peptide and tight junction molecule production, suggesting a role for indole compounds during the mucosal healing process. Thus, indole compounds may represent a novel treatment strategy for UC patients. In this review, we describe the origin and function of this indole compound-containing Chinese herb, as well as the drug development of indole compounds.

β2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses.

PubMed

Moriyama, Saya; Brestoff, Jonathan R; Flamar, Anne-Laure; Moeller, Jesper B; Klose, Christoph S N; Rankin, Lucille C; Yudanin, Naomi A; Monticelli, Laurel A; Putzel, Gregory Garbès; Rodewald, Hans-Reimer; Artis, David

2018-03-02

The type 2 inflammatory response is induced by various environmental and infectious stimuli. Although recent studies identified group 2 innate lymphoid cells (ILC2s) as potent sources of type 2 cytokines, the molecular pathways controlling ILC2 responses are incompletely defined. Here we demonstrate that murine ILC2s express the β 2 -adrenergic receptor (β 2 AR) and colocalize with adrenergic neurons in the intestine. β 2 AR deficiency resulted in exaggerated ILC2 responses and type 2 inflammation in intestinal and lung tissues. Conversely, β 2 AR agonist treatment was associated with impaired ILC2 responses and reduced inflammation in vivo. Mechanistically, we demonstrate that the β 2 AR pathway is a cell-intrinsic negative regulator of ILC2 responses through inhibition of cell proliferation and effector function. Collectively, these data provide the first evidence of a neuronal-derived regulatory circuit that limits ILC2-dependent type 2 inflammation. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Role of non-steroidal anti-inflammatory drugs on intestinal permeability and nonalcoholic fatty liver disease.

PubMed

Utzeri, Erika; Usai, Paolo

2017-06-14

The use of non-steroidal anti-inflammatory drugs (NSAIDs) is widespread worldwide thanks to their analgesic, anti-inflammatory and antipyretic effects. However, even more attention is placed upon the recurrence of digestive system complications in the course of their use. Recent data suggests that the complications of the lower gastro-intestinal tract may be as frequent and severe as those of the upper tract. NSAIDs enteropathy is due to enterohepatic recycling of the drugs resulting in a prolonged and repeated exposure of the intestinal mucosa to the compound and its metabolites. Thus leading to so-called topical effects, which, in turn, lead to an impairment of the intestinal barrier. This process determines bacterial translocation and toxic substances of intestinal origin in the portal circulation, leading to an endotoxaemia. This condition could determine a liver inflammatory response and might promote the development of non-alcoholic steatohepatitis, mostly in patients with risk factors such as obesity, metabolic syndrome and a high fat diet, which may induce a small intestinal bacterial overgrowth and dysbiosis. This alteration of gut microbiota may contribute to nonalcoholic fatty liver disease and its related disorders in two ways: firstly causing a malfunction of the tight junctions that play a critical role in the increase of intestinal permeability, and then secondly leading to the development of insulin resistance, body weight gain, lipogenesis, fibrogenesis and hepatic oxidative stress.

Role of non-steroidal anti-inflammatory drugs on intestinal permeability and nonalcoholic fatty liver disease

PubMed Central

Utzeri, Erika; Usai, Paolo

2017-01-01

The use of non-steroidal anti-inflammatory drugs (NSAIDs) is widespread worldwide thanks to their analgesic, anti-inflammatory and antipyretic effects. However, even more attention is placed upon the recurrence of digestive system complications in the course of their use. Recent data suggests that the complications of the lower gastro-intestinal tract may be as frequent and severe as those of the upper tract. NSAIDs enteropathy is due to enterohepatic recycling of the drugs resulting in a prolonged and repeated exposure of the intestinal mucosa to the compound and its metabolites. Thus leading to so-called topical effects, which, in turn, lead to an impairment of the intestinal barrier. This process determines bacterial translocation and toxic substances of intestinal origin in the portal circulation, leading to an endotoxaemia. This condition could determine a liver inflammatory response and might promote the development of non-alcoholic steatohepatitis, mostly in patients with risk factors such as obesity, metabolic syndrome and a high fat diet, which may induce a small intestinal bacterial overgrowth and dysbiosis. This alteration of gut microbiota may contribute to nonalcoholic fatty liver disease and its related disorders in two ways: firstly causing a malfunction of the tight junctions that play a critical role in the increase of intestinal permeability, and then secondly leading to the development of insulin resistance, body weight gain, lipogenesis, fibrogenesis and hepatic oxidative stress. PMID:28652650

KLF6 contributes to myeloid cell plasticity in the pathogenesis of intestinal inflammation

PubMed Central

Goodman, Wendy A.; Omenetti, Sara; Date, Dipali; Di Martino, Luca; De Salvo, Carlo; Kim, Gun-Dong; Chowdhry, Saleem; Bamias, Giorgos; Cominelli, Fabio; Pizarro, Theresa T.; Mahabeleshwar, Ganapati H.

2016-01-01

Inflammatory bowel disease (IBD) is associated with dysregulated macrophage responses, such that quiescent macrophages acquire a pro-inflammatory activation state and contribute to chronic intestinal inflammation. The transcriptional events governing macrophage activation and gene expression in the context of chronic inflammation such as IBD remain incompletely understood. Here, we identify Kruppel-like transcription factor-6 (KLF6) as a critical regulator of pathogenic myeloid cell activation in human and experimental IBD. We found that KLF6 was significantly upregulated in myeloid cells and intestinal tissue from IBD patients and experimental models of IBD, particularly in actively inflamed regions of the colon. Using complementary gain- and loss-of-function studies, we observed that KLF6 promotes pro-inflammatory gene expression through enhancement of NFκB signaling, while simultaneously suppressing anti-inflammatory gene expression through repression of STAT3 signaling. To study the in vivo role of myeloid KLF6, we treated myeloid-specific KLF6-knockout mice (Mac-KLF6-KO) with dextran sulfate-sodium (DSS) and found that Mac-KLF6-KO mice were protected against chemically-induced colitis; this highlights the central role of myeloid KLF6 in promoting intestinal inflammation. Collectively, our results point to a novel gene regulatory program underlying pathogenic, pro-inflammatory macrophage activation in the setting of chronic intestinal inflammation. PMID:26838049

Netrin-1 guides inflammatory cell migration to control mucosal immune responses during intestinal inflammation

PubMed Central

Aherne, Carol M.; Collins, Colm B.; Eltzschig, Holger K.

2013-01-01

The intestinal epithelium is a dynamic barrier playing an active role in intestinal homeostasis and inflammation. Intestinal barrier function is dysregulated during inflammatory bowel disease (IBD), with epithelial cells playing a significant part in generating an inflammatory milieu through the release of signals that attract leukocytes to the intestinal lamina propria. However, it is increasingly appreciated that the intestinal epithelium mediates a counterbalancing response to drive resolution. Drawing analogies with neuronal development, where the balance of chemoattractive and chemorepellent signals is key to directed neuronal movement it has been postulated that such secreted cues play a role in leukocyte migration. Netrin-1 is one of the best-described neuronal guidance molecules, which has been shown to play a significant role in directed migration of leukocytes. Prior to our study the potential role of netrin-1 in IBD was poorly characterized. We defined netrin-1 as an intestinal epithelial-derived protein capable of limiting neutrophil recruitment to attenuate acute colitis. Our study highlights that the intestinal epithelium releases factors during acute inflammation that are responsible for fine-tuning the immune response. Exploration of these epithelial-mediated protective mechanisms will shed light on the complexity of the intestinal epithelial barrier in health and disease. PMID:24665394

Lactobacillus johnsonii ameliorates intestinal, extra-intestinal and systemic pro-inflammatory immune responses following murine Campylobacter jejuni infection.

PubMed

Bereswill, Stefan; Ekmekciu, Ira; Escher, Ulrike; Fiebiger, Ulrike; Stingl, Kerstin; Heimesaat, Markus M

2017-05-18

Campylobacter jejuni infections are progressively increasing worldwide. Probiotic treatment might open novel therapeutic or even prophylactic approaches to combat campylobacteriosis. In the present study secondary abiotic mice were generated by broad-spectrum antibiotic treatment and perorally reassociated with a commensal murine Lactobacillus johnsonii strain either 14 days before (i.e. prophylactic regimen) or 7 days after (i.e. therapeutic regimen) peroral C. jejuni strain 81-176 infection. Following peroral reassociation both C. jejuni and L. johnsonii were able to stably colonize the murine intestinal tract. Neither therapeutic nor prophylactic L. johnsonii application, however, could decrease intestinal C. jejuni burdens. Notably, C. jejuni induced colonic apoptosis could be ameliorated by prophylactic L. johnsonii treatment, whereas co-administration of L. johnsonii impacted adaptive (i.e. T and B lymphocytes, regulatory T cells), but not innate (i.e. macrophages and monocytes) immune cell responses in the intestinal tract. Strikingly, C. jejuni induced intestinal, extra-intestinal and systemic secretion of pro-inflammatory mediators (such as IL-6, MCP-1, TNF and nitric oxide) could be alleviated by peroral L. johnsonii challenge. In conclusion, immunomodulatory probiotic species might offer valuable strategies for prophylaxis and/or treatment of C. jejuni induced intestinal, extra-intestinal as well as systemic pro-inflammatory immune responses in vivo.

Exercise training reduces inflammatory mediators in the intestinal tract of healthy older adult mice.

PubMed

Packer, Nicholas; Hoffman-Goetz, Laurie

2012-06-01

Aging is associated with increased intestinal inflammation and elevated risk of chronic diseases including inflammatory bowel diseases and colon cancer; many epidemiologic studies show that regular exercise reduces risk. This study examined the effects of long-term voluntary exercise on inflammatory mediators expressed in the intestine of older (15-16 months), healthy C57BL/6 mice. Animals were assigned to four months of freewheel running (WR; n = 20) or to a "sedentary" no wheel running (NWR; n = 20) control group. Intestinal lymphocytes were harvested and analysed for expression of (1) pro-inflammatory (TNF-α, IL-1β) and pleiotropic (IL-6) cytokines, and (2) pro-(caspase-3/-7) and anti-(Bcl-2) apoptotic proteins. Training was confirmed by skeletal muscle enzyme activity; stress was assessed by plasma 8-iso-PGF(2α) and corticosterone. The WR mice had a lower expression of TNF-α, caspase-7, and 8-isoprostanes (p < .05) compared to sedentary controls, suggesting that long-term exercise may "protect" the bowel by reducing inflammatory cytokine and apoptotic protein expression.

Helicobacter pylori infection and inflammatory bowel disease: Is there a link?

PubMed Central

Papamichael, Konstantinos; Konstantopoulos, Panagiotis; Mantzaris, Gerassimos J

2014-01-01

Helicobacter pylori (H. pylori) infection is one of the most widely spread infectious diseases in humans. It can cause chronic gastritis, peptic ulcer disease and gastric malignancies and has been associated with extra-gastric disorders. H. pylori elicit a chronic systemic inflammatory response which, under certain conditions, may trigger autoimmune reactions and may be implicated in the pathogenesis of autoimmune diseases. Although the pathogenesis of inflammatory bowel disease (IBD) is unknown, it is thought to result from complex interactions between environmental factors and microbiota in the gut of individuals who are genetically susceptible. Several bacterial and viral agents have been implicated in the aetiology of IBD. In theory, H. pylori infection could be involved in the pathogenesis of IBD by inducing alterations in gastric and/or intestinal permeability or by causing immunological derangements resulting in absorption of antigenic material and autoimmunity via various immunological pathways. Similar mechanisms may also be responsible for the co-existence of IBD with other autoimmune diseases and/or extra-intestinal manifestations. However, the epidemiological data fail to support this association. In fact, various studies indicate that the prevalence of H. pylori infection is low in patients with IBD, suggesting a protective role for this infection in the development of IBD. In this report, we aim to shed light on proposed mechanisms and confounding factors underlying the potential link between H. pylori infection and IBD. PMID:24914359

Helicobacter pylori infection and inflammatory bowel disease: is there a link?

PubMed

Papamichael, Konstantinos; Konstantopoulos, Panagiotis; Mantzaris, Gerassimos J

2014-06-07

Helicobacter pylori (H. pylori) infection is one of the most widely spread infectious diseases in humans. It can cause chronic gastritis, peptic ulcer disease and gastric malignancies and has been associated with extra-gastric disorders. H. pylori elicit a chronic systemic inflammatory response which, under certain conditions, may trigger autoimmune reactions and may be implicated in the pathogenesis of autoimmune diseases. Although the pathogenesis of inflammatory bowel disease (IBD) is unknown, it is thought to result from complex interactions between environmental factors and microbiota in the gut of individuals who are genetically susceptible. Several bacterial and viral agents have been implicated in the aetiology of IBD. In theory, H. pylori infection could be involved in the pathogenesis of IBD by inducing alterations in gastric and/or intestinal permeability or by causing immunological derangements resulting in absorption of antigenic material and autoimmunity via various immunological pathways. Similar mechanisms may also be responsible for the co-existence of IBD with other autoimmune diseases and/or extra-intestinal manifestations. However, the epidemiological data fail to support this association. In fact, various studies indicate that the prevalence of H. pylori infection is low in patients with IBD, suggesting a protective role for this infection in the development of IBD. In this report, we aim to shed light on proposed mechanisms and confounding factors underlying the potential link between H. pylori infection and IBD.

Prostaglandin E(2) synthase inhibition as a therapeutic target.

PubMed

Iyer, Jitesh P; Srivastava, Punit K; Dev, Rishabh; Dastidar, Sunanda G; Ray, Abhijit

2009-07-01

Most NSAIDs function by inhibiting biosynthesis of PGE(2) by inhibition of COX-1 and/or COX-2. Since COX-1 has a protective function in the gastro-intestinal tract (GIT), non-selective inhibition of both cycloxy genases leads to moderate to severe gastro-intestinal intolerance. Attempts to identify selective inhibitors of COX-2, led to the identification of celecoxib and rofecoxib. However, long-term use of these drugs has serious adverse effects of sudden myocardial infarction and thrombosis. Drug-mediated imbalance in the levels of prostaglandin I(2) (PGI(2)) and thromboxane A(2) (TXA(2)) with a bias towards TXA(2) may be the primary reason for these events. This resulted in the drugs being withdrawn from the market, leaving a need for an effective and safe anti-inflammatory drug. Recently, the focus of research has shifted to enzymes downstream of COX in the prosta glandin biosynthetic pathway such as prostaglandin E(2) synthases. Microsomal prostaglandin E(2) synthase-1 (mPGES-1) specifically isomerizes PGH(2) to PGE(2), under inflammatory conditions. In this review, we examine the biology of mPGES-1 and its role in disease. Progress in designing molecules that can selectively inhibit mPGES-1 is reviewed. mPGES-1 has the potential to be a target for anti-inflammatory therapy, devoid of adverse GIT and cardiac effects and warrants further investigation.

Genomics of immune response to typhoid and cholera vaccines

PubMed Central

Majumder, Partha P.

2015-01-01

Considerable variation in antibody response (AR) was observed among recipients of an injectable typhoid vaccine and an oral cholera vaccine. We sought to find whether polymorphisms in genes of the immune system, both innate and adaptive, were associated with the observed variation in response. For both vaccines, we were able to discover and validate several polymorphisms that were significantly associated with immune response. For the typhoid vaccines, these polymorphisms were on genes that belonged to pathways of polysaccharide recognition, signal transduction, inhibition of T-cell proliferation, pro-inflammatory signalling and eventual production of antimicrobial peptides. For the cholera vaccine, the pathways included epithelial barrier integrity, intestinal homeostasis and leucocyte recruitment. Even though traditional wisdom indicates that both vaccines should act as T-cell-independent antigens, our findings reveal that the vaccines induce AR using different pathways. PMID:25964454

Investigation of JAKs/STAT‐3 in lipopolysaccharide‐induced intestinal epithelial cells

PubMed Central

Fu, L.; Wei, L.‐W.; Zhao, M.‐D.; Zhu, J.‐L.; Chen, S.‐Y.; Jia, X.‐B.

2016-01-01

Summary Janus‐activated kinase (JAKs)‐signal transducer and activator of transcription 3 (STAT‐3) signalling play critical roles in immunoregulation and immunopathology, which involve inflammatory responses and enteritis. JAK phosphorylates STAT‐3 in response to stimulation by cytokines or growth factors, and then activates or represses the gene expression. STAT‐3 is activated persistently in cancer cells and contributes to the malignant progression of various types of cancer and inflammation. To elucidate the different roles of JAKs in the activation of STAT‐3, the lipopolysaccharide‐induced primary intestinal epithelial cell (IEC) acute inflammatory model was established. Small interference RNAs (siRNAs) were then employed to attenuate the expression levels of JAKs. Real‐time quantitative reverse transcription–polymerase chain reaction (PCR) (qRT–PCR) revealed that JAK mRNA levels were reduced efficiently by JAK‐specific siRNAs. Under the IEC inflammatory model transfected with si‐JAK, which equates to effective silencing, qRT–PCR and Western blot assays, suggested that knockdowns of JAK attenuated the JAK‐induced down‐regulation of STAT‐3 at the mRNA or protein levels. In particular, JAK1 played a key role, which was consistent with the RNA‐Seq results. Subsequently, the expression levels of proinflammatory cytokines interleukin (IL)‐1β and tumour necrosis factor (TNF)‐α were down‐regulated in the IEC inflammatory model transfected with si‐JAK1. JAK1 appears as a direct activator for STAT‐3, whereas treatments targeting JAK1 repressed STAT‐3 sufficiently pathways in the IEC inflammatory model. Therefore, the control of JAK1 using siRNAs has the potential to be an effective strategy against enteritis. PMID:27357529

Anti-inflammatory activity of traditional Chinese medicinal herbs.

PubMed

Pan, Min-Hsiung; Chiou, Yi-Shiou; Tsai, Mei-Ling; Ho, Chi-Tang

2011-10-01

Accumulating epidemiological and clinical evidence shows that inflammation is an important risk factor for various human diseases. Thus, suppressing chronic inflammation has the potential to delay, prevent, and control various chronic diseases, including cerebrovascular, cardiovascular, joint, skin, pulmonary, blood, lymph, liver, pancreatic, and intestinal diseases. Various natural products from traditional Chinese medicine (TCM) have been shown to safely suppress proinflammatory pathways and control inflammation-associated disease. In vivo and/or in vitro studies have demonstrated that anti-inflammatory effects of TCM occur by inhibition of the expression of master transcription factors (for example, nuclear factor-κB (NF-κB)), pro-inflammatory cytokines (for example, tumor necrosis factor-α (TNF-α), chemokines (for example, chemokine (C-C motif) ligand (CCL)-24), intercellular adhesion molecule expression and pro-inflammatory mediators (for example, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2)). However, a handful of review articles have focused on the anti-inflammatory activities of TCM and explore their possible mechanisms of action. In this review, we summarize recent research attempting to identify the anti-inflammatory constituents of TCM and their molecular targets that may create new opportunities for innovation in modern pharmacology.

miR-122 targets NOD2 to decrease intestinal epithelial cell injury in Crohn’s disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Yu; Wang, Chengxiao; Liu, Ying

2013-08-16

Highlights: •NOD2 is a target gene of miR-122. •miR-122 inhibits LPS-induced apoptosis by suppressing NOD2 in HT-29 cells. •miR-122 reduces the expression of pro-inflammatory cytokines (TNF-α and IFN-γ). •miR-122 promotes the release of anti-inflammatory cytokines (IL-4 and IL-10). •NF-κB signaling pathway is involved in inflammatory response induced by LPS. -- Abstract: Crohn’s disease (CD) is one of the two major types of inflammatory bowel disease (IBD) thought to be caused by genetic and environmental factors. Recently, miR-122 was found to be deregulated in association with CD progression. However, the underlying molecular mechanisms remain unclear. In the present study, the genemore » nucleotide-binding oligomerization domain 2 (NOD2/CARD15), which is strongly associated with susceptibility to CD, was identified as a functional target of miR-122. MiR-122 inhibited LPS-induced apoptosis by suppressing NOD2 in HT-29 cells. NOD2 interaction with LPS initiates signal transduction mechanisms resulting in the activation of nuclear factor κB (NF-κB) and the stimulation of downstream pro-inflammatory events. The activation of NF-κB was inhibited in LPS-stimulated HT-29 cells pretreated with miR-122 precursor or NOD2 shRNA. The expression of the pro-inflammatory cytokines TNF-α and IFN-γ was significantly decreased, whereas therelease of the anti-inflammatory cytokines IL-4 and IL-10 was increased in LPS-stimulated HT-29 cells pretreated with miR-122 precursor, NOD2 shRNA or the NF-κB inhibitor QNZ. Taken together, these results indicate that miR-122 and its target gene NOD2 may play an important role in the injury of intestinal epithelial cells induced by LPS.« less

Intestinal fibrosis is reduced by early elimination of inflammation in a mouse model of IBD: impact of a "Top-Down" approach to intestinal fibrosis in mice.

PubMed

Johnson, Laura A; Luke, Amy; Sauder, Kay; Moons, David S; Horowitz, Jeffrey C; Higgins, Peter D R

2012-03-01

The natural history of Crohn's disease follows a path of progression from an inflammatory to a fibrostenosing disease, with most patients requiring surgical resection of fibrotic strictures. Potent antiinflammatory therapies reduce inflammation but do not appear to alter the natural history of intestinal fibrosis. The aim of this study was to determine the relationship between intestinal inflammation and fibrogenesis and the impact of a very early "top-down" interventional approach on fibrosis in vivo. In this study we removed the inflammatory stimulus from the Salmonella typhimurium mouse model of intestinal fibrosis by eradicating the S. typhimurium infection with levofloxacin at sequential timepoints during the infection. We evaluated the effect of this elimination of the inflammatory stimulus on the natural history of inflammation and fibrosis as determined by gross pathology, histopathology, mRNA expression, and protein expression. Fibrogenesis is preceded by inflammation. Delayed eradication of the inflammatory stimulus by antibiotic treatment represses inflammation without preventing fibrosis. Early intervention significantly ameliorates but does not completely prevent subsequent fibrosis. This study demonstrates that intestinal fibrosis develops despite removal of an inflammatory stimulus and elimination of inflammation. Early intervention ameliorates but does not abolish subsequent fibrosis, suggesting that fibrosis, once initiated, is self-propagating, suggesting that a very early top-down interventional approach may have the most impact on fibrostenosing disease. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

Modulation of microbiota as treatment for intestinal inflammatory disorders: An uptodate

PubMed Central

Gallo, Antonella; Passaro, Giovanna; Gasbarrini, Antonio; Landolfi, Raffaele; Montalto, Massimo

2016-01-01

Alterations of intestinal microflora may significantly contribute to the pathogenesis of different inflammatory and autoimmune disorders. There is emerging interest on the role of selective modulation of microflora in inducing benefits in inflammatory intestinal disorders, by as probiotics, prebiotics, synbiotics, antibiotics, and fecal microbiota transplantation (FMT). To summarize recent evidences on microflora modulation in main intestinal inflammatory disorders, PubMed was searched using terms microbiota, intestinal flora, probiotics, prebiotics, fecal transplantation. More than three hundred articles published up to 2015 were selected and reviewed. Randomized placebo-controlled trials and meta-analysis were firstly included, mainly for probiotics. A meta-analysis was not performed because of the heterogeneity of these studies. Most of relevant data derived from studies on probiotics, reporting some efficacy in ulcerative colitis and in pouchitis, while disappointing results are available for Crohn’s disease. Probiotic supplementation may significantly reduce rates of rotavirus diarrhea. Efficacy of probiotics in NSAID enteropathy and irritable bowel syndrome is still controversial. Finally, FMT has been recently recognized as an efficacious treatment for recurrent Clostridium difficile infection. Modulation of intestinal flora represents a very interesting therapeutic target, although it still deserves some doubts and limitations. Future studies should be encouraged to provide new understanding about its therapeutical role. PMID:27621567

Inflammatory responses and intestinal injury development during acute Trypanosoma cruzi infection are associated with the parasite load.

PubMed

Vazquez, Bruna Perez; Vazquez, Thaís Perez; Miguel, Camila Botelho; Rodrigues, Wellington Francisco; Mendes, Maria Tays; de Oliveira, Carlo José Freire; Chica, Javier Emílio Lazo

2015-04-03

Chagas disease is caused by the protozoan Trypanosoma cruzi and is characterized by cardiac, gastrointestinal, and nervous system disorders. Although much about the pathophysiological process of Chagas disease is already known, the influence of the parasite burden on the inflammatory process and disease progression remains uncertain. We used an acute experimental disease model to evaluate the effect of T. cruzi on intestinal lesions and assessed correlations between parasite load and inflammation and intestinal injury at 7 and 14 days post-infection. Low (3 × 10(2)), medium (3 × 10(3)), and high (3 × 10(4)) parasite loads were generated by infecting C57BL/6 mice with "Y"-strain trypomastigotes. Statistical analysis was performed using analysis of variance with Tukey's multiple comparison post-test, Kruskal-Wallis test with Dunn's multiple comparison, χ2 test and Spearman correlation. High parasite load-bearing mice more rapidly and strongly developed parasitemia. Increased colon width, inflammatory infiltration, myositis, periganglionitis, ganglionitis, pro-inflammatory cytokines (e.g., TNF-α, INF-γ, IL-2, IL-17, IL-6), and intestinal amastigote nests were more pronounced in high parasite load-bearing animals. These results were remarkable because a positive correlation was observed between parasite load, inflammatory infiltrate, amastigote nests, and investigated cytokines. These experimental data support the idea that the parasite load considerably influences the T. cruzi-induced intestinal inflammatory response and contributes to the development of the digestive form of the disease.

IFN-λ suppresses intestinal inflammation by non-translational regulation of neutrophil function.

PubMed

Broggi, Achille; Tan, Yunhao; Granucci, Francesca; Zanoni, Ivan

2017-10-01

Interferon-λ (IFN-λ) is a central regulator of mucosal immunity; however, its signaling specificity relative to that of type I interferons is poorly defined. IFN-λ can induce antiviral interferon-stimulated genes (ISGs) in epithelia, while the effect of IFN-λ in non-epithelial cells remains unclear. Here we report that neutrophils responded to IFN-λ. We found that in addition to inducing ISG transcription, IFN-λ (but not IFN-β) specifically activated a translation-independent signaling pathway that diminished the production of reactive oxygen species and degranulation in neutrophils. In mice, IFN-λ was elicited by enteric viruses and acted on neutrophils to decrease oxidative stress and intestinal damage. Thus, IFN-λ acted as a unique immunomodulatory agent by modifying transcriptional and non-translational neutrophil responses, which might permit a controlled development of the inflammatory process.

Intestinal anti-inflammatory effects of total alkaloid extract from Fumaria capreolata in the DNBS model of mice colitis and intestinal epithelial CMT93 cells.

PubMed

Bribi, Noureddine; Algieri, Francesca; Rodriguez-Nogales, Alba; Vezza, Teresa; Garrido-Mesa, Jose; Utrilla, María Pilar; Del Mar Contreras, María; Maiza, Fadila; Segura-Carretero, Antonio; Rodriguez-Cabezas, Maria Elena; Gálvez, Julio

2016-08-15

Fumaria capreolata L. (Papaveraceae) is a botanical drug used in North Africa for its gastro-intestinal and anti-inflammatory properties. It is characterized for the presence of several alkaloids that could be responsible for some of its effects, including an immunomodulatory activity. To test in vivo the intestinal anti-inflammatory properties of the total alkaloid fraction extracted from the aerial parts of F. capreolata (AFC), and to evaluate its effects on an intestinal epithelial cell line. AFC was chemically characterized by liquid chromatography coupled to diode array detection and high resolution mass spectrometry. Different doses of AFC (25, 50 and 100mg/kg) were assayed in the DNBS model of experimental colitis in mice, and the colonic damage was evaluated both histologically and biochemically. In addition, in vitro experiments were performed with this alkaloid fraction on the mouse intestinal epithelial cell line CMT93 stimulated with LPS. The chemical analysis of AFC revealed the presence of 23 alkaloids, being the most abundants stylopine, protopine and coptisine. Oral administration of AFC produced a significant inhibition of the release and the expression of IL-6 and TNF-α in the colonic tissue. It also suppressed in vivo the transcription of other pro-inflammatory mediators such as IL-1β, iNOS, IL-12 and IL-17. Furthermore, AFC showed an immunomodulatory effect in vitro since it was able to inhibit the mRNA expression of IL-6, TNF-α and ICAM-1. Moreover, the beneficial effect of AFC in the colitic mice could also be associated with the normalization of the expression of MUC-2 and ZO-1, which are important for the intestinal epithelial integrity. The present study suggests that AFC, containing 1.3% of stylopine and 0.9% of protopine, significantly exerted intestinal anti-inflammatory effects in an experimental model of mouse colitis. This fact could be related to a modulation of the intestinal immune response and a restoration of the intestinal epithelial function. Copyright © 2016 Elsevier GmbH. All rights reserved.

Effects of Mesalamine Treatment on Gut Barrier Integrity Following Burn Injury

PubMed Central

Cannon, Abigail R.; Akhtar, Suhail; Hammer, Adam M.; Morris, Niya L.; Javorski, Mike J.; Li, Xiaoling; Kennedy, Richard H.; Gamelli, Richard L.; Choudhry, Mashkoor A.

2016-01-01

Gut barrier disruption is often implicated in pathogenesis associated with burn and other traumatic injuries. In this study, we examined whether therapeutic intervention with mesalamine (5-ASA), a common anti-inflammatory treatment for patients with inflammatory bowel disease, reduces intestinal inflammation and maintains normal barrier integrity after burn injury. Male C57BL/6 mice were administered an ~20% total body surface area dorsal scald burn and resuscitated with either 1mL normal saline or 100mg/kg of 5-ASA dissolved in saline. We examined intestinal transit and permeability along with levels of small intestine epithelial cell pro-inflammatory cytokines and tight junction protein expression one day after burn injury in the presence or absence of 5-ASA. A significant decrease in intestinal transit was observed one day after burn injury, which accompanied a significant increase in gut permeability. We found a substantial increase in the levels of IL-6 (by ~1.5 fold) and IL-18 (by ~2.5 fold) in small intestine epithelial cells one day after injury. Furthermore, burn injury decreases expression of the tight junction proteins claudin-4, claudin-8, and occludin. Treatment with 5-ASA after burn injury prevented the burn induced increase in permeability, partially restored normal intestinal transit, normalized levels of the pro-inflammatory cytokines IL-6 and IL-18, and restored tight junction protein expression of claudin-4 and occludin to that of sham levels. Together these findings suggest that 5-ASA can potentially be used as treatment to decrease intestinal inflammation and normalize intestinal function after burn injury. PMID:27388883

Intestinal anti-inflammatory effects of RGD-functionalized silk fibroin nanoparticles in trinitrobenzenesulfonic acid-induced experimental colitis in rats

PubMed Central

Rodriguez-Nogales, Alba; Algieri, Francesca; De Matteis, Laura; Lozano-Perez, A. Abel; Garrido-Mesa, Jose; Vezza, Teresa; de la Fuente, J M.; Cenis, Jose Luis; Gálvez, Julio; Rodriguez-Cabezas, Maria Elena

2016-01-01

Background Current treatment of inflammatory bowel disease is based on the use of immunosuppressants or anti-inflammatory drugs, which are characterized by important side effects that can limit their use. Previous research has been performed by administering these drugs as nanoparticles that target the ulcerated intestinal regions and increase their bioavailability. It has been reported that silk fibroin can act as a drug carrier and shows anti-inflammatory properties. Purpose This study was designed to enhance the interaction of the silk fibroin nanoparticles (SFNs) with the injured intestinal tissue by functionalizing them with the peptide motif RGD (arginine–glycine–aspartic acid) and to evaluate the intestinal anti-inflammatory properties of these RGD-functionalized silk fibroin nanoparticles (RGD-SFNs) in the trinitrobenzenesulfonic acid (TNBS) model of rat colitis. Materials and methods SFNs were prepared by nanoprecipitation in methanol, and the linear RGD peptide was linked to SFNs using glutaraldehyde as the crosslinker. The SFNs (1 mg/rat) and RGD-SFNs (1 mg/rat) were administered intrarectally to TNBS-induced colitic rats for 7 days. Results The SFN treatments ameliorated the colonic damage, reduced neutrophil infiltration, and improved the compromised oxidative status of the colon. However, only the rats treated with RGD-SFNs showed a significant reduction in the expression of different pro-inflammatory cytokines (interleukin [IL]-1β, IL-6, and IL-12) and inducible nitric oxide synthase in comparison with the TNBS control group. Moreover, the expression of both cytokine-induced neutrophil chemoattractant-1 and monocyte chemotactic protein-1 was significantly diminished by the RGD-SFN treatment. However, both treatments improved the intestinal wall integrity by increasing the gene expression of some of its markers (trefoil factor-3 and mucins). Conclusion SFNs displayed intestinal anti-inflammatory properties in the TNBS model of colitis in rats, which were improved by functionalization with the RGD peptide. PMID:27877040

Hymenaea stigonocarpa Mart. ex Hayne: A tropical medicinal plant with intestinal anti-inflammatory activity in TNBS model of intestinal inflammation in rats.

PubMed

Orsi, Patrícia Rodrigues; Seito, Leonardo Noboru; Di Stasi, Luiz Claudio

2014-01-01

Stem bark and fruit pulp of Hymenaea stigonocarpa Mart ex. Hayne (Fabaceae) has been popularly used to treat inflammation and gastrointestinal diseases including ulcers, diarrhea and gastric pain. The aim of this study was to investigate the intestinal anti-inflammatory activity of a methanol extract derived from the stem bark and diet with fruit pulp of Hymenaea stigonocarpa in the TNBS model of intestinal inflammation in rats. The intestinal anti-inflammatory activity of stem bark extract (100, 200 and 400mg/kg) and fruit pulp (10% and 5% in diet) was measured against the intestinal inflammatory process induced by TNBS (trinitrobenzesulphonic acid) in rats. The protective effects were evaluated as follows: evaluation of intestinal damage (damage score, extension of lesion, colon weight/length ratio), incidence of diarrhea and adherence to adjacent organs, colon glutathione (GSH) and malondialdehyde (MDA) contents, myeloperoxidase (MPO) and alkaline phosphatase (AP) activities. In addition, in vitro studies on lipid peroxidation in rat brain membranes and phytochemical profile were performed with both stem bark and fruit pulp. Treatment with 100, 200 and 400mg/kg of stem bark extract and 10% fruit pulp flour showed protective effects in the TNBS-induced colon damage, which was related to inhibition of MPO and AP activities, reduction in colon MDA content, and counteraction of GSH depletion induced by inflammatory process. A concentration-dependent inhibitory effect on the lipid peroxidation in rat brain membranes for stem bark and fruit pulp was determined, with an IC50 value of 5.25 ± 0.23 μg/mL and 27.33 ± 0.09 μg/mL, respectively. Similar phytochemical composition was observed in fruit and stem bark, including mainly flavonoids, condensed tannins and terpenes. Stem bark extract and fruit pulp flour of Hymenaea stigonocarpa prevented TNBS-induced colonic damage in rats and this protective effect were associated to an improvement of intestinal oxidative stress. The observed anti-inflammatory and antioxidant effects may be associated to the presence of flavonoids and tannins in the stem bark and fruit pulp of Hymenaea stigonocarpa. © 2013 Published by Elsevier Ireland Ltd.

Extra-adrenal glucocorticoid synthesis in the intestinal epithelium: more than a drop in the ocean?

PubMed

Noti, Mario; Sidler, Daniel; Brunner, Thomas

2009-07-01

Glucocorticoids (GC) are lipophilic hormones commonly used as therapeutics in acute and chronic inflammatory disorders such as inflammatory bowel disease due to their attributed anti-inflammatory and immunosuppressive actions. Although the adrenal glands are the major source of endogenous GC, there is increasing evidence for the production of extra-adrenal GC in the brain, thymus, skin, vasculature, and the intestine. However, the physiological relevance of extra-adrenal-produced GC remains still ambiguous. Therefore, this review attracts attention to discuss possible biological benefits of extra-adrenal-synthesized GC, especially focusing on the impact of locally synthesized GC in the regulation of intestinal immune responses.

Ethanol and dietary unsaturated fat (corn oil/linoleic acid enriched) cause intestinal inflammation and impaired intestinal barrier defense in mice chronically fed alcohol.

PubMed

Kirpich, Irina A; Feng, Wenke; Wang, Yuhua; Liu, Yanlong; Beier, Juliane I; Arteel, Gavin E; Falkner, K Cameron; Barve, Shirish S; McClain, Craig J

2013-05-01

Alcohol and dietary fat both play an important role in alcohol-mediated multi-organ pathology, including gut and liver. In the present study we hypothesized that the combination of alcohol and dietary unsaturated fat (USF) would result in intestinal inflammatory stress and mucus layer alterations, thus contributing to disruption of intestinal barrier integrity. C57BL/6N mice were fed Lieber-DeCarli liquid diets containing EtOH and enriched in USF (corn oil/linoleic acid) or SF (medium chain triglycerides: beef tallow) for 8 weeks. Intestinal histology, morphometry, markers of inflammation, as well as levels of mucus protective factors were evaluated. Alcohol and dietary USF triggered an intestinal pro-inflammatory response, characterized by increase in Tnf-α, MCP1, and MPO activity. Further, alcohol and dietary USF, but not SF, resulted in alterations of the intestinal mucus layer, characterized by decreased expression of Muc2 in the ileum. A strong correlation was observed between down-regulation of the antimicrobial factor Cramp and increased Tnf-α mRNA. Therefore, dietary unsaturated fat (corn oil/LA enriched) is a significant contributing factor to EtOH-mediated intestinal inflammatory response and mucus layer alterations in rodents. Copyright © 2013 Elsevier Inc. All rights reserved.

Human Milk Oligosaccharides and Synthetic Galactosyloligosaccharides Contain 3′-, 4-, and 6′-Galactosyllactose and Attenuate Inflammation in Human T84, NCM-460, and H4 Cells and Intestinal Tissue Ex Vivo12

PubMed Central

Ko, Jae Sung; Leone, Serena; Nanthakumar, N Nanda

2016-01-01

Background: The immature intestinal mucosa responds excessively to inflammatory insult, but human milk protects infants from intestinal inflammation. The ability of galactosyllactoses [galactosyloligosaccharides (GOS)], newly found in human milk oligosaccharides (HMOS), to suppress inflammation was not known. Objective: The objective was to test whether GOS can directly attenuate inflammation and to explore the components of immune signaling modulated by GOS. Methods: Galactosyllactose composition was measured in sequential human milk samples from days 1 through 21 of lactation and in random colostrum samples from 38 mothers. Immature [human normal fetal intestinal epithelial cell (H4)] and mature [human metastatic colonic epithelial cell (T84) and human normal colon mucosal epithelial cell (NCM-460)] enterocyte cell lines were treated with the pro-inflammatory molecules tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β) or infected with Salmonella or Listeria. The inflammatory response was measured as induction of IL-8, monocyte chemoattractant protein 1 (MCP-1), or macrophage inflammatory protein-3α (MIP-3α) protein by ELISA and mRNA by quantitative reverse transcriptase-polymerase chain reaction. The ability of HMOS or synthetic GOS to attenuate this inflammation was tested in vitro and in immature human intestinal tissue ex vivo. Results: The 3 galactosyllactoses (3′-GL, 4-GL, and 6′-GL) expressed in colostrum rapidly declined over early lactation (P < 0.05). In H4 cells, HMOS attenuated TNF-α– and IL-1β–induced expression of IL-8, MIP-3α, and MCP-1 to 48–51% and pathogen-induced IL-8 and MCP-1 to 26–30% of positive controls (P < 0.001). GOS reduced TNF-α– and IL-1β–induced inflammatory responses to 25–26% and pathogen-induced IL-8 and MCP-1 to 36–39% of positive controls (P < 0.001). GOS and HMOS mitigated nuclear translocation of nuclear transcription factor κB (NF-κB) p65. HMOS quenched the inflammatory response to Salmonella infection by immature human intestinal tissue ex vivo to 26% and by GOS to 50% of infected controls (P < 0.01). Conclusion: Galactosyllactose attenuated NF-κB inflammatory signaling in human intestinal epithelial cells and in human immature intestine. Thus, galactosyllactoses are strong physiologic anti-inflammatory agents in human colostrum and early milk, contributing to innate immune modulation. The potential clinical utility of galactosyllactose warrants investigation. PMID:26701795

Preinduced intestinal HSP70 improves visceral hypersensitivity and abnormal intestinal motility in PI-IBS mouse model.

PubMed

Lan, Cheng; Sun, Xiao-Ning; Zhou, Xu-Chun; Yang, Bo; Huang, Bai-Li; Deng, Tao-Zhi; He, Zhou-Tao; Han, Xiang-Yang

2016-03-01

To investigate the impact of the preinduced intestinal heat shock protein 70 (HSP70) on the visceral hypersensitivity and abnormal intestinal motility in a post-infectious irritable bowel syndrome (PI-IBS) mouse model. Eighty-four female C57BL/6 mice were randomly assigned to four groups: control group (n = 21) and induction + PI-IBS group (n = 21), PI-IBS group (n = 21) and induction group (n = 21). The mice in PI-IBS group were infected in vivo with Trichinella spiralis by oral administration. The visceral hypersensitivity and intestinal motility were evaluated respectively with abdominal withdrawal reflex and colon transportation test. The intestinal HSP70 protein and mRNA level was measured by Western blot and real-time PCR. Meanwhile, the intestinal proinflammatory cytokines IL-10 and TNF-α level was detected by ELISA. Compared with their counterparts in PI-IBS group, the animals in the Induction + PI-IBS group show significantly increased intestinal level of HSP70 and obviously ameliorative clinical figures, including abdominal withdrawal reflex score, intestine transportation time and Bristol scores (P < 0.05). Meanwhile, the intestinal post-inflammatory cytokines remarkably changed, including increased IL-10 level and decreased TNF-α level (P < 0.05). Intestinal HSP70 may play a potential protective role through improving the imbalance between the intestinal post-inflammatory and anti-inflammatory cytokines in PI-IBS. Copyright © 2016 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

[Role of the small intestinal decompression tube and Gastrografin in the treatment of early postoperative inflammatory small bowel obstruction].

PubMed

Li, Wei; Li, Zhixia; An, Dali; Liu, Jing; Zhang, Xiaohu

2014-03-01

To evaluate the role of the small intestinal decompression tube (SIDT) and Gastrografin in the treatment of early postoperative inflammatory small bowel obstruction (EPISBO). Twelve patients presented EPISBO after abdominal surgery in our department from April 2011 to July 2012. Initially, nasogastric tube decompression and other conventional conservative treatment were administrated. After 14 days, obstruction symptom improvement was not obvious, then the SIDT was used. At the same time, Gastrografin was injected into the small bowel through the SIDT in order to demonstrate the site of obstruction of small bowel and its efficacy. In 11 patients after this management, obstruction symptoms disappeared, bowel function recovered within 3 weeks, and oral feeding occurred gradually. Another patient did not pass flatus after 4 weeks and was reoperated. After postoperative follow-up of 6 months, no case relapsed with intestinal obstruction. For severe and long course of early postoperative inflammatory intestinal obstruction, intestinal decompression tube plus Gastrografin is safe and effective, and can avoid unnecessary reoperation.

IL-17A alone weakly affects the transcriptome of intestinal epithelial cells but strongly modulates the TNF-α-induced expression of inflammatory mediators and inflammatory bowel disease susceptibility genes.

PubMed

Friedrich, Matthias; Diegelmann, Julia; Beigel, Florian; Brand, Stephan

2014-09-01

In contrast to anti-TNF-α antibodies, anti-IL-17A antibodies lacked clinical efficacy in a trial with patients suffering from Crohn's disease. We therefore analyzed how IL-17A modulates the inflammatory response elicited by TNF-α in intestinal epithelial cells (IEC). Target mRNA levels in IEC and colonic biopsies were assessed by RNA microarray and quantitative real-time PCR. Signaling pathways were analyzed using receptor neutralization and pharmacological inhibitors. Target protein levels were determined by immunoblotting. Microarray analysis demonstrated that IL-17A alone is a weak inducer of gene expression in IEC (29 regulated transcripts), but significantly affected the TNF-α-induced expression of 547 genes, with strong amplification of proinflammatory chemokines and cytokines (>200-fold increase of CCL20, CXCL1, and CXCL8). Interestingly, IL-17A differentially modulated the TNF-α-induced expression of several inflammatory bowel disease susceptibility genes in IEC (increase of JAK2 mRNA, decrease of FUT2, ICAM1, and LTB mRNA). Negative regulation of ICAM-1 by IL-17A was verified on protein level. The significance of these findings is emphasized by inflamed lesions of patients with inflammatory bowel disease demonstrating significant correlations (P < 0.01, Rho, 0.57-0.85) for JAK2, ICAM1, and LTB mRNA with IL17A and TNF mRNA. Our study demonstrates the modulation of inflammatory bowel disease susceptibility gene mRNA in IEC as a novel important property of IL-17A. Given the weak impact of sole IL-17A stimulation on IEC target gene expression, our study provides an important explanation for the lack of clinical efficacy of sole IL-17A neutralization, but suggests a beneficial effect of combined IL-17A/TNF-α that is currently in clinical development.

A Critical Role for Monocytes/Macrophages During Intestinal Inflammation-associated Lymphangiogenesis

PubMed Central

Becker, Felix; Kurmaeva, Elvira; Gavins, Felicity N. E.; Stevenson, Emily V.; Navratil, Aaron R.; Jin, Long; Tsunoda, Ikuo; Orr, A. Wayne; Alexander, Jonathan S.; Ostanin, Dmitry V.

2016-01-01

Background Inflammation-associated lymphangiogenesis (IAL) is frequently observed in inflammatory bowel diseases. IAL is believed to limit inflammation by enhancing fluid and immune cell clearance. Although monocytes/macrophages (MΦ) are known to contribute to intestinal pathology in inflammatory bowel disease, their role in intestinal IAL has never been studied mechanistically. We investigated contributions of monocytes/MΦ to the development of intestinal inflammation and IAL. Methods Because inflammatory monocytes express CC chemokine receptor 2 (CCR2), we used CCR2 diphtheria toxin receptor transgenic (CCR2.DTR) mice, in which monocytes can be depleted by diphtheria toxin injection, and CCR2−/− mice, which have reduced circulating monocytes. Acute or chronic colitis was induced by dextran sodium sulfate or adoptive transfer of CD4+CD45RBhigh T cells, respectively. Intestinal inflammation was assessed by flow cytometry, immunofluorescence, disease activity, and histopathology, whereas IAL was assessed by lymphatic vessel morphology and density. Results We demonstrated that intestinal MΦ expressed vascular endothelial growth factor-C/D. In acute colitis, monocyte-depleted mice were protected from intestinal injury and showed reduced IAL, which was reversed after transfer of wild-type monocytes into CCR2−/− mice. In chronic colitis, CCR2 deficiency did not attenuate inflammation but reduced IAL. Conclusions We propose a dual role of MΦ in (1) promoting acute inflammation and (2) contributing to IAL. Our data suggest that intestinal inflammation and IAL could occur independently, because IAL was reduced in the absence of monocytes/MΦ, even when inflammation was present. Future inflammatory bowel disease therapies might exploit promotion of IAL and suppression of MΦ independently, to restore lymphatic clearance and reduce inflammation. PMID:26950310

Fructo-oligosaccharide attenuates the production of pro-inflammatory cytokines and the activation of JNK/Jun pathway in the lungs of D-galactose-treated Balb/cJ mice.

PubMed

Yeh, Shu-Lan; Wu, Tzu-Chin; Chan, Shu-Ting; Hong, Meng-Jun; Chen, Hsiao-Ling

2014-01-01

This study determined the effects of long-term D-galactose (DG) injection on the lung pro-inflammatory and fibrotic status and whether fructo-oligosaccharide (FO) could attenuate such effects. Forty Balb/cJ mice (12 weeks of age) were divided into four groups: control (s.c. saline) (basal diet), DG (s.c. 1.2 g DG/kg body weight) (basal diet), DG + FO (FO diet, 2.5% w/w FO), and DG + E (vitamin E diet, α-tocopherol 0.2% w/w) serving as an antioxidant control group. These animals were killed after 49 day of treatments. Another group of naturally aging (NA) mice without any injection was killed at 64 weeks of age to be an aging control group. D-galactose treatment, generally similar to NA, increased the lung pro-inflammatory status, as shown in the IL-6 and IL-1β levels and the expression of phospho-Jun and phospho-JNK, and the fibrotic status as shown in the hydroxyproline level compared to the vehicle. FO diminished the DG-induced increases in the lung IL-1β level and expressions of total Jun, phospho-JNK, and attenuated DG effects on lung IL-6 and hydroxyproline, while α-tocopherol exerted anti-inflammatory effects on all parameters determined. FO, as well as α-tocopherol, modulated the large bowel ecology by increasing the fecal bifidobacteria and cecal butyrate levels compared with DG. D-galactose treatment mimicked the lung pro-inflammatory status as shown in the NA mice. FO attenuated the DG-induced lung pro-inflammatory status and down-regulated JNK/Jun pathway in the lung, which could be mediated by the prebiotic effects and metabolic products of FO in the large intestine.

Vitamin D ameliorates impaired wound healing in streptozotocin-induced diabetic mice by suppressing NF-κB-mediated inflammatory genes.

PubMed

Yuan, YiFeng; Das, Sushant K; Li, MaoQuan

2018-04-27

Diabetic wounds are characterized by delayed wound healing due to persistent inflammation and excessive production of reactive oxygen species. Vitamin D, which is well acknowledged to enhance intestinal calcium absorption and increase in plasma calcium level, has recently been shown to display beneficial effects in various vascular diseases by promoting angiogenesis and inhibiting inflammatory responses. However, the role of Vitamin D in diabetic wound healing is still unclear. In the present study, we investigated the role of Vitamin D in cutaneous wound healing in streptozotocin (STZ)-induced diabetic mice. Four weeks after injection of STZ, a full thickness excisional wound was created with a 6-mm diameter sterile biopsy punch on the dorsum of the mice. Vitamin D was given consecutively for 14 days by intraperitoneal injection. Vitamin D supplementation significantly accelerated wound healing in diabetic mice and improved the healing quality as assessed by measuring the wound closure rate and histomorphometric analyses. By monitoring the level of pro-inflammatory cytokines tumor necrosis factor-α ( TNF-α ), interleukin (IL) 6 ( IL-6 ), IL-1β ) in the wounds, reduced inflammatory response was found in VD treatment group. Furthermore, nuclear factor κB (NF-κB) pathway was found to be involved in the process of diabetic wound healing by assessing the relative proteins in diabetic wounds. Vitamin D supplementation obviously suppressed NF-κB pathway activation. These results demonstrated that Vitamin D improves impaired wound healing in STZ-induced diabetic mice through suppressing NF-κB-mediated inflammatory gene expression. © 2018 The Author(s).

Intestinal, extra-intestinal and systemic sequelae of Toxoplasma gondii induced acute ileitis in mice harboring a human gut microbiota

PubMed Central

von Klitzing, Eliane; Ekmekciu, Ira; Kühl, Anja A.; Bereswill, Stefan

2017-01-01

Background Within seven days following peroral high dose infection with Toxoplasma gondii susceptible conventionally colonized mice develop acute ileitis due to an underlying T helper cell (Th) -1 type immunopathology. We here addressed whether mice harboring a human intestinal microbiota developed intestinal, extra-intestinal and systemic sequelae upon ileitis induction. Methodology/Principal findings Secondary abiotic mice were generated by broad-spectrum antibiotic treatment and associated with a complex human intestinal microbiota following peroral fecal microbiota transplantation. Within three weeks the human microbiota had stably established in the murine intestinal tract as assessed by quantitative cultural and culture-independent (i.e. molecular 16S rRNA based) methods. At day 7 post infection (p.i.) with 50 cysts of T. gondii strain ME49 by gavage human microbiota associated (hma) mice displayed severe clinical, macroscopic and microscopic sequelae indicating acute ileitis. In diseased hma mice increased numbers of innate and adaptive immune cells within the ileal mucosa and lamina propria and elevated intestinal secretion of pro-inflammatory mediators including IFN-γ, IL-12 and nitric oxide could be observed at day 7 p.i. Ileitis development was accompanied by substantial shifts in intestinal microbiota composition of hma mice characterized by elevated total bacterial loads and increased numbers of intestinal Gram-negative commensals such as enterobacteria and Bacteroides / Prevotella species overgrowing the small and large intestinal lumen. Furthermore, viable bacteria translocated from the inflamed ileum to extra-intestinal including systemic compartments. Notably, pro-inflammatory immune responses were not restricted to the intestinal tract as indicated by increased pro-inflammatory cytokine secretion in extra-intestinal (i.e. liver and kidney) and systemic compartments including spleen and serum. Conclusion/Significance With respect to the intestinal microbiota composition “humanized” mice display acute ileitis following peroral high dose T. gondii infection. Thus, hma mice constitute a suitable model to further dissect the interactions between pathogens, human microbiota and vertebrate host immunity during acute intestinal inflammation. PMID:28414794

Intestinal, extra-intestinal and systemic sequelae of Toxoplasma gondii induced acute ileitis in mice harboring a human gut microbiota.

PubMed

von Klitzing, Eliane; Ekmekciu, Ira; Kühl, Anja A; Bereswill, Stefan; Heimesaat, Markus M

2017-01-01

Within seven days following peroral high dose infection with Toxoplasma gondii susceptible conventionally colonized mice develop acute ileitis due to an underlying T helper cell (Th) -1 type immunopathology. We here addressed whether mice harboring a human intestinal microbiota developed intestinal, extra-intestinal and systemic sequelae upon ileitis induction. Secondary abiotic mice were generated by broad-spectrum antibiotic treatment and associated with a complex human intestinal microbiota following peroral fecal microbiota transplantation. Within three weeks the human microbiota had stably established in the murine intestinal tract as assessed by quantitative cultural and culture-independent (i.e. molecular 16S rRNA based) methods. At day 7 post infection (p.i.) with 50 cysts of T. gondii strain ME49 by gavage human microbiota associated (hma) mice displayed severe clinical, macroscopic and microscopic sequelae indicating acute ileitis. In diseased hma mice increased numbers of innate and adaptive immune cells within the ileal mucosa and lamina propria and elevated intestinal secretion of pro-inflammatory mediators including IFN-γ, IL-12 and nitric oxide could be observed at day 7 p.i. Ileitis development was accompanied by substantial shifts in intestinal microbiota composition of hma mice characterized by elevated total bacterial loads and increased numbers of intestinal Gram-negative commensals such as enterobacteria and Bacteroides / Prevotella species overgrowing the small and large intestinal lumen. Furthermore, viable bacteria translocated from the inflamed ileum to extra-intestinal including systemic compartments. Notably, pro-inflammatory immune responses were not restricted to the intestinal tract as indicated by increased pro-inflammatory cytokine secretion in extra-intestinal (i.e. liver and kidney) and systemic compartments including spleen and serum. With respect to the intestinal microbiota composition "humanized" mice display acute ileitis following peroral high dose T. gondii infection. Thus, hma mice constitute a suitable model to further dissect the interactions between pathogens, human microbiota and vertebrate host immunity during acute intestinal inflammation.

Managing heat and immune stress in athletes with evidence-based strategies.

PubMed

Pyne, David B; Guy, Joshua H; Edwards, Andrew M

2014-09-01

Heat and immune stress can affect athletes in a wide range of sports and environmental conditions. The classical thermoregulatory model of heat stress has been well characterized, as has a wide range of practical strategies largely centered on cooling and heat-acclimation training. In the last decade evidence has emerged of an inflammatory pathway that can also contribute to heat stress. Studies are now addressing the complex and dynamic interplay between hyperthermia, the coagulation cascade, and a systemic inflammatory response occurring after transient damage to the gastrointestinal tract. Damage to the intestinal mucosal membrane increases permeability, resulting in leakage of endotoxins into the circulation. Practical strategies that target both thermoregulatory and inflammatory causes of heat stress include precooling; short-term heat-acclimation training; nutritional countermeasures including hydration, energy replacement, and probiotic supplementation; pacing strategies during events; and postevent cooling measures. Cooperation between international, national, and local sporting organizations is required to ensure that heat-management policies and strategies are implemented effectively to promote athletes' well-being and performance.

Regulation of obesity-related insulin resistance with gut anti-inflammatory agents.

PubMed

Luck, Helen; Tsai, Sue; Chung, Jason; Clemente-Casares, Xavier; Ghazarian, Magar; Revelo, Xavier S; Lei, Helena; Luk, Cynthia T; Shi, Sally Yu; Surendra, Anuradha; Copeland, Julia K; Ahn, Jennifer; Prescott, David; Rasmussen, Brittany A; Chng, Melissa Hui Yen; Engleman, Edgar G; Girardin, Stephen E; Lam, Tony K T; Croitoru, Kenneth; Dunn, Shannon; Philpott, Dana J; Guttman, David S; Woo, Minna; Winer, Shawn; Winer, Daniel A

2015-04-07

Obesity has reached epidemic proportions, but little is known about its influence on the intestinal immune system. Here we show that the gut immune system is altered during high-fat diet (HFD) feeding and is a functional regulator of obesity-related insulin resistance (IR) that can be exploited therapeutically. Obesity induces a chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations. Reduction of the gut immune system, using beta7 integrin-deficient mice (Beta7(null)), decreases HFD-induced IR. Treatment of wild-type HFD C57BL/6 mice with the local gut anti-inflammatory, 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters. These beneficial effects are dependent on adaptive and gut immunity and are associated with reduced gut permeability and endotoxemia, decreased visceral adipose tissue inflammation, and improved antigen-specific tolerance to luminal antigens. Thus, the mucosal immune system affects multiple pathways associated with systemic IR and represents a novel therapeutic target in this disease. Copyright © 2015 Elsevier Inc. All rights reserved.

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation

PubMed Central

Zaiss, Mario M.; Rapin, Alexis; Lebon, Luc; Dubey, Lalit Kumar; Mosconi, Ilaria; Sarter, Kerstin; Piersigilli, Alessandra; Menin, Laure; Walker, Alan W.; Rougemont, Jacques; Paerewijck, Oonagh; Geldhof, Peter; McCoy, Kathleen D.; Macpherson, Andrew J.; Croese, John; Giacomin, Paul R.; Loukas, Alex; Junt, Tobias; Marsland, Benjamin J.; Harris, Nicola L.

2015-01-01

Summary Intestinal helminths are potent regulators of their host’s immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions. PMID:26522986

Ginsenoside Rb1 Treatment Attenuates Pulmonary Inflammatory Cytokine Release and Tissue Injury following Intestinal Ischemia Reperfusion Injury in Mice

PubMed Central

Zhou, Zhen; Meng, Qing-tao; Sun, Qian; Su, Wating; Xia, Zhengyuan; Xia, Zhong-yuan

2015-01-01

Objective. Intestinal ischemia reperfusion (II/R) injury plays a critical role in remote organ dysfunction, such as lung injury, which is associated with nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. In the present study, we tested whether ginsenoside Rb1 attenuated II/R induced lung injury by Nrf2/HO-1 pathway. Methods. II/R injury was induced in male C57BL/6J mice by 45 min of superior mesenteric artery (SMA) occlusion followed by 2 hours of reperfusion. Ginsenoside Rb1 was administrated prior to reperfusion with or without ATRA (all-transretinoic acid, the inhibitor of Nrf2/ARE signaling pathway) administration before II/R. Results. II/R induced lung histological injury, which is accompanied with increased levels of malondialdehyde (MDA), interleukin- (IL-) 6, and tumor necrosis factor- (TNF-) α but decreased levels of superoxide dismutase (SOD) and IL-10 in the lung tissues. Ginsenoside Rb1 reduced lung histological injury and the levels of TNF-α and MDA, as well as wet/dry weight ratio. Interestingly, the increased Nrf2 and HO-1 expression induced by II/R in the lung tissues was promoted by ginsenoside Rb1 treatment. All these changes could be inhibited or prevented by ATRA. Conclusion. Ginsenoside Rb1 is capable of ameliorating II/R induced lung injuries by activating Nrf2/HO-1 pathway. PMID:26161243

Role of innate immunity and altered intestinal motility in LPS- and MnCl2-induced intestinal intussusception in mice

PubMed Central

Killoran, Kristin E.; Miller, Amber D.; Uray, Karen S.; Weisbrodt, Norman W.; Pautler, Robia G.; Goyert, Sanna M.; van Rooijen, Nico

2014-01-01

Intestinal intussusception (ISS) commonly causes intestinal obstruction in children. One mechanism that has been proposed to cause ISS is inflammation-induced alteration of intestinal motility. We investigated whether innate inflammatory factors or altered motility is required for induction of ISS by LPS. We compared rates of ISS among BALB/c and C57BL/6 mice, mice lacking lymphocytes or depleted of phagocytes, or mice with defects in the Toll-like receptor 4 (TLR4) signaling pathway following administration of LPS or the Ca2+ analog MnCl2. At 6 or 2 h after administration of LPS or MnCl2, respectively, mice underwent image analysis to assess intestinal contraction rate or laparotomy to identify ISS. LPS-induced ISS (LPS-ISS) was observed in BALB/c mice, but not in C57BL/6 mice or any BALB/c mice with disruptions of TLR4 signaling. LPS-induced serum TNF-α, IL-6, and nitric oxide (NO) and intestinal NO levels were similar in BALB/c and C57BL/6 mice. The rate of LPS-ISS was significantly reduced in phagocyte-depleted, but not lymphocyte-deficient, mice. Intestinal contraction rates were reduced in LPS-ISS-susceptible BALB/c mice, but not in LPS-ISS-resistant C57BL/6 or TLR4 mutant mice, suggesting a role for reduced intestinal contraction rate in LPS-ISS susceptibility. This was tested with MnCl2, a Ca2+ antagonist that reduced intestinal contraction rates and induced ISS, irrespective of mouse strain. Therefore, LPS-ISS is initiated by innate immune signaling that requires TLR4 and phagocytes but may be independent of TNF-α, IL-6, and NO levels. Furthermore, alteration of intestinal motility, specifically, reduced intestinal contraction rate, is a key factor in the development of ISS. PMID:24407593

Morinda citrifolia (Noni) Fruit Juice Reduces Inflammatory Cytokines Expression and Contributes to the Maintenance of Intestinal Mucosal Integrity in DSS Experimental Colitis.

PubMed

Coutinho de Sousa, Beatriz; Reis Machado, Juliana; da Silva, Marcos Vinicius; da Costa, Thiago Alvares; Lazo-Chica, Javier Emilio; Degasperi, Thatiane do Prado; Rodrigues Junior, Virmondes; Sales-Campos, Helioswilton; Uber Bucek, Elizabeth; Freire Oliveira, Carlo José

2017-01-01

Morinda citrifolia L. (noni) has been shown to treat different disorders. However, data concerning its role in the treatment of intestinal inflammation still require clarification. In the current study, we investigated the effects of noni fruit juice (NFJ) in the treatment of C57BL/6 mice, which were continuously exposed to dextran sulfate sodium (DSS) for 9 consecutive days. NFJ consumption had no impact on the reduction of the clinical signs of the disease or on weight loss. Nonetheless, when a dilution of 1 : 10 was used, the intestinal architecture of the mice was preserved, accompanied by a reduction in the inflammatory infiltrate. Regardless of the concentration of NFJ, a decrease in both the activity of myeloperoxidase and the key inflammatory cytokines, TNF- α and IFN- γ , was also observed in the intestine. Furthermore, when NFJ was diluted 1 : 10 and 1 : 100, a reduction in the production of nitric oxide and IL-17 was detected in gut homogenates. Overall, the treatment with NFJ was effective in different aspects associated with disease progression and worsening. These results may point to noni fruit as an important source of anti-inflammatory molecules with a great potential to inhibit the progression of inflammatory diseases, such as inflammatory bowel disease.

Morinda citrifolia (Noni) Fruit Juice Reduces Inflammatory Cytokines Expression and Contributes to the Maintenance of Intestinal Mucosal Integrity in DSS Experimental Colitis

PubMed Central

Coutinho de Sousa, Beatriz; da Costa, Thiago Alvares; Lazo-Chica, Javier Emilio; Degasperi, Thatiane do Prado; Rodrigues Junior, Virmondes; Uber Bucek, Elizabeth

2017-01-01

Morinda citrifolia L. (noni) has been shown to treat different disorders. However, data concerning its role in the treatment of intestinal inflammation still require clarification. In the current study, we investigated the effects of noni fruit juice (NFJ) in the treatment of C57BL/6 mice, which were continuously exposed to dextran sulfate sodium (DSS) for 9 consecutive days. NFJ consumption had no impact on the reduction of the clinical signs of the disease or on weight loss. Nonetheless, when a dilution of 1 : 10 was used, the intestinal architecture of the mice was preserved, accompanied by a reduction in the inflammatory infiltrate. Regardless of the concentration of NFJ, a decrease in both the activity of myeloperoxidase and the key inflammatory cytokines, TNF-α and IFN-γ, was also observed in the intestine. Furthermore, when NFJ was diluted 1 : 10 and 1 : 100, a reduction in the production of nitric oxide and IL-17 was detected in gut homogenates. Overall, the treatment with NFJ was effective in different aspects associated with disease progression and worsening. These results may point to noni fruit as an important source of anti-inflammatory molecules with a great potential to inhibit the progression of inflammatory diseases, such as inflammatory bowel disease. PMID:28194046

Pro-inflammatory NF-κB and early growth response gene 1 regulate epithelial barrier disruption by food additive carrageenan in human intestinal epithelial cells.

PubMed

Choi, Hye Jin; Kim, Juil; Park, Seong-Hwan; Do, Kee Hun; Yang, Hyun; Moon, Yuseok

2012-06-20

The widely used food additive carrageenan (CGN) has been shown to induce intestinal inflammation, ulcerative colitis-like symptoms, or neoplasm in the gut epithelia in animal models, which are also clinical features of human inflammatory bowel disease. In this study, the effects of CGN on pro-inflammatory transcription factors NF-κB and early growth response gene 1 product (EGR-1) were evaluated in terms of human intestinal epithelial barrier integrity. Both pro-inflammatory transcription factors were elevated by CGN and only NF-κB activation was shown to be involved in the induction of pro-inflammatory cytokine interleukin-8. Moreover, the integrity of the in vitro epithelial monolayer under the CGN insult was maintained by both activated pro-inflammatory transcription factors NF-κB and EGR-1. Suppression of NF-κB or EGR-1 aggravated barrier disruption by CGN, which was associated with the reduced gene expression of tight junction component zonula occludens 1 and its irregular localization in the epithelial monolayer. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Immune deficiency vs. immune excess in inflammatory bowel diseases-STAT3 as a rheo-STAT of intestinal homeostasis.

PubMed

Leppkes, Moritz; Neurath, Markus F; Herrmann, Martin; Becker, Christoph

2016-01-01

Genome-wide association studies have provided many genetic alterations, conferring susceptibility to multifactorial polygenic diseases, such as inflammatory bowel diseases. Yet, how specific genetic alterations functionally affect intestinal inflammation often remains elusive. It is noteworthy that a large overlap of genes involved in immune deficiencies with those conferring inflammatory bowel disease risk has been noted. This has provided new arguments for the debate on whether inflammatory bowel disease arises from either an excess or a deficiency in the immune system. In this review, we highlight the functional effect of an inflammatory bowel disease-risk allele, which cannot be deduced from genome-wide association studies data alone. As exemplified by the transcription factor signal transducer and activator of transcription 3 (STAT3), we show that a single gene can have a plethora of effects in various cell types of the gut. These effects may individually contribute to the restoration of intestinal homeostasis on the one hand or pave the way for excessive immunopathology on the other, as an inflammatory "rheo-STAT". © Society for Leukocyte Biology.

Differential Alteration in Intestinal Epithelial Cell Expression of Toll-Like Receptor 3 (TLR3) and TLR4 in Inflammatory Bowel Disease

PubMed Central

Cario, Elke; Podolsky, Daniel K.

2000-01-01

Initiation and perpetuation of the inflammatory intestinal responses in inflammatory bowel disease (IBD) may result from an exaggerated host defense reaction of the intestinal epithelium to endogenous lumenal bacterial flora. Intestinal epithelial cell lines constitutively express several functional Toll-like receptors (TLRs) which appear to be key regulators of the innate response system. The aim of this study was to characterize the expression pattern of TLR2, TLR3, TLR4, and TLR5 in primary intestinal epithelial cells from patients with IBD. Small intestinal and colonic biopsy specimens were collected from patients with IBD (Crohn's disease [CD], ulcerative colitis [UC]) and controls. Non-IBD specimens were assessed by immunofluorescence histochemistry using polyclonal antibodies specific for TLR2, TLR3, TLR4, and TLR5. Primary intestinal epithelial cells (IEC) of normal mucosa constitutively expressed TLR3 and TLR5, while TLR2 and TLR4 were only barely detectable. In active IBD, the expression of TLR3 and TLR4 was differentially modulated in the intestinal epithelium. TLR3 was significantly downregulated in IEC in active CD but not in UC. In contrast, TLR4 was strongly upregulated in both UC and CD. TLR2 and TLR5 expression remained unchanged in IBD. These data suggest that IBD may be associated with distinctive changes in selective TLR expression in the intestinal epithelium, implying that alterations in the innate response system may contribute to the pathogenesis of these disorders. PMID:11083826

Extracellular cathepsin K exerts antimicrobial activity and is protective against chronic intestinal inflammation in mice.

PubMed

Sina, Christian; Lipinski, Simone; Gavrilova, Olga; Aden, Konrad; Rehman, Ateequr; Till, Andreas; Rittger, Andrea; Podschun, Rainer; Meyer-Hoffert, Ulf; Haesler, Robert; Midtling, Emilie; Pütsep, Katrin; McGuckin, Michael A; Schreiber, Stefan; Saftig, Paul; Rosenstiel, Philip

2013-04-01

Cathepsin K is a lysosomal cysteine protease that has pleiotropic roles in bone resorption, arthritis, atherosclerosis, blood pressure regulation, obesity and cancer. Recently, it was demonstrated that cathepsin K-deficient (Ctsk(-/-) ) mice are less susceptible to experimental autoimmune arthritis and encephalomyelitis, which implies a functional role for cathepsin K in chronic inflammatory responses. Here, the authors address the relevance of cathepsin K in the intestinal immune response during chronic intestinal inflammation. Chronic colitis was induced by administration of 2% dextran sodium sulphate (DSS) in distilled water. Mice were assessed for disease severity, histopathology and endoscopic appearance. Furthermore, DSS-exposed Ctsk(-/-) mice were treated by rectal administration of recombinant cathepsin K. Intestinal microflora was assessed by real-time PCR and 16srDNA molecular fingerprinting of ileal and colonic mucosal and faecal samples. Using Ctsk(-/-) mice, the authors demonstrate a protective role of cathepsin K against chronic DSS colitis. Dissecting the underlying mechanisms the authors found cathepsin K to be present in intestinal goblet cells and the mucin layer. Furthermore, a direct cathepsin K-mediated bactericidal activity against intestinal bacteria was demonstrated, which potentially explains the alteration of intestinal microbiota observed in Ctsk(-/-) mice. Rectal administration of recombinant cathepsin K in DSS-treated Ctsk(-/-) mice ameliorates the severity of intestinal inflammation. These data identify extracellular cathepsin K as an intestinal antibacterial factor with anti-inflammatory potential and suggest that topical administration of cathepsin K might provide a therapeutic option for patients with inflammatory bowel disease.

Low-molecular-weight fucoidan and high-stability fucoxanthin from brown seaweed exert prebiotics and anti-inflammatory activities in Caco-2 cells.

PubMed

Hwang, Pai-An; Phan, Nam Nhut; Lu, Wen-Jung; Ngoc Hieu, Bui Thi; Lin, Yen-Chang

2016-01-01

The aim of this study is to investigate the anti-inflammatory effects of low-molecular-weight fucoidan (LMF) and high-stability fucoxanthin (HS-Fucox) in a lipopolysaccharide-induced inflammatory Caco-2 cell line co-culture with B. lactis. We used various methods such as transepithelial resistance (TER) assay, cytokine secretion assay, and tight junction protein mRNA expression assay to examine LMF and HS-Fucox anti-inflammatory properties. LMF and HS-Fucox activated probiotic growth and reduced the inflammation of the intestinal epithelial cells. Moreover, the combination of LMFHS-Fucox dramatically enhanced the intestinal epithelial barrier and immune function against the lipopolysaccharide effect by inhibiting IL-1β and TNF-α and promoting IL-10 and IFN-γ. These findings suggested that LMF and HS-Fucox, alone or in combination, could be the potential natural compounds to enhance the immune system and have an anti-inflammatory effect on the intestinal cells.

Mechanisms of the anti-inflammatory effects of the natural secosteroids physalins in a model of intestinal ischaemia and reperfusion injury.

PubMed

Vieira, Angélica T; Pinho, Vanessa; Lepsch, Lucilia B; Scavone, Cristóforo; Ribeiro, Ivone M; Tomassini, Therezinha; Ribeiro-dos-Santos, Ricardo; Soares, Milena B P; Teixeira, Mauro M; Souza, Danielle G

2005-09-01

Reperfusion of an ischaemic tissue is associated with an intense inflammatory response and inflammation-mediated tissue injury. Physalins, a group of substances with secosteroidal chemical structure, are found in Physalis angulata stems and leaves. Here, we assessed the effects of physalins on the local, remote and systemic injuries following intestinal ischaemia and reperfusion (I/R) in mice and compared with the effects of dexamethasone. Following I/R injury, dexamethasone (10 mg kg(-1)) or physalin B or F markedly prevented neutrophil influx, the increase in vascular permeability in the intestine and the lungs. Maximal inhibition occurred at 20 mg kg(-1). Moreover, there was prevention of haemorrhage in the intestine of reperfused animals. Dexamethasone or physalins effectively suppressed the increase in tissue (intestine and lungs) and serum concentrations of TNF-alpha. Interestingly, treatment with the compounds was associated with enhancement of IL-10. The anti-inflammatory effects of dexamethasone or physalins were reversed by pretreatment with the corticoid receptor antagonist RU486 (25 mg kg(-1)). The drug compounds suppressed steady-state concentrations of corticosterone, but did not alter the reperfusion-associated increase in levels of corticosterone. The IL-10-enhancing effects of the drugs were not altered by RU486. In conclusion, the in vivo anti-inflammatory actions of physalins, natural steroidal compounds, appear to be mostly due to the activation of glucocorticoid receptors. Compounds derived from these natural secosteroids may represent novel therapeutic options for the treatment of inflammatory diseases.

Distinct inflammatory and cytopathic characteristics of Escherichia coli isolates from inflammatory bowel disease patients.

PubMed

Jensen, Stina Rikke; Mirsepasi-Lauridsen, Hengameh Chloé; Thysen, Anna Hammerich; Brynskov, Jørn; Krogfelt, Karen A; Petersen, Andreas Munk; Pedersen, Anders Elm; Brix, Susanne

2015-12-01

Escherichia coli (E. coli) may be implicated in the pathogenesis of inflammatory bowel disease (IBD), as implied from a higher prevalence of mucosa-associated E. coli in the gut of IBD-affected individuals. However, it is unclear whether different non-diarrheagenic E. coli spp. segregate from each other in their ability to promote intestinal inflammation. Herein we compared the inflammation-inducing properties of non-diarrheagenic LF82, 691-04A, E. coli Nissle 1917 (ECN) and eleven new intestinal isolates from different locations in five IBD patients and one healthy control. Viable E. coli were cultured with human monocyte-derived dendritic cells (moDCs) and monolayers of intestinal epithelial cells (IECs), followed by analysis of secreted cytokines, intracellular levels of reactive oxygen species and cellular death. The IBD-associated E. coli LF82 induced the same dose-dependent inflammatory cytokine profile as ECN and ten of the new E. coli isolates displayed as high level IL-12p70, IL-1β, IL-23 and TNF-α from moDCs irrespective of their site of isolation (ileum/colon/faeces), disease origin (diseased/non-diseased) or known virulence factors. Contrarily, 691-04A and one new IBD E. coli isolate induced a different cellular phenotype with enhanced killing of moDCs and IECs, coupled to elevated IL-18. The cytopathic nature of 691-04A and one other IBD E. coli isolate suggests that colonization with specific non-diarrheagenic E. coli could promote intestinal barrier leakage and profound intestinal inflammation, while LF82, ECN and the remaining non-diarrheagenic E. coli isolates hold notorious pro-inflammatory characteristics that can progress inflammation in case of intestinal barrier leakage. Copyright © 2015 Elsevier GmbH. All rights reserved.

Hypo-responsiveness of interleukin-8 production in human embryonic epithelial intestine 407 cells independent of NF-{kappa}B pathway: New lessons from endotoxin and ribotoxic deoxynivalenol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moon, Yuseok; Yang, Hyun; Park, Seung-Hwan

Mucosal epithelium senses external toxic insults and transmits the danger signals into the epithelial cells in order to activate a broad range of inflammatory responses. However, pre-exposure to the commensal endotoxins can induce inflammatory tolerance and maintain the homeostasis without excessive immune responses. We recently reported that ribotoxin deoxynivalenol (DON) and its derivatives elicited the pro-inflammatory response as the mucosal insults in human epithelial cells. Taking the knowledge into consideration, we tested the hypothesis that endotoxin pre-exposure can attenuate ribotoxin-induced epithelial interleukin-8 (IL-8) production via a tolerance mechanism. Pre-exposure to endotoxin repressed IL-8 release and its gene expression. However, inflammatorymore » tolerance was not mediated by the attenuated NF-{kappa}B activation which has been generally recognized as the major mediator of LPS-mediated toll-like receptor (TLR) signaling pathway. Instead, pre-exposure to endotoxin was observed to trigger the delayed induction of peroxisome proliferator-activated receptor gamma (PPAR-{gamma}) which contributed to the diminished IL-8 production in the human epithelial cells. Moreover, endogenous PPAR-{gamma} agonist suppressed toxicant-mediated interleukin-8 production and IL-8 mRNA stability. Taken together, endotoxin induced hypo-production of pro-inflammatory cytokine IL-8 in the human epithelial cells, which was associated with the delayed activation of PPAR-{gamma} expression by pre-existing endotoxin.« less

Nutrition Facts in Multiple Sclerosis

PubMed Central

Rossano, Rocco

2015-01-01

The question whether dietary habits and lifestyle have influence on the course of multiple sclerosis (MS) is still a matter of debate, and at present, MS therapy is not associated with any information on diet and lifestyle. Here we show that dietary factors and lifestyle may exacerbate or ameliorate MS symptoms by modulating the inflammatory status of the disease both in relapsing-remitting MS and in primary-progressive MS. This is achieved by controlling both the metabolic and inflammatory pathways in the human cell and the composition of commensal gut microbiota. What increases inflammation are hypercaloric Western-style diets, characterized by high salt, animal fat, red meat, sugar-sweetened drinks, fried food, low fiber, and lack of physical exercise. The persistence of this type of diet upregulates the metabolism of human cells toward biosynthetic pathways including those of proinflammatory molecules and also leads to a dysbiotic gut microbiota, alteration of intestinal immunity, and low-grade systemic inflammation. Conversely, exercise and low-calorie diets based on the assumption of vegetables, fruit, legumes, fish, prebiotics, and probiotics act on nuclear receptors and enzymes that upregulate oxidative metabolism, downregulate the synthesis of proinflammatory molecules, and restore or maintain a healthy symbiotic gut microbiota. Now that we know the molecular mechanisms by which dietary factors and exercise affect the inflammatory status in MS, we can expect that a nutritional intervention with anti-inflammatory food and dietary supplements can alleviate possible side effects of immune-modulatory drugs and the symptoms of chronic fatigue syndrome and thus favor patient wellness. PMID:25694551

Cancer in Inflammatory Bowel Disease: lessons from animal models

PubMed Central

Sussman, Daniel; Santaolalla, Rebeca; Strobel, Sebastian; Dheer, Rishu; Abreu, Maria T.

2012-01-01

Purpose of the review Human colitis-associated cancers (CAC) represent a heterogeneous group of conditions in which multiple oncogenic pathways are involved. In this manuscript we reviewed the latest studies using genetic, chemically induced, bacterial and innate immunity induced experimental models of colitis-associated cancer. Recent findings Using the azoxymethane-dextran sodium sulfate model wound healing pathways seems to be required in the development of CAC. There is also an emerging understanding that commensal and/or pathogenic bacteria can promote tumorigenesis, through T cell mediated inflammation. Using specific transgenic mice (villin-CD98, T cell SMAD7, villin-TLR4) or specific knock-out mice, investigators have identified that derangements in epithelial or innate and adaptive immune pathways can result in CAC. Subtle perturbations in epithelial repair—both too little or too exuberant, can render mice susceptible to tumorigenesis. Summary With the aid of animal models, we have witnessed a rapid expansion of our knowledge of the molecular and immunologic mechanisms underlying inflammatory cancers. Though animal models have contributed a discrete amount of information to our understanding of tumorigenesis in the setting of intestinal inflammation it is clear that no single animal model will be able to adequately recapitulate the pathogenesis of complex CRCs, but each model gets us one step closer to comprehending the nature of CAC. PMID:22614440

Review article: anti-inflammatory mechanisms of action of Saccharomyces boulardii.

PubMed

Pothoulakis, C

2009-10-15

Saccharomyces boulardii, a well-studied probiotic, can be effective in inflammatory gastrointestinal diseases with diverse pathophysiology, such as inflammatory bowel disease (IBD), and bacterially mediated or enterotoxin-mediated diarrhoea and inflammation. To discuss the mechanisms of action involved in the intestinal anti-inflammatory action of S. boulardii. Review of the literature related to the anti-inflammatory effects of this probiotic. Several mechanisms of action have been identified directed against the host and pathogenic microorganisms. S. boulardii and S. boulardii secreted-protein(s) inhibit production of proinflammatory cytokines by interfering with the global mediator of inflammation nuclear factor kappaB, and modulating the activity of the mitogen-activated protein kinases ERK1/2 and p38. S. boulardii activates expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) that protects from gut inflammation and IBD. S. boulardii also suppresses 'bacteria overgrowth' and host cell adherence, releases a protease that cleaves C. difficile toxin A and its intestinal receptor and stimulates antibody production against toxin A. Recent results indicate that S. boulardii may interfere with IBD pathogenesis by trapping T cells in mesenteric lymph nodes. The multiple anti-inflammatory mechanisms exerted by S. boulardii provide molecular explanations supporting its effectiveness in intestinal inflammatory states.

Influence of deoxynivalenol on NF-kappaB activation and IL-8 secretion in human intestinal Caco-2 cells.

PubMed

Van De Walle, Jacqueline; Romier, Béatrice; Larondelle, Yvan; Schneider, Yves-Jacques

2008-04-01

Deoxynivalenol (DON) is the most prevalent trichothecene mycotoxin in crops in Europe and North America. In human intestinal Caco-2 cells, DON activates the mitogen-activated protein kinases (MAPKs). We hypothesized a link between DON ingestion and intestinal inflammation, and used Caco-2 cells to assess the effects of DON, at plausible intestinal concentrations (250-10,000 ng/ml), on inflammatory mediators acting downstream the MAPKs cascade i.e. activation of nuclear factor-kappaB (NF-kappaB) and interleukin-8 (IL-8) secretion. In addition, Caco-2 cells were co-exposed to pro-inflammatory stimuli in order to mimic an inflamed intestinal epithelium. Dose-dependent increases in NF-kappaB activity and IL-8 secretion were observed, reaching 1.4- and 7.6-fold, respectively using DON at 10 microg/ml. Phosphorylation of inhibitor-kappaB (IkappaB) increased (1.6-fold) at DON levels <0.5 microg/ml. Exposure of Caco-2 cells to pro-inflammatory agents, i.e. 25 ng/ml interleukin-1beta, 100 ng/ml tumor necrosis factor-alpha or 10 microg/ml lipopolysaccharides, activated NF-kappaB and increased IL-8 secretion. Synergistic interactions between these stimuli and DON were observed. These data show that DON induces NF-kappaB activation and IL-8 secretion dose-dependently in Caco-2 cells, and this effect was accentuated upon pro-inflammatory stimulation, suggesting DON exposure could cause or exacerbate intestinal inflammation.

Implementation of Mass Cytometry as a Tool for Mechanism of Action Studies in Inflammatory Bowel Disease.

PubMed

Tyler, Christopher J; Pérez-Jeldres, Tamara; Ehinger, Erik; Capaldo, Brian; Karuppuchamy, Thangaraj; Boyer, Joshua D; Patel, Derek; Dulai, Parambir; Boland, Brigid S; Lannigan, Joanne; Eckmann, Lars; Ernst, Peter B; Sandborn, William J; Ho, Samuel B; Rivera-Nieves, Jesús

2018-06-08

Novel therapeutics for inflammatory bowel disease (IBD) are under development, yet mechanistic readouts at the tissue level are lacking. Techniques to assess intestinal immune composition could represent a valuable tool for mechanism of action (MOA) studies of novel drugs. Mass cytometry enables analysis of intestinal inflammatory cell infiltrate and corresponding molecular fingerprints with unprecedented resolution. Here, we aimed to optimize the methodology for isolation and cryopreservation of cells from intestinal tissue to allow for the potential implementation of mass cytometry in MOA studies. We investigated key technical issues, including minimal tissue requirements, cell isolation protocols, and cell storage, using intestinal biopsies and peripheral blood from healthy individuals. High-dimensional mass cytometry was employed for the analyses of biopsy-derived intestinal cellular subsets. Dithiothreitol and mechanical dissociation decreased epithelial cell contamination and allowed for isolation of adequate cell numbers from 2 to 4 colonic or ileal biopsies (6 × 104±2 × 104) after a 20-minute collagenase digestion, allowing for reliable detection of most major immune cell subsets. Biopsies and antibody-labeled mononuclear cells could be cryopreserved for later processing and acquisition (viability > 70%; P < 0.05). Mass cytometry represents a unique tool for deep immunophenotyping intestinal cell composition. This technique has the potential to facilitate analysis of drug actions at the target tissue by identifying specific cellular subsets and their molecular signatures. Its widespread implementation may impact not only IBD research but also other gastrointestinal conditions where inflammatory cells play a role in pathogenesis.

Dysbiosis of the gut microbiota in disease.

PubMed

Carding, Simon; Verbeke, Kristin; Vipond, Daniel T; Corfe, Bernard M; Owen, Lauren J

2015-01-01

There is growing evidence that dysbiosis of the gut microbiota is associated with the pathogenesis of both intestinal and extra-intestinal disorders. Intestinal disorders include inflammatory bowel disease, irritable bowel syndrome (IBS), and coeliac disease, while extra-intestinal disorders include allergy, asthma, metabolic syndrome, cardiovascular disease, and obesity.

Probiotics and prebiotics in inflammatory bowel disease: microflora 'on the scope'.

PubMed

Damaskos, Dimitrios; Kolios, George

2008-04-01

The intestinal microflora is a large bacterial community that colonizes the gut, with a metabolic activity equal to an organ and various functions that affect the physiology and pathology of the host's mucosal immune system. Intestinal bacteria are useful in promotion of human health, but certain components of microflora, in genetically susceptible individuals, contribute to various pathological disorders, including inflammatory bowel disease. Clinical and experimental observations indicate an imbalance in protective and harmful microflora components in these disorders. Manipulation of gut flora to enhance its protective and beneficial role represents a promising field of new therapeutic strategies of inflammatory bowel disease. In this review, we discuss the implication of gut flora in the intestinal inflammation that justifies the role of probiotics and prebiotics in the prevention and treatment of inflammatory bowel disease and we address the evidence for therapeutic benefits from their use in experimental models of colitis and clinical trials.

Bifidobacterium breve MCC-117 Induces Tolerance in Porcine Intestinal Epithelial Cells: Study of the Mechanisms Involved in the Immunoregulatory Effect

PubMed Central

MURATA, Kozue; TOMOSADA, Yohsuke; VILLENA, Julio; CHIBA, Eriko; SHIMAZU, Tomoyuki; ASO, Hisashi; IWABUCHI, Noriyuki; XIAO, Jin-zhong; SAITO, Tadao; KITAZAWA, Haruki

2014-01-01

Bifidobacterium breve MCC-117 is able to significantly reduce the expression of inflammatory cytokines in porcine intestinal epithelial (PIE) cells and to improve IL-10 levels in CD4+CD25high Foxp3+ lymphocytes in response to heat-stable enterotoxigenic Escherichia coli (ETEC) pathogen-associated molecular patterns (PAMPs), while the immunoregulatory effect of B. adolescentis ATCC15705 was significantly lower than that observed for the MCC-117 strain. Considering the different capacities of the two bifidobacterium strains to activate toll-like receptor (TLR)-2 and their differential immunoregulatory activities in PIE and immune cells, we hypothesized that comparative studies with both strains could provide important information regarding the molecular mechanism(s) involved in the anti-inflammatory activity of bifidobacteria. In this work, we demonstrated that the anti-inflammatory effect of B. breve MCC-117 was achieved by a complex interaction of multiple negative regulators of TLRs as well as inhibition of multiple signaling pathways. We showed that B. breve MCC-117 reduced heat-stable ETEC PAMP-induced NF-κB, p38 MAPK and PI3 K activation and expression of pro-inflammatory cytokines in PIE cells. In addition, we demonstrated that B. breve MCC-117 may activate TLR2 synergistically and cooperatively with one or more other pattern recognition receptors (PRRs), and that interactions may result in a coordinated sum of signals that induce the upregulation of A20, Bcl-3, Tollip and SIGIRR. Upregulation of these negative regulators could have an important physiological impact on maintaining or reestablishing homeostatic TLR signals in PIE cells. Therefore, in the present study, we gained insight into the molecular mechanisms involved in the immunoregulatory effect of B. breve MCC-117. PMID:24936377

Toll-like Receptor Signaling Activation by Entamoeba histolytica Induces Beta Defensin 2 in Human Colonic Epithelial Cells: Its Possible Role as an Element of the Innate Immune Response

PubMed Central

Ayala-Sumuano, Jorge-Tonatiuh; Téllez-López, Victor M.; Domínguez-Robles, M. del Carmen; Shibayama-Salas, Mineko; Meza, Isaura

2013-01-01

Background Entamoeba histolytica, a protozoan parasite of humans, produces dysenteric diarrhea, intestinal mucosa damage and extraintestinal infection. It has been proposed that the intestinal microbiota composition could be an important regulatory factor of amebic virulence and tissue invasion, particularly if pathogenic bacteria are present. Recent in vitro studies have shown that Entamoeba histolytica trophozoites induced human colonic CaCo2 cells to synthesize TLR-2 and TLR-4 and proinflammatory cytokines after binding to the amebic Gal/GalNac lectin carbohydrate recognition domain. The magnitude of the inflammatory response induced by trophozoites and the subsequent cell damage were synergized when cells had previously been exposed to pathogenic bacteria. Methodology/Principal Findings We show here that E. histolytica activation of the classic TLR pathway in CaCo2 cells is required to induce β defensin-2 (HBD2) mRNA expression and production of a 5-kDa cationic peptide with similar properties to the antimicrobial HBD2 expressed by CaCo2 cells exposed to enterotoxigenic Escherichia coli. The induced peptide showed capacity to permeabilize membranes of bacteria and live trophozoites. This activity was abrogated by inhibition of TLR2/4-NFκB pathway or by neutralization with an anti-HBD2 antibody. Conclusions/Significance Entamoeba histolytica trophozoites bind to human intestinal cells and induce expression of HBD2; an antimicrobial molecule with capacity to destroy pathogenic bacteria and trophozoites. HDB2's possible role as a modulator of the course of intestinal infections, particularly in mixed ameba/bacteria infections, is discussed. PMID:23469306

Dextran sulphate sodium (DSS) causes intestinal histopathology and inflammatory changes consistent with increased gut leakiness in chickens.

PubMed

Zou, X; Ji, J; Wang, J; Qu, H; Shu, D M; Guo, F Y; Luo, C L

2018-04-01

1. The clinical severity, histological changes, indicators of gut leakiness and inflammatory cytokine profiles were studied in chickens with dextran sulphate sodium (DSS)-induced intestinal inflammation. 2. The experimental groups (1.25%, 1.5% and 2.5% DSS) showed clinical signs, such as loose stools and weight loss, which increased with additional treatment days and, as expected, the effects of DSS-induced intestinal inflammation were time and dose-dependent. 3. After 10 d, histological manifestations were evident, including goblet cell depletion, mucus layer loss, significantly shorter villi and a thinner total ileal mucosa. 4. The d(-)-lactate value, which was used as a gut leakiness indicator, was significantly increased in the 2.5% DSS group. 5. Expression of the inflammatory cytokines interleukin-1Beta, tumour necrosis factor alpha and interleukin-10 in the serum significantly increased with DSS treatment. 6. This study indicates that the experimental intestinal inflammation induced by DSS is an ideal model to study the pathogenic mechanisms of intestinal inflammation in chickens and to test the efficacy of therapies.

Trust your gut: galvanizing nutritional interest in intestinal cholesterol metabolism for protection against cardiovascular diseases.

PubMed

Wegner, Casey J; Kim, Bohkyung; Lee, Jiyoung

2013-01-16

Recent studies have demonstrated that the intestine is a key target organ for overall health and longevity. Complementing these studies is the discovery of the trans-intestinal cholesterol efflux pathway and the emerging role of the intestine in reverse cholesterol transport. The surfacing dynamics of the regulation of cholesterol metabolism in the intestine provides an attractive platform for intestine-specific nutritional intervention strategies to lower blood cholesterol levels for protection against cardiovascular diseases. Notably, there is mounting evidence that stimulation of pathways associated with calorie restriction may have a large effect on the regulation of cholesterol removal by the intestine. However, intestinal energy metabolism, specifically the idiosyncrasies surrounding intestinal responses to energy deprivation, is poorly understood. The goal of this paper is to review recent insights into cholesterol regulation by the intestine and to discuss the potential for positive regulation of intestine-driven cholesterol removal through the nutritional induction of pathways associated with calorie restriction.

Trust Your Gut: Galvanizing Nutritional Interest in Intestinal Cholesterol Metabolism for Protection against Cardiovascular Diseases

PubMed Central

Wegner, Casey J.; Kim, Bohkyung; Lee, Jiyoung

2013-01-01

Recent studies have demonstrated that the intestine is a key target organ for overall health and longevity. Complementing these studies is the discovery of the trans-intestinal cholesterol efflux pathway and the emerging role of the intestine in reverse cholesterol transport. The surfacing dynamics of the regulation of cholesterol metabolism in the intestine provides an attractive platform for intestine-specific nutritional intervention strategies to lower blood cholesterol levels for protection against cardiovascular diseases. Notably, there is mounting evidence that stimulation of pathways associated with calorie restriction may have a large effect on the regulation of cholesterol removal by the intestine. However, intestinal energy metabolism, specifically the idiosyncrasies surrounding intestinal responses to energy deprivation, is poorly understood. The goal of this paper is to review recent insights into cholesterol regulation by the intestine and to discuss the potential for positive regulation of intestine-driven cholesterol removal through the nutritional induction of pathways associated with calorie restriction. PMID:23325147

Toll-like receptors in inflammatory bowel diseases: a decade later.

PubMed

Cario, Elke

2010-09-01

Differential alteration of Toll-like receptor (TLR) expression in inflammatory bowel disease (IBD) was first described 10 years ago. Since then, studies from many groups have led to the current concept that TLRs represent key mediators of innate host defense in the intestine, involved in maintaining mucosal as well as commensal homeostasis. Recent findings in diverse murine models of colitis have helped to reveal the mechanistic importance of TLR dysfunction in IBD pathogenesis. It has become evident that environment, genetics, and host immunity form a multidimensional and highly interactive regulatory triad that controls TLR function in the intestinal mucosa. Imbalanced relationships within this triad may promote aberrant TLR signaling, critically contributing to acute and chronic intestinal inflammatory processes in IBD colitis and associated cancer.

Human cytokine responses induced by Gram-positive cell walls of normal intestinal microbiota

PubMed Central

Chen, T; Isomäki, P; Rimpiläinen, M; Toivanen, P

1999-01-01

The normal microbiota plays an important role in the health of the host, but little is known of how the human immune system recognizes and responds to Gram-positive indigenous bacteria. We have investigated cytokine responses of peripheral blood mononuclear cells (PBMC) to Gram-positive cell walls (CW) derived from four common intestinal indigenous bacteria, Eubacterium aerofaciens (Eu.a.), Eubacterium limosum(Eu.l.), Lactobacillus casei(L.c.), and Lactobacillus fermentum (L.f.). Our results indicate that Gram-positive CW of the normal intestinal microbiota can induce cytokine responses of the human PBMC. The profile, level and kinetics of these responses are similar to those induced by lipopolysaccharide (LPS) or CW derived from a pathogen, Streptococcus pyogenes (S.p.). Bacterial CW are capable of inducing production of a proinflammatory cytokine, tumour necrosis factor-alpha (TNF-α), and an anti-inflammatory cytokine, IL-10, but not that of IL-4 or interferon-gamma (IFN-γ). Monocytes are the main cell population in PBMC to produce TNF-α and IL-10. Induction of cytokine secretion is serum-dependent; both CD14-dependent and -independent pathways are involved. These findings suggest that the human cytokine responses induced by Gram-positive CW of the normal intestinal microbiota are similar to those induced by LPS or Gram-positive CW of the pathogens. PMID:10540188

Human Intestinal Barrier Function in Health and Disease

PubMed Central

König, Julia; Wells, Jerry; Cani, Patrice D; García-Ródenas, Clara L; MacDonald, Tom; Mercenier, Annick; Whyte, Jacqueline; Troost, Freddy; Brummer, Robert-Jan

2016-01-01

The gastrointestinal tract consists of an enormous surface area that is optimized to efficiently absorb nutrients, water, and electrolytes from food. At the same time, it needs to provide a tight barrier against the ingress of harmful substances, and protect against a reaction to omnipresent harmless compounds. A dysfunctional intestinal barrier is associated with various diseases and disorders. In this review, the role of intestinal permeability in common disorders such as infections with intestinal pathogens, inflammatory bowel disease, irritable bowel syndrome, obesity, celiac disease, non-celiac gluten sensitivity, and food allergies will be discussed. In addition, the effect of the frequently prescribed drugs proton pump inhibitors and non-steroidal anti-inflammatory drugs on intestinal permeability, as well as commonly used methods to assess barrier function will be reviewed. PMID:27763627

Clinical importance of IL-22 cascade in IBD.

PubMed

Mizoguchi, Atsushi; Yano, Arisa; Himuro, Hidetomo; Ezaki, Yui; Sadanaga, Takayuki; Mizoguchi, Emiko

2018-04-01

IL-22 is a relatively new cytokine that is characterized by several unique biological properties. In the intestines, the effect of IL-22 is restricted mainly to non-lymphoid cells such as epithelial cells. Interestingly, the expression pattern and major cellular source of IL-22 have distinct difference between large and small intestines. IL-22 possesses an ability to constitutively activate STAT3 for promoting epithelial cell regeneration and reinforcing mucosal barrier integrity through stimulating the expression of anti-bacterial peptide and mucins. Of note, IL-22 is characterized as a two-faced cytokine that can play not only protective but also deleterious roles in the intestinal inflammation depending on the cytokine environment such as the expression levels of IL-23, T-bet, and IL-22 binding protein. Most importantly, clinical relevance of IL-22 to inflammatory bowel disease has been well highlighted. Mucosal healing, which represents the current therapeutic goal for IBD, can be induced by IL-22. Indeed, indigo naturalis, which can activate IL-22 pathway through Ahr, has been shown in a clinical trial to exhibit a strong therapeutic effect on ulcerative colitis. Despite the beneficial effect of IL-22, continuous activation of the IL-22 pathway increases the risk of colitis-associated cancer, particularly in patients with an extended history of IBD. This review article discusses how IL-22 regulates colitis, how beneficial versus deleterious effects of IL-22 is determined, and why IL-22 represents a promising target for IBD therapy.

Dietary zinc deficiency reduced growth performance, intestinal immune and physical barrier functions related to NF-κB, TOR, Nrf2, JNK and MLCK signaling pathway of young grass carp (Ctenopharyngodon idella).

PubMed

Song, Zheng-Xing; Jiang, Wei-Dan; Liu, Yang; Wu, Pei; Jiang, Jun; Zhou, Xiao-Qiu; Kuang, Sheng-Yao; Tang, Ling; Tang, Wu-Neng; Zhang, Yong-An; Feng, Lin

2017-07-01

Our study investigated the effects of dietary zinc (Zn) deficiency on growth performance, intestinal immune and physical barrier functions of young grass carp (Ctenopharyngodon idella). A total of 630 grass carp (244.14 ± 0.40 g) were fed graded levels of zinc lactate (10.71, 30.21, 49.84, 72.31, 92.56, 110.78 mg Zn/kg diet) and one zinc sulfate group (56.9 mg Zn/kg diet) for 60 days. At the end of the feeding trial, fish were challenged with Aeromonas hydrophila for 14 days. These results indicated that compared with optimal dietary Zn level, dietary Zn deficiency (10.71 mg/kg diet) decreased the production of antibacterial compounds, up-regulated pro-inflammatory cytokines related to nuclear factor kappa B (NF-κB) and down-regulated anti-inflammatory cytokines related to target of rapamycin (TOR) in three intestinal segments of young grass carp (P < 0.05), suggesting that dietary Zn deficiency could impair intestinal immune barrier of fish; decreased the activities and mRNA levels of antioxidant enzymes related to NF-E2-related factor 2 (Nrf2), up-regulated the mRNA levels of caspase-3, -7, -8, -9 related to p38 mitogen activated protein (p38 MAPK) and c-Jun N-terminal protein kinase (JNK), down-regulated the mRNA levels of tight junction complexes (TJs) related to myosin light chain kinase (MLCK) in three intestinal segments of young grass carp (P < 0.05), demonstrating that dietary Zn deficiency could injury intestinal physical barrier of fish. Besides, the Zn requirements (zinc lactate as Zn source) based on percent weight gain (PWG), against enteritis morbidity, acid phosphatase (ACP) activity in the proximal intestine (PI) and malondialdehyde (MDA) content in the PI of young grass carp was estimated to be 61.2, 61.4, 69.2 and 69.5 mg/kg diet, respectively. Finally, based on specific growth rate (SGR), feed efficiency (FE) and against enteritis morbidity of young grass carp, the efficacy of zinc lactate relative to zinc sulfate were 132.59%, 135.27% and 154.04%, respectively. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bifidobacterium pseudocatenulatum CECT7765 promotes a TLR2-dependent anti-inflammatory response in intestinal lymphocytes from mice with cirrhosis.

PubMed

Moratalla, Alba; Gómez-Hurtado, Isabel; Moya-Pérez, Ángela; Zapater, Pedro; Peiró, Gloria; González-Navajas, José M; Gómez Del Pulgar, Eva Maria; Such, José; Sanz, Yolanda; Francés, Rubén

2016-02-01

Intestinal homeostasis plays an important role in bacteria-derived complications in cirrhosis. Intestinal lymphocytes are responsible for immune effector functions and can be modulated by certain probiotics. We evaluate the interaction between Bifidobacterium pseudocatenulatum CECT7765 and intestinal lymphocytes in mice with cirrhosis. Cirrhosis was induced by intragastrical administration of carbon tetrachloride in Balb/C mice. One week prior to laparotomy, animals received B. pseudocatenulatum CECT7765 (10(7), 10(9) or 10(10) cfu/daily) or placebo. Chemokine receptor and cytokine expression were evaluated in intestinal lymphocytes. Gut permeability was studied by FITC-LPS recovery in vivo. Luminal antigens, inflammation and functional markers were evaluated in liver samples. Bifidobacterium pseudocatenulatum CECT7765 decreased the expression of pro-inflammatory chemokine receptors CCR6, CCR9, CXCR3 and CXCR6 in intestinal lymphocytes from cirrhotic mice in a concentration-dependent manner. The bifidobacterial strain induced a shift towards an anti-inflammatory cytokine profile in this cell subset. B. pseudocatenulatum CECT7765-induced inflammatory modulation was TLR2-mediated, as in vitro TLR2 blockade inhibited the reduction of TNF-alpha and its receptors and the increase of IL-10 and IL-10 receptor secretion. The recovery rate of administered fluorescence-labelled endotoxin was significantly and dose-dependently lowered with the bifidobacterial strain. The reduced intestinal permeability was associated with a decreased burden of bacterial antigens in the liver of mice treated with B. pseudocatenulatum CECT7765. Liver function and inflammation were improved with the use of the bifidobacterial strain at the highest dose tested (10(10) cfu). Bifidobacterium pseudocatenulatum CECT7765 improves gut homeostasis and prevents gut-derived complications in experimental chronic liver disease.

Effects of shenling baizhu powder herbal formula on intestinal microbiota in high-fat diet-induced NAFLD rats.

PubMed

Zhang, Yupei; Tang, Kairui; Deng, Yuanjun; Chen, Runsen; Liang, Shu; Xie, Huijun; He, Yifang; Chen, Yanning; Yang, Qinhe

2018-06-01

Worldwide, non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease closely associated with obesity, diabetes and other metabolic diseases. Shenling Baizhu powder (SLBZP), a formulation of a variety of natural medicinal plants, has hepatoprotective properties and clinical efficacy in treating non-infectious intestinal disease. SLBZP has improved NAFLD symptoms; however, its mechanism of action is unknown. We established an NAFLD model in rats given a high-fat diet (HFD), administered different interventions and measured serum biochemical indices and inflammatory factors. Liver tissues were stained with hematoxylin and eosin (HE) and oil red O, and colon tissues were analyzed by immunohistochemistry. The expression profiles of liver TLR4 pathway related protein was confirmed by western blotting. Changes in intestinal microbiota composition were analyzed using a 16S rDNA sequencing technique. Of note, SLBZP effectively reduced body weight in HFD-fed rats (p < 0.05). Serum biochemical analysis indicated that SLBZP decreased the serum level of total cholesterol (TC) and improved liver function. Additionally, SLBZP decreased the serum level of endotoxin, tumor necrosis factor α (TNF-α), interleukin-1β (IL-β) (p < 0.05), and decreased the expression of TLR4 pathway related protein. Pathological examination showed that SLBZP alleviates hepatic steatosis and repairs colon mucosa. Microbiome analysis revealed that SLBZP improved the abundance of intestinal microbiota. In taxonomy-based analysis, compared with control rats, SLBZP-treated rats showed obvious changes in intestinal microbiota composition. Moreover, SLBZP increased the relative abundance of short-chain fatty acid (SCFA)-producing bacteria, including Bifidobacterium and Anaerostipes. Taken together, these results suggest that the effects of SLBZP against NAFLD may be related to the increased abundance of beneficial gut microbiota and decreased levels of LPS in the portal vein. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Caspase recruitment domain 9, microbiota, and tryptophan metabolism: dangerous liaisons in inflammatory bowel diseases.

PubMed

Lamas, Bruno; Richard, Mathias L; Sokol, Harry

2017-07-01

Inflammatory bowel diseases (IBDs) develop as a result of a combination of genetic predisposition, dysbiosis of the gut microbiota, and environmental influences. Here, we describe an example of how caspase recruitment domain 9 (CARD9), one of the numerous IBD susceptibility genes, participate to colitis susceptibility by shaping gut microbiota to produce tryptophan metabolites. Recent study showed that CARD9 mice are more susceptible to colitis as a result of impaired interleukin 22 signaling pathway. Furthermore, aryl hydrocarbon receptor (AhR) ligands from tryptophan metabolism by the gut microbiota participate to intestinal homeostasis by inducing production of interleukin 22 by intestinal immune cells. These data suggest an interaction between CARD9 and the ability of gut microbiota to produce AhR ligands. The microbiota from CARD9 mice fails to metabolize tryptophan leading to defective AhR activation which contributes to the susceptibility of mice to colitis by decreased interleukin 22 production. These effects were abrogated in the presence of AhR agonist. Reduced production of AhR ligands is also observed in the microbiota from individuals with IBD, particularly in those with CARD9 risk alleles associated with IBD. Correcting impaired microbiota functions, such as ability to produce AhR ligands, is an attractive strategy in IBD.

Intestinal barrier: A gentlemen’s agreement between microbiota and immunity

PubMed Central

Caricilli, Andrea Moro; Castoldi, Angela; Câmara, Niels Olsen Saraiva

2014-01-01

Our body is colonized by more than a hundred trillion commensals, represented by viruses, bacteria and fungi. This complex interaction has shown that the microbiome system contributes to the host’s adaptation to its environment, providing genes and functionality that give flexibility of diet and modulate the immune system in order not to reject these symbionts. In the intestine, specifically, the microbiota helps developing organ structures, participates of the metabolism of nutrients and induces immunity. Certain components of the microbiota have been shown to trigger inflammatory responses, whereas others, anti-inflammatory responses. The diversity and the composition of the microbiota, thus, play a key role in the maintenance of intestinal homeostasis and explain partially the link between intestinal microbiota changes and gut-related disorders in humans. Tight junction proteins are key molecules for determination of the paracellular permeability. In the context of intestinal inflammatory diseases, the intestinal barrier is compromised, and decreased expression and differential distribution of tight junction proteins is observed. It is still unclear what is the nature of the luminal or mucosal factors that affect the tight junction proteins function, but the modulation of the immune cells found in the intestinal lamina propria is hypothesized as having a role in this modulation. In this review, we provide an overview of the current understanding of the interaction of the gut microbiota with the immune system in the development and maintenance of the intestinal barrier. PMID:24891972

An integrative view of microbiome-host interactions in inflammatory bowel diseases

PubMed Central

Wlodarska, Marta; Kostic, Aleksandar D.; Xavier, Ramnik J.

2015-01-01

Summary The intestinal microbiota, which is composed of bacteria, viruses, and micro-eukaryotes, acts as an accessory organ system with distinct functions along the intestinal tract that are critical for health. This review focuses on how the microbiota drives intestinal disease through alterations in microbial community architecture, disruption of the mucosal barrier, modulation of innate and adaptive immunity, and dysfunction of the enteric nervous system. Inflammatory bowel disease is used as a model system to understand these microbial-driven pathologies, but the knowledge gained in this space is extended to less well studied intestinal diseases that may also have an important microbial component, including environmental enteropathy and chronic colitis-associated colorectal cancer. PMID:25974300

Results of the 4th scientific workshop of the ECCO (Group II): markers of intestinal fibrosis in inflammatory bowel disease.

PubMed

Rieder, Florian; de Bruyn, Jessica R; Pham, Bao Tung; Katsanos, Konstantinos; Annese, Vito; Higgins, Peter D R; Magro, Fernando; Dotan, Iris

2014-10-01

The fourth scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on intestinal fibrosis in inflammatory bowel disease (IBD). The objective was to better understand basic mechanisms and markers of intestinal fibrosis as well as to suggest new therapeutic targets to prevent or treat fibrosis. The results of this workshop are presented in three separate manuscripts. This section describes markers of fibrosis in IBD, identifies unanswered questions in the field and provides a framework for future studies addressing the unmet needs in the field of intestinal fibrosis. Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health.

PubMed

Laurans, Ludivine; Venteclef, Nicolas; Haddad, Yacine; Chajadine, Mouna; Alzaid, Fawaz; Metghalchi, Sarvenaz; Sovran, Bruno; Denis, Raphael G P; Dairou, Julien; Cardellini, Marina; Moreno-Navarrete, Jose-Maria; Straub, Marjolene; Jegou, Sarah; McQuitty, Claire; Viel, Thomas; Esposito, Bruno; Tavitian, Bertrand; Callebert, Jacques; Luquet, Serge H; Federici, Massimo; Fernandez-Real, José Manuel; Burcelin, Remy; Launay, Jean-Marie; Tedgui, Alain; Mallat, Ziad; Sokol, Harry; Taleb, Soraya

2018-06-25

The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood 1,2 . Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells 3,4 . However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome 5-9 and may promote atherosclerosis and vascular inflammation 6 , suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity 10-13 , yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target.

Anti-inflammatory and antioxidant effects of infliximab in a rat model of intestinal ischemia/reperfusion injury.

PubMed

Pergel, Ahmet; Kanter, Mehmet; Yucel, Ahmet Fikret; Aydin, Ibrahim; Erboga, Mustafa; Guzel, Ahmet

2012-11-01

The aim of this study was to investigate the possible protective effects of infliximab on oxidative stress, cell proliferation and apoptosis in the rat intestinal mucosa after ischemia/reperfusion (I/R). A total of 30 male Wistar albino rats were divided into three groups: sham, I/R and I/R+ infliximab; each group comprised 10 animals. Sham group animals underwent laparotomy without I/R injury. I/R groups after undergoing laparotomy, 1 hour of superior mesenteric artery ligation occurred, which was followed by 1 hour of reperfusion. In the infliximab group, 3 days before I/R, infliximab (3 mg/kg) was administered intravenously. All animals were killed at the end of reperfusion and intestinal tissues samples were obtained for biochemical and histopathological investigation in all groups. To date, no biochemical and histopathological changes have been reported regarding intestinal I/R injury in rats due to infliximab treatment. Infliximab treatment significantly decreased the elevated tissue malondialdehyde levels and increased reduced superoxide dismutase and glutathione peroxidase enzyme activities in intestinal tissues samples. I/R caused severe histopathological injury including mucosal erosions, inflammatory cell infiltration, necrosis, hemorrhage, and villous congestion. Infliximab treatment significantly attenuated the severity of intestinal I/R injury, inhibiting I/R-induced apoptosis, and cell proliferation. Because of its anti-inflammatory and antioxidant effects, infliximab pretreatment may have protective effects on the experimental intestinal I/R model of rats.

RIP3 AND pMLKL promote necroptosis-induced inflammation and alter membrane permeability in intestinal epithelial cells.

PubMed

Negroni, Anna; Colantoni, Eleonora; Pierdomenico, Maria; Palone, Francesca; Costanzo, Manuela; Oliva, Salvatore; Tiberti, Antonio; Cucchiara, Salvatore; Stronati, Laura

2017-11-01

Necroptosis is an inflammatory form of programmed cell death requiring receptor-interacting protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). The aim of this study is to examine in depth in vitro and ex vivo the contribution of necroptosis to intestinal inflammation. In vitro: we used an intestinal cell line, HCT116RIP3, produced in our laboratory and overexpressing RIP3. Ex vivo: intestinal mucosal biopsies were taken from patients with inflammatory bowel disease (IBD) (20 with Crohn's disease; 20 with ulcerative colitis) and from 20 controls. RIP3-induced necroptosis triggers MLKL activation, increases cytokine/alarmin expression (IL-8, IL-1β, IL-33, HMGB1), NF-kBp65 translocation and NALP3 inflammasome assembly. It also affects membrane permeability by altering cell-cell junctional proteins (E-cadherin, Occludin, Zonulin-1). Targeting necroptosis through Necrostatin-1 significantly reduces intestinal inflammation in vitro and in cultured intestinal explants from IBD. We show for the first time in vitro and ex vivo that RIP3-driven necroptosis seriously affects intestinal inflammation by increasing pMLKL, activating different cytokines and alarmins, and altering epithelial permeability. The inhibition of necroptosis causes a significant decrease of all these effects. These data strongly support the view that targeting necroptosis may represent a promising new option for the treatment of inflammatory enteropathies. Copyright © 2017. Published by Elsevier Ltd.

Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium

PubMed Central

Bastide, Pauline; Darido, Charbel; Pannequin, Julie; Kist, Ralf; Robine, Sylvie; Marty-Double, Christiane; Bibeau, Frédéric; Scherer, Gerd; Joubert, Dominique; Hollande, Frédéric; Blache, Philippe; Jay, Philippe

2007-01-01

The HMG-box transcription factor Sox9 is expressed in the intestinal epithelium, specifically, in stem/progenitor cells and in Paneth cells. Sox9 expression requires an active β-catenin–Tcf complex, the transcriptional effector of the Wnt pathway. This pathway is critical for numerous aspects of the intestinal epithelium physiopathology, but processes that specify the cell response to such multipotential signals still remain to be identified. We inactivated the Sox9 gene in the intestinal epithelium to analyze its physiological function. Sox9 inactivation affected differentiation throughout the intestinal epithelium, with a disappearance of Paneth cells and a decrease of the goblet cell lineage. Additionally, the morphology of the colon epithelium was severely altered. We detected general hyperplasia and local crypt dysplasia in the intestine, and Wnt pathway target genes were up-regulated. These results highlight the central position of Sox9 as both a transcriptional target and a regulator of the Wnt pathway in the regulation of intestinal epithelium homeostasis. PMID:17698607

Inflammatory parameters in Caco-2 cells: effect of stimuli nature, concentration, combination and cell differentiation.

PubMed

Van De Walle, Jacqueline; Hendrickx, Aurélie; Romier, Béatrice; Larondelle, Yvan; Schneider, Yves-Jacques

2010-08-01

Enterocytes regulate gut maintenance and defence by secreting and responding to inflammatory mediators and by modulating the intestinal epithelial permeability. In order to develop an in vitro model of the acute phase of intestinal inflammation, Caco-2 cells were exposed to the inflammatory mediators IL-1beta, TNF-alpha, IFN-gamma and LPS, and the importance of several experimental parameters, i.e. cell differentiation, stimulus nature, concentration and combination on the inflammatory response was assessed by measuring the production of IL-6, IL-8, PGE-2 and NO and by evaluating the monolayer permeability. A maximal increase in IL-8, IL-6 and PGE-2 production and monolayer permeability was observed when using the cytokines simultaneously at their highest level, but this relied mainly on IL-1beta. The effects of TNF-alpha on IL-8 and IL-6 or NO production were stronger upon combination with IL-1beta or IFN-gamma, respectively, whereas cells were unaffected by the presence of LPS. Although NO production, induced by IFN-gamma-containing combinations, was observed only in differentiated cells, general inflammatory response was higher in proliferating cells. The use of a mixture of IL-1beta, TNF-alpha and IFN-gamma thus accurately mimics intestinal inflammatory processes, but cell differentiation and stimuli combination are important parameters to take into account for in vitro studies on intestinal inflammation. Copyright (c) 2010. Published by Elsevier Ltd.

Lactobacillus gasseri in the Upper Small Intestine Impacts an ACSL3-Dependent Fatty Acid-Sensing Pathway Regulating Whole-Body Glucose Homeostasis.

PubMed

Bauer, Paige V; Duca, Frank A; Waise, T M Zaved; Dranse, Helen J; Rasmussen, Brittany A; Puri, Akshita; Rasti, Mozhgan; O'Brien, Catherine A; Lam, Tony K T

2018-03-06

Long-chain acyl-CoA synthetase (ACSL)-dependent upper small intestinal lipid metabolism activates pre-absorptive pathways to regulate metabolic homeostasis, but whether changes in the upper small intestinal microbiota alter specific fatty acid-dependent pathways to impact glucose homeostasis remains unknown. We here first find that upper small intestinal infusion of Intralipid, oleic acid, or linoleic acid pre-absorptively increases glucose tolerance and lowers glucose production in rodents. High-fat feeding impairs pre-absorptive fatty acid sensing and reduces upper small intestinal Lactobacillus gasseri levels and ACSL3 expression. Transplantation of healthy upper small intestinal microbiota to high-fat-fed rodents restores L. gasseri levels and fatty acid sensing via increased ACSL3 expression, while L. gasseri probiotic administration to non-transplanted high-fat-fed rodents is sufficient to restore upper small intestinal ACSL3 expression and fatty acid sensing. In summary, we unveil a glucoregulatory role of upper small intestinal L. gasseri that impacts an ACSL3-dependent glucoregulatory fatty acid-sensing pathway. Copyright © 2018 Elsevier Inc. All rights reserved.

Mechanisms of the anti-inflammatory effects of the natural secosteroids physalins in a model of intestinal ischaemia and reperfusion injury

PubMed Central

Vieira, Angélica T; Pinho, Vanessa; Lepsch, Lucilia B; Scavone, Cristóforo; Ribeiro, Ivone M; Tomassini, Therezinha; Ribeiro-dos-Santos, Ricardo; Soares, Milena B P; Teixeira, Mauro M; Souza, Danielle G

2005-01-01

Reperfusion of an ischaemic tissue is associated with an intense inflammatory response and inflammation-mediated tissue injury. Physalins, a group of substances with secosteroidal chemical structure, are found in Physalis angulata stems and leaves. Here, we assessed the effects of physalins on the local, remote and systemic injuries following intestinal ischaemia and reperfusion (I/R) in mice and compared with the effects of dexamethasone. Following I/R injury, dexamethasone (10 mg kg−1) or physalin B or F markedly prevented neutrophil influx, the increase in vascular permeability in the intestine and the lungs. Maximal inhibition occurred at 20 mg kg−1. Moreover, there was prevention of haemorrhage in the intestine of reperfused animals. Dexamethasone or physalins effectively suppressed the increase in tissue (intestine and lungs) and serum concentrations of TNF-α. Interestingly, treatment with the compounds was associated with enhancement of IL-10. The anti-inflammatory effects of dexamethasone or physalins were reversed by pretreatment with the corticoid receptor antagonist RU486 (25 mg kg−1). The drug compounds suppressed steady-state concentrations of corticosterone, but did not alter the reperfusion-associated increase in levels of corticosterone. The IL-10-enhancing effects of the drugs were not altered by RU486. In conclusion, the in vivo anti-inflammatory actions of physalins, natural steroidal compounds, appear to be mostly due to the activation of glucocorticoid receptors. Compounds derived from these natural secosteroids may represent novel therapeutic options for the treatment of inflammatory diseases. PMID:16025143

Chronic Trichuris muris Infection Decreases Diversity of the Intestinal Microbiota and Concomitantly Increases the Abundance of Lactobacilli.

PubMed

Holm, Jacob Bak; Sorobetea, Daniel; Kiilerich, Pia; Ramayo-Caldas, Yuliaxis; Estellé, Jordi; Ma, Tao; Madsen, Lise; Kristiansen, Karsten; Svensson-Frej, Marcus

2015-01-01

The intestinal microbiota is vital for shaping the local intestinal environment as well as host immunity and metabolism. At the same time, epidemiological and experimental evidence suggest an important role for parasitic worm infections in maintaining the inflammatory and regulatory balance of the immune system. In line with this, the prevalence of persistent worm infections is inversely correlated with the incidence of immune-associated diseases, prompting the use of controlled parasite infections for therapeutic purposes. Despite this, the impact of parasite infection on the intestinal microbiota, as well as potential downstream effects on the immune system, remain largely unknown. We have assessed the influence of chronic infection with the large-intestinal nematode Trichuris muris, a close relative of the human pathogen Trichuris trichiura, on the composition of the murine intestinal microbiota by 16S ribosomal-RNA gene-based sequencing. Our results demonstrate that persistent T. muris infection dramatically affects the large-intestinal microbiota, most notably with a drop in the diversity of bacterial communities, as well as a marked increase in the relative abundance of the Lactobacillus genus. In parallel, chronic T. muris infection resulted in a significant shift in the balance between regulatory and inflammatory T cells in the intestinal adaptive immune system, in favour of inflammatory cells. Together, these data demonstrate that chronic parasite infection strongly influences the intestinal microbiota and the adaptive immune system. Our results illustrate the complex interactions between these factors in the intestinal tract, and contribute to furthering the understanding of this interplay, which is of crucial importance considering that 500 million people globally are suffering from these infections and their potential use for therapeutic purposes.

Transcriptome Analysis of Three Sheep Intestinal Regions reveals Key Pathways and Hub Regulatory Genes of Large Intestinal Lipid Metabolism.

PubMed

Chao, Tianle; Wang, Guizhi; Ji, Zhibin; Liu, Zhaohua; Hou, Lei; Wang, Jin; Wang, Jianmin

2017-07-13

The large intestine, also known as the hindgut, is an important part of the animal digestive system. Recent studies on digestive system development in ruminants have focused on the rumen and the small intestine, but the molecular mechanisms underlying sheep large intestine metabolism remain poorly understood. To identify genes related to intestinal metabolism and to reveal molecular regulation mechanisms, we sequenced and compared the transcriptomes of mucosal epithelial tissues among the cecum, proximal colon and duodenum. A total of 4,221 transcripts from 3,254 genes were identified as differentially expressed transcripts. Between the large intestine and duodenum, differentially expressed transcripts were found to be significantly enriched in 6 metabolism-related pathways, among which PPAR signaling was identified as a key pathway. Three genes, CPT1A, LPL and PCK1, were identified as higher expression hub genes in the large intestine. Between the cecum and colon, differentially expressed transcripts were significantly enriched in 5 lipid metabolism related pathways, and CEPT1 and MBOAT1 were identified as hub genes. This study provides important information regarding the molecular mechanisms of intestinal metabolism in sheep and may provide a basis for further study.

Inflammatory bowel disease exacerbation associated with Epstein-Barr virus infection.

PubMed

Dimitroulia, Evangelia; Pitiriga, Vassiliki C; Piperaki, Evangelia-Theophano; Spanakis, Nicholas E; Tsakris, Athanassios

2013-03-01

Epstein-Barr virus infection is associated with inflammatory bowel disease, but its role as a pathogenetic or exacerbating factor remains unclear. The aim of this study was to evaluate the association between Epstein-Barr virus infection and inflammatory bowel disease, particularly in regard to exacerbation of disease activity. This was a nonrandomized crosssectional study in subgroups of patients with inflammatory bowel disease compared with a control group with noninflammatory disease. Participants were patients treated for ulcerative colitis or Crohn's disease and individuals undergoing evaluation for noninflammatory disease recruited from 2 urban adult gastrointestinal referral centers in Greece. Diagnosis of inflammatory bowel disease was based on standard clinical and endoscopic criteria. Demographic and clinical characteristics of all participants were recorded. Whole blood samples and fresh tissue samples from biopsy of intestinal sites were obtained from each participant. The presence of Epstein-Barr virus was determined by amplifying the LMP1 gene of the virus in blood and intestinal tissue samples. The study comprised 94 patients with inflammatory bowel disease (63 with ulcerative colitis and 31 with Crohn's disease) and 45 controls with noninflammatory disease. Of the 94 patients, 67 (71.3%) had disease exacerbation and 27 (28.7%) were in remission. The prevalence of Epstein-Barr virus genome was significantly higher in patients than in controls for intestinal tissue (44 patients, 46.8% vs 6 controls, 13.3%; p = 0.001), but not for whole blood (24 patients, 25.5% vs 9 controls, 20%; p = 0.3). The viral genome was found significantly more frequently in intestinal samples from patients with disease exacerbation compared with patients in remission (38 patients with exacerbation, 56.7% vs 6 patients in remission, 22.2%; p = 0.001), but no significant difference was found for whole blood (18 patients with exacerbation, 26.8% vs 6 patients in remission, 22.2%; p = 0.79). Neither disease exacerbation nor the presence of virus genome was related to demographic or clinical characteristics. The exact location of Epstein-Barr virus in the intestinal tissues could not be specified because morphological data by immunohistochemistry or in situ hybridization were not available. Although causality could not be determined, the significantly higher prevalence of Epstein-Barr virus in intestinal tissue from patients with inflammatory bowel disease compared with controls and in patients with exacerbation compared with patients in remission suggests a potential viral involvement in the severity of inflammatory bowel disease. These findings merit further investigation in view of a potential for usefulness of antiviral therapy against Epstein-Barr virus infection in patients with exacerbation of inflammatory bowel disease.

Inflammatory Bowel Disease.

PubMed

2016-01-01

Inflammation response plays an important role in host survival, and it also leads to acute and chronic inflammatory diseases such as rheumatoid arthritis, bowel diseases, allergic rhinitis, asthma, atopic dermatitis and various neurodegenerative diseases. During the course of inflammation, the ROS level increases. In addition to ROS, several inflammatory mediators produced at the site lead to numerous cell-mediated damages. Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic intestinal disorder resulting from a dysfunctional epithelial, innate and adaptive immune response to intestinal microorganisms. The methods involving indomethacin-induced enterocolitis in rats with macroscopic changes of IBD, myeloperoxidase assay, microscopic (histologic) characters and biochemical parameters are discussed.

The Role of Physical Exercise in Inflammatory Bowel Disease

PubMed Central

Bilski, Jan; Brzozowski, Bartosz; Mazur-Bialy, Agnieszka; Sliwowski, Zbigniew; Brzozowski, Tomasz

2014-01-01

We reviewed and analyzed the relationship between physical exercise and inflammatory bowel disease (IBD) which covers a group of chronic, relapsing, and remitting intestinal disorders including Crohn's disease (CD) and ulcerative colitis. The etiology of IBD likely involves a combination of genetic predisposition and environmental risk factors. Physical training has been suggested to be protective against the onset of IBD, but there are inconsistencies in the findings of the published literature. Hypertrophy of the mesenteric white adipose tissue (mWAT) is recognized as a characteristic feature of CD, but its importance for the perpetuation of onset of this intestinal disease is unknown. Adipocytes synthesize proinflammatory and anti-inflammatory cytokines. Hypertrophy of mWAT could play a role as a barrier to the inflammatory process, but recent data suggest that deregulation of adipokine secretion is involved in the pathogenesis of CD. Adipocytokines and macrophage mediators perpetuate the intestinal inflammatory process, leading to mucosal ulcerations along the mesenteric border, a typical feature of CD. Contracting skeletal muscles release biologically active myokines, known to exert the direct anti-inflammatory effects, and inhibit the release of proinflammatory mediators from visceral fat. Further research is required to confirm these observations and establish exercise regimes for IBD patients. PMID:24877092

The role of physical exercise in inflammatory bowel disease.

PubMed

Bilski, Jan; Brzozowski, Bartosz; Mazur-Bialy, Agnieszka; Sliwowski, Zbigniew; Brzozowski, Tomasz

2014-01-01

We reviewed and analyzed the relationship between physical exercise and inflammatory bowel disease (IBD) which covers a group of chronic, relapsing, and remitting intestinal disorders including Crohn's disease (CD) and ulcerative colitis. The etiology of IBD likely involves a combination of genetic predisposition and environmental risk factors. Physical training has been suggested to be protective against the onset of IBD, but there are inconsistencies in the findings of the published literature. Hypertrophy of the mesenteric white adipose tissue (mWAT) is recognized as a characteristic feature of CD, but its importance for the perpetuation of onset of this intestinal disease is unknown. Adipocytes synthesize proinflammatory and anti-inflammatory cytokines. Hypertrophy of mWAT could play a role as a barrier to the inflammatory process, but recent data suggest that deregulation of adipokine secretion is involved in the pathogenesis of CD. Adipocytokines and macrophage mediators perpetuate the intestinal inflammatory process, leading to mucosal ulcerations along the mesenteric border, a typical feature of CD. Contracting skeletal muscles release biologically active myokines, known to exert the direct anti-inflammatory effects, and inhibit the release of proinflammatory mediators from visceral fat. Further research is required to confirm these observations and establish exercise regimes for IBD patients.

Intestinal interleukin-13 in pediatric inflammatory bowel disease patients.

PubMed

Kadivar, Khadijeh; Ruchelli, Eduardo D; Markowitz, Jonathan E; Defelice, Magee L; Strogatz, Melissa L; Kanzaria, Mitul M; Reddy, Krishna P; Baldassano, Robert N; von Allmen, Daniel; Brown, Kurt A

2004-09-01

Interleukin-13 (IL-13) is a multifunctional cytokine whose net principle action is to diminish inflammatory responses. Dysregulation of IL-13 production has been proposed to contribute to intestinal inflammation in inflammatory bowel disease (IBD) patients. Previous studies implicate IL-13 in IBD pathogenesis; however, they fail to accurately reflect in vivo intestinal IL-13 production. We evaluate IL-13, IL-6, and IL-1beta elaborations from colonic organ cultures of pediatric IBD patients Endoscopic lamina propria biopsies or surgical specimens from pediatric patients with IBD were organ cultured and supernatants evaluated by enzyme-linked immunosorbent assay for IL-1beta, IL-6, and IL-13. IL-13 concentrations were significantly reduced in ulcerative colitis (UC) patients when compared with normal controls (P = 0.002) and Crohn disease (CD) patients (P = 0.001). End-stage UC patients at colectomy had lower intestinal IL-13 production than all other UC patients (P = 0.002). No significant correlation was found between IL-13 concentration and histologic disease severity (P = 0.134). Diminished intestinal IL-13 production is present in UC patients and wanes further with clinical disease progression. These findings suggest that UC patients may be differentiated from CD patients by intestinal IL-13 quantitation, and UC patients may benefit from IL-13 enhancing therapies. Copyright 2004 Lippincott Williams & Wilkins

Therapeutic Effects of Resiniferatoxin Related with Immunological Responses for Intestinal Inflammation in Trichinellosis.

PubMed

Muñoz-Carrillo, José Luis; Muñoz-López, José Luis; Muñoz-Escobedo, José Jesús; Maldonado-Tapia, Claudia; Gutiérrez-Coronado, Oscar; Contreras-Cordero, Juan Francisco; Moreno-García, María Alejandra

2017-12-01

The immune response against Trichinella spiralis at the intestinal level depends on the CD4+ T cells, which can both suppress or promote the inflammatory response through the synthesis of diverse cytokines. During the intestinal phase, the immune response is mixed (Th1/Th2) with the initial predominance of the Th1 response and the subsequent domination of Th2 response, which favor the development of intestinal pathology. In this context, the glucocorticoids (GC) are the pharmacotherapy for the intestinal inflammatory response in trichinellosis. However, its therapeutic use is limited, since studies have shown that treatment with GC suppresses the host immune system, favoring T. spiralis infection. In the search for novel pharmacological strategies that inhibit the Th1 immune response (proinflammatory) and assist the host against T. spiralis infection, recent studies showed that resiniferatoxin (RTX) had anti-inflammatory activity, which decreased the serum levels of IL-12, INF-γ, IL-1β, TNF-α, NO, and PGE2, as well the number of eosinophils in the blood, associated with decreased intestinal pathology and muscle parasite burden. These researches demonstrate that RTX is capable to inhibit the production of Th1 cytokines, contributing to the defense against T. spiralis infection, which places it as a new potential drug modulator of the immune response.

Therapeutic Effects of Resiniferatoxin Related with Immunological Responses for Intestinal Inflammation in Trichinellosis

PubMed Central

Muñoz-Carrillo, José Luis; Muñoz-López, José Luis; Muñoz-Escobedo, José Jesús; Maldonado-Tapia, Claudia; Gutiérrez-Coronado, Oscar; Contreras-Cordero, Juan Francisco; Moreno-García, María Alejandra

2017-01-01

The immune response against Trichinella spiralis at the intestinal level depends on the CD4+ T cells, which can both suppress or promote the inflammatory response through the synthesis of diverse cytokines. During the intestinal phase, the immune response is mixed (Th1/Th2) with the initial predominance of the Th1 response and the subsequent domination of Th2 response, which favor the development of intestinal pathology. In this context, the glucocorticoids (GC) are the pharmacotherapy for the intestinal inflammatory response in trichinellosis. However, its therapeutic use is limited, since studies have shown that treatment with GC suppresses the host immune system, favoring T. spiralis infection. In the search for novel pharmacological strategies that inhibit the Th1 immune response (proinflammatory) and assist the host against T. spiralis infection, recent studies showed that resiniferatoxin (RTX) had anti-inflammatory activity, which decreased the serum levels of IL-12, INF-γ, IL-1β, TNF-α, NO, and PGE2, as well the number of eosinophils in the blood, associated with decreased intestinal pathology and muscle parasite burden. These researches demonstrate that RTX is capable to inhibit the production of Th1 cytokines, contributing to the defense against T. spiralis infection, which places it as a new potential drug modulator of the immune response. PMID:29320813

Review article: Anti-inflammatory mechanisms of action of Saccharomyces boulardii

PubMed Central

Pothoulakis, C.

2009-01-01

SUMMARY Background Saccharomyces boulardii (S. boulardii), a well-studied probiotic, can be effective in inflammatory gastrointestinal diseases with diverse pathophysiology, such as Inflammatory Bowel Disease (IBD), and bacterially – or enterotoxin-mediated diarrhea and inflammation. Aim Discuss the mechanisms of action involved in the intestinal anti-inflammatory action of S. boulardii Methods Review of the literature related to the anti-inflammatory effects of this probiotic. Results Several mechanisms of action have been identified directed against the host and pathogenic microorganisms. S. boulardii and S. boulardii secreted protein(s) inhibit production of proinflammatory cytokines by interfering with the global mediator of inflammation nuclear factor κB, and modulating the activity of the mitogen-activated protein kinases ERK1/2 and p38. S. boulardii activates expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) that protects from gut inflammation and IBD. S. boulardii also suppresses “bacteria overgrowth” and host cell adherence, releases a protease that cleaves C. difficile toxin A and its intestinal receptor, and stimulates antibody production against toxin A. Recent results indicate that S. boulardii may interfere with IBD pathogenesis by trapping T cells in mesenteric lymph nodes. Conclusions The multiple anti-inflammatory mechanisms exerted by S. boulardii provide molecular explanations supporting its effectiveness in intestinal inflammatory states. PMID:19706150

miR-34a-5p Inhibition Alleviates Intestinal Ischemia/Reperfusion-Induced Reactive Oxygen Species Accumulation and Apoptosis via Activation of SIRT1 Signaling.

PubMed

Wang, Guangzhi; Yao, Jihong; Li, Zhenlu; Zu, Guo; Feng, Dongcheng; Shan, Wen; Li, Yang; Hu, Yan; Zhao, Yongfu; Tian, Xiaofeng

2016-06-10

Reactive oxygen species (ROS) generation and massive epithelial apoptosis are critical in the pathogenesis of intestinal ischemia/reperfusion (I/R) injury. We previously found that the Sirtuin 1 (SIRT1)-mediated antioxidant pathway was impaired in the intestine after I/R. Here, we investigate the potential role of SIRT1-targeting microRNAs (miRNAs) in regulating ROS accumulation and apoptosis in intestinal I/R, and the important role SIRT1 involved in. C57BL/6 mice were subjected to intestinal I/R induced by occlusion of the superior mesenteric artery followed by reperfusion. Caco-2 cells were incubated under hypoxia/reoxygenation condition to mimic I/R in vivo. We find that SIRT1 is gradually repressed during the early reperfusion, and that this repression results in intestinal ROS accumulation and apoptosis. Using bioinformatics analysis and real-time PCR, we demonstrate that miR-34a-5p and miR-495-3p are significantly increased among the 41 putative miRNAs that can target SIRT1. Inhibition of miR-34a-5p, but not miR-495-3p, attenuates intestinal I/R injury, as demonstrated by repressing p66shc upregulation, manganese superoxide dismutase repression, and the caspase-3 activation in vitro and in vivo; it further alleviates systemic injury, as demonstrated by reducing inflammatory cytokine release, attenuating lung and liver lesions, and improving survival. Interestingly, SIRT1 plays an indispensable role in the protection afforded by miR-34a-5p inhibition. This study provides the first evidence of miRNAs in regulating oxidative stress and apoptosis in intestinal I/R. miR-34a-5p knockdown attenuates intestinal I/R injury through promoting SIRT1-mediated suppression of epithelial ROS accumulation and apoptosis. This may represent a novel prophylactic approach to intestinal I/R injury. Antioxid. Redox Signal. 24, 961-973.

Selenium and inflammatory bowel disease.

PubMed

Kudva, Avinash K; Shay, Ashley E; Prabhu, K Sandeep

2015-07-15

Dietary intake of the micronutrient selenium is essential for normal immune functions. Selenium is cotranslationally incorporated as the 21st amino acid, selenocysteine, into selenoproteins that function to modulate pathways involved in inflammation. Epidemiological studies have suggested an inverse association between selenium levels and inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis that can potentially progress to colon cancer. However, the underlying mechanisms are not well understood. Here we summarize the current literature on the pathophysiology of IBD, which is multifactorial in origin with unknown etiology. We have focused on a few selenoproteins that mediate gastrointestinal inflammation and activate the host immune response, wherein macrophages play a pivotal role. Changes in cellular oxidative state coupled with altered expression of selenoproteins in macrophages drive the switch from a proinflammatory phenotype to an anti-inflammatory phenotype to efficiently resolve inflammation in the gut and restore epithelial barrier integrity. Such a phenotypic plasticity is accompanied by changes in cytokines, chemokines, and bioactive metabolites, including eicosanoids that not only mitigate inflammation but also partake in restoring gut homeostasis through diverse pathways involving differential regulation of transcription factors such as nuclear factor-κB and peroxisome proliferator-activated receptor-γ. The role of the intestinal microbiome in modulating inflammation and aiding in selenium-dependent resolution of gut injury is highlighted to provide novel insights into the beneficial effects of selenium in IBD. Copyright © 2015 the American Physiological Society.

[Crohns disease and ulcerative colitis - current view on genetic determination, immunopathogenesis and biologic therapy].

PubMed

Buc, M

2017-01-01

Crohns disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the intestine, also called inflammatory bowel diseases (IBD), which are not caused by pathogenic microorganisms but result from non-specific inflammatory processes in the bowel. IBD are polygenic diseases, as evidenced by the genome-wide association studies (GWAS), which have discovered more than 200 genes or genetic regions to be associated with IBD. Some of them are specific for CD or UC; however, there are 110 overlapping genes. In the pathogenesis of CD, activation of adaptive immunity mediated by TH1, TH17, or TH1/TH17 cells is induced because of disturbances in the mechanisms of innate immunity and autophagocytosis. By comparison, the major events that trigger autoimmune processes in UC are an increased translocation of commensal bacteria into the submucosa because of loose inter-epithelial connections with subsequent activation of ILC2, TH9, TH2, and NKT cells. Knowledge of the pathogenesis of a disease enables an effective therapy, which is especially true for biological therapy. It is noteworthy that monoclonal antibodies directed against the major protagonists underlying both CD and UC have failed. It points to the complexity of immunopathologic processes that run in both diseases. One can suppose that a blockade of one inflammatory pathway is circumvented by an alternative pathway. TNF is the principal pro-inflammatory cytokine that plays a major role in CD and UC as well. It was therefore decided to treat IBD patients with anti-TNF monoclonal antibodies, infliximab or adalimumab. Approximately one half of the CD patients and one third of the UC patients respond to this treatment.

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation.

PubMed

Zaiss, Mario M; Rapin, Alexis; Lebon, Luc; Dubey, Lalit Kumar; Mosconi, Ilaria; Sarter, Kerstin; Piersigilli, Alessandra; Menin, Laure; Walker, Alan W; Rougemont, Jacques; Paerewijck, Oonagh; Geldhof, Peter; McCoy, Kathleen D; Macpherson, Andrew J; Croese, John; Giacomin, Paul R; Loukas, Alex; Junt, Tobias; Marsland, Benjamin J; Harris, Nicola L

2015-11-17

Intestinal helminths are potent regulators of their host's immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Dietary l-threonine supplementation attenuates lipopolysaccharide-induced inflammatory responses and intestinal barrier damage of broiler chickens at an early age.

PubMed

Chen, Yueping; Zhang, Hao; Cheng, Yefei; Li, Yue; Wen, Chao; Zhou, Yanmin

2018-06-01

This study was conducted to investigate the protective effects of l-threonine (l-Thr) supplementation on growth performance, inflammatory responses and intestinal barrier function of young broilers challenged with lipopolysaccharide (LPS). A total of 144 1-d-old male chicks were allocated to one of three treatments: non-challenged broilers fed a basal diet (control group), LPS-challenged broilers fed a basal diet without l-Thr supplementation and LPS-challenged broilers fed a basal diet supplemented with 3·0 g/kg l-Thr. LPS challenge was performed intraperitoneally at 17, 19 and 21 d of age, whereas the control group received physiological saline injection. Compared with the control group, LPS challenge impaired growth performance of broilers, and l-Thr administration reversed LPS-induced increase in feed/gain ratio. LPS challenge elevated blood cell counts related to inflammation, and pro-inflammatory cytokine concentrations in serum (IL-1β and TNF-α), spleen (IL-1β and TNF-α) and intestinal mucosa (jejunal interferon-γ (IFN-γ) and ileal IL-1β). The concentrations of intestinal cytokines in LPS-challenged broilers were reduced by l-Thr supplementation. LPS administration increased circulating d-lactic acid concentration, whereas it reduced villus height, the ratio between villus height and crypt depth and goblet density in both jejunum and ileum. LPS-induced decreases in jejunal villus height, intestinal villus height:crypt depth ratio and ileal goblet cell density were reversed with l-Thr supplementation. Similarly, LPS-induced alterations in the intestinal mRNA abundances of genes related to intestinal inflammation and barrier function (jejunal toll-like receptor 4, IFN- γ and claudin-3, and ileal IL-1 β and zonula occludens-1) were normalised with l-Thr administration. It can be concluded that l-Thr supplementation could attenuate LPS-induced inflammatory responses and intestinal barrier damage of young broilers.

Toll-like receptors in inflammatory bowel diseases: A decade later

PubMed Central

Cario, Elke

2010-01-01

Differential alteration of Toll-like receptor (TLR) expression in inflammatory bowel disease (IBD) was first described 10 years ago. Since then, studies from many groups have led to the current concept that TLRs represent key mediators of innate host defense in the intestine, involved in maintaining mucosal as well as commensal homeostasis. Recent findings in diverse murine models of colitis have helped to reveal the mechanistic importance of TLR dysfunction in IBD pathogenesis. It has become evident that environment, genetics, and host immunity form a multidimensional and highly interactive regulatory triad that controls TLR function in the intestinal mucosa. Imbalanced relationships within this triad may promote aberrant TLR signaling, critically contributing to acute and chronic intestinal inflammatory processes in IBD colitis and associated cancer. (Inflamm Bowel Dis 2010) PMID:20803699

Anti-inflammatory activity of hydroalcoholic extracts of Lavandula dentata L. and Lavandula stoechas L.

PubMed

Algieri, Francesca; Rodriguez-Nogales, Alba; Vezza, Teresa; Garrido-Mesa, Jose; Garrido-Mesa, Natividad; Utrilla, M Pilar; González-Tejero, M Reyes; Casares-Porcel, Manuel; Molero-Mesa, Joaquin; Del Mar Contreras, Maria; Segura-Carretero, Antonio; Pérez-Palacio, José; Diaz, Caridad; Vergara, Noemí; Vicente, Francisca; Rodriguez-Cabezas, M Elena; Galvez, Julio

2016-08-22

Plants from genus Lavandula have been used as anti-inflammatory drugs in Mediterranean traditional medicine. Nowadays, there is a growing interest for complementary medicine, including herbal remedies, to treat inflammatory bowel disease (IBD). To test the anti-inflammatory properties of Lavandula dentata and Lavandula stoechas extracts in two inflammatory experimental models: TNBS model of rat colitis and the carrageenan-induced paw edema in mice, in order to mimic the intestinal conditions and the extra-intestinal manifestations of human IBD, respectively. The extracts were characterized through the qualitative HPLC analysis. Then, they were assayed in vitro and in vivo. In vitro studies were performed in BMDMs and CMT-93 epithelial cells with different concentrations of the extracts (ranging from 0.1 to 100µg/ml). The extracts were tested in vivo in the TNBS model of rat colitis (10 and 25mg/kg) and in the carrageenan-induced paw edema in mice (10, 25 and 100mg/kg). L. dentata and L. stoechas extracts displayed immunomodulatory properties in vitro down-regulating different mediators of inflammation like cytokines and nitric oxide. They also showed anti-inflammatory effects in the TNBS model of colitis as evidenced by reduced myeloperoxidase activity and increased total glutathione content, indicating a decrease of neutrophil infiltration and an improvement of the oxidative state. Besides, both extracts modulated the expression of pro-inflammatory cytokines and chemokines, and ameliorated the altered epithelial barrier function. They also displayed anti-inflammatory effects in the carrageenan-induced paw edema in mice, since a significant reduction of the paw thickness was observed. This was associated with a down-regulation of the expression of different inducible enzymes like MMP-9, iNOS and COX-2 and pro-inflammatory cytokines, all involved in the maintenance of the inflammatory condition. L. dentata and L. stoechas extracts showed intestinal anti-inflammatory effect, confirming their potential use as herbal remedies in gastrointestinal disorders. In addition, their anti-inflammatory effect was also observed in other locations, thus suggesting a possible use for the treatment of the extra-intestinal symptoms of IBD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The intestinal barrier in multiple sclerosis: implications for pathophysiology and therapeutics.

PubMed

Camara-Lemarroy, Carlos R; Metz, Luanne; Meddings, Jonathan B; Sharkey, Keith A; Wee Yong, V

2018-05-30

Biological barriers are essential for the maintenance of homeostasis in health and disease. Breakdown of the intestinal barrier is an essential aspect of the pathophysiology of gastrointestinal inflammatory diseases, such as inflammatory bowel disease. A wealth of recent studies has shown that the intestinal microbiome, part of the brain-gut axis, could play a role in the pathophysiology of multiple sclerosis. However, an essential component of this axis, the intestinal barrier, has received much less attention. In this review, we describe the intestinal barrier as the physical and functional zone of interaction between the luminal microbiome and the host. Besides its essential role in the regulation of homeostatic processes, the intestinal barrier contains the gut mucosal immune system, a guardian of the integrity of the intestinal tract and the whole organism. Gastrointestinal disorders with intestinal barrier breakdown show evidence of CNS demyelination, and content of the intestinal microbiome entering into the circulation can impact the functions of CNS microglia. We highlight currently available studies suggesting that there is intestinal barrier dysfunction in multiple sclerosis. Finally, we address the mechanisms by which commonly used disease-modifying drugs in multiple sclerosis could alter the intestinal barrier and the microbiome, and we discuss the potential of barrier-stabilizing strategies, including probiotics and stabilization of tight junctions, as novel therapeutic avenues in multiple sclerosis.

Huangqin-Tang and Ingredients in Modulating the Pathogenesis of Ulcerative Colitis.

PubMed

Wang, Chunyan; Tang, Xudong; Zhang, Li

2017-01-01

Ulcerative colitis (UC) is the most common inflammatory bowel disease worldwide. Current therapies in UC cause limitations, and herb medicine provides an important choice for UC treatment. Huangqin-Tang (HQT) is a well-known classical traditional Chinese herbal formula and has been used in China for thousands of years. A large number of pharmacological studies demonstrated HQT and its ingredients to be effective in treating UC. Though the therapeutic effect has been evaluated, comprehensive up-to-date reviews in this field are not yet available. Here we aim to review our current understanding of HQT and its ingredients in treating UC and how the agents modulate the main pathogenesis of the disease, including the intestinal environment, immune imbalance, inflammatory pathways, and oxidative stress. The summary on this issue may provide better understanding of HQT and its ingredients in treating UC and possibly help in promoting its clinical application.

Transcriptome analysis reveals regional and temporal differences in mucosal immune system development in the small intestine of neonatal calves.

PubMed

Liang, Guanxiang; Malmuthuge, Nilusha; Bao, Hua; Stothard, Paul; Griebel, Philip J; Guan, Le Luo

2016-08-11

Postnatal development of the mammalian mucosal immune system is crucial for responding to the rapid colonization by commensal bacteria and possible exposure to pathogens. This study analyzed expression patterns for mRNAs and their relationship with microRNAs (miRNAs) in the bovine small intestine during the critical neonatal period (0 to 42 days). This analysis revealed molecular mechanisms regulating the postnatal development of the intestinal mucosal immune system. Small intestine samples (jejunum and ileum) were collected from newborn male, Holstein calves immediately post-partum (n = 3) and at 7 (n = 5), 21 (n = 5), and 42 (n = 5) days of age and the transcriptomes were profiled using RNA-Seq. When analyzing all time points collectively, greater expression of genes encoding the complement functional pathway, as well as lower expression of genes encoding Toll-like receptors and NOD-like receptors were observed in the jejunum when compared to the ileum. In addition, significant changes in the expression of immune-related genes were detected within the first week post-partum in both jejunum and ileum. For example, increased expression of genes encoding tight junction proteins (claudin 1, claudin 4 and occludin), an antimicrobial peptide (Regenerating Islet-Derived 3-γ), NOD-like receptors (NACHT, LRR and PYD domain-containing protein 3), regulatory T cell marker (forkhead box P3), and both anti-inflammatory (interleukin 10) and pro-inflammatory (interleukin 8) cytokines was observed throughout the small intestine of 7-day-old calves when compared to newborn calves. Moreover, the expression of mucosal immune-related genes were either positively or negatively correlated with total bacterial population depending on both intestinal region and age. The integrated analysis of miRNAs and mRNAs supported the conclusion that miRNAs may regulate temporal changes in the expression of genes encoding tight junction proteins (miR-335), cytokines (miR-335) and bacterial recognition (miR-100) during the first week of small intestine development. The rapid development of transcriptional differences between jejunum and ileum reveal that these two intestinal regions make distinct contributions to the intestinal mucosal immune system during the early neonatal period. In addition, transcriptome analysis indicates that the first week after birth is a very dynamic developmental period for the intestinal mucosal immune system and these changes may be regulated by both miRNAs and microbial colonization. Findings from this study indicate that a detailed analysis of both the abundance and diversity of the colonizing microbiome may be necessary to understand factors regulating the rapid development of the mucosal immune system during the first week of life.

Identification of a probiotic bacteria-derived activator of the aryl hydrocarbon receptor that inhibits colitis.

PubMed

Fukumoto, Suguru; Toshimitsu, Takayuki; Matsuoka, Shuji; Maruyama, Atsushi; Oh-Oka, Kyoko; Takamura, Takeyuki; Nakamura, Yuki; Ishimaru, Kayoko; Fujii-Kuriyama, Yoshiaki; Ikegami, Shuji; Itou, Hiroyuki; Nakao, Atsuhito

2014-01-01

The aryl hydrocarbon receptor (AhR) recognizes environmental xenobiotics and is originally thought to be involved in the metabolism (detoxification) of the substances. Recently, AhR is highlighted as an important regulator of inflammation. Notably, accumulating evidence suggests that activation of the AhR suppresses inflammatory bowel diseases (IBDs). Therefore, non-toxic AhR activators become attractive drug candidates for IBD. This study identified 1,4-dihydroxy-2-naphthoic acid (DHNA), a precursor of menaquinone (vitamin K2) abundantly produced by Propionibacterium freudenreichii ET-3 isolated from Swiss-type cheese, as an AhR activator. DHNA activated the AhR pathway in human intestinal epithelial cell line Caco2 cells and in the mouse intestine. Oral treatment of mice with DHNA induced anti-microbial proteins RegIIIβ and γ in the intestine, altered intestinal microbial flora and inhibited dextran sodium sulfate (DSS)-induced colitis, which recapitulated the phenotypes of AhR activation in the gut. As DHNA is commercially available in Japan as a prebiotic supplement without severe adverse effects, DHNA or its derivatives might become a promising drug candidate for IBD via AhR activation. The results also implicate that intestinal AhR might act not only as a sensor for xenobiotics in diet and water but also for commensal bacterial activity because DHNA is a precursor of vitamin K2 produced by vitamin K2-synthesizing commensal bacteria as well as propionic bacteria. Hence, DHNA might be a key bacterial metabolite in the host-microbe interaction to maintain intestinal microbial ecosystem.

[Intestinal flora and Crohn's disease].

PubMed

Desreumaux, P; Colombel, J-F

2003-07-01

The pathogenesis of inflammatory bowel diseases (IBD) proceeds through stages of initiation, amplification and healing. Abundant clinical and experimental data incriminate luminal bacteria or bacterial products in both the initiation and perpetuation of chronic intestinal inflammation. Macrophage and T-cell activation with accompanying inflammatory cytokine production appears to be an early event. Studies of lymphocyte responsiveness to autologous and heterologous intestinal bacteria have suggested that this activation may result from a breakdown in tolerance to the enteric flora in IBD. This lack of tolerance might be due to an imbalance between protective and aggressive commensal luminal bacterial species (dysbiosis), a decreased barrier function and/or an impaired mucosal clearance allowing the access of bacteria to the mucosal immune system and lack of regulatory mediators or cells. There is still controversy over whether the virulence traits of bacteria are expressed broadly or just in a small subset of bacteria. Individual bacterial species within the indigenous flora vary in their capacity to drive intestinal inflammation. In experimental models, some bacteria such as Bacteroides vulgatus can cause colitis alone when monoassociated in the HLA-B27 transgenic rat model. Others, including Lactobacillus and Bifidobacterium species have no proinflammatory capacity and have been used as probiotics. In patients with IBD, systematic approach to this issue is hampered by the limited knowledge of intestinal flora. Adherent-invasive Escherichia coli are a possible candidate for the onset and/or persistence of intestinal inflammation in patients with Crohn's disease, since they possess all the virulence factors that allow the bacteria to cross the intestinal barrier, to move to deep tissues, and to continuously activate macrophages. The recent identification of NOD2/CARD15 as a susceptibility gene for Crohn's disease has provided another link between the immune response to enteric bacteria and the development of mucosal inflammation. NOD2/CARD15 is composed of two caspase recruitment domain (CARD), a nucleotide-binding domain (NBD) and a leucin-rich-repeat (LRR) region. The LRR domain of NOD2/CARD15 has binding activity for bacterial peptidoglycans and its deletion stimulates the NF-kappaB pathway. The most frequent variants of NOD2/CARD15 observed in Crohn's disease tend to cluster in the LRR and its adjacent regions. This suggests that the LRR domain of CD-associated variants is likely to be impaired in its recognition of microbial components. Continuing studies are investigating the pathophysiological mechanisms induced by NOD2/CARD15 variants in the intestinal mucosa.

Innate immune signalling at intestinal mucosal surfaces: a fine line between host protection and destruction.

PubMed

Cario, Elke

2008-11-01

Emerging evidence underscores that inappropriate innate immune responses driven by commensals contribute to the pathogenesis of chronic inflammatory bowel diseases in genetically susceptible hosts. The present review focuses on defining the recently described mechanistic functions through which the innate immune signalling apparatus shapes mucosal homeostasis of the intestine in health and disease. Commensal-induced innate immune signalling actively drives at least six major interdependent functions to control homeostasis in the healthy intestinal mucosa: 1) barrier preservation, 2) inhibition of apoptosis and inflammation, 3) acceleration of wound repair and tissue regeneration, 4) exclusion of harmful pathogens through autophagy and other antimicrobial defenses, while 5) maintaining immune tolerance towards harmless commensals, and 6) linkage to adaptive immunity. Any disturbance of this peaceful and mutually beneficial host-commensal relationship may imbalance innate immune signalling, which predisposes to chronic intestinal inflammation and associated tumourigenesis in inflammatory bowel diseases. Recent advances have highlighted the complex mechanistics and functional diversity of innate immunity that paradoxically mediate both protective and destructive responses in the intestinal mucosa. Related signalling targets may offer novel therapeutic approaches in the treatment of inflammatory bowel diseases and inflammation-related cancer.

Intimin, tir, and shiga toxin 1 do not influence enteropathogenic responses to shiga toxin-producing Escherichia coli in bovine ligated intestinal loops.

PubMed

Stevens, Mark P; Marchès, Olivier; Campbell, June; Huter, Veronika; Frankel, Gad; Phillips, Alan D; Oswald, Eric; Wallis, Timothy S

2002-02-01

Shiga toxin-producing Escherchia coli (STEC) comprises a group of attaching and effacing (A/E) enteric pathogens of animals and humans. Natural and experimental infection of calves with STEC may result in acute enteritis or subclinical infection, depending on serotype- and host-specific factors. To quantify intestinal secretory and inflammatory responses to STEC in the bovine intestine, serotypes that are associated with human disease (O103:H2 and O157:H7) were introduced into ligated mid-ileal loops in gnotobiotic and conventional calves, and fluid accumulation and recruitment of radiolabeled neutrophils were measured after 12 h. STEC serotype O103:H2, but not serotype O157:H7, elicited strong enteropathogenic responses. To determine if the inflammatory response to STEC O103:H2 in calves requires Shiga toxin 1 or intimate bacterial attachment to the intestinal epithelium, defined mutations were made in the stx1, eae, and tir genes. Our data indicate that some STEC induce intestinal inflammatory responses in calves by a mechanism that is independent of A/E-lesion formation, intimin, or Shiga toxin 1. This may have implications for strategies to reduce STEC carriage in cattle.

IFN-γ-mediated induction of an apical IL-10 receptor on polarized intestinal epithelia.

PubMed

Kominsky, Douglas J; Campbell, Eric L; Ehrentraut, Stefan F; Wilson, Kelly E; Kelly, Caleb J; Glover, Louise E; Collins, Colm B; Bayless, Amanda J; Saeedi, Bejan; Dobrinskikh, Evgenia; Bowers, Brittelle E; MacManus, Christopher F; Müller, Werner; Colgan, Sean P; Bruder, Dunja

2014-02-01

Cytokines secreted at sites of inflammation impact the onset, progression, and resolution of inflammation. In this article, we investigated potential proresolving mechanisms of IFN-γ in models of inflammatory bowel disease. Guided by initial microarray analysis, in vitro studies revealed that IFN-γ selectively induced the expression of IL-10R1 on intestinal epithelia. Further analysis revealed that IL-10R1 was expressed predominantly on the apical membrane of polarized epithelial cells. Receptor activation functionally induced canonical IL-10 target gene expression in epithelia, concomitant with enhanced barrier restitution. Furthermore, knockdown of IL-10R1 in intestinal epithelial cells results in impaired barrier function in vitro. Colonic tissue isolated from murine colitis revealed that levels of IL-10R1 and suppressor of cytokine signaling 3 were increased in the epithelium and coincided with increased tissue IFN-γ and IL-10 cytokines. In parallel, studies showed that treatment of mice with rIFN-γ was sufficient to drive expression of IL-10R1 in the colonic epithelium. Studies of dextran sodium sulfate colitis in intestinal epithelial-specific IL-10R1-null mice revealed a remarkable increase in disease susceptibility associated with increased intestinal permeability. Together, these results provide novel insight into the crucial and underappreciated role of epithelial IL-10 signaling in the maintenance and restitution of epithelial barrier and of the temporal regulation of these pathways by IFN-γ.

EFFECT OF PREGNANE XENOBIOTIC RECEPTOR ACTIVATION ON INFLAMMATORY BOWEL DISEASE TREATED WITH RIFAXIMIN.

PubMed

Wan, Y C; Li, T; Han, Y-D; Zhang, H-Y; Lin, H; Zhang, B

2015-01-01

The causes and pathogenesis of Inflammatory Bowel Disease (IBD) are still not clearly understood. This study aims to prove the important role of rifaximin played in inflammatory reaction caused by abnormity of the intestinal mucosal immune system. Intestinal microflora can greatly promote and maintain the inflammatory reaction of IBD, therefore, antibiotics can be used to treat IBD. Rifaximin is a medicine usually used for local intestinal infection. Many clinical and basic studies have shown that both a single application of rifaximin and the joint application with other medicines could achieve a good efficacy. This paper studied the activation of Pregnane Xenobiotic Receptor (PXR) in treating IBD with rifaximin and analyzed its efficacy in IBD when PXR was involved in the transport of medicine and metabolism. The results prove that rifaximin can not only serve as an anti-microbial drug, but can activate PXR and actually weaken the reaction of IBD. Thus it is safe to say that rifaximin has great potential in treating IBD.

Muscadine Grape (Vitis rotundifolia) or Wine Phytochemicals Reduce Intestinal Inflammation in Mice with Dextran Sulfate Sodium-Induced Colitis.

PubMed

Li, Ruiqi; Kim, Min-Hyun; Sandhu, Amandeep K; Gao, Chi; Gu, Liwei

2017-02-01

The objective of this study was to determine the anti-inflammatory effects of phytochemical extracts from muscadine grapes or wine on dextran sulfate sodium (DSS)-induced colitis in mice and to investigate cellular mechanisms. Two groups of C57BL/6J mice were gavaged with muscadine grape phytochemicals (MGP) or muscadine wine phytochemicals (MWP), respectively, for 14 days. Acute colitis was induced by 3% DSS in drinking water for 7 days. An additional two groups of mice served as healthy and disease controls. Results indicated that MGP or MWP significantly prevented weight loss, reduced disease activity index, and preserved colonic length compared to the colitis group (p ≤ 0.05). MGP or MWP significantly decreased myeloperoxidase activity as well as the levels of IL-1β, IL-6, and TNF-α in colon (p ≤ 0.05). MGP or MWP caused down-regulation of the NF-κB pathway by inhibiting the phosphorylation and degradation of IκB in a dose-dependent manner. These findings suggest that phytochemicals from muscadine grape or wine mitigate ulcerative colitis via attenuation of pro-inflammatory cytokine production and modulation of the NF-κB pathway.

How Shigella Utilizes Ca(2+) Jagged Edge Signals during Invasion of Epithelial Cells.

PubMed

Bonnet, Mariette; Tran Van Nhieu, Guy

2016-01-01

Shigella, the causative agent of bacillary dysentery invades intestinal epithelial cells using a type III secretion system (T3SS). Through the injection of type III effectors, Shigella manipulates the actin cytoskeleton to induce its internalization in epithelial cells. At early invasion stages, Shigella induces atypical Ca(2+) responses confined at entry sites allowing local cytoskeletal remodeling for bacteria engulfment. Global Ca(2+) increase in the cell triggers the opening of connexin hemichannels at the plasma membrane that releases ATP in the extracellular milieu, favoring Shigella invasion and spreading through purinergic receptor signaling. During intracellular replication, Shigella regulates inflammatory and death pathways to disseminate within the epithelium. At later stages of infection, Shigella downregulates hemichannel opening and the release of extracellular ATP to dampen inflammatory signals. To avoid premature cell death, Shigella activates cell survival by upregulating the PI3K/Akt pathway and downregulating the levels of p53. Furthermore, Shigella interferes with pro-apoptotic caspases, and orients infected cells toward a slow necrotic cell death linked to mitochondrial Ca(2+) overload. In this review, we will focus on the role of Ca(2+) responses and their regulation by Shigella during the different stages of bacterial infection.

How Shigella Utilizes Ca2+ Jagged Edge Signals during Invasion of Epithelial Cells

PubMed Central

Bonnet, Mariette; Tran Van Nhieu, Guy

2016-01-01

Shigella, the causative agent of bacillary dysentery invades intestinal epithelial cells using a type III secretion system (T3SS). Through the injection of type III effectors, Shigella manipulates the actin cytoskeleton to induce its internalization in epithelial cells. At early invasion stages, Shigella induces atypical Ca2+ responses confined at entry sites allowing local cytoskeletal remodeling for bacteria engulfment. Global Ca2+ increase in the cell triggers the opening of connexin hemichannels at the plasma membrane that releases ATP in the extracellular milieu, favoring Shigella invasion and spreading through purinergic receptor signaling. During intracellular replication, Shigella regulates inflammatory and death pathways to disseminate within the epithelium. At later stages of infection, Shigella downregulates hemichannel opening and the release of extracellular ATP to dampen inflammatory signals. To avoid premature cell death, Shigella activates cell survival by upregulating the PI3K/Akt pathway and downregulating the levels of p53. Furthermore, Shigella interferes with pro-apoptotic caspases, and orients infected cells toward a slow necrotic cell death linked to mitochondrial Ca2+ overload. In this review, we will focus on the role of Ca2+ responses and their regulation by Shigella during the different stages of bacterial infection. PMID:26904514

Probiotics modulate gut microbiota and improve insulin sensitivity in DIO mice.

PubMed

Bagarolli, Renata A; Tobar, Natália; Oliveira, Alexandre G; Araújo, Tiago G; Carvalho, Bruno M; Rocha, Guilherme Z; Vecina, Juliana F; Calisto, Kelly; Guadagnini, Dioze; Prada, Patrícia O; Santos, Andrey; Saad, Sara T O; Saad, Mario J A

2017-12-01

Obesity and type 2 diabetes are characterized by subclinical inflammatory process. Changes in composition or modulation of the gut microbiota may play an important role in the obesity-associated inflammatory process. In the current study, we evaluated the effects of probiotics (Lactobacillus rhamnosus, L. acidophilus and Bifidobacterium bifidumi) on gut microbiota, changes in permeability, and insulin sensitivity and signaling in high-fat diet and control animals. More importantly, we investigated the effects of these gut modulations on hypothalamic control of food intake, and insulin and leptin signaling. Swiss mice were submitted to a high-fat diet (HFD) with probiotics or pair-feeding for 5 weeks. Metagenome analyses were performed on DNA samples from mouse feces. Blood was drawn to determine levels of glucose, insulin, LPS, cytokines and GLP-1. Liver, muscle, ileum and hypothalamus tissue proteins were analyzed by Western blotting and real-time polymerase chain reaction. In addition, liver and adipose tissues were analyzed using histology and immunohistochemistry. The HFD induced huge alterations in gut microbiota accompanied by increased intestinal permeability, LPS translocation and systemic low-grade inflammation, resulting in decreased glucose tolerance and hyperphagic behavior. All these obesity-related features were reversed by changes in the gut microbiota profile induced by probiotics. Probiotics also induced an improvement in hypothalamic insulin and leptin resistance. Our data demonstrate that the intestinal microbiome is a key modulator of inflammatory and metabolic pathways in both peripheral and central tissues. These findings shed light on probiotics as an important tool to prevent and treat patients with obesity and insulin resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

Intermittent fasting promotes bacterial clearance and intestinal IgA production in Salmonella typhimurium-infected mice.

PubMed

Godínez-Victoria, M; Campos-Rodriguez, R; Rivera-Aguilar, V; Lara-Padilla, E; Pacheco-Yepez, J; Jarillo-Luna, R A; Drago-Serrano, M E

2014-05-01

The impact of intermittent fasting versus ad libitum feeding during Salmonella typhimurium infection was evaluated in terms of duodenum IgA levels, bacterial clearance and intestinal and extra-intestinal infection susceptibility. Mice that were intermittently fasted for 12 weeks or fed ad libitum were infected with S. typhimurium and assessed at 7 and 14 days post-infection. Next, we evaluated bacterial load in the faeces, Peyer's patches, spleen and liver by plate counting, as well as total and specific intestinal IgA and plasmatic corticosterone levels (by immunoenzymatic assay) and lamina propria IgA levels in plasma cells (by cytofluorometry). Polymeric immunoglobulin receptor, α- and J-chains, Pax-5 factor, pro-inflammatory cytokine (tumour necrosis factor-α and interferon-γ) and anti-inflammatory cytokine (transforming growth factor-β) mRNA levels were assessed in mucosal and liver samples (by real-time PCR). Compared with the infected ad libitum mice, the intermittently fasted infected animals had (1) lower intestinal and systemic bacterial loads; (2) higher SIgA and IgA plasma cell levels; (3) higher mRNA expression of most intestinal parameters; and (4) increased or decreased corticosterone levels on day 7 and 14 post-infection, respectively. No contribution of liver IgA was observed at the intestinal level. Apparently, the changes following metabolic stress induced by intermittent fasting during food deprivation days increased the resistance to S. typhimurium infection by triggering intestinal IgA production and presumably, pathogen elimination by phagocytic inflammatory cells. © 2014 John Wiley & Sons Ltd.

Acute ileitis facilitates infection with multidrug resistant Pseudomonas aeruginosa in human microbiota-associated mice.

PubMed

von Klitzing, Eliane; Ekmekciu, Ira; Bereswill, Stefan; Heimesaat, Markus M

2017-01-01

The rising incidence of multidrug resistant (MDR) Gram-negative bacteria including Pseudomonas aeruginosa has become a serious issue in prevention of its spread particularly among hospitalized patients. It is, however, unclear whether distinct conditions such as acute intestinal inflammation facilitate P. aeruginosa infection of vertebrate hosts. To address this, we analysed P. aeruginosa infection in human microbiota-associated (hma) mice with acute ileitis induced by peroral Toxoplasma gondii challenge. When perorally infected with P. aeruginosa at day 3 post ileitis induction, hma mice displayed higher intestinal P. aeruginosa loads as compared to hma mice without ileitis. However, the overall intestinal microbiota composition was not disturbed by P. aeruginosa (except for lowered bifidobacterial populations), and the infection did not further enhance ileal immune cell responses. Pro-inflammatory cytokines including IFN-γ and IL-12p70 were similarly increased in ileum and mesenteric lymph nodes of P. aeruginosa infected and uninfected hma mice with ileitis. The anti-inflammatory cytokine IL-10 increased multifold upon ileitis induction, but interestingly more distinctly in P. aeruginosa infected as compared to uninfected controls. Immune responses were not restricted to the intestines as indicated by elevated pro-inflammatory cytokine levels in liver and kidney upon ileitis induction. However, except for hepatic TNF-α levels, P. aeruginosa infection did not result in more distinct pro-inflammatory cytokine secretion in liver and kidney of hma mice with ileitis. Whereas viable intestinal bacteria were more frequently detected in systemic compartments such as spleen and cardiac blood of P. aeruginosa infected than uninfected mice at day 7 following ileitis induction, P. aeruginosa infection did not exacerbate systemic pro-inflammatory sequelae, but resulted in lower IL-10 serum levels. Acute intestinal inflammation facilitates infection of the vertebrate host with MDR bacteria including P. aeruginosa and might also pose particularly hospitalized patients at risk for acquisition. Since acute T. gondii induced inflammation might mask immunopathology caused by P. aeruginosa , a subacute or chronic inflammation model might be better suited to investigate the potential role of P. aeruginosa infection in the aggravation of intestinal disease.

Neural reflex pathways in intestinal inflammation: hypotheses to viable therapy.

PubMed

Willemze, Rose A; Luyer, Misha D; Buurman, Wim A; de Jonge, Wouter J

2015-06-01

Studies in neuroscience and immunology have clarified much of the anatomical and cellular basis for bidirectional interactions between the nervous and immune systems. As with other organs, intestinal immune responses and the development of immunity seems to be modulated by neural reflexes. Sympathetic immune modulation and reflexes are well described, and in the past decade the parasympathetic efferent vagus nerve has been added to this immune-regulation network. This system, designated 'the inflammatory reflex', comprises an afferent arm that senses inflammation and an efferent arm that inhibits innate immune responses. Intervention in this system as an innovative principle is currently being tested in pioneering trials of vagus nerve stimulation using implantable devices to treat IBD. Patients benefit from this treatment, but some of the working mechanisms remain to be established, for instance, treatment is effective despite the vagus nerve not always directly innervating the inflamed tissue. In this Review, we will focus on the direct neuronal regulatory mechanisms of immunity in the intestine, taking into account current advances regarding the innervation of the spleen and lymphoid organs, with a focus on the potential for treatment in IBD and other gastrointestinal pathologies.

Non-Systemic Drugs: A Critical Review

PubMed Central

Charmot, Dominique

2012-01-01

Non-systemic drugs act within the intestinal lumen without reaching the systemic circulation. The first generation included polymeric resins that sequester phosphate ions, potassium ions, or bile acids for the treatment of electrolyte imbalances or hypercholesteremia. The field has evolved towards non-absorbable small molecules or peptides targeting luminal enzymes or transporters for the treatment of mineral metabolism disorders, diabetes, gastrointestinal (GI) disorders, and enteric infections. From a drug design and development perspective, non-systemic agents offer novel opportunities to address unmet medical needs while minimizing toxicity risks, but also present new challenges, including developing a better understanding and control of non-transcellular leakage pathways into the systemic circulation. The pharmacokinetic-pharmacodynamic relationship of drugs acting in the GI tract can be complex due to the variability of intestinal transit, interaction with chyme, and the complex environment of the surface epithelia. We review the main classes of non-absorbable agents at various stages of development, and their therapeutic potential and limitations. The rapid progress in the identification of intestinal receptors and transporters, their functional characterization and role in metabolic and inflammatory disorders, will undoubtedly renew interest in the development of novel, safe, non-systemic therapeutics. PMID:22300258

Avian Influenza Virus Subtype H9N2 Affects Intestinal Microbiota, Barrier Structure Injury, and Inflammatory Intestinal Disease in the Chicken Ileum.

PubMed

Li, Hongxin; Liu, Xiaolin; Chen, Feiyang; Zuo, Kejing; Wu, Che; Yan, Yiming; Chen, Weiguo; Lin, Wencheng; Xie, Qingmei

2018-05-18

Avian influenza virus subtype H9N2 (H9N2 AIV) has caused significant losses to the poultry industry due to the high mortality associated with secondary infections attributable to E. coli . This study tries to address the underlying secondary mechanisms after H9N2 AIV infection. Initially, nine day-old specific pathogen-free chickens were assigned to control (uninfected) and H9N2-infected groups, respectively. Using Illumina sequencing, histological examination, and quantitative real-time PCR, it was found that H9N2 AIV caused intestinal microbiota disorder, injury, and inflammatory damage to the intestinal mucosa. Notably, the genera Escherichia , especially E. coli , significantly increased ( p < 0.01) at five days post-infection (dpi), while Lactobacillus , Enterococcus , and other probiotic organisms were significantly reduced ( p < 0.01). Simultaneously, the mRNA expression of tight junction proteins ( ZO-1 , claudin 3, and occludin), TFF2, and Muc2 were significantly reduced ( p < 0.01), indicating the destruction of the intestinal epithelial cell tight junctions and the damage of mucin layer construction. Moreover, the mRNA expression of proinflammatory cytokines IFN-γ, IL-22, IFN-α, and IL-17A in intestinal epithelial cells were significantly upregulated, resulting in the inflammatory response and intestinal injury. Our findings may provide a theoretical basis for observed gastroenteritis-like symptoms such as diarrhea and secondary E. coli infection following H9N2 AIV infection.

Interplay between intestinal alkaline phosphatase, diet, gut microbes and immunity.

PubMed

Estaki, Mehrbod; DeCoffe, Daniella; Gibson, Deanna L

2014-11-14

Intestinal alkaline phosphatase (IAP) plays an essential role in intestinal homeostasis and health through interactions with the resident microbiota, diet and the gut. IAP's role in the intestine is to dephosphorylate toxic microbial ligands such as lipopolysaccharides, unmethylated cytosine-guanosine dinucleotides and flagellin as well as extracellular nucleotides such as uridine diphosphate. IAP's ability to detoxify these ligands is essential in protecting the host from sepsis during acute inflammation and chronic inflammatory conditions such as inflammatory bowel disease. Also important in these complications is IAP's ability to regulate the microbial ecosystem by forming a complex relationship between microbiota, diet and the intestinal mucosal surface. Evidence reveals that diet alters IAP expression and activity and this in turn can influence the gut microbiota and homeostasis. IAP's ability to maintain a healthy gastrointestinal tract has accelerated research on its potential use as a therapeutic agent against a multitude of diseases. Exogenous IAP has been shown to have beneficial effects when administered during ulcerative colitis, coronary bypass surgery and sepsis. There are currently a handful of human clinical trials underway investigating the effects of exogenous IAP during sepsis, rheumatoid arthritis and heart surgery. In light of these findings IAP has been marked as a novel agent to help treat a variety of other inflammatory and infectious diseases. The purpose of this review is to highlight the essential characteristics of IAP in protection and maintenance of intestinal homeostasis while addressing the intricate interplay between IAP, diet, microbiota and the intestinal epithelium.

Interplay between intestinal alkaline phosphatase, diet, gut microbes and immunity

PubMed Central

Estaki, Mehrbod; DeCoffe, Daniella; Gibson, Deanna L

2014-01-01

Intestinal alkaline phosphatase (IAP) plays an essential role in intestinal homeostasis and health through interactions with the resident microbiota, diet and the gut. IAP’s role in the intestine is to dephosphorylate toxic microbial ligands such as lipopolysaccharides, unmethylated cytosine-guanosine dinucleotides and flagellin as well as extracellular nucleotides such as uridine diphosphate. IAP’s ability to detoxify these ligands is essential in protecting the host from sepsis during acute inflammation and chronic inflammatory conditions such as inflammatory bowel disease. Also important in these complications is IAP’s ability to regulate the microbial ecosystem by forming a complex relationship between microbiota, diet and the intestinal mucosal surface. Evidence reveals that diet alters IAP expression and activity and this in turn can influence the gut microbiota and homeostasis. IAP’s ability to maintain a healthy gastrointestinal tract has accelerated research on its potential use as a therapeutic agent against a multitude of diseases. Exogenous IAP has been shown to have beneficial effects when administered during ulcerative colitis, coronary bypass surgery and sepsis. There are currently a handful of human clinical trials underway investigating the effects of exogenous IAP during sepsis, rheumatoid arthritis and heart surgery. In light of these findings IAP has been marked as a novel agent to help treat a variety of other inflammatory and infectious diseases. The purpose of this review is to highlight the essential characteristics of IAP in protection and maintenance of intestinal homeostasis while addressing the intricate interplay between IAP, diet, microbiota and the intestinal epithelium. PMID:25400448

Abortive Intestinal Infection With an Escherichia coli-Shigella flexneri Hybrid Strain

PubMed Central

Formal, Samuel B.; LaBrec, E. H.; Kent, T. H.; Falkow, S.

1965-01-01

Formal, Samuel B., (Walter Reed Army Institute of Research, Washington, D.C.), E. H. LaBrec, T. H. Kent, and S. Falkow. Abortive intestinal infection with an Escherichia coli-Shigella flexneri hybrid strain. J. Bacteriol. 89:1374–1382. 1965.—The mechanism of the apparent loss of virulence of an Escherichia coli-Shigella flexneri hybrid strain was studied. The parent Shigella strain caused a fatal enteric infection when fed to starved guinea pigs, and signs of dysentery followed its oral administration to monkeys. The hybrid strain failed to produce any apparent symptoms when fed to either of these species. The parent strain was shown to invade the intestinal mucosa of starved guinea pigs. This caused a severe inflammatory reaction in the lamina propria, which progressed to ulceration of the intestinal epithelium and resulted in death of the animal. The hybrid strain also invaded the intestinal mucosa and produced an inflammatory reaction. In this case, the inflammatory reaction subsided, the intestine returned to normal within 4 days after challenge, and the animal survived. Both fluorescent-antibody techniques and in vivo growth studies have shown that the hybrid strain can not maintain itself in the intestinal mucosa. Preliminary studies have indicated that a similar situation also exists in the monkey. It is concluded that the virulence of dysentery bacilli rests not only in the capacity to reach the lamina propria, but also in the ability to multiply in this region. Images PMID:14293011

Rebamipide ameliorates radiation-induced intestinal injury in a mouse model.

PubMed

Shim, Sehwan; Jang, Hyo-Sun; Myung, Hyun-Wook; Myung, Jae Kyung; Kang, Jin-Kyu; Kim, Min-Jung; Lee, Seung Bum; Jang, Won-Suk; Lee, Sun-Joo; Jin, Young-Woo; Lee, Seung-Sook; Park, Sunhoo

2017-08-15

Radiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. Radiation exposure produces an uncontrolled inflammatory cascade and epithelial cell loss leading to impaired epithelial barrier function. The goal of this study was to determine the effect of rebamipide on regeneration of the intestinal epithelia after radiation injury. The abdomens of C57BL/6 mice were exposed to 13Gy of irradiation (IR) and then the mice were treated with rebamipide. Upon IR, intestinal epithelia were destroyed structurally at the microscopic level and bacterial translocation was increased. The intestinal damage reached a maximum level on day 6 post-IR and intestinal regeneration occurred thereafter. We found that rebamipide significantly ameliorated radiation-induced intestinal injury. In mice treated with rebamipide after IR, intestinal barrier function recovered and expression of the tight junction components of the intestinal barrier were upregulated. Rebamipide administration reduced radiation-induced intestinal mucosal injury. The levels of proinflammatory cytokines and matrix metallopeptidase 9 (MMP9) were significantly reduced upon rebamipide administration. Intestinal cell proliferation and β-catenin expression also increased upon rebamipide administration. These data demonstrate that rebamipide reverses impairment of the intestinal barrier by increasing intestinal cell proliferation and attenuating the inflammatory response by inhibiting MMP9 and proinflammatory cytokine expression in a murine model of radiation-induced enteritis. Copyright © 2017 Elsevier Inc. All rights reserved.

Using Corticosteroids to Reshape the Gut Microbiome: Implications for Inflammatory Bowel Diseases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Edmond Y.; Inoue, Takuya; Leone, Vanessa A.

Introduction—Commensal gut microbiota play an important role in regulating metabolic and inflammatory conditions. Reshaping intestinal microbiota through pharmacologic means may be a viable treatment option. Here we sought to delineate the functional characteristics of glucocorticoid-mediated alterations on gut microbiota and their subsequent repercussions on host mucin regulation and colonic inflammation. Methods—Adult male C57Bl/6 mice, germ-free (GF), Muc2-heterozygote (±), or Muc2-knockout (-/-) were injected with dexamethasone, a synthetic glucocorticoid, for four weeks. Fecal samples were collected for gut microbiota analysis via 16S rRNA T-RFLP and amplicon sequencing. Intestinal mucosa was collected for mucin gene expression studies. GF mice were conventionalized withmore » gut microbes from treated- and non-treated groups to determine their functional capacities in recipient hosts. Results—Exposure to DEX in WT mice led to substantial shifts in gut microbiota over a four-week period. Furthermore, a significant down-regulation of colonic Muc2 gene expression was observed after treatment. Muc2-knockout mice harbored a pro-inflammatory environment of gut microbes, characterized by the increase or decrease in prevalence of specific microbiota populations such as Clostridiales and Lactobacillaceae, respectively. This colitogenic phenotype was transmissible to IL10-knockout (IL10-KO) mice, a genetically susceptible model of colonic inflammatory disorders. Microbiota from donors pre-treated with DEX, however, ameliorated symptoms of inflammation. We conclude that commensal gut bacteria may be a key mediator of the anti-inflammatory effects observed in the large intestine after GC exposure. These findings underscore the notion that intestinal microbes comprise a “microbial organ” essential for host physiology that can be targeted by therapeutic approaches to restore intestinal homeostasis.« less

TAM receptor-dependent regulation of SOCS3 and MAPKs contributes to pro-inflammatory cytokine downregulation following chronic NOD2 stimulation of human macrophages1

PubMed Central

Zheng, Shasha; Hedl, Matija; Abraham, Clara

2014-01-01

Microbial-induced cytokine regulation is critical to intestinal immune homeostasis. Acute stimulation of NOD2, the Crohn’s disease-associated sensor of bacterial peptidoglycan, induces cytokines. However, cytokines are attenuated after chronic NOD2 and pattern recognition receptor (PRR) stimulation of macrophages; similar attenuation is observed in intestinal macrophages. The role of Tyro3, Axl and Mer (TAM) receptors in regulating chronic PRR stimulation and NOD2-induced outcomes has not been examined. Moreover, TAM receptors have been relatively less investigated in human macrophages. Whereas TAM receptors did not downregulate acute NOD2-induced cytokines in primary human macrophages, they were essential for downregulating signaling and pro-inflammatory cytokine secretion after chronic NOD2 and TLR4 stimulation. Axl and Mer were similarly required in mice for cytokine downregulation after chronic NOD2 stimulation in vivo and in intestinal tissues. Consistently, TAM expression was increased in human intestinal myeloid-derived cells. Chronic NOD2 stimulation led to IL-10- and TGFβ-dependent TAM upregulation in human macrophages, which in turn, upregulated SOCS3 expression. Restoring SOCS3 expression under TAM knockdown conditions restored chronic NOD2-mediated pro-inflammatory cytokine downregulation. In contrast to the upregulated pro-inflammatory cytokines, attenuated IL-10 secretion was maintained in TAM-deficient macrophages upon chronic NOD2 stimulation. The level of MAPK activation in TAM-deficient macrophages after chronic NOD2 stimulation was insufficient to upregulate IL-10 secretion; however, full restoration of MAPK activation under these conditions restored c-Fos, c-Jun, MAFK and PU.1 binding to the IL-10 promoter and IL-10 secretion. Therefore, TAM receptors are critical for downregulating pro-inflammatory cytokines under the chronic NOD2 stimulation conditions observed in the intestinal environment. PMID:25567680

Using Corticosteroids to Reshape the Gut Microbiome: Implications for Inflammatory Bowel Diseases

DOE PAGES

Huang, Edmond Y.; Inoue, Takuya; Leone, Vanessa A.; ...

2015-05-01

Introduction—Commensal gut microbiota play an important role in regulating metabolic and inflammatory conditions. Reshaping intestinal microbiota through pharmacologic means may be a viable treatment option. Here we sought to delineate the functional characteristics of glucocorticoid-mediated alterations on gut microbiota and their subsequent repercussions on host mucin regulation and colonic inflammation. Methods—Adult male C57Bl/6 mice, germ-free (GF), Muc2-heterozygote (±), or Muc2-knockout (-/-) were injected with dexamethasone, a synthetic glucocorticoid, for four weeks. Fecal samples were collected for gut microbiota analysis via 16S rRNA T-RFLP and amplicon sequencing. Intestinal mucosa was collected for mucin gene expression studies. GF mice were conventionalized withmore » gut microbes from treated- and non-treated groups to determine their functional capacities in recipient hosts. Results—Exposure to DEX in WT mice led to substantial shifts in gut microbiota over a four-week period. Furthermore, a significant down-regulation of colonic Muc2 gene expression was observed after treatment. Muc2-knockout mice harbored a pro-inflammatory environment of gut microbes, characterized by the increase or decrease in prevalence of specific microbiota populations such as Clostridiales and Lactobacillaceae, respectively. This colitogenic phenotype was transmissible to IL10-knockout (IL10-KO) mice, a genetically susceptible model of colonic inflammatory disorders. Microbiota from donors pre-treated with DEX, however, ameliorated symptoms of inflammation. We conclude that commensal gut bacteria may be a key mediator of the anti-inflammatory effects observed in the large intestine after GC exposure. These findings underscore the notion that intestinal microbes comprise a “microbial organ” essential for host physiology that can be targeted by therapeutic approaches to restore intestinal homeostasis.« less

R-Spondins Are Expressed by the Intestinal Stroma and are Differentially Regulated during Citrobacter rodentium- and DSS-Induced Colitis in Mice.

PubMed

Kang, Eugene; Yousefi, Mitra; Gruenheid, Samantha

2016-01-01

The R-spondin family of proteins has recently been described as secreted enhancers of β-catenin activation through the canonical Wnt signaling pathway. We previously reported that Rspo2 is a major determinant of susceptibility to Citrobacter rodentium-mediated colitis in mice and recent genome-wide association studies have revealed RSPO3 as a candidate Crohn's disease-specific inflammatory bowel disease susceptibility gene in humans. However, there is little information on the endogenous expression and cellular source of R-spondins in the colon at steady state and during intestinal inflammation. RNA sequencing and qRT-PCR were used to assess the expression of R-spondins at steady state and in two mouse models of colonic inflammation. The cellular source of R-spondins was assessed in specific colonic cell populations isolated by cell sorting. Data mining from publicly available datasets was used to assess the expression of R-spondins in the human colon. At steady state, colonic expression of R-spondins was found to be exclusive to non-epithelial CD45- lamina propria cells, and Rspo3/RSPO3 was the most highly expressed R-spondin in both mouse and human colon. R-spondin expression was found to be highly dynamic and differentially regulated during C. rodentium infection and dextran sodium sulfate (DSS) colitis, with notably high levels of Rspo3 expression during DSS colitis, and high levels of Rspo2 expression during C. rodentium infection, specifically in susceptible mice. Our data are consistent with the hypothesis that in the colon, R-spondins are expressed by subepithelial stromal cells, and that Rspo3/RSPO3 is the family member most implicated in colonic homeostasis. The differential regulation of the R-spondins in different models of intestinal inflammation indicate they respond to specific pathogenic and inflammatory signals that differ in the two models and provides further evidence that this family of proteins plays a key role in linking intestinal inflammation and homeostasis.

Herpes Simplex Virus Type 1 Infects Enteric Neurons and Triggers Gut Dysfunction via Macrophage Recruitment.

PubMed

Brun, Paola; Qesari, Marsela; Marconi, Peggy C; Kotsafti, Andromachi; Porzionato, Andrea; Macchi, Veronica; Schwendener, Reto A; Scarpa, Marco; Giron, Maria C; Palù, Giorgio; Calistri, Arianna; Castagliuolo, Ignazio

2018-01-01

Herpes Simplex Virus type 1 (HSV-1), a neurotropic pathogen widespread in human population, infects the enteric nervous system (ENS) in humans and rodents and causes intestinal neuromuscular dysfunction in rats. Although infiltration of inflammatory cells in the myenteric plexus and neurodegeneration of enteric nerves are common features of patients suffering from functional intestinal disorders, the proof of a pathogenic link with HSV-1 is still unsettled mainly because the underlying mechanisms are largely unknown. In this study we demonstrated that following intragastrical administration HSV-1 infects neurons within the myenteric plexus resulting in functional and structural alterations of the ENS. By infecting mice with HSV-1 replication-defective strain we revealed that gastrointestinal neuromuscular anomalies were however independent of viral replication. Indeed, enteric neurons exposed to UV-inactivated HSV-1 produced monocyte chemoattractant protein-1 (MCP-1/CCL2) to recruit activated macrophages in the longitudinal muscle myenteric plexus. Infiltrating macrophages produced reactive oxygen and nitrogen species and directly harmed enteric neurons resulting in gastrointestinal dysmotility. In HSV-1 infected mice intestinal neuromuscular dysfunctions were ameliorated by in vivo administration of (i) liposomes containing dichloromethylene bisphosphonic acid (clodronate) to deplete tissue macrophages, (ii) CCR2 chemokine receptor antagonist RS504393 to block the CCL2/CCR2 pathway, (iii) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and AR-C 102222 to quench production of nitrogen reactive species produced via iNOS. Overall these data demonstrate that HSV-1 infection makes enteric neurons recruit macrophages via production of a specific chemoattractant factor. The resulting inflammatory reaction is mandatory for intestinal dysmotility. These findings provide insights into the neuro-immune communication that occurs in the ENS following HSV-1 infection and allow recognition of an original pathophysiologic mechanism underlying gastrointestinal diseases as well as identification of novel therapeutic targets.

Loss of Dok-1 and Dok-2 in mice causes severe experimental colitis accompanied by reduced expression of IL-17A and IL-22

DOE Office of Scientific and Technical Information (OSTI.GOV)

Waseda, Masazumi; Arimura, Sumimasa; Shimura, Eri

Appropriate immune responses and mucosal barrier functions are required for the maintenance of intestinal homeostasis. Defects in this defense system may lead to inflammatory disorders such as inflammatory bowel disease. Downstream of tyrosine kinases 1 (Dok-1) and its closest homolog, Dok-2, are preferentially expressed in immune cells, and play essential roles in the negative regulation of multiple signaling pathways in both innate and adaptive immunity. However, the function of these proteins in intestinal homeostasis remained unclear. Here we show that Dok-1/-2 double knockout (DKO) mice were highly susceptible to dextran sodium sulfate (DSS)-induced colitis compared with Dok-1 or Dok-2 singlemore » KO and wild type (WT) mice. Furthermore, DSS-treated Dok-1/-2 DKO mice exhibited increased colonic tissue damage accompanied by reduced proliferation of the epithelial cells relative to WT controls, suggesting that Dok-1/-2 DKO mice have defects in the repair of intestinal epithelial lesions. In addition, the levels of the Th17 cytokines IL-17A and IL-22, which have protective roles in DSS-induced colitis, were reduced in DSS-treated Dok-1/-2 DKO mice compared with WT mice. Taken together, our results demonstrate that Dok-1 and Dok-2 negatively regulate intestinal inflammation, apparently through the induction of IL-17A and IL-22 expression. - Highlights: • Dok-1 and Dok-2 play a cooperative role in protection against DSS-induced colitis. • Dok-1/-2 double KO (DKO) mice show extensive ulceration of the colon after DSS treatment. • Proliferation of colonic epithelium is inhibited in DSS-treated Dok-1/-2 DKO mice. • Expression of IL-17A and IL-22 is reduced in the colon of DSS-treated Dok-1/-2 DKO mice.« less

The intestinal complement system in inflammatory bowel disease: Shaping intestinal barrier function.

PubMed

Sina, Christian; Kemper, Claudia; Derer, Stefanie

2018-06-01

The complement system is part of innate sensor and effector systems such as the Toll-like receptors (TLRs). It recognizes and quickly systemically and/or locally respond to microbial-associated molecular patterns (MAMPs) with a tailored defense reaction. MAMP recognition by intestinal epithelial cells (IECs) and appropriate immune responses are of major importance for the maintenance of intestinal barrier function. Enterocytes highly express various complement components that are suggested to be pivotal for proper IEC function. Appropriate activation of the intestinal complement system seems to play an important role in the resolution of chronic intestinal inflammation, while over-activation and/or dysregulation may worsen intestinal inflammation. Mice deficient for single complement components suffer from enhanced intestinal inflammation mimicking the phenotype of patients with chronic inflammatory bowel disease (IBD) such as Crohn's disease (CD) or ulcerative colitis (UC). However, the mechanisms leading to complement expression in IECs seem to differ markedly between UC and CD patients. Hence, how IECs, intestinal bacteria and epithelial cell expressed complement components interact in the course of IBD still remains to be mostly elucidated to define potential unique patterns contributing to the distinct subtypes of intestinal inflammation observed in CD and UC. Copyright © 2018 Elsevier Ltd. All rights reserved.

Maintaining intestinal health: the genetics and immunology of very early onset inflammatory bowel disease.

PubMed

Kelsen, Judith R; Baldassano, Robert N; Artis, David; Sonnenberg, Gregory F

2015-09-01

Inflammatory bowel disease (IBD) is a multifactoral disease caused by dysregulated immune responses to commensal or pathogenic microbes in the intestine, resulting in chronic intestinal inflammation. An emerging population of patients with IBD occurring before the age of 5 represent a unique form of disease, termed Very Early Onset (VEO)-IBD, which is phenotypically- and genetically-distinct from older-onset IBD. VEO-IBD is associated with increased disease severity, aggressive progression and poor responsiveness to most conventional therapies. Further investigation into the causes and pathogenesis of VEO-IBD will help improve treatment strategies, and may lead to a better understanding of the mechanisms that are essential to maintain intestinal health or provoke the development of targeted therapeutic strategies to limit intestinal disease. Here we discuss the phenotypic nature of VEO-IBD, the recent identification of novel gene variants associated with disease, and functional immunologic studies interrogating the contribution of specific genetic variants to the development of chronic intestinal inflammation.

What are the effects of proton pump inhibitors on the small intestine?

PubMed Central

Fujimori, Shunji

2015-01-01

Generally, proton-pump inhibitors (PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating nonsteroidal anti-inflammatory drug-induced small intestinal injury. Several meta-analyses and systematic reviews have reported that patients treated with PPIs, as well as post-gastrectomy patients, have a higher frequency of small intestinal bacterial overgrowth (SIBO) compared to patients who lack the aforementioned conditions. Furthermore, there is insufficient evidence that these conditions induce Clostridium difficile infection. At this time, PPI-induced dysbiosis is considered a type of SIBO. It now seems likely that intestinal bacterial flora influence many diseases, such as inflammatory bowel disease, diabetes mellitus, obesity, non-alcoholic fatty liver disease, and autoimmune diseases. When attempting to control intestinal bacterial flora with probiotics, prebiotics, and fecal microbiota transplantation, etc., the influence of acid suppression therapy, especially PPIs, should not be overlooked. PMID:26078557

What are the effects of proton pump inhibitors on the small intestine?

PubMed

Fujimori, Shunji

2015-06-14

Generally, proton-pump inhibitors (PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating nonsteroidal anti-inflammatory drug-induced small intestinal injury. Several meta-analyses and systematic reviews have reported that patients treated with PPIs, as well as post-gastrectomy patients, have a higher frequency of small intestinal bacterial overgrowth (SIBO) compared to patients who lack the aforementioned conditions. Furthermore, there is insufficient evidence that these conditions induce Clostridium difficile infection. At this time, PPI-induced dysbiosis is considered a type of SIBO. It now seems likely that intestinal bacterial flora influence many diseases, such as inflammatory bowel disease, diabetes mellitus, obesity, non-alcoholic fatty liver disease, and autoimmune diseases. When attempting to control intestinal bacterial flora with probiotics, prebiotics, and fecal microbiota transplantation, etc., the influence of acid suppression therapy, especially PPIs, should not be overlooked.

[Portuguese Consensus on the Diagnosis, Prevention and Treatment of Anaemia in Inflammatory Bowel Disease].

PubMed

Magro, Fernando; Ramos, Jaime; Correia, Luís; Lago, Paula; Peixe, Paula; Gonçalves, Ana Rita; Rodrigues, Ãngela; Vieira, Catarina; Ferreira, Daniela; Pereira Silva, João; Túlio, Maria Ana; Salgueiro, Paulo; Fernandes, Samuel

2016-02-01

Anaemia can be considered the most common extra-intestinal manifestation in inflammatory bowel disease. Nevertheless, anaemia is often under-diagnosed and under-treated both in adults and children with inflammatory bowel disease. Herein, we report the consensus statements on the management of anaemia in inflammatory bowel disease developed by the Portuguese Working Group on Inflammatory Bowel Disease (known as Grupo de Estudo da Doença Inflamatória Intestinal - GEDII) to aid clinicians in daily management of inflammatory bowel disease patients. A comprehensive literature review was conducted in order to prepare consensus statements on the following topics: (1) prevalence and diagnosis of anaemia in inflammatory bowel disease, (2) iron supplementation for the prevention of anaemia in inflammatory bowel disease and (3) treatment of anaemia in inflammatory bowel disease. The final statements for each topic were discussed at a consensus meeting and rated according to the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. It was concluded that anaemia has a high incidence and prevalence in inflammatory bowel disease, particularly in those with active disease and hospitalised. Patients with anaemia had decreased quality of life and frequently complained of fatigue. Absolute indications for intravenous therapy should be considered: (1) moderate to severe anaemia (haemoglobin < 10.5 g/dL) or clearly symptomatic anaemia; (2) previous intolerance to oral iron supplements; (3) inappropriate response to oral iron; (4) active severe intestinal disease; (5) need for a quick therapeutic response (e.g. surgery in the short term); (6) concomitant therapy with erythropoiesis-stimulating agent; and (7) patient's preference.

Induction of dsRNA-activated protein kinase links mitochondrial unfolded protein response to the pathogenesis of intestinal inflammation.

PubMed

Rath, Eva; Berger, Emanuel; Messlik, Anja; Nunes, Tiago; Liu, Bo; Kim, Sandy C; Hoogenraad, Nick; Sans, Miquel; Sartor, R Balfour; Haller, Dirk

2012-09-01

Inflammatory bowel diseases (IBDs) feature multiple cellular stress responses, including endoplasmic reticulum (ER) unfolded protein responses (UPRs). UPRs represent autoregulatory pathways that adjust organelle capacity to cellular demand. A similar mechanism, mitochondrial UPR (mtUPR), has been described for mitochondria. ER UPR in intestinal epithelial cells (IECs) contributes to the development of intestinal inflammation, and since mitochondrial alterations and dysfunction are implicated in the pathogenesis of IBDs, the authors characterised mtUPR in the context of intestinal inflammation. Truncated ornithine transcarbamylase was used to selectively induce mtUPR in a murine IEC line. Dextran sodium sulphate (DSS) was administered to PKR (double-stranded-RNA-activated protein kinase) knockout mice to induce IEC stress in vivo and to test for their susceptibility to DSS-induced colitis. Expression levels of the mitochondrial chaperone chaperonin 60 (CPN60) and PKR were quantified in IECs from patients with IBDs and from murine models of colitis using immunohistochemistry and Western blot analysis. Selective mtUPR induction by truncated ornithine transcarbamylase transfection triggered the phosphorylation of eukaryotic translation initiation factor (eIF) 2α and cJun through the recruitment of PKR. Using pharmacological inhibitors and small inhibitory RNA, the authors identified mtUPR-induced eIF2α phosphorylation and transcription factor activation (cJun/AP1) as being dependent on the activities of the mitochondrial protease ClpP and the cytoplasmic kinase PKR. Pkr(-/-) mice failed to induce CPN60 in IECs upon DSS treatment at early time points and subsequently showed an almost complete resistance to DSS-induced colitis. Under inflammatory conditions, primary IECs from patients with IBDs and two murine models of colitis exhibited a strong induction of the mtUPR marker protein CPN60 associated with enhanced expression of PKR. PKR integrates mtUPR into the disease-relevant ER UPR via eIF2α phosphorylation and AP1 activation. Induction of mtUPR and PKR was observed in IECs from murine models and patients with IBDs. The authors' results indicate that PKR might link mitochondrial stress to intestinal inflammation.

Intestine-Specific Mttp Deletion Decreases Mortality and Prevents Sepsis-Induced Intestinal Injury in a Murine Model of Pseudomonas aeruginosa Pneumonia

PubMed Central

Dominguez, Jessica A.; Xie, Yan; Dunne, W. Michael; Yoseph, Benyam P.; Burd, Eileen M.; Coopersmith, Craig M.; Davidson, Nicholas O.

2012-01-01

Background The small intestine plays a crucial role in the pathophysiology of sepsis and has been referred to as the “motor” of the systemic inflammatory response. One proposed mechanism is that toxic gut-derived lipid factors, transported in mesenteric lymph, induce systemic injury and distant organ failure. However, the pathways involved are yet to be defined and the role of intestinal chylomicron assembly and secretion in transporting these lipid factors is unknown. Here we studied the outcome of sepsis in mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO), which exhibit a block in chylomicron assembly together with lipid malabsorption. Methodology/Principal Findings Mttp-IKO mice and controls underwent intratracheal injection with either Pseudomonas aeruginosa or sterile saline. Mttp-IKO mice exhibited decreased seven-day mortality, with 0/20 (0%) dying compared to 5/17 (29%) control mice (p<0.05). This survival advantage in Mttp-IKO mice, however, was not associated with improvements in pulmonary bacterial clearance or neutrophil infiltration. Rather, Mttp-IKO mice exhibited protection against sepsis-associated decreases in villus length and intestinal proliferation and were also protected against increased intestinal apoptosis, both central features in control septic mice. Serum IL-6 levels, a major predictor of mortality in human and mouse models of sepsis, were elevated 8-fold in septic control mice but remained unaltered in septic Mttp-IKO mice. Serum high density lipoprotein (HDL) levels were reduced in septic control mice but were increased in septic Mttp-IKO mice. The decreased levels of HDL were associated with decreased hepatic expression of apolipoprotein A1 in septic control mice. Conclusions/Significance These studies suggest that strategies directed at blocking intestinal chylomicron secretion may attenuate the progression and improve the outcome of sepsis through effects mediated by metabolic and physiological adaptations in both intestinal and hepatic lipid flux. PMID:23145105

Carboxymethyl pachyman (CMP) reduces intestinal mucositis and regulates the intestinal microflora in 5-fluorouracil-treated CT26 tumour-bearing mice.

PubMed

Wang, Canhong; Yang, Shuxian; Gao, Li; Wang, Lili; Cao, Li

2018-05-23

The compound 5-fluorouracil (5-FU) is the first choice chemotherapeutic agent for the treatment of colorectal cancer (CRC), but intestinal mucositis is a primary limiting factor in anticancer therapy. There is currently no broadly effective targeted treatment to cure this side effect. Carboxymethylated pachyman (CMP) is a polysaccharide that is modified from the structure of pachyman isolated from Poria cocos (Chinese name: Fu Ling). Meanwhile, recent studies have shown that CMP exhibits immune regulatory, anti-inflammatory and antioxidant activities. Therefore, the purpose of this study was to evaluate the intestinal protective effect of CMP in 5-FU-treated CT26 tumour-bearing mice and to further explore its underlying mechanism(s) of action. Initially, a CT26 colon carcinoma xenograft mice model was established. The colon length, colon tissue injury, intestinal flora, short-chain fatty acids (SCFAs) and indicators linked to inflammation, antioxidation and apoptosis were then measured. Our results showed that CMP in combination with 5-FU reversed intestinal shortening (p < 0.01) and alleviated 5-FU-induced colon injury (p < 0.001) via suppression of ROS production; increasing the levels of CAT, GSH-Px and GSH; decreasing expression of NF-κB, p-p38 and Bax; and elevating the levels of Nrf2 and Bcl-2. More importantly, CMP had a significant impact and counteracted the intestinal microflora disorders produced by 5-FU by increasing the proportion of Bacteroidetes, lactobacilli, and butyric acid-producing and acetic acid-producing bacteria and restoring the intestinal flora diversity. Overall, this work suggested that CMP could regulate the ecological balance of the intestinal flora and reduce colon injuries induced by 5-FU in CT26 tumour-bearing mice, and the mechanism involved may be associated with the regulation of the NF-κB, Nrf2-ARE and MAPK/P38 pathways.

The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ogawa, Eiichi; Hosokawa, Masaya; Faculty of Human Sciences, Tezukayama Gakuin University, Osaka

2011-01-07

Research highlights: {yields} Exogenous GIP inhibits intestinal motility through a somatostatin-mediated pathway. {yields} Exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility. {yields} The GIP-receptor-mediated action in intestine does not involve in GLP-1-mediated pathway. -- Abstract: Gastric inhibitory polypeptide (GIP) is released from the small intestine upon meal ingestion and increases insulin secretion from pancreatic {beta} cells. Although the GIP receptor is known to be expressed in small intestine, the effects of GIP in small intestine are not fully understood. This study was designed to clarify the effect of GIP on intestinal glucose absorption and intestinal motility. Intestinal glucosemore » absorption in vivo was measured by single-pass perfusion method. Incorporation of [{sup 14}C]-glucose into everted jejunal rings in vitro was used to evaluate the effect of GIP on sodium-glucose co-transporter (SGLT). Motility of small intestine was measured by intestinal transit after oral administration of a non-absorbed marker. Intraperitoneal administration of GIP inhibited glucose absorption in wild-type mice in a concentration-dependent manner, showing maximum decrease at the dosage of 50 nmol/kg body weight. In glucagon-like-peptide-1 (GLP-1) receptor-deficient mice, GIP inhibited glucose absorption as in wild-type mice. In vitro examination of [{sup 14}C]-glucose uptake revealed that 100 nM GIP did not change SGLT-dependent glucose uptake in wild-type mice. After intraperitoneal administration of GIP (50 nmol/kg body weight), small intestinal transit was inhibited to 40% in both wild-type and GLP-1 receptor-deficient mice. Furthermore, a somatostatin receptor antagonist, cyclosomatostatin, reduced the inhibitory effect of GIP on both intestinal transit and glucose absorption in wild-type mice. These results demonstrate that exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility through a somatostatin-mediated pathway rather than through a GLP-1-mediated pathway.« less

Gastrointestinal disorders associated with migraine: A comprehensive review

PubMed Central

Cámara-Lemarroy, Carlos R; Rodriguez-Gutierrez, Rene; Monreal-Robles, Roberto; Marfil-Rivera, Alejandro

2016-01-01

Migraine is a recurrent and commonly disabling primary headache disorder that affects over 17% of women and 5%-8% of men. Migraine susceptibility is multifactorial with genetic, hormonal and environmental factors all playing an important role. The physiopathology of migraine is complex and still not fully understood. Many different neuropeptides, neurotransmitters and brain pathways have been implicated. In connection with the myriad mechanisms and pathways implicated in migraine, a variety of multisystemic comorbidities (e.g., cardiovascular, psychiatric and other neurological conditions) have been found to be closely associated with migraine. Recent reports demonstrate an increased frequency of gastrointestinal (GI) disorders in patients with migraine compared with the general population. Helicobacter pylori infection, irritable bowel syndrome, gastroparesis, hepatobiliary disorders, celiac disease and alterations in the microbiota have been linked to the occurrence of migraine. Several mechanisms involving the gut-brain axis, such as a chronic inflammatory response with inflammatory and vasoactive mediators passing to the circulatory system, intestinal microbiota modulation of the enteric immunological milieu and dysfunction of the autonomic and enteric nervous system, have been postulated to explain these associations. However, the precise mechanisms and pathways related to the gut-brain axis in migraine need to be fully elucidated. In this review, we survey the available literature linking migraine with GI disorders. We discuss the possible physiopathological mechanisms, and clinical implications as well as several future areas of interest for research. PMID:27688656

Gastrointestinal disorders associated with migraine: A comprehensive review.

PubMed

Cámara-Lemarroy, Carlos R; Rodriguez-Gutierrez, Rene; Monreal-Robles, Roberto; Marfil-Rivera, Alejandro

2016-09-28

Migraine is a recurrent and commonly disabling primary headache disorder that affects over 17% of women and 5%-8% of men. Migraine susceptibility is multifactorial with genetic, hormonal and environmental factors all playing an important role. The physiopathology of migraine is complex and still not fully understood. Many different neuropeptides, neurotransmitters and brain pathways have been implicated. In connection with the myriad mechanisms and pathways implicated in migraine, a variety of multisystemic comorbidities (e.g., cardiovascular, psychiatric and other neurological conditions) have been found to be closely associated with migraine. Recent reports demonstrate an increased frequency of gastrointestinal (GI) disorders in patients with migraine compared with the general population. Helicobacter pylori infection, irritable bowel syndrome, gastroparesis, hepatobiliary disorders, celiac disease and alterations in the microbiota have been linked to the occurrence of migraine. Several mechanisms involving the gut-brain axis, such as a chronic inflammatory response with inflammatory and vasoactive mediators passing to the circulatory system, intestinal microbiota modulation of the enteric immunological milieu and dysfunction of the autonomic and enteric nervous system, have been postulated to explain these associations. However, the precise mechanisms and pathways related to the gut-brain axis in migraine need to be fully elucidated. In this review, we survey the available literature linking migraine with GI disorders. We discuss the possible physiopathological mechanisms, and clinical implications as well as several future areas of interest for research.

Liver injury following small intestinal ischemia reperfusion in rats is attenuated by Pistacia lentiscus oil: antioxidant and anti-inflammatory effects.

PubMed

Saidi, Saber Abdelkader; Ncir, Marwa; Chaaben, Rim; Jamoussi, Kamel; van Pelt, Jos; Elfeki, Abdelfattah

2017-10-01

Intestinal ischemia-reperfusion (IIR) not only leads to severe intestine damage but also induced subsequent destruction of remote organs. We investigated the protective effect of Pistascia lentiscus L. (Anacardiaceae) oil on IIR. Wistar rats were divided into three groups: sham, intestinal IR and P. lentiscus pretreatment (n = 18 each). In the pretreatment group, oil was administered 1 h before induction of warm ischemia. IIR led to severe liver damage manifested as a significant (p < .05) increase of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Pistacia lentiscus oil decreased the visible intestinal damage, as well as a significant decrease in serum AST and ALT levels. In addition, Pistacia lentiscus reduce liver injury, as evidenced by the decrease in liver tissue myeloperoxidase activity and lipoperoxidation (MDA) level. Pistascia lentiscus attenuates liver injury induced by IIR, attributable to the antioxidant and anti-inflammatory effect.

Short chain fatty acids (butyric acid) and intestinal diseases

PubMed

Manrique Vergara, David; González Sánchez, María Eugenia

2017-10-15

Short chain fatty acids contain up to 6 carbon atoms. Among them, butyric acid stands out for its key role in pathologies with intestinal affectation. Butyric acid is the main energetic substrate of the colonocyte, it stimulates the absorption of sodium and water in the colon, and presents trophic action on the intestinal cells. To review the clinical use of formulations for the oral use of butyric acid. Review of published articles on oral supplementation with butyric acid in intestinal pathologies. The publications mainly deal with the use of oral butyric acid in pathologies involving inflammation and / or alterations of intestinal motility. Highlighting the clinical potential in inflammatory bowel diseases and irritable bowel syndrome. The use of oral supplementation with butyric acid is a promising strategy in pathologies such as inflammatory bowel diseases and irritable bowel syndrome. Bio-available butyric acid formulations with acceptable organoleptic characteristics are being advanced.

α7 Nicotinic Agonist AR-R17779 Protects Mice against 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis in a Spleen-Dependent Way.

PubMed

Grandi, Andrea; Zini, Irene; Flammini, Lisa; Cantoni, Anna M; Vivo, Valentina; Ballabeni, Vigilio; Barocelli, Elisabetta; Bertoni, Simona

2017-01-01

The existence of a cholinergic anti-inflammatory pathway negatively modulating the inflammatory and immune responses in various clinical conditions and experimental models has long been postulated. In particular, the protective involvement of the vagus nerve and of nicotinic Ach receptors (nAChRs) has been proposed in intestinal inflammation and repeatedly investigated in DSS- and TNBS-induced colitis. However, the role of α 7 nAChRs stimulation is still controversial and the potential contribution of α 4 β 2 nAChRs has never been explored in this experimental condition. Our aims were therefore to pharmacologically investigate the role played by both α 7 and α 4 β 2 nAChRs in the modulation of the local and systemic inflammatory responses activated in TNBS-induced colitis in mice and to assess the involvement of the spleen in nicotinic responses. To this end, TNBS-exposed mice were sub-acutely treated with various subcutaneous doses of highly selective agonists (AR-R17779 and TC-2403) and antagonists (methyllycaconitine and dihydro-β-erythroidine) of α 7 and α 4 β 2 nAChRs, respectively, or with sulfasalazine 50 mg/kg per os and clinical and inflammatory responses were evaluated by means of biochemical, histological and flow cytometry assays. α 4 β 2 ligands evoked weak and contradictory effects, while α 7 nAChR agonist AR-R17779 emerged as the most beneficial treatment, able to attenuate several local markers of colitis severity and to revert the rise in splenic T-cells and in colonic inflammatory cytokines levels induced by haptenization. After splenectomy, AR-R17779 lost its protective effects, demonstrating for the first time that, in TNBS-model of experimental colitis, the anti-inflammatory effect of exogenous α 7 nAChR stimulation is strictly spleen-dependent. Our findings showed that the selective α 7 nAChRs agonist AR-R17779 exerted beneficial effects in a model of intestinal inflammation characterized by activation of the adaptive immune system and that the spleen is essential to mediate this cholinergic protection.

Inhibition of macrophage function prevents intestinal inflammation and postoperative ileus in rodents

PubMed Central

Wehner, Sven; Behrendt, Florian F; Lyutenski, Boris N; Lysson, Mariola; Bauer, Anthony J; Hirner, Andreas; Kalff, Jörg C

2007-01-01

Background Abdominal surgery results in a molecular and cellular inflammatory response in the intestine, leading to postoperative ileus. It was hypothesised that resident macrophages within the intestinal muscularis have an important role in this local inflammation. Aims To investigate whether chemical or genetic depletion of resident muscularis macrophages would lead to a reduction in the local inflammation and smooth‐muscle dysfunction. Methods Two rodent models were used to deplete and inactivate macrophages: (1) a rat model in which resident macrophages were depleted by chlodronate liposomes; (2) a model of mice with osteopetrosis mice, completely lacking the resident muscularis macrophages, used as an additional genetic approach. Animals with normal or altered intestinal macrophages underwent surgical intestinal manipulation. The inflammatory response was investigated by quantitative reverse transcriptase‐polymerase chain reaction for mRNA of MIP‐1α, interleukin (IL)1β, IL6, intracellular adhesion molecule 1 (ICAM‐1) and monocyte chemotractant protein 1 (MCP)‐1 in the isolated small bowel muscularis. In addition, muscularis whole mounts were used for histochemical and immunohistochemical analysis to quantify leucocyte infiltration and detect cytokine expression. Subsequently, in vitro muscle contractility and in vivo gastrointestinal transit were measured. Results Both models resulted in markedly decreased expression of MIP‐1α, IL1β, IL6, ICAM‐1 and MCP‐1 after manipulation compared with controls. In addition to this decrease in inflammatory mediators, recruitment of leucocytes into the muscularis was also diminished. Macrophage‐altered animals had near normal in vitro jejunal circular muscle function and gastrointestinal transit despite surgical manipulation. Conclusions Resident intestinal muscularis macrophages are initially involved in inflammatory responses resulting in postoperative ileus. Depletion and inactivation of the muscularis macrophage network prevents postoperative ileus. PMID:16809419

Nutritional modulators of ulcerative colitis: Clinical efficacies and mechanistic view

PubMed Central

Sung, Mi-Kyung; Park, Mi-Young

2013-01-01

Ulcerative colitis (UC) is an inflammation-associated disease of the colon and rectum. The onset and progress of the disease are directly influenced by the nature of the intestinal microflora, the intestinal barrier function, and the immunological responses of the host. The epithelial invasion of pathogenic bacteria due to excess contact and/or barrier dysfunction is related to inflammation mediated by intestinal immune responses. Although the etiology of UC is not clearly understood, recent studies have shown a rising incidence of UC worldwide, and this phenomenon is more prominent in Asian countries and in Asian immigrants in Western countries. The increased prevalence of UC also contributes to an increased risk of developing colorectal cancer. Environmental factors, including changes in dietary habits, have been suggested as major risk factors of UC. A systematic review showed a negative association between UC risk and vegetable intake, whereas total fat, omega-6 fatty acids and meat intake were positively associated with an increased risk of UC. Individual dietary factors and energy balance have been suggested as having important roles in inducing changes in the microbial population and intestinal barrier integrity and in regulating inflammatory immune responses, directly or indirectly. Excess energy intake is now known to increase pathogenic microbial populations. Likewise, the application of appropriate probiotics may reverse the pathogenic progression of the disease. In the meantime, dietary anti-inflammatory compounds, including omega-3 fatty acids and other phytochemicals, may directly suppress inflammatory responses in the course of UC development. In this review, the increased prevalence of UC and its management are interpreted from the standpoint of nutritional modulation to regulate the intestinal microflora population, intestinal epithelium permeability, and inflammatory responses. PMID:23467687

Nutritional modulators of ulcerative colitis: clinical efficacies and mechanistic view.

PubMed

Sung, Mi-Kyung; Park, Mi-Young

2013-02-21

Ulcerative colitis (UC) is an inflammation-associated disease of the colon and rectum. The onset and progress of the disease are directly influenced by the nature of the intestinal microflora, the intestinal barrier function, and the immunological responses of the host. The epithelial invasion of pathogenic bacteria due to excess contact and/or barrier dysfunction is related to inflammation mediated by intestinal immune responses. Although the etiology of UC is not clearly understood, recent studies have shown a rising incidence of UC worldwide, and this phenomenon is more prominent in Asian countries and in Asian immigrants in Western countries. The increased prevalence of UC also contributes to an increased risk of developing colorectal cancer. Environmental factors, including changes in dietary habits, have been suggested as major risk factors of UC. A systematic review showed a negative association between UC risk and vegetable intake, whereas total fat, omega-6 fatty acids and meat intake were positively associated with an increased risk of UC. Individual dietary factors and energy balance have been suggested as having important roles in inducing changes in the microbial population and intestinal barrier integrity and in regulating inflammatory immune responses, directly or indirectly. Excess energy intake is now known to increase pathogenic microbial populations. Likewise, the application of appropriate probiotics may reverse the pathogenic progression of the disease. In the meantime, dietary anti-inflammatory compounds, including omega-3 fatty acids and other phytochemicals, may directly suppress inflammatory responses in the course of UC development. In this review, the increased prevalence of UC and its management are interpreted from the standpoint of nutritional modulation to regulate the intestinal microflora population, intestinal epithelium permeability, and inflammatory responses.

High Fat Diets Induce Colonic Epithelial Cell Stress and Inflammation that is Reversed by IL-22

PubMed Central

Gulhane, Max; Murray, Lydia; Lourie, Rohan; Tong, Hui; Sheng, Yong H.; Wang, Ran; Kang, Alicia; Schreiber, Veronika; Wong, Kuan Yau; Magor, Graham; Denman, Stuart; Begun, Jakob; Florin, Timothy H.; Perkins, Andrew; Cuív, Páraic Ó.; McGuckin, Michael A.; Hasnain, Sumaira Z.

2016-01-01

Prolonged high fat diets (HFD) induce low-grade chronic intestinal inflammation in mice, and diets high in saturated fat are a risk factor for the development of human inflammatory bowel diseases. We hypothesized that HFD-induced endoplasmic reticulum (ER)/oxidative stress occur in intestinal secretory goblet cells, triggering inflammatory signaling and reducing synthesis/secretion of proteins that form the protective mucus barrier. In cultured intestinal cells non-esterified long-chain saturated fatty acids directly increased oxidative/ER stress leading to protein misfolding. A prolonged HFD elevated the intestinal inflammatory cytokine signature, alongside compromised mucosal barrier integrity with a decrease in goblet cell differentiation and Muc2, a loss in the tight junction protein, claudin-1 and increased serum endotoxin levels. In Winnie mice, that develop spontaneous colitis, HFD-feeding increased ER stress, further compromised the mucosal barrier and increased the severity of colitis. In obese mice IL-22 reduced ER/oxidative stress and improved the integrity of the mucosal barrier, and reversed microbial changes associated with obesity with an increase in Akkermansia muciniphila. Consistent with epidemiological studies, our experiments suggest that HFDs are likely to impair intestinal barrier function, particularly in early life, which partially involves direct effects of free-fatty acids on intestinal cells, and this can be reversed by IL-22 therapy. PMID:27350069

Divergent Roles of Interferon-γ and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation.

PubMed

Brasseit, Jennifer; Kwong Chung, Cheong K C; Noti, Mario; Zysset, Daniel; Hoheisel-Dickgreber, Nina; Genitsch, Vera; Corazza, Nadia; Mueller, Christoph

2018-01-01

Aberrant interferon gamma (IFNγ) expression is associated with the pathogenesis of numerous autoimmune- and inflammatory disorders, including inflammatory bowel diseases (IBD). However, the requirement of IFNγ for the pathogenesis of chronic intestinal inflammation remains controversial. The aim of this study was thus to investigate the role of IFNγ in experimental mouse models of innate and adaptive immune cell-mediated intestinal inflammation using genetically and microbiota-stabilized hosts. While we find that IFNγ drives acute intestinal inflammation in the anti-CD40 colitis model in an innate lymphoid cell (ILC)-dependent manner, IFNγ secreted by both transferred CD4 T cells and/or cells of the lymphopenic Rag1 -/- recipient mice was dispensable for CD4 T cell-mediated colitis. In the absence of IFNγ, intestinal inflammation in CD4 T cell recipient mice was associated with enhanced IL17 responses; consequently, targeting IL17 signaling in IFNγ-deficient mice reduced T cell-mediated colitis. Intriguingly, in contrast to the anti-CD40 model of colitis, depletion of ILC in the Rag1 -/- recipients of colitogenic CD4 T cells did not prevent induction of colonic inflammation. Together, our findings demonstrate that IFNγ represents an essential, or a redundant, pro-inflammatory cytokine for the induction of intestinal inflammation, depending on the experimental mouse model used and on the nature of the critical disease inducing immune cell populations involved.

IL-23 Blockade for Crohn s disease: next generation of anti-cytokine therapy.

PubMed

Furfaro, Federica; Gilardi, Daniela; Allocca, Mariangela; Cicerone, Clelia; Correale, Carmen; Fiorino, Gionata; Danese, Silvio

2017-05-01

Adaptive immunity in intestinal inflammation may play a key role in the pathogenesis of Crohn's disease. In particular, interleukin (IL)-23 may be a key mediator in chronic intestinal inflammation by inducing the differentiation of naïve CD4 + T cells into Th17, with the production of several pro-inflammatory cytokines. Furthermore, IL-23 induces interferon-γ (IFN- γ) production from activated T cells, a critical cytokine in innate and adaptive immunity against infections. Areas covered: We aim to review the available data from literature regarding the role of IL-23, with a more specific focus on the recent progresses in the therapeutic modulation of this cytokine. Expert commentary: Increased knowledge regarding the role of IL-23 has allowed for the development of effective therapeutic progresses by blocking the IL-23 mediated pathways. Primary or secondary loss of response to anti-TNF therapies in Crohn's disease patients during the first year is widely described in literature: the development of new drugs, with alternative mechanisms of action, is thus a key point to consider for the optimal management of these subjects. Drugs blocking the IL-12/23 pathway showed a good efficacy and safety profile in immune-mediated diseases Further studies are necessary regarding the role of the single blockade of IL-23.

The Role of Intestinal Alkaline Phosphatase in Inflammatory Disorders of Gastrointestinal Tract.

PubMed

Bilski, Jan; Mazur-Bialy, Agnieszka; Wojcik, Dagmara; Zahradnik-Bilska, Janina; Brzozowski, Bartosz; Magierowski, Marcin; Mach, Tomasz; Magierowska, Katarzyna; Brzozowski, Tomasz

2017-01-01

Over the past few years, the role of intestinal alkaline phosphatase (IAP) as a crucial mucosal defence factor essential for maintaining gut homeostasis has been established. IAP is an important apical brush border enzyme expressed throughout the gastrointestinal tract and secreted both into the intestinal lumen and into the bloodstream. IAP exerts its effects through dephosphorylation of proinflammatory molecules including lipopolysaccharide (LPS), flagellin, and adenosine triphosphate (ATP) released from cells during stressful events. Diminished activity of IAP could increase the risk of disease through changes in the microbiome, intestinal inflammation, and intestinal permeability. Exogenous IAP exerts a protective effect against intestinal and systemic inflammation in a variety of diseases and represents a potential therapeutic agent in diseases driven by gut barrier dysfunction such as IBD. The intestinal protective mechanisms are impaired in IBD patients due to lower synthesis and activity of endogenous IAP, but the pathomechanism of this enzyme deficiency remains unclear. IAP has been safely administered to humans and the human recombinant form of IAP has been developed. This review was designed to provide an update in recent research on the involvement of IAP in intestinal inflammatory processes with focus on IBD in experimental animal models and human patients.

The Role of Intestinal Alkaline Phosphatase in Inflammatory Disorders of Gastrointestinal Tract

PubMed Central

Wojcik, Dagmara; Zahradnik-Bilska, Janina; Mach, Tomasz

2017-01-01

Over the past few years, the role of intestinal alkaline phosphatase (IAP) as a crucial mucosal defence factor essential for maintaining gut homeostasis has been established. IAP is an important apical brush border enzyme expressed throughout the gastrointestinal tract and secreted both into the intestinal lumen and into the bloodstream. IAP exerts its effects through dephosphorylation of proinflammatory molecules including lipopolysaccharide (LPS), flagellin, and adenosine triphosphate (ATP) released from cells during stressful events. Diminished activity of IAP could increase the risk of disease through changes in the microbiome, intestinal inflammation, and intestinal permeability. Exogenous IAP exerts a protective effect against intestinal and systemic inflammation in a variety of diseases and represents a potential therapeutic agent in diseases driven by gut barrier dysfunction such as IBD. The intestinal protective mechanisms are impaired in IBD patients due to lower synthesis and activity of endogenous IAP, but the pathomechanism of this enzyme deficiency remains unclear. IAP has been safely administered to humans and the human recombinant form of IAP has been developed. This review was designed to provide an update in recent research on the involvement of IAP in intestinal inflammatory processes with focus on IBD in experimental animal models and human patients. PMID:28316376

Altered gut microbiota associated with intestinal disease in grass carp (Ctenopharyngodon idellus).

PubMed

Tran, Ngoc Tuan; Zhang, Jing; Xiong, Fan; Wang, Gui-Tang; Li, Wen-Xiang; Wu, Shan-Gong

2018-05-18

Gut microbiota plays a crucial importance in their host. Disturbance of the microbial structure and function is known to be associated with inflammatory intestinal disorders. Enteritis is a significant cause of high mortality in fish species, including grass carp (Ctenopharyngodon idellus). Study regarding the association between microbial alternations and enteritis in grass carp is still absent. In this study, changes in the gut microbiota of grass carp suffering from enteritis were investigated using NGS-based 16S rRNA sequencing. Six healthy and ten abnormal fish (showing reddening anus, red odiferous fluid accumulating in the abdominal capacity, and flatulence and haemorrhage in the intestine) were collected from a fish farm in Huanggang Fisheries Institute (Hubei, China). Our results revealed that the diversity, structure, and function of gut microbiota were significantly different between diseased and healthy fish (P < 0.05). Particularly, members of the genera Dechloromonas, Methylocaldum, Planctomyces, Rhodobacter, Caulobacter, Flavobacterium, and Pseudomonas were significantly increased in diseased fish compared with that in healthy fish (P < 0.05). Predicted function indicated that microbiota significantly changed the specific metabolic pathways (related to amino acid metabolism, xenobiotics biodegradation and metabolism, and carbohydrate metabolism) in diseased fish (P < 0.05). Taken together, our findings point out the association between changes of the gut microbiota and enteritis in grass carp, which provide basic information useful for diagnoses, prevention, and treatment of intestinal diseases occurring in cultured fish.

Thalidomide Improves the Intestinal Mucosal Injury and Suppresses Mesenteric Angiogenesis and Vasodilatation by Down-Regulating Inflammasomes-Related Cascades in Cirrhotic Rats

PubMed Central

Li, Tzu-Hao; Huang, Chia-Chang; Yang, Ying-Ying; Lee, Kuei-Chuan; Hsieh, Shie-Liang; Hsieh, Yun-Cheng; Alan, Lin; Lin, Han-Chieh; Lee, Shou-Dong; Tsai, Chang-Youh

2016-01-01

Background and Aims By blocking TNFα-related effects, thalidomide not only inhibits hepatic fibrogenesis but improves peripheral vasodilatation and portal hypertension in cirrhotic rats. Nonetheless, the investigation of thalidomide's effects on splanchnic and collateral microcirculation has been limited. Our study explored the roles of intestinal and mesenteric TNFα along with inflammasome-related pathway in relation to cirrhosis and the splanchnic/collateral microcirculation. Methods Using in vivo and in vitro approaches, mechanisms of the effects of thalidomide on intestinal and mesenteric inflammatory, vasodilatory and angiogenic cascades-related abnormalities were explored in cirrhotic rats that had received 1-month thalidomide (C-T) treatment. Results In cirrhotic rats, high tumor necrosis factor (TNF)α, vascular endothelial growth factor (VEGF) and nitric oxide (NO)x levels were associated with the NOD-like receptors protein 3 (NLRP3), IL-1β and caspase-1 inflammasome over-expression in splenorenal shunt and mesenteric tissues. The thalidomide-related inhibition of mesenteric and splenorenal shunt inflammasome expression was accompanied by a significantly decreased intestinal mucosal injury and inflammasome immunohistochemical staining expression. Suppression of various angiogenic cascades, namely VEGF-NOS-NO, was paralleled by a decrease in mesenteric angiogenesis as detected by CD31 immunofluorescence staining and by reduced portosystemic shunting (PSS) in C-T rats. The down-regulation of the mesenteric and collateral vasodilatory VEGF-NOS-NO cascades resulted in a correction of vasoconstrictive hypo-responsiveness and in an attenuation of vasodilatory hyper-responsiveness when analyzed by in situ perfusion of the superior mesenteric arterial (SMA) and portosystemic collaterals. There was also a decrease in SMA blood flow and an increase in SMA resistance in the C-T rats. Additionally, acute incubation with thalidomide abolished TNFα-augmented VEGF-mediated migration of and tube formation of human umbilical vein endothelial cells, which was accompanied by corresponding changes in inflammatory and angiogenic substances release. Conclusions The suppression of inflammasome over-expression by chronic thalidomide treatment ameliorates inflammatory, angiogenic and vasodilatory cascades-related pathogenic changes in the splanchnic and collateral microcirculation of cirrhotic rats. Thalidomide seems to be a promising agent that might bring about beneficial changes to the disarrangements of peripheral, hepatic, splanchnic and collateral systems in cirrhosis. PMID:26820153

Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD)

PubMed

Duchmann, R; Kaiser, I; Hermann, E; Mayet, W; Ewe, K; Meyer zum Büschenfelde, K H

1995-12-01

Hyporesponsiveness to a universe of bacterial and dietary antigens from the gut lumen is a hallmark of the intestinal immune system. Since hyperresponsiveness against these antigens might be associated with inflammation, we studied the immune response to the indigenous intestinal microflora in peripheral blood, inflamed and non-inflamed human intestine. Lamina propria monocuclear cells (LPMC) isolated from inflamed intestine but not peripheral blood mononuclear cells (PBMC) of IBD patients with active inflammatory disease strongly proliferated after co-culture with sonicates of bacteria from autologous intestine (BsA). Proliferation was inhibitable by anti-MHC class II MoAb, suggesting that it was driven by antigen. LPMC from adjacent non-inflamed intestinal areas of the same IBD patients and PBMC or LPMC isolated from non-inflamed intestine of controls and patients with IBD in remission, in contrast, did not proliferate. PBMC or LPMC which had been tolerant to bacteria from autologous intestine, however, strongly proliferated after co-culture with bacterial sonicates from heterologous intestine (BsH). This proliferation was associated with an expansion of CD8+ T cells, increased expression of activation markers on both CD4+ and CD8+ lymphocyte subsets, and production of IL-12, interferon-gamma (IFN-gamma), and IL-10 protein. These results show that tolerance selectively exists to intestinal flora from autologous but not heterologous intestine, and that tolerance is broken in intestinal inflammation. This may be an important mechanism for the perpetuation of chronic IBD.

Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD)

PubMed Central

Duchmann, R; Kaiser, I; Hermann, E; Mayet, W; Ewe, K; Meyer zum Büschenfelde, K H

1995-01-01

Hyporesponsiveness to a universe of bacterial and dietary antigens from the gut lumen is a hallmark of the intestinal immune system. Since hyperresponsiveness against these antigens might be associated with inflammation, we studied the immune response to the indigenous intestinal microflora in peripheral blood, inflamed and non-inflamed human intestine. Lamina propria monocuclear cells (LPMC) isolated from inflamed intestine but not peripheral blood mononuclear cells (PBMC) of IBD patients with active inflammatory disease strongly proliferated after co-culture with sonicates of bacteria from autologous intestine (BsA). Proliferation was inhibitable by anti-MHC class II MoAb, suggesting that it was driven by antigen. LPMC from adjacent non-inflamed intestinal areas of the same IBD patients and PBMC or LPMC isolated from non-inflamed intestine of controls and patients with IBD in remission, in contrast, did not proliferate. PBMC or LPMC which had been tolerant to bacteria from autologous intestine, however, strongly proliferated after co-culture with bacterial sonicates from heterologous intestine (BsH). This proliferation was associated with an expansion of CD8+ T cells, increased expression of activation markers on both CD4+ and CD8+ lymphocyte subsets, and production of IL-12, interferon-gamma (IFN-gamma), and IL-10 protein. These results show that tolerance selectively exists to intestinal flora from autologous but not heterologous intestine, and that tolerance is broken in intestinal inflammation. This may be an important mechanism for the perpetuation of chronic IBD. PMID:8536356

Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism

PubMed Central

Vujkovic-Cvijin, Ivan; Dunham, Richard M.; Iwai, Shoko; Maher, M. Cyrus; Albright, Rebecca G.; Broadhurst, Mara J.; Hernandez, Ryan D.; Lederman, Michael M.; Huang, Yong; Somsouk, Ma; Deeks, Steven G.; Hunt, Peter W.; Lynch, Susan V.; McCune, Joseph M.

2014-01-01

Progressive HIV infection is characterized by dysregulation of the intestinal immune barrier, translocation of immunostimulatory microbial products, and chronic systemic inflammation that is thought to drive progression of disease to AIDS. Elements of this pathologic process persist despite viral suppression during highly active antiretroviral therapy (HAART) and drivers of these phenomena remain poorly understood. Disrupted intestinal immunity can precipitate dysbiosis that induces chronic inflammation in the mucosa and periphery of mice. However, putative microbial drivers of HIV-associated immunopathology versus recovery have not been identified in humans. Using high-resolution bacterial community profiling, we identified a dysbiotic mucosal-adherent community enriched in Proteobacteria and depleted of Bacteroidia members that was associated with markers of mucosal immune disruption, T cell activation, and chronic inflammation in HIV-infected subjects. Furthermore, this dysbiosis was evident among HIV-infected subjects undergoing HAART, and the extent of dysbiosis correlated with activity of the kynurenine pathway of tryptophan metabolism and plasma concentrations of the inflammatory cytokine interleukin-6 (IL-6), two established markers of disease progression. Gut-resident bacteria with capacity to metabolize tryptophan through the kynurenine pathway were found to be enriched in HIV-infected subjects, strongly correlated with kynurenine levels in HIV-infected subjects, and capable of kynurenine production in vitro. These observations demonstrate a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection, which is apparent even in the setting of viral suppression during HAART. This link suggests that gut-resident microbial populations may influence intestinal homeostasis during HIV disease. PMID:23843452

Allyl methyl disulfide inhibits IL-8 and IP-10 secretion in intestinal epithelial cells via the NF-кB signaling pathway.

PubMed

Zhang, Yongchun; Wang, Ying; Zhang, Fang; Wang, Kaiming; Liu, Guangpu; Yang, Min; Luan, Yuxia; Zhao, Zhongxi; Zhang, Jianqiang; Cao, Xinke; Zhang, Daizhou

2015-07-01

Garlic and its active constituents have shown versatile medicinal activities in the prevention and treatment of various disorders. Allyl methyl disulfide (AMDS) was identified as one of the major bioactive components in an effective inhalation fork remedy using fresh garlic paste in our previous study. In this work, we investigated the immunological properties of AMDS to elucidate the underlying mechanisms of the fork inhalation treatment using fresh garlic. The inhibition effect of AMDS on TNF-α-induced IL-8 and IP-10 production in intestinal epithelial cell lines HT-29 and Caco-2 was first evaluated. Pretreatment of the cells with AMDS attenuated IL-8 and IP-10 secretion induced by TNF-α in a dose-dependent manner in the non-cytotoxic concentration range of 20 to 150 μM. Mechanistic studies revealed that AMDS suppressed the accumulation of IL-8 mRNA and inhibited IкBα degradation and NF-кB p65 translocation into the nucleus at both the transcriptional and translational levels, suggesting that the attenuation effort of AMDS on cytokine IL-8 secretion might at least be partially related to the NF-κB signaling pathway. These results suggest that AMDS may be a promising phytochemical agent in the treatment of immunological disorders, such as ulcerative colitis, Crohn's disease, intestinal inflammatory diseases and others. In addition, the mechanistic study data indicated that immune modulation could be one of the therapeutic mechanisms of the effective fork treatment containing AMDS as one of the major components. Copyright © 2015 Elsevier B.V. All rights reserved.

High intestinal and systemic levels of decoy receptor 3 (DcR3) and its ligand TL1A in active ulcerative colitis.

PubMed

Bamias, Giorgos; Kaltsa, Garyfallia; Siakavellas, Spyros I; Papaxoinis, Kostis; Zampeli, Evanthia; Michopoulos, Spyros; Zouboulis-Vafiadis, Irene; Ladas, Spiros D

2010-11-01

Decoy receptor-3 (DcR3) is a member of the TNF receptor superfamily of proteins, which has been implicated in anti-apoptotic and anti-inflammatory pathways, via binding to TL1A, LIGHT and Fas-L. The role of the TL1A/DcR3 ligand/receptor pair in ulcerative colitis (UC) has not been studied. We investigated the systemic (peripheral blood) and local (large intestine) expression of DcR3 and TL1A in 64 patients with UC and 56 healthy controls. DcR3 serum concentrations were highly elevated in patients with active UC (P<0.0001 vs. healthy controls). This elevation was clearly related to the presence of intestinal inflammation as it was less frequently observed in patients in remission (P=0.003 vs. active UC) whereas effective treatment resulted in disappearance or significant decrease of serum DcR3 (P=0.006 vs. pre-treatment). Furthermore, DcR3 mRNA transcripts were significantly elevated in inflamed areas of the colon (P=0.002 vs. non-affected of the same patient). In addition to DcR3 elevation, we found increased circulating levels of TL1A in patients with either active or inactive UC in comparison to healthy controls (P<0.001 for both). We conclude that elevated serum DcR3 may serve as an indicator of active colonic inflammation in patients with UC. TL1A/DcR3-mediated pathways may participate in the pathogenesis of UC. Copyright © 2010 Elsevier Inc. All rights reserved.

The importance of intestinal ultrasound and elastographic techniques in inflammatory bowel diseases.

PubMed

Marin, Andreea; Tribus, Laura; Fierbinteanu-Braticevici, Carmen

2018-05-02

Inflammatory bowel diseases have an important impact upon the economic and social status due to their increasing incidence and prevalence, often affecting young people. At the moment, the therapeutic goal goes beyond the improvement of symptoms and laboratory parameters, being represented by endoscopic mucosal healing, changing the disease's natural history. Even though endoscopy is the gold standard for the assessment of mucosal healing, it is an invasive maneuver and it lacks good repeatability. These patients require frequent evaluation; therefore, interest for noninvasive techniques has risen.As a consequence, the importance of intestinal ultrasound has increased lately and recent studies support its use to assess the degree of inflammation, to differentiate between remission and relapse, to monitor therapy response and guide treatment, to evaluate prognosis, and to diagnose complications. Another promising noninvasive imagistic technique is elastography which has gained interest because of its capacity to discriminate between inflammatory and fibrotic tissue, taking into account the different therapeutic options for the fibrotic strictures compared to inflammatory processes. This review summarizes the actual recommendations regarding the use of intestinal ultrasound and elastographic techniques for the diagnosis and monitoring of inflammatory bowel diseases.

Constitutive and regulated secretion of secretory leukocyte proteinase inhibitor by human intestinal epithelial cells.

PubMed

Si-Tahar, M; Merlin, D; Sitaraman, S; Madara, J L

2000-06-01

Epithelial cells participate in immune regulation and mucosal integrity by generating a range of biologically active mediators. In the intestine, little is known about the potential endogenous anti-inflammatory molecules. Secretory leukocyte proteinase inhibitor (SLPI) is a major serine proteinase inhibitor, a potent antibiotic, and thus a potential anti-inflammatory molecule, although it is not known if it is secreted by intestinal epithelial cells. We show, by reverse-transcription polymerase chain reaction, the presence of SLPI messenger RNA in human model intestinal epithelial cell lines (Caco2-BBE, T84, and HT29-Cl.19A) and human jejunum and colon biopsy specimens. The polymerase chain reaction product was cloned and sequenced and is identical to that of SLPI isolated previously from the human parotid gland. As analyzed by enzyme-linked immunosorbent assay, the constitutive secretion of SLPI occurs in a markedly polarized manner toward the apical surface and is enhanced by inflammatory mediators including tumor necrosis factor alpha and interleukin 1beta (approximately 3.5-fold increase over control value). SLPI release is also stimulated by activation of protein kinase C isoenzymes, but not by activation of adenosine 3',5'-cyclic monophosphate- or Ca(2+)-regulated signaling molecules. SLPI protein is detectable in intestinal lavage fluids collected from normal adult humans. Recombinant SLPI attenuates digestive enzyme (trypsin)- or leukocyte proteinase (elastase)-induced permeability alteration of a model epithelia in a dose-dependent manner. Moreover, SLPI exhibits an antibacterial activity against at least one major intestinal pathogen, Salmonella typhimurium. In contrast, SLPI does not influence epithelial barrier integrity as assessed by transepithelial conductance measurements or electrogenic ion transport. These results establish that human intestinal epithelium expresses and apically secretes SLPI, a molecule that may significantly contribute to the protection against attack from inflammatory cells and digestive enzymes, as well as against microbial infection.

Intraluminal Administration of Poly I:C Causes an Enteropathy That Is Exacerbated by Administration of Oral Dietary Antigen

PubMed Central

Araya, Romina E.; Jury, Jennifer; Bondar, Constanza

2014-01-01

Systemic administration of polyinosinic:polycytidylic acid (poly I:C), mimics virally-induced activation of TLR3 signalling causing acute small intestine damage, but whether and how mucosal administration of poly I:C causes enteropathy is less clear. Our aim was to investigate the inflammatory pathways elicited after intraluminal administration of poly I:C and determine acute and delayed consequences of this locally induced immune activation. Intraluminal poly I:C induced rapid mucosal immune activation in C57BL/6 mice involving IFNβ and the CXCL10/CXCR3 axis, that may drive inflammation towards a Th1 profile. Intraluminal poly I:C also caused enteropathy and gut dysfunction in gliadin-sensitive NOD-DQ8 mice, and this was prolonged by concomitant oral administration of gliadin. Our results indicate that small intestine pathology can be induced in mice by intraluminal administration of poly I:C and that this is exacerbated by subsequent oral delivery of a relevant dietary antigen. PMID:24915573

Adenosine and Hypoxia-Inducible Factor Signaling in Intestinal Injury and Recovery

PubMed Central

Eltzschig, Holger K.

2013-01-01

The gastrointestinal mucosa has proven to be an interesting tissue in which to investigate disease-related metabolism. In this review, we outline some of the evidence that implicates hypoxia-mediated adenosine signaling as an important signature within both healthy and diseased mucosa. Studies derived from cultured cell systems, animal models, and human patients have revealed that hypoxia is a significant component of the inflammatory microenvironment. These studies have revealed a prominent role for hypoxia-induced factor (HIF) and hypoxia signaling at several steps along the adenine nucleotide metabolism and adenosine receptor signaling pathways. Likewise, studies to date in animal models of intestinal inflammation have demonstrated an almost uniformly beneficial influence of HIF stabilization on disease outcomes. Ongoing studies to define potential similarities with and differences between innate and adaptive immune responses will continue to teach us important lessons about the complexity of the gastrointestinal tract. Such information has provided new insights into disease pathogenesis and, importantly, will provide insights into new therapeutic targets. PMID:21942704

Intraluminal administration of poly I:C causes an enteropathy that is exacerbated by administration of oral dietary antigen.

PubMed

Araya, Romina E; Jury, Jennifer; Bondar, Constanza; Verdu, Elena F; Chirdo, Fernando G

2014-01-01

Systemic administration of polyinosinic:polycytidylic acid (poly I:C), mimics virally-induced activation of TLR3 signalling causing acute small intestine damage, but whether and how mucosal administration of poly I:C causes enteropathy is less clear. Our aim was to investigate the inflammatory pathways elicited after intraluminal administration of poly I:C and determine acute and delayed consequences of this locally induced immune activation. Intraluminal poly I:C induced rapid mucosal immune activation in C57BL/6 mice involving IFNβ and the CXCL10/CXCR3 axis, that may drive inflammation towards a Th1 profile. Intraluminal poly I:C also caused enteropathy and gut dysfunction in gliadin-sensitive NOD-DQ8 mice, and this was prolonged by concomitant oral administration of gliadin. Our results indicate that small intestine pathology can be induced in mice by intraluminal administration of poly I:C and that this is exacerbated by subsequent oral delivery of a relevant dietary antigen.

Selenoprotein Expression in Macrophages Is Critical for Optimal Clearance of Parasitic Helminth Nippostrongylus brasiliensis*

PubMed Central

Nelson, Shakira M.; Shay, Ashley E.; James, Jamaal L.; Carlson, Bradley A.; Urban, Joseph F.; Prabhu, K. Sandeep

2016-01-01

The plasticity of macrophages is evident in helminthic parasite infections, providing protection from inflammation. Previously we demonstrated that the micronutrient selenium induces a phenotypic switch in macrophage activation from a classically activated (pro-inflammatory; M1/CAM) toward an alternatively activated (anti-inflammatory; M2/AAM) phenotype, where cyclooxygenase (COX)-dependent cyclopentenone prostaglandin J2 (15d-PGJ2) plays a key role. Here, we hypothesize that dietary selenium modulates macrophage polarization toward an AAM phenotype to assist in the increasing clearance of adult Nippostrongylus brasiliensis, a gastrointestinal nematode parasite. Mice on a selenium-adequate (0.08 ppm) diet significantly augmented intestinal AAM presence while decreasing adult worms and fecal egg production when compared with infection of mice on selenium-deficient (<0.01 ppm) diet. Further increase in dietary selenium to supraphysiological levels (0.4 ppm) had very little or no impact on worm expulsion. Normal adult worm clearance and enhanced AAM marker expression were observed in the selenium-supplemented Trspfl/flCreWT mice that express selenoproteins driven by tRNASec (Trsp), whereas N. brasiliensis-infected Trspfl/flCreLysM selenium-supplemented mice showed a decreased clearance, with lowered intestinal expression of several AAM markers. Inhibition of the COX pathway with indomethacin resulted in delayed worm expulsion in selenium-adequate mice. This was rescued with 15d-PGJ2, which partially recapitulated the effect of selenium supplementation on fecal egg output in addition to increasing markers of AAMs in the small intestine. Antagonism of PPARγ blocked the effect of selenium. These results suggest that optimal expression of selenoproteins and selenium-dependent production of COX-derived endogenous prostanoids, such as Δ12-PGJ2 and 15d-PGJ2, may regulate AAM activation to enhance anti-helminthic parasite responses. PMID:26644468

Modulation of NF-κB and Nrf2 control of inflammatory responses in FHs 74 Int cell line is tocopherol isoform-specific

PubMed Central

Elisia, Ingrid

2013-01-01

The present study investigates the relative ability of α-, γ-, and δ-tocopherol (Toc) to modulate cell signaling events that are associated with inflammatory responses in fetal-derived intestinal (FHs 74 Int) cells. Secretion of the proinflammatory cytokine IL-8 in FHs 74 Int cells was stimulated in the following order: α-Toc < γ-Toc < δ-Toc. A similar proinflammatory response was observed when inflammation was induced in FHs 74 Int cells. Modulation of IL-8 expression by Toc corresponded to an isoform-specific modulation of NF-κB and nuclear factor-erythroid 2-related factor 2 (Nrf2) cell signaling pathways involved in expression of proinflammatory cytokines and antioxidant enzymes, respectively. δ-Toc and, to a lesser extent, γ-Toc activated NF-κB and Nrf2 signaling, as indicated by the greater nuclear translocation of transcription factors. Activation of NF-κB signaling by γ- and δ-Toc was accompanied by upregulation of NF-κB target genes, such as IL-8 and prostaglandin-endoperoxide synthase 2, with and without a prior IFNγ-PMA challenge. Nevertheless, γ- and δ-Toc, particularly δ-Toc, concurrently downregulated glutamate-cysteine ligase, a Nrf2 target gene that encodes for glutathione biosynthesis. This observation was substantiated by confirmation that γ- and δ-Toc were effective at decreasing glutamate-cysteine ligase protein expression and cellular glutathione content. Downregulation of glutathione content in fetal intestinal cells corresponded to induction of apoptosis-mediated cytotoxicity. In conclusion, γ- and δ-Toc are biologically active isoforms of vitamin E and show superior bioactivity to α-Toc in modulating cell signaling events that contribute to a proinflammatory response in fetal-derived intestinal cells. PMID:24136788

Intestinal Helminths Regulate Lethal Acute Graft Versus Host Disease and Preserve Graft Versus Tumor Effect in Mice

PubMed Central

Li, Yue; Chen, Hung-lin; Bannick, Nadine; Henry, Michael; Holm, Adrian N.; Metwali, Ahmed; Urban, Joseph F.; Rothman, Paul B.; Weiner, George J.; Blazar, Bruce R.; Elliott, David E.; Ince, M. Nedim

2014-01-01

Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor; GVT) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation, called graft-versus-host disease (GVHD). High dose steroids or other immune suppressives are used to treat GVHD that have limited ability to control the inflammation while incurring long-term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen-sensitized inflammation of GVHD, sustain GVT and prevent mortality in bone marrow transplantation. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus)-infected or uninfected Balb/C recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation along with reduction in GVHD lethality and maintenance of GVT. H. polygyrus colonization promoted the survival of TGFβ generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGFβ-dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD, when T cells unresponsive to TGFβ-mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD, employing regulatory T cells and TGFβ-dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT. PMID:25527786

AMP-18 Targets p21 to Maintain Epithelial Homeostasis.

PubMed

Chen, Peili; Li, Yan Chun; Toback, F Gary

2015-01-01

Dysregulated homeostasis of epithelial cells resulting in disruption of mucosal barrier function is an important pathogenic mechanism in inflammatory bowel diseases (IBD). We have characterized a novel gastric protein, Antrum Mucosal Protein (AMP)-18, that has pleiotropic properties; it is mitogenic, anti-apoptotic and can stimulate formation of tight junctions. A 21-mer synthetic peptide derived from AMP-18 exhibits the same biological functions as the full-length protein and is an effective therapeutic agent in mouse models of IBD. In this study we set out to characterize therapeutic mechanisms and identify molecular targets by which AMP-18 maintains and restores disrupted epithelial homeostasis in cultured intestinal epithelial cells and a mouse model of IBD. Tumor necrosis factor (TNF)-α, a pro-inflammatory cytokine known to mediate gastrointestinal (GI) mucosal injury in IBD, was used to induce intestinal epithelial cell injury, and study the effects of AMP-18 on apoptosis and the cell cycle. An apoptosis array used to search for targets of AMP-18 in cells exposed to TNF-α identified the cyclin-dependent kinase inhibitor p21 WAF1/CIP1. Treatment with AMP-18 blunted increases in p21 expression and apoptosis, while reversing disturbed cell cycle kinetics induced by TNF-α. AMP-18 appears to act through PI3K/AKT pathways to increase p21 phosphorylation, thereby reducing its nuclear accumulation to overcome the antiproliferative effects of TNF-α. In vitamin D receptor-deficient mice with TNBS-induced IBD, the observed increase in p21 expression in colonic epithelial cells was suppressed by treatment with AMP peptide. The results indicate that AMP-18 can maintain and/or restore the homeostatic balance between proliferation and apoptosis in intestinal epithelial cells to protect and repair mucosal barrier homeostasis and function, suggesting a therapeutic role in IBD.

Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice.

PubMed

Li, Yue; Chen, Hung-Lin; Bannick, Nadine; Henry, Michael; Holm, Adrian N; Metwali, Ahmed; Urban, Joseph F; Rothman, Paul B; Weiner, George J; Blazar, Bruce R; Elliott, David E; Ince, M Nedim

2015-02-01

Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor [GVT]) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation called graft-versus-host disease (GVHD). High-dose steroids or other immunosuppressive drugs are used to treat GVHD that have limited ability to control the inflammation while incurring long-term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT, and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen-sensitized inflammation of GVHD, sustain GVT, and prevent mortality in BMT. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus)-infected or uninfected BALB/c recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation and reduced GVHD-related mortality, but maintained GVT. H. polygyrus colonization promoted the survival of TGF-β-generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGF-β-dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD when T cells unresponsive to TGF-β-mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD using Tregs and TGF-β-dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT. Copyright © 2015 by The American Association of Immunologists, Inc.

Treatment of non-steroidal anti-inflammatory drug induced enteropathy.

PubMed Central

Bjarnason, I; Hopkinson, N; Zanelli, G; Prouse, P; Smethurst, P; Gumpel, J M; Levi, A J

1990-01-01

Non-steroidal anti-inflammatory drug induced small intestinal inflammation may have an adverse effect on the joints of patients with rheumatoid arthritis. We therefore assessed small intestinal and joint inflammation in patients with rheumatoid arthritis before and after three to nine months' treatment with sulphasalazine (n = 40) and other second line drugs (n = 20), while keeping the dosage of non-steroidal anti-inflammatory drug at the same level. Sulphasalazine significantly decreased the mean (SD) faecal excretion of 111indium labelled leucocytes from 2.39 (2.22)% to 1.33 (1.13)% (normal less than 1%, p less than 0.01) and improved the joint inflammation as assessed by a variety of parameters. There was no significant correlation between the effects of sulphasalazine treatment on the intestine and the joints. Treatment with other second line drugs had no significant effect on the faecal excretion of 111indium (1.58 (1.04)% and 1.86 (1.51)%, respectively) but improved joint inflammation significantly. The lack of correlation between the intestinal and joint inflammation and their response to treatment suggests that the two are not causally related. PMID:1973396

Impaired intestinal immune barrier and physical barrier function by phosphorus deficiency: Regulation of TOR, NF-κB, MLCK, JNK and Nrf2 signalling in grass carp (Ctenopharyngodon idella) after infection with Aeromonas hydrophila.

PubMed

Chen, Kang; Zhou, Xiao-Qiu; Jiang, Wei-Dan; Wu, Pei; Liu, Yang; Jiang, Jun; Kuang, Sheng-Yao; Tang, Ling; Tang, Wu-Neng; Zhang, Yong-An; Feng, Lin

2018-03-01

In aquaculture, the occurrence of enteritis has increased and dietary nutrition is considered as one of the major strategies to solve this problem. In the present study, we assume that dietary phosphorus might enhance intestinal immune barrier and physical barrier function to reduce the occurrence of enteritis in fish. To test this assumption, a total of 540 grass carp (Ctenopharyngodon idella) were investigated by feeding graded levels of available phosphorus (0.95-8.75 g/kg diet) and then infection with Aeromonas hydrophila. The results firstly showed that phosphorus deficiency decreased the ability to combat enteritis, which might be related to the impairment of intestinal immune barrier and physical barrier function. Compared with optimal phosphorus level, phosphorus deficiency decreased fish intestinal antimicrobial substances activities or contents and down-regulated antimicrobial peptides mRNA levels leading to the impairment of intestinal immune response. Phosphorus deficiency down-regulated fish intestinal anti-inflammatory cytokines mRNA levels and up-regulated the mRNA levels of pro-inflammatory cytokines [except IL-1β and IL-12p35 in distal intestine (DI) and IL-12p40] causing aggravated of intestinal inflammatory responses, which might be related to the signalling molecules target of rapamycin and nuclear factor kappa B. In addition, phosphorus deficiency disturbed fish intestinal tight junction function and induced cell apoptosis as well as oxidative damage leading to impaired of fish intestinal physical barrier function, which might be partially associated with the signalling molecules myosin light chain kinase, c-Jun N-terminal protein kinase and NF-E2-related factor 2, respectively. Finally, based on the ability to combat enteritis, dietary available phosphorus requirement for grass carp (254.56-898.23 g) was estimated to be 4.68 g/kg diet. Copyright © 2017. Published by Elsevier Ltd.

Alcohol, Intestinal Bacterial Growth, Intestinal Permeability to Endotoxin, and Medical Consequences

PubMed Central

Purohit, Vishnudutt; Bode, J. Christian; Bode, Christiane; Brenner, David A.; Choudhry, Mashkoor A.; Hamilton, Frank; Kang, Y. James; Keshavarzian, Ali; Rao, Radhakrishna; Sartor, R. Balfour; Swanson, Christine; Turner, Jerrold R.

2008-01-01

This report is a summary of the symposium on Alcohol, Intestinal Bacterial Growth, Intestinal Permeability to Endotoxin, and Medical Consequences, organized by National Institute on Alcohol Abuse and Alcoholism, Office of Dietary Supplements, and National Institute of Diabetes and Digestive and Kidney Diseases of National Institutes of Health in Rockville, Maryland, October 11, 2006. Alcohol exposure can promote the growth of Gram negative bacteria in the intestine which may result in accumulation of endotoxin. In addition, alcohol metabolism by Gram negative bacteria and intestinal epithelial cells can result in accumulation of acetaldehyde, which in turn can increase intestinal permeability to endotoxin by increasing tyrosine phosphorylation of tight junction and adherens junction proteins. Alcohol-induced generation of nitric oxide may also contribute to increased permeability to endotoxin by reacting with tubulin, which may cause damage to microtubule cytoskeleton and subsequent disruption of intestinal barrier function. Increased intestinal permeability can lead to increased transfer of endotoxin from the intestine to the liver and general circulation where endotoxin may trigger inflammatory changes in the liver and other organs. Alcohol may also increase intestinal permeability to peptidoglycan which can initiate inflammatory response in liver and other organs. In addition, acute alcohol exposure may potentiate the effect of burn injury on intestinal bacterial growth and permeability. Decreasing the number of Gram negative bacteria in the intestine can result in decreased production of endotoxin as well as acetaldehyde which is expected to decrease intestinal permeability to endotoxin. In addition, intestinal permeability may be preserved by administering epidermal growth factor, L-glutamine, oats supplementation, or zinc thereby preventing the transfer of endotoxin to the general circulation. Thus reducing the number of intestinal Gram negative bacteria and preserving intestinal permeability to endotoxin may attenuate alcoholic liver and other organ injuries. PMID:18504085

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells.

PubMed

Layunta, Elena; Latorre, Eva; Forcén, Raquel; Grasa, Laura; Castro, Marta; Arias, Maykel A; Alcalde, Ana I; Mesonero, José Emilio

2018-06-15

Serotonin (5-HT) is a chief modulator of intestinal activity. The effects of 5-HT depend on its extracellular availability, which is mainly controlled by serotonin transporter (SERT), expressed in enterocytes. On the other hand, innate immunity, mediated by Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs), is known to control intestinal microbiota and maintain intestinal homeostasis. The dysregulation of the intestinal serotonergic system and innate immunity has been observed in inflammatory bowel diseases (IBD), the incidence of which has severely increased all over the world. The aim of the present study, therefore, was to analyze the effect of NOD2 on intestinal SERT activity and expression, as well as to study the crosstalk of NOD2 with TLR2 and TLR4. Intestinal epithelial cell line Caco-2/TC7 was used to analyze SERT activity and SERT, NOD2, TLR2 and TLR4 molecular expression by real-time PCR and western blotting. Moreover, intestinal tract (ileum and colon) from mice deficient in TLR2, TLR4 or TLR2/4 receptors was used to test the interdependence of NOD2 with these TLR receptors. NOD2 activation inhibits SERT activity in Caco-2/TC7 cells, mainly due to the decrement of SERT molecular expression, with RIP2/RICK being the intracellular pathway involved in this effect. This inhibitory effect on SERT would yield an increment of extracellular 5-HT availability. In this sense, 5-HT strongly inhibits NOD2 expression. In addition, NOD2 showed greater interdependence with TLR2 than with TLR4. Indeed, NOD2 expression significantly increased in both cells treated with TLR2 agonists and the intestinal tract of Tlr2-/- mice. It may be inferred from our data that NOD2 could play a role in intestinal pathophysiology not only through its inherent innate immune role but also due to its interaction with other receptors as TLR2 and the modulation of the intestinal serotonergic system decreasing SERT activity and expression. © 2018 The Author(s). Published by S. Karger AG, Basel.

Intimin, Tir, and Shiga Toxin 1 Do Not Influence Enteropathogenic Responses to Shiga Toxin-Producing Escherichia coli in Bovine Ligated Intestinal Loops

PubMed Central

Stevens, Mark P.; Marchès, Olivier; Campbell, June; Huter, Veronika; Frankel, Gad; Phillips, Alan D.; Oswald, Eric; Wallis, Timothy S.

2002-01-01

Shiga toxin-producing Escherchia coli (STEC) comprises a group of attaching and effacing (A/E) enteric pathogens of animals and humans. Natural and experimental infection of calves with STEC may result in acute enteritis or subclinical infection, depending on serotype- and host-specific factors. To quantify intestinal secretory and inflammatory responses to STEC in the bovine intestine, serotypes that are associated with human disease (O103:H2 and O157:H7) were introduced into ligated mid-ileal loops in gnotobiotic and conventional calves, and fluid accumulation and recruitment of radiolabeled neutrophils were measured after 12 h. STEC serotype O103:H2, but not serotype O157:H7, elicited strong enteropathogenic responses. To determine if the inflammatory response to STEC O103:H2 in calves requires Shiga toxin 1 or intimate bacterial attachment to the intestinal epithelium, defined mutations were made in the stx1, eae, and tir genes. Our data indicate that some STEC induce intestinal inflammatory responses in calves by a mechanism that is independent of A/E-lesion formation, intimin, or Shiga toxin 1. This may have implications for strategies to reduce STEC carriage in cattle. PMID:11796630

Biological and clinical implications of herbal medicine and natural products for the treatment of inflammatory bowel disease.

PubMed

Guo, Bao-Jian; Bian, Zhao-Xiang; Qiu, Hong-Cong; Wang, Yi-Tao; Wang, Ying

2017-08-01

Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders that includes Crohn's disease (CD) and ulcerative colitis (UC). Homeostasis of various regulatory factors involved with intestinal immunity is disrupted in IBD, including the intestinal epithelial barrier, macrophages, and cellular mediators such as cytokines and chemokines. No successful treatment is currently available for the management of IBD. Natural products and herbal medicines have exhibited efficacy for UC and CD in experimental models and clinical trials with the following activities: (1) maintenance of integrity of the intestinal epithelial barrier, (2) regulation of macrophage activation, (3) modulation of innate and adaptive immune response, and (4) inhibition of TNF-α activity. Here, we discuss the major factors involved in the pathogenesis of IBD and the current development of natural products and herbs for the treatment of IBD. © 2017 New York Academy of Sciences.

Lipid Absorption Defects in Intestine-specific Microsomal Triglyceride Transfer Protein and ATP-binding Cassette Transporter A1-deficient Mice*

PubMed Central

Iqbal, Jahangir; Parks, John S.; Hussain, M. Mahmood

2013-01-01

We have previously described apolipoprotein B (apoB)-dependent and -independent cholesterol absorption pathways and the role of microsomal triglyceride transfer protein (MTP) and ATP-binding cassette transporter A1 (ABCA1) in these pathways. To assess the contribution of these pathways to cholesterol absorption and to determine whether there are other pathways, we generated mice that lack MTP and ABCA1, individually and in combination, in the intestine. Intestinal deletions of Mttp and Abca1 decreased plasma cholesterol concentrations by 45 and 24%, respectively, whereas their combined deletion reduced it by 59%. Acute cholesterol absorption was reduced by 28% in the absence of ABCA1, and it was reduced by 92–95% when MTP was deleted in the intestine alone or together with ABCA1. MTP deficiency significantly reduced triglyceride absorption, although ABCA1 deficiency had no effect. ABCA1 deficiency did not affect cellular lipids, but Mttp deficiency significantly increased intestinal levels of triglycerides and free fatty acids. Accumulation of intestinal free fatty acids, but not triglycerides, in Mttp-deficient intestines was prevented when mice were also deficient in intestinal ABCA1. Combined deficiency of these genes increased intestinal fatty acid oxidation as a consequence of increased expression of peroxisome proliferator-activated receptor-γ (PPARγ) and carnitine palmitoyltransferase 1α (CPT1α). These studies show that intestinal MTP and ABCA1 are critical for lipid absorption and are the main determinants of plasma and intestinal lipid levels. Reducing their activities might lower plasma lipid concentrations. PMID:24019513

High SMAD7 and p-SMAD2,3 expression is associated with environmental enteropathy in children.

PubMed

Syed, Sana; Dinallo, Vincenzo; Iqbal, Najeeha T; Di Iorio, Laura; Di Fusco, Davide; Guleria, Shan; Amadi, Beatrice C; Sadiq, Kamran; Moskaluk, Christopher; Ali, S Asad; Kelly, Paul; Monteleone, Giovanni

2018-02-01

Enteropathies such as Crohn's disease are associated with enteric inflammation characterized by impaired TGF-β signaling, decreased expression of phosphorylated (p)-SMAD2,3 and increased expression of SMAD7 (an inhibitor of SMAD3 phosphorylation). Environmental enteropathy (EE) is an acquired inflammatory disease of the small intestine (SI), which is associated with linear growth disruption, cognitive deficits, and reduced oral vaccine responsiveness in children <5 y in resource-poor countries. We aimed to characterize EE inflammatory pathways by determining SMAD7 and p-SMAD2,3 levels (using Western blotting) in EE duodenal biopsies (N = 19 children, 7 from Pakistan, 12 from Zambia) and comparing these with healthy controls (Ctl) and celiac disease (CD) patients from Italy. Densitometric analysis of immunoblots showed that EE SI biopsies expressed higher levels of both SMAD7 (mean±SD in arbitrary units [a.u.], Ctl = 0.47±0.20 a.u., EE = 1.13±0.25 a.u., p-value = 0.03) and p-SMAD2,3 (mean±SD, Ctl = 0.38±0.14 a.u., EE = 0.60±0.10 a.u., p-value = 0.03). Immunohistochemistry showed that, in EE, SMAD7 is expressed in both the epithelium and in mononuclear cells of the lamina propria (LP). In contrast, p-SMAD3 in EE is expressed much more prominently in epithelial cells than in the LP. The high SMAD7 immunoreactivity and lack of p-SMAD3 expression in the LP suggests defective TGF-β signaling in the LP in EE similar to a previously reported SMAD7-mediated inflammatory pathway in refractory CD and Crohn's disease. However, Western blot densitometry showed elevated p-SMAD2,3 levels in EE, possibly suggesting a different inflammatory pathway than Crohn's disease but more likely reflecting cumulative protein expression from across all compartments of the mucosa as opposed to the LP alone. Further studies are needed to substantiate these preliminary results and to illustrate the relationship between SMAD proteins, TGF-β signaling, and inflammatory cytokine production, all of which may be potential therapeutic targets.

Dysplasia and cancer in inflammatory bowel disease 10 years after diagnosis: results of a population-based European collaborative follow-up study.

PubMed

Katsanos, K H; Vermeire, S; Christodoulou, D K; Riis, L; Wolters, F; Odes, S; Freitas, J; Hoie, Ole; Beltrami, Marina; Fornaciari, G; Clofent, J; Bodini, P; Vatn, M; Nunes, Paula Borralho; Moum, B; Munkholm, P; Limonard, C; Stockbrugger, R; Rutgeerts, P; Tsianos, E V

2007-01-01

To determine dysplasia and cancer in the 1991-2004 European Collaborative Inflammatory Bowel Disease (EC-IBD) Study Group cohort. A patient questionnaire and a physician per patient form were completed for each of the 1,141 inflammatory bowel disease patients (776 ulcerative colitis/365 Crohn's disease) from 9 centers (7 countries) derived from the EC-IBD cohort. Rates of detection of intestinal cancer and dysplasia as well as extra-intestinal neoplasms were computed. Patient follow-up time was 10.3 +/- 0.8 (range 9.4-11) years. The mean age of the whole group of IBD patients was 37.8 +/- 11.3 (range 16-76) years. Thirty-eight patients (3.3%; 26 with ulcerative colitis/12 with Crohn's disease, 21 males/17 females, aged 61.3 +/- 13.4, range 33-77 years), were diagnosed with 42 cancers. Cancers occurred 5.4 +/- 3.3 (range 0-11) years after inflammatory bowel disease diagnosis. Colorectal cancer was diagnosed in 8 (1 Crohn's disease and 7 ulcerative colitis patients--0.3 and 0.9% of the Crohn's disease and ulcerative colitis cohort, respectively) of 38 patients and 30 cancers were extra-intestinal. Four of 38 patients (10.5%) were diagnosed as having 2 cancers and they were younger compared to patients with one cancer (p = 0.0008). There was a trend for a higher prevalence of intestinal cancer in the northern centers (0.9%) compared to southern centers (0.3%, p = NS). Southern centers had more cases of extra-intestinal cancer compared to northern centers (2 vs. 3.8%, p = 0.08). Ten patients (0.9%; 8 with ulcerative colitis/2 with Crohn's disease, 8 males, aged 62.3 +/- 14.1 years) had colorectal dysplasia. In the first decade of the EC-IBD Study Group cohort follow-up study, the prevalence of cancer was as expected with most patients having a single neoplasm and an extra-intestinal neoplasm. In northern centers there was a trend for more intestinal cancers, while in southern centers there was a trend for more extra-intestinal cancers compared to northern centers. 2007 S. Karger AG, Basel

Potential role of chitinases and chitin-binding proteins in host-microbial interactions during the development of intestinal inflammation

PubMed Central

Tran, Hoa T.; Barnich, Nicolas; Mizoguchi, Emiko

2011-01-01

Summary The small and large intestines contain an abundance of luminal antigens derived from food products and enteric microorganisms. The function of intestinal epithelial cells is tightly regulated by several factors produced by enteric bacteria and the epithelial cells themselves. Epithelial cells actively participate in regulating the homeostasis of intestine, and failure of this function leads to abnormal and host-microbial interactions resulting in the development of intestinal inflammation. Major determinants of host susceptibility against luminal commensal bacteria include genes regulating mucosal immune responses, intestinal barrier function and microbial defense. Of note, it has been postulated that commensal bacterial adhesion and invasion on/into host cells may be strongly involved in the pathogenesis of inflammatory bowel disease (IBD). During the intestinal inflammation, the composition of the commensal flora is altered, with increased population of aggressive and detrimental bacteria and decreased populations of protective bacteria. In fact, some pathogenic bacteria, including Adherent Invasive Escherichia coli, Listeria monocytogenes and Vibrio cholerae are likely to initiate their adhesion to the host cells by expressing accessory molecules such as chitinases and/or chitin-binding proteins on themselves. In addition, several inducible molecules (e.g., chitinase 3-like-1, CEACAM6) are also induced on the host cells (e.g. epithelial cells, lamina proprial macrophages) under inflammatory conditions, and are actively participated in the host-microbial interactions. In this review, we will summarize and discuss the potential roles of these important molecules during the development of acute and chronic inflammatory conditions. PMID:21938682

Agmatine attenuates intestinal ischemia and reperfusion injury by reducing oxidative stress and inflammatory reaction in rats.

PubMed

Turan, Inci; Ozacmak, Hale Sayan; Ozacmak, V Haktan; Barut, Figen; Araslı, Mehmet

2017-11-15

Oxidative stress and inflammatory response are major factors causing several tissue injuries in intestinal ischemia and reperfusion (I/R). Agmatine has been reported to attenuate I/R injury of various organs. The present study aims to analyze the possible protective effects of agmatine on intestinal I/R injury in rats. Four groups were designed: sham control, agmatine-treated control, I/R control, and agmatine-treated I/R groups. IR injury of small intestine was induced by the occlusion of the superior mesenteric artery for half an hour to be followed by a 3-hour-long reperfusion. Agmatine (10mg/kg) was administered intraperitoneally before reperfusion period. After 180min of reperfusion period, the contractile responses to both carbachol and potassium chloride (KCl) were subsequently examined in an isolated-organ bath. Malondialdehyde (MDA), reduced glutathione (GSH), and the activity of myeloperoxidase (MPO) were measured in intestinal tissue. Plasma cytokine levels were determined. The expression of the intestinal inducible nitric oxide synthase (iNOS) was also assessed by immunohistochemistry. The treatment with agmatine appeared to be significantly effective in reducing the MDA content and MPO activity besides restoring the content of GSH. The treatment also attenuated the histological injury. The increases in the I/R induced expressions of iNOS, IFN-γ, and IL-1α were brought back to the sham control levels by the treatment as well. Our findings indicate that the agmatine pretreatment may ameliorate reperfusion induced injury in small intestine mainly due to reducing inflammatory response and oxidative stress. Copyright © 2017 Elsevier Inc. All rights reserved.

[Various pathways leading to the progression of chronic liver diseases].

PubMed

Egresi, Anna; Lengyel, Gabriella; Somogyi, Anikó; Blázovics, Anna; Hagymási, Krisztina

2016-02-21

As the result of various effects (viruses, metabolic diseases, nutritional factors, toxic agents, autoimmune processes) abnormal liver function, liver steatosis and connective tissue remodeling may develop. Progression of this process is complex including various pathways and a number of factors. The authors summarize the factors involved in the progression of chronic liver disease. They describe the role of cells and the produced inflammatory mediators and cytokines, as well as the relationship between the disease and the intestinal flora. They emphasize the role of oxidative stress, mitochondrial dysfunction and cell death in disease progression. Insulin resistance and micro-elements (iron, copper) in relation to liver damage are also discussed, and genetic and epigenetic aspects underlying disease progression are summarized. Discovery of novel treatment options, assessment of the effectiveness of treatment, as well as the success and proper timing of liver transplantation may depend on a better understanding of the process of disease progression.

Long-term enteral arginine supplementation in rats with intestinal ischemia and reperfusion.

PubMed

Lee, Chien-Hsing; Hsiao, Chien-Chou; Hung, Ching-Yi; Chang, Yu-Jun; Lo, Hui-Chen

2012-06-01

The effects of short-term enteral arginine supplementation on intestinal ischemia-reperfusion (IR) injury have been widely studied, especially the ischemic preconditioning supplementation. The aim of this study was to investigate the effects of long-term intra-duodenal supplementation of arginine on intestinal morphology, arginine-associated amino acid metabolism, and inflammatory responses in rats with intestinal IR. Male Wistar rats with or without three hours of ileal ischemia underwent duodenal cannulation for continuous infusion of formula with 2% arginine or commercial protein powder for 7 d. The serological examinations, plasma amino acid and cytokine profiles, and intestinal morphology were assessed. Intestinal IR injury had significant impacts on the decreases in circulating red blood cells, hemoglobin, ileum mass, and villus height and crypt depth of the distal jejunum. In addition, arginine supplementation decreased serum cholesterol and increased plasma arginine concentrations. In rats with intestinal IR injury, arginine supplementation significantly decreased serum nitric oxide, plasma citrulline and ornithine, and the mucosal protein content of the ileum. These results suggest that long-term intra-duodenal arginine administration may not have observable benefits on intestinal morphology or inflammatory response in rats with intestinal ischemia and reperfusion injury. Therefore, the necessity of long-term arginine supplementation for patients with intestinal ischemia and reperfusion injury remains questionable and requires further investigation. Copyright © 2012 Elsevier Inc. All rights reserved.

Toll-like receptors 2 and 4 modulate intestinal IL-10 differently in ileum and colon

PubMed Central

Layunta, Elena; Grasa, Laura; Pardo, Julián; García, Santiago; Alcalde, Ana I

2017-01-01

Background Inflammatory bowel diseases are consequence of an intestinal homeostasis breakdown in which innate immune dysregulation is implicated. Toll-like receptor (TLR)2 and TLR4 are immune recognition receptors expressed in the intestinal epithelium, the first physical-physiological barrier for microorganisms, to inform the host of the presence of Gram-positive and Gram-negative organisms. Interleukin (IL)-10 is an essential anti-inflammatory cytokine that contributes to maintenance of intestinal homeostasis. Aim Our main aim was to investigate intestinal IL-10 synthesis and release, and whether TLR2 and TLR4 are determinants of IL-10 expression in the intestinal tract. Methods We used Caco-2 cell line as an enterocyte-like cell model, and also ileum and colon from mice deficient in TLR2, TLR4 or TLR2/4 to test the involvement of TLR signaling. Results Intestinal epithelial cells are able to synthesize and release IL-10 and their expression is increased after TLR2 or TLR4 activation. IL-10 regulation seems to be tissue specific, with IL-10 expression in the ileum regulated by a compensation between TLR2 and TLR4 expression, whereas in the colon, TLR2 and TLR4 affect IL-10 expression independently. Conclusions Intestinal epithelial cells could release IL-10 in response to TLR activation, playing an intestinal tissue-dependent and critical intestinal immune role. PMID:29774159

Toll-like receptors 2 and 4 modulate intestinal IL-10 differently in ileum and colon.

PubMed

Latorre, Eva; Layunta, Elena; Grasa, Laura; Pardo, Julián; García, Santiago; Alcalde, Ana I; Mesonero, José E

2018-04-01

Inflammatory bowel diseases are consequence of an intestinal homeostasis breakdown in which innate immune dysregulation is implicated. Toll-like receptor (TLR)2 and TLR4 are immune recognition receptors expressed in the intestinal epithelium, the first physical-physiological barrier for microorganisms, to inform the host of the presence of Gram-positive and Gram-negative organisms. Interleukin (IL)-10 is an essential anti-inflammatory cytokine that contributes to maintenance of intestinal homeostasis. Our main aim was to investigate intestinal IL-10 synthesis and release, and whether TLR2 and TLR4 are determinants of IL-10 expression in the intestinal tract. We used Caco-2 cell line as an enterocyte-like cell model, and also ileum and colon from mice deficient in TLR2, TLR4 or TLR2/4 to test the involvement of TLR signaling. Intestinal epithelial cells are able to synthesize and release IL-10 and their expression is increased after TLR2 or TLR4 activation. IL-10 regulation seems to be tissue specific, with IL-10 expression in the ileum regulated by a compensation between TLR2 and TLR4 expression, whereas in the colon, TLR2 and TLR4 affect IL-10 expression independently. Intestinal epithelial cells could release IL-10 in response to TLR activation, playing an intestinal tissue-dependent and critical intestinal immune role.

Exercise and gut immune function: evidence of alterations in colon immune cell homeostasis and microbiome characteristics with exercise training.

PubMed

Cook, Marc D; Allen, Jacob M; Pence, Brandt D; Wallig, Matthew A; Gaskins, H Rex; White, Bryan A; Woods, Jeffrey A

2016-02-01

There is robust evidence that habitual physical activity is anti-inflammatory and protective against developing chronic inflammatory disease. Much less is known about the effects of habitual moderate exercise in the gut, the compartment that has the greatest immunological responsibility and interactions with the intestinal microbiota. The link between the two has become evident, as recent studies have linked intestinal dysbiosis, or the disproportionate balance of beneficial to pathogenic microbes, with increased inflammatory disease susceptibility. Limited animal and human research findings imply that exercise may have a beneficial role in preventing and ameliorating such diseases by having an effect on gut immune function and, recently, microbiome characteristics. Emerging data from our laboratory show that different forms of exercise training differentially impact the severity of intestinal inflammation during an inflammatory insult (for example, ulcerative colitis) and may be jointly related to gut immune cell homeostasis and microbiota-immune interactions. The evidence we review and present will provide data in support of rigorous investigations concerning the effects of habitual exercise on gut health and disease.

Anti-inflammatory effect and modulation of cytochrome P450 activities by Artemisia annua tea infusions in human intestinal Caco-2 cells.

PubMed

Melillo de Magalhães, Pedro; Dupont, Isabelle; Hendrickx, Aurélie; Joly, Aurélie; Raas, Thomas; Dessy, Stéphanie; Sergent, Thérèse; Schneider, Yves-Jacques

2012-09-15

In an attempt to understand the beneficial health effects of Artemisia annua other than its anti-malaria properties, extracts from different cultivars prepared as tea infusions were investigated using Caco-2 cells on the intestinal inflammation and cytochrome P450 (CYP) activities. The characterisation of their phenolic compound (PC) profile revealed rosmarinic and chlorogenic acids as the main PCs. The extracts, assayed on Caco-2 cells at a plausible intestinal concentration, significantly decreased the secretion of pro-inflammatory cytokines, IL-8 and IL-6. This effect could be attributable at least to their content in rosmarinic acid, detected as a potent anti-inflammatory compound. The extracts also inhibited the activity of CYP3A4, whose expression was induced by 1,25-dihydroxyvitamin D(3), and of CYP1A1, induced by benzo(a)pyrene. Our results highlight the advantage of drinking A. annua infusions for their potent anti-inflammatory effect, linked to PC content, which could synergise their antimalarial activity. Copyright © 2012 Elsevier Ltd. All rights reserved.

Enterohemorrhagic Escherichia coli senses low biotin status in the large intestine for colonization and infection

PubMed Central

Yang, Bin; Feng, Lu; Wang, Fang; Wang, Lei

2015-01-01

Enterohemorrhagic Escherichia coli (EHEC) is an important foodborne pathogen that infects humans by colonizing the large intestine. Here we identify a virulence-regulating pathway in which the biotin protein ligase BirA signals to the global regulator Fur, which in turn activates LEE (locus of enterocyte effacement) genes to promote EHEC adherence in the low-biotin large intestine. LEE genes are repressed in the high-biotin small intestine, thus preventing adherence and ensuring selective colonization of the large intestine. The presence of this pathway in all nine EHEC serotypes tested indicates that it is an important evolutionary strategy for EHEC. The pathway is incomplete in closely related small-intestinal enteropathogenic E. coli due to the lack of the Fur response to BirA. Mice fed with a biotin-rich diet show significantly reduced EHEC adherence, indicating that biotin might be useful to prevent EHEC infection in humans. PMID:25791315

Using corticosteroids to reshape the gut microbiome: implications for inflammatory bowel diseases.

PubMed

Huang, Edmond Y; Inoue, Takuya; Leone, Vanessa A; Dalal, Sushila; Touw, Ketrija; Wang, Yunwei; Musch, Mark W; Theriault, Betty; Higuchi, Kazuhide; Donovan, Sharon; Gilbert, Jack; Chang, Eugene B

2015-05-01

Commensal gut microbiota play an important role in regulating metabolic and inflammatory conditions. Reshaping intestinal microbiota through pharmacologic means may be a viable treatment option. We sought to delineate the functional characteristics of glucocorticoid-mediated alterations on gut microbiota and their subsequent repercussions on host mucin regulation and colonic inflammation. Adult male C57Bl/6 mice, germ-free, Muc2-heterozygote (±), or Muc2-knockout (-/-) were injected with dexamethasone, a synthetic glucocorticoid, for 4 weeks. Fecal samples were collected for gut microbiota analysis through 16S rRNA terminal restriction fragment length polymorphism and amplicon sequencing. Intestinal mucosa was collected for mucin gene expression studies. Germ-free mice were conventionalized with gut microbes from treated and nontreated groups to determine their functional capacities in recipient hosts. Exposure to dexamethasone in wild-type mice led to substantial shifts in gut microbiota over a 4-week period. Furthermore, a significant downregulation of colonic Muc2 gene expression was observed after treatment. Muc2-knockout mice harbored a proinflammatory environment of gut microbes, characterized by the increase or decrease in prevalence of specific microbiota populations such as Clostridiales and Lactobacillaceae, respectively. This colitogenic phenotype was transmissible to IL10-knockout mice, a genetically susceptible model of colonic inflammatory disorders. Microbiota from donors pretreated with dexamethasone, however, ameliorated symptoms of inflammation. Commensal gut bacteria may be a key mediator of the anti-inflammatory effects observed in the large intestine after glucocorticoid exposure. These findings underscore the notion that intestinal microbes comprise a "microbial organ" essential for host physiology that can be targeted by therapeutic approaches to restore intestinal homeostasis.

Profound Chemopreventative Effects of a Hydrogen Sulfide-Releasing NSAID in the APCMin/+ Mouse Model of Intestinal Tumorigenesis

PubMed Central

Paul-Clark, Mark; Elsheikh, Wagdi; Kirkby, Nicholas; Chan, Melissa; Devchand, Pallavi; Agbor, Terence A.; Flannigan, Kyle L.; Cheadle, Charlotte; Freydin, Maxim; Ianaro, Angela; Mitchell, Jane A.; Wallace, John L.

2016-01-01

Nonsteroidal anti-inflammatory drugs have been shown to reduce the incidence of gastrointestinal cancers, but the propensity of these drugs to cause ulcers and bleeding limits their use. H2S has been shown to be a powerful cytoprotective and anti-inflammatory substance in the digestive system. This study explored the possibility that a H2S-releasing nonsteroidal anti-inflammatory drug (ATB-346) would be effective in a murine model of hereditary intestinal cancer (APCMin+ mouse) and investigated potential mechanisms of action via transcriptomics analysis. Daily treatment with ATB-346 was significantly more effective at preventing intestinal polyp formation than naproxen. Significant beneficial effects were seen with a treatment period of only 3–7 days, and reversal of existing polyps was observed in the colon. ATB-346, but not naproxen, significantly decreased expression of intestinal cancer-associated signaling molecules (cMyc, β-catenin). Transcriptomic analysis identified 20 genes that were up-regulated in APCMin+ mice, 18 of which were reduced to wild-type levels by one week of treatment with ATB-346. ATB-346 is a novel, gastrointestinal-sparing anti-inflammatory drug that potently and rapidly prevents and reverses the development of pre-cancerous lesions in a mouse model of hereditary intestinal tumorigenesis. These effects may be related to the combined effects of suppression of cyclooxygenase and release of H2S, and correction of most of the APCMin+-associated alterations in the transcriptome. ATB-346 may represent a promising agent for chemoprevention of tumorigenesis in the GI tract and elsewhere. PMID:26910063

[Trans-intestinal cholesterol excretion (TICE): a new route for cholesterol excretion].

PubMed

Blanchard, Claire; Moreau, François; Cariou, Bertrand; Le May, Cédric

2014-10-01

The small intestine plays a crucial role in dietary and biliary cholesterol absorption, as well as its lymphatic secretion as chylomicrons (lipoprotein exogenous way). Recently, a new metabolic pathway called TICE (trans-intestinal excretion of cholesterol) that plays a central role in cholesterol metabolism has emerged. TICE is an inducible way, complementary to the hepatobiliary pathway, allowing the elimination of the plasma cholesterol directly into the intestine lumen through the enterocytes. This pathway is poorly characterized but several molecular actors of TICE have been recently identified. Although it is a matter of debate, two independent studies suggest that TICE is involved in the anti-atherogenic reverse cholesterol transport pathway. Thus, TICE is an innovative drug target to reduce -cardiovascular diseases. © 2014 médecine/sciences – Inserm.

Arctigenin from Fructus Arctii (Seed of Burdock) Reinforces Intestinal Barrier Function in Caco-2 Cell Monolayers

PubMed Central

Shin, Hee Soon; Jung, Sun Young; Back, Su Yeon; Do, Jeong-Ryong; Shon, Dong-Hwa

2015-01-01

Fructus Arctii is used as a traditional herbal medicine to treat inflammatory diseases in oriental countries. This study aimed to investigate effect of F. Arctii extract on intestinal barrier function in human intestinal epithelial Caco-2 cells and to reveal the active component of F. Arctii. We measured transepithelial electrical resistance (TEER) value (as an index of barrier function) and ovalbumin (OVA) permeation (as an index of permeability) to observe the changes of intestinal barrier function. The treatment of F. Arctii increased TEER value and decreased OVA influx on Caco-2 cell monolayers. Furthermore, we found that arctigenin as an active component of F. Arctii increased TEER value and reduced permeability of OVA from apical to the basolateral side but not arctiin. In the present study, we revealed that F. Arctii could enhance intestinal barrier function, and its active component was an arctigenin on the functionality. We expect that the arctigenin from F. Arctii could contribute to prevention of inflammatory, allergic, and infectious diseases by reinforcing intestinal barrier function. PMID:26550018

Heads up! How the intestinal epithelium safeguards mucosal barrier immunity through the inflammasome and beyond.

PubMed

Cario, Elke

2010-11-01

The intestinal epithelium serves as a highly dynamic immunologic frontier - exhibiting both innate and adaptive immune features. This review focuses on recent advances and novel insights into key intrinsic processes of the intestinal epithelium to closely monitor its intracellular and extracellular environment, communicate messages to neighbouring cells and rapidly initiate active defensive and repair measures, if necessary. The intestinal epithelium is uniquely equipped with a vast array of features to control immune barrier homeostasis at the gates of the healthy intestinal mucosa. Deficient Toll-like receptor or NOD-like receptor signalling in the intestinal epithelium may imbalance commensal-dependent homeostasis, facilitating mucosal injury and leading to inflammatory disease. Dysfunction of the NLRP3 inflammasome may trigger aggravation of mucosal inflammation and cancer and has been associated with human inflammatory bowel diseases. Deregulated autophagy may alter inflammasome activity. Exciting progress has been made in better understanding the complex diversity of physiological functions of innate immune responses in the intestinal epithelial barrier. Regulatory platforms of signalling mechanisms exist which are closely related and interact. However, many questions remain to be answered and more puzzles have arisen which are highlighted here.

Potential of Lactobacillus plantarum CCFM639 in Protecting against Aluminum Toxicity Mediated by Intestinal Barrier Function and Oxidative Stress.

PubMed

Yu, Leilei; Zhai, Qixiao; Tian, Fengwei; Liu, Xiaoming; Wang, Gang; Zhao, Jianxin; Zhang, Hao; Narbad, Arjan; Chen, Wei

2016-12-02

Aluminum (Al) is a ubiquitous metal that can seriously harm the health of animals and humans. In our previous study, we demonstrated that Lactobacillus plantarum CCFM639 can decrease Al burden in the tissues of mice by inhibiting intestinal Al absorption. The main aim of the present research was to investigate whether the protection by the strain is also associated with enhancement of the intestinal barrier, alleviation of oxidative stress and modulation of the inflammatory response. In an in vitro cell model, two protection modes (intervention and therapy) were examined and the results indicated that L. plantarum CCFM639 alleviated Al-induced cytotoxicity. In a mouse model, L. plantarum CCFM639 treatment was found to significantly alleviate oxidative stress in the intestinal tract, regulate the function of the intestinal mucosal immune system, restore the integrity of tight junction proteins and maintain intestinal permeability. These results suggest that in addition to Al sequestration, L. plantarum CCFM639 can also inhibit Al absorption by protecting the intestinal barrier, alleviating Al-induced oxidative stress and inflammatory response. Therefore, L. plantarum CCFM639 has the potential to be a dietary supplement ingredient that provides protection against Al-induced gut injury.

Intermittent fasting modulates IgA levels in the small intestine under intense stress: a mouse model.

PubMed

Lara-Padilla, Eleazar; Godínez-Victoria, Marycarmen; Drago-Serrano, Maria Elisa; Reyna-Garfias, Humberto; Arciniega-Martínez, Ivonne Maciel; Abarca-Rojano, Edgar; Cruz-Hernández, Teresita Rocío; Campos-Rodríguez, Rafael

2015-08-15

Intermittent fasting prolongs the lifespan and unlike intense stress provides health benefits. Given the role of the immunoglobulin A (IgA) in the intestinal homeostasis, the aim of this study was to assess the impact of intermittent fasting plus intense stress on secretory IgA (SIgA) production and other mucosal parameters in the duodenum and ileum. Two groups of six mice, with intermittent fasting or fed ad libitum for 12weeks, were submitted to a session of intense stress by a bout of forced swimming. Unstressed ad libitum fed or intermittently fasted groups were included as controls. After sacrifice, we evaluated intestinal SIgA and plasma adrenal hormones, lamina propria IgA+ plasma-cells, mRNA expression of polymeric immunoglobulin receptor, α- and J-chains in the liver and intestinal mucosa, as well as pro- (tumor necrosis factor-α, interleukin-6 and Interferon-γ) and anti- (interleukin-2, -4, -10 and transforming growth factor-β) inflammatory cytokines in mucosal samples. Under intense stress, intermittent fasting down- or up-modulated the levels of most parameters in the duodenum and ileum, respectively while up-regulated corticosterone levels without affecting epinephrine. Our data suggest intermittent fasting plus intense stress elicited neuroendocrine pathways that differentially controlled IgA and pIgR expression in duodenum and ileum. These findings provide experimental foundations for a presumable impact of intermittent fasting under intense stress on the intestinal homeostasis or inflammation by triggering or reducing the IgA production in ileum or duodenum respectively. Copyright © 2015 Elsevier B.V. All rights reserved.

Saccharomyces boulardii CNCM I-745 Restores intestinal Barrier Integrity by Regulation of E-cadherin Recycling.

PubMed

Terciolo, Chloé; Dobric, Aurélie; Ouaissi, Mehdi; Siret, Carole; Breuzard, Gilles; Silvy, Françoise; Marchiori, Bastien; Germain, Sébastien; Bonier, Renaté; Hama, Adel; Owens, Roisin; Lombardo, Dominique; Rigot, Véronique; André, Frédéric

2017-08-01

Alteration in intestinal permeability is the main factor underlying the pathogenesis of many diseases affecting the gut, such as inflammatory bowel disease [IBD]. Characterization of molecules targeting the restoration of intestinal barrier integrity is therefore vital for the development of alternative therapies. The yeast Saccharomyces boulardii CNCM I-745 [Sb], used to prevent and treat antibiotic-associated infectious and functional diarrhea, may have a beneficial effect in the treatment of IBD. We analyzed the impact of Sb supernatant on tissue integrity and components of adherens junctions using cultured explants of colon from both IBD and healthy patients. To evaluate the pathways by which Sb regulates the expression of E-cadherin at the cell surface, we developed in vitro assays using human colonic cell lines, including cell aggregation, a calcium switch assay, real-time measurement of transepithelial electrical resistance [TEER] and pulse-chase experiments. We showed that Sb supernatant treatment of colonic explants protects the epithelial morphology and maintains E-cadherin expression at the cell surface. In vitro experiments revealed that Sb supernatant enhances E-cadherin delivery to the cell surface by re-routing endocytosed E-cadherin back to the plasma membrane. This process, involving Rab11A-dependent recycling endosome, leads to restoration of enterocyte adherens junctions, in addition to the overall restoration and strengthening of intestinal barrier function. These findings open new possibilities of discovering novel options for prevention and therapy of diseases that affect intestinal permeability. Copyright © 2017 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

Gut-lung crosstalk in pulmonary involvement with inflammatory bowel diseases.

PubMed

Wang, Hui; Liu, Jing-Shi; Peng, Shao-Hua; Deng, Xi-Yun; Zhu, De-Mao; Javidiparsijani, Sara; Wang, Gui-Rong; Li, Dai-Qiang; Li, Long-Xuan; Wang, Yi-Chun; Luo, Jun-Ming

2013-10-28

Pulmonary abnormalities, dysfunction or hyper-reactivity occurs in association with inflammatory bowel disease (IBD) more frequently than previously recognized. Emerging evidence suggests that subtle inflammation exists in the airways among IBD patients even in the absence of any bronchopulmonary symptoms, and with normal pulmonary functions. The pulmonary impairment is more pronounced in IBD patients with active disease than in those in remission. A growing number of case reports show that the IBD patients develop rapidly progressive respiratory symptoms after colectomy, with failure to isolate bacterial pathogens on repeated sputum culture, and often request oral corticosteroid therapy. All the above evidence indicates that the inflammatory changes in both the intestine and lung during IBD. Clinical or subclinical pulmonary inflammation accompanies the main inflammation of the bowel. Although there are clinical and epidemiological reports of chronic inflammation of the pulmonary and intestinal mucosa in IBD, the detailed mechanisms of pulmonary-intestinal crosstalk remain unknown. The lung has no anatomical connection with the main inflammatory site of the bowel. Why does the inflammatory process shift from the gastrointestinal tract to the airways? The clinical and subclinical pulmonary abnormalities, dysfunction, or hyper-reactivity among IBD patients need further evaluation. Here, we give an overview of the concordance between chronic inflammatory reactions in the airways and the gastrointestinal tract. A better understanding of the possible mechanism of the crosstalk among the distant organs will be beneficial in identifying therapeutic strategies for mucosal inflammatory diseases such as IBD and allergy.

Gut-lung crosstalk in pulmonary involvement with inflammatory bowel diseases

PubMed Central

Wang, Hui; Liu, Jing-Shi; Peng, Shao-Hua; Deng, Xi-Yun; Zhu, De-Mao; Javidiparsijani, Sara; Wang, Gui-Rong; Li, Dai-Qiang; Li, Long-Xuan; Wang, Yi-Chun; Luo, Jun-Ming

2013-01-01

Pulmonary abnormalities, dysfunction or hyper-reactivity occurs in association with inflammatory bowel disease (IBD) more frequently than previously recognized. Emerging evidence suggests that subtle inflammation exists in the airways among IBD patients even in the absence of any bronchopulmonary symptoms, and with normal pulmonary functions. The pulmonary impairment is more pronounced in IBD patients with active disease than in those in remission. A growing number of case reports show that the IBD patients develop rapidly progressive respiratory symptoms after colectomy, with failure to isolate bacterial pathogens on repeated sputum culture, and often request oral corticosteroid therapy. All the above evidence indicates that the inflammatory changes in both the intestine and lung during IBD. Clinical or subclinical pulmonary inflammation accompanies the main inflammation of the bowel. Although there are clinical and epidemiological reports of chronic inflammation of the pulmonary and intestinal mucosa in IBD, the detailed mechanisms of pulmonary-intestinal crosstalk remain unknown. The lung has no anatomical connection with the main inflammatory site of the bowel. Why does the inflammatory process shift from the gastrointestinal tract to the airways? The clinical and subclinical pulmonary abnormalities, dysfunction, or hyper-reactivity among IBD patients need further evaluation. Here, we give an overview of the concordance between chronic inflammatory reactions in the airways and the gastrointestinal tract. A better understanding of the possible mechanism of the crosstalk among the distant organs will be beneficial in identifying therapeutic strategies for mucosal inflammatory diseases such as IBD and allergy. PMID:24187454

Intestinal microbiota, probiotics and prebiotics in inflammatory bowel disease

PubMed Central

Orel, Rok; Kamhi Trop, Tina

2014-01-01

It has been presumed that aberrant immune response to intestinal microorganisms in genetically predisposed individuals may play a major role in the pathogenesis of the inflammatory bowel disease, and there is a good deal of evidence supporting this hypothesis. Commensal enteric bacteria probably play a central role in pathogenesis, providing continuous antigenic stimulation that causes chronic intestinal injury. A strong biologic rationale supports the use of probiotics and prebiotics for inflammatory bowel disease therapy. Many probiotic strains exhibit anti-inflammatory properties through their effects on different immune cells, pro-inflammatory cytokine secretion depression, and the induction of anti-inflammatory cytokines. There is very strong evidence supporting the use of multispecies probiotic VSL#3 for the prevention or recurrence of postoperative pouchitis in patients. For treatment of active ulcerative colitis, as well as for maintenance therapy, the clinical evidence of efficacy is strongest for VSL#3 and Escherichia coli Nissle 1917. Moreover, some prebiotics, such as germinated barley foodstuff, Psyllium or oligofructose-enriched inulin, might provide some benefit in patients with active ulcerative colitis or ulcerative colitis in remission. The results of clinical trials in the treatment of active Crohn’s disease or the maintenance of its remission with probiotics and prebiotics are disappointing and do not support their use in this disease. The only exception is weak evidence of advantageous use of Saccharomyces boulardii concomitantly with medical therapy in maintenance treatment. PMID:25206258

Intestinal microbiota, probiotics and prebiotics in inflammatory bowel disease.

PubMed

Orel, Rok; Kamhi Trop, Tina

2014-09-07

It has been presumed that aberrant immune response to intestinal microorganisms in genetically predisposed individuals may play a major role in the pathogenesis of the inflammatory bowel disease, and there is a good deal of evidence supporting this hypothesis. Commensal enteric bacteria probably play a central role in pathogenesis, providing continuous antigenic stimulation that causes chronic intestinal injury. A strong biologic rationale supports the use of probiotics and prebiotics for inflammatory bowel disease therapy. Many probiotic strains exhibit anti-inflammatory properties through their effects on different immune cells, pro-inflammatory cytokine secretion depression, and the induction of anti-inflammatory cytokines. There is very strong evidence supporting the use of multispecies probiotic VSL#3 for the prevention or recurrence of postoperative pouchitis in patients. For treatment of active ulcerative colitis, as well as for maintenance therapy, the clinical evidence of efficacy is strongest for VSL#3 and Escherichia coli Nissle 1917. Moreover, some prebiotics, such as germinated barley foodstuff, Psyllium or oligofructose-enriched inulin, might provide some benefit in patients with active ulcerative colitis or ulcerative colitis in remission. The results of clinical trials in the treatment of active Crohn's disease or the maintenance of its remission with probiotics and prebiotics are disappointing and do not support their use in this disease. The only exception is weak evidence of advantageous use of Saccharomyces boulardii concomitantly with medical therapy in maintenance treatment.

A Central Role for Heme Oxygenase-1 in the Control of Intestinal Epithelial Chemokine Expression.

PubMed

Onyiah, Joseph C; Schaefer, Rachel E M; Colgan, Sean P

2018-05-23

In mucosal inflammatory disorders, the protective influence of heme oxygenase-1 (HO-1) and its metabolic byproducts, carbon monoxide (CO) and biliverdin, is a topic of significant interest. Mechanisms under investigation include the regulation of macrophage function and mucosal cytokine expression. While there is an increasing recognition of the importance of epithelial-derived factors in the maintenance of intestinal mucosal homeostasis, the contribution of intestinal epithelial cell (IEC) HO-1 on inflammatory responses has not previously been investigated. We examined the influence of modulating HO-1 expression on the inflammatory response of human IECs. Engineered deficiency of HO-1 in Caco-2 and T84 IECs led to increased proinflammatory chemokine expression in response to pathogenic bacteria and inflammatory cytokine stimulation. Crosstalk with activated leukocytes also led to increased chemokine expression in HO-1-deficient cells in an IL-1β dependent manner. Treatment of Caco-2 cells with a pharmacological inducer of HO-1 led to the inhibition of chemokine expression. Mechanistic studies suggest that HO-1 and HO-1-related transcription factors, but not HO-1 metabolic products, are partly responsible for the influence of HO-1 on chemokine expression. In conclusion, our data identify HO-1 as a central regulator of IEC chemokine expression that may contribute to homeo-stasis in the intestinal mucosa. © 2018 S. Karger AG, Basel.

Intestinal alkaline phosphatase is protective to the preterm rat pup intestine.

PubMed

Heinzerling, Nathan P; Liedel, Jennifer L; Welak, Scott R; Fredrich, Katherine; Biesterveld, Ben E; Pritchard, Kirkwood A; Gourlay, David M

2014-06-01

Necrotizing enterocolitis (NEC) is the most common surgical emergency in neonates, with a mortality rate between 10 and 50%. The onset of necrotizing enterocolitis is highly variable and associated with numerous risk factors. Prior research has shown that enteral supplementation with intestinal alkaline phosphatase (IAP) decreases the severity of NEC. The aim of this study is to investigate whether IAP is protective to the preterm intestine in the presence of formula feeding and in the absence of NEC. Preterm rat pups were fed formula with or without supplementation with IAP, and intestine was obtained on day of life 3 for analysis of IAP activity, mRNA expression of TNFα, IL-6 and iNOS and permeability and cytokine expression after LPS exposure. There was no difference in the absolute and intestine specific alkaline phosphatase activity in both groups. Rat pups fed IAP had decreased mRNA expression of the inflammatory cytokines TNFα, IL-6 and iNOS. Pups supplemented with IAP had decreased permeability and inflammatory cytokine expression after exposure to LPS ex vivo when compared to formula fed controls. Our results support that IAP is beneficial to preterm intestine and decreases intestinal injury and inflammation caused by LPS. Copyright © 2014 Elsevier Inc. All rights reserved.

Intestinal Alkaline Phosphatase Is Protective to the Preterm Rat Pup Intestine

PubMed Central

Heinzerling, Nathan P.; Liedel, Jennifer L.; Welak, Scott R.; Fredrich, Katherine; Biesterveld, Ben E.; Pritchard, Kirkwood A.; Gourlay, David M.

2014-01-01

Background Necrotizing enterocolitis (NEC) is the most common surgical emergency in neonates, with a mortality rate between 10 and 50%. The onset of necrotizing enterocolitis is highly variable and associated with numerous risk factors. Prior research has shown enteral supplementation with intestinal alkaline phosphatase (IAP) decreases the severity of NEC. The aim of this study is to investigate whether IAP is protective to the preterm intestine in the presence of formula feeding and in the absence of NEC. Methods Preterm rat pups were fed formula with or without supplementation with IAP, and intestine was obtained on day of life 3 for analysis of IAP activity, mRNA expression of TNF-a, IL-6 and iNOS and permeability and cytokine expression after LPS. exposure. Results There was no difference in the absolute and intestine specific alkaline phosphatase activity in both groups. Rat pups fed IAP had decreased mRNA expression of the inflammatory cytokines TNFα, IL-6 and iNOS. Pups supplemented with IAP had decreased permeability and inflammatory cytokine expression after exposure to LPS ex vivo when compared to formula fed controls. Conclusions Our results support that IAP is beneficial to preterm intestine and decreases intestinal injury and inflammation caused by LPS. PMID:24888842

Helminth infection in mice improves insulin sensitivity via modulation of gut microbiota and fatty acid metabolism.

PubMed

Pace, Fernanda; Carvalho, Bruno M; Zanotto, Tamires M; Santos, Andrey; Guadagnini, Dioze; Silva, Kelly L C; Mendes, Maria Carolina S; Rocha, Guilherme Z; Alegretti, Silmara M; Santos, Gustavo A; Catharino, Rodrigo R; Paroni, Rita; Folli, Franco; Saad, Mário José A

2018-06-01

Intestinal helminths are prevalent in individuals who live in rural areas of developing countries, where obesity, type 2 diabetes, and metabolic syndrome are rare. In the present study, we analyzed the modulation of the gut microbiota in mice infected with the helminth Strongyloides venezuelensis, and fed either a standard rodent chow diet or high-fat diet (HFD). To investigate the effects of the microbiota modulation on the metabolism, we analyzed the expression of tight-junction proteins present in the gut epithelium, inflammatory markers in the serum and tissue and quantified glucose tolerance and insulin sensitivity and resistance. Additionally, the levels of lipids related to inflammation were evaluated in the feces and serum. Our results show that infection with Strongyloides venezuelensis results in a modification of the gut microbiota, most notably by increasing Lactobacillus spp. These modifications in the microbiota alter the host metabolism by increasing the levels of anti-inflammatory cytokines, switching macrophages from a M1 to M2 pattern in the adipose tissue, increasing the expression of tight junction proteins in the intestinal cells (thereby reducing the permeability) and decreasing LPS in the serum. Taken together, these changes correlate with improved insulin signaling and sensitivity, which could also be achieved with HFD mice treated with probiotics. Additionally, helminth infected mice produce higher levels of oleic acid, which participates in anti-inflammatory pathways. These results suggest that modulation of the microbiota by helminth infection or probiotic treatment causes a reduction in subclinical inflammation, which has a positive effect on the glucose metabolism of the host. Copyright © 2018 Elsevier Ltd. All rights reserved.

Bifidobacterium breve - HT-29 cell line interaction: modulation of TNF-α induced gene expression.

PubMed

Boesten, R J; Schuren, F H J; Willemsen, L E M; Vriesema, A; Knol, J; De Vos, W M

2011-06-01

To provide insight in the molecular basis for intestinal host-microbe interactions, we determined the genome-wide transcriptional response of human intestinal epithelial cells following exposure to cells of Bifidobacterium breve. To select an appropriate test system reflecting inflammatory conditions, the responsiveness to TNF-α was compared in T84, Caco-2 and HT-29 cells. The highest TNF-α response was observed in HT-29 cells and this cell line was selected for exposure to the B. breve strains M-16V, NR246 and UCC2003. After one hour of bacterial pre-incubation followed by two hours of additional TNF-α stimulation, B. breve M-16V (86%), but to a much lesser extent strains NR246 (50%) or UCC2003 (32%), showed a strain-specific reduction of the HT-29 transcriptional response to the inflammatory treatment. The most important functional groups of genes that were transcriptionally suppressed by the presence of B. breve M-16V, were found to be involved in immune regulation and apoptotic processes. About 54% of the TNF-α induced genes were solely suppressed by the presence of B. breve M-16V. These included apoptosis-related cysteine protease caspase 7 (CASP7), interferon regulatory factor 3 (IRF3), amyloid beta (A4) precursor proteinbinding family A member 1 (APBA1), NADPH oxidase (NOX5), and leukemia inhibitory factor receptor (LIFR). The extracellular IL-8 concentration was determined by an immunological assay but did not change significantly, indicating that B. breve M-16V only partially modulates the TNF-α pathway. In conclusion, this study shows that B. breve strains modulate gene expression in HT-29 cells under inflammatory conditions in a strain-specific way.

Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs.

PubMed

Cummings, Ryan J; Barbet, Gaetan; Bongers, Gerold; Hartmann, Boris M; Gettler, Kyle; Muniz, Luciana; Furtado, Glaucia C; Cho, Judy; Lira, Sergio A; Blander, J Magarian

2016-11-24

Recognition and removal of apoptotic cells by professional phagocytes, including dendritic cells and macrophages, preserves immune self-tolerance and prevents chronic inflammation and autoimmune pathologies. The diverse array of phagocytes that reside within different tissues, combined with the necessarily prompt nature of apoptotic cell clearance, makes it difficult to study this process in situ. The full spectrum of functions executed by tissue-resident phagocytes in response to homeostatic apoptosis, therefore, remains unclear. Here we show that mouse apoptotic intestinal epithelial cells (IECs), which undergo continuous renewal to maintain optimal barrier and absorptive functions, are not merely extruded to maintain homeostatic cell numbers, but are also sampled by a single subset of dendritic cells and two macrophage subsets within a well-characterized network of phagocytes in the small intestinal lamina propria. Characterization of the transcriptome within each subset before and after in situ sampling of apoptotic IECs revealed gene expression signatures unique to each phagocyte, including macrophage-specific lipid metabolism and amino acid catabolism, and a dendritic-cell-specific program of regulatory CD4 + T-cell activation. A common 'suppression of inflammation' signature was noted, although the specific genes and pathways involved varied amongst dendritic cells and macrophages, reflecting specialized functions. Apoptotic IECs were trafficked to mesenteric lymph nodes exclusively by the dendritic cell subset and served as critical determinants for the induction of tolerogenic regulatory CD4 + T-cell differentiation. Several of the genes that were differentially expressed by phagocytes bearing apoptotic IECs overlapped with susceptibility genes for inflammatory bowel disease. Collectively, these findings provide new insights into the consequences of apoptotic cell sampling, advance our understanding of how homeostasis is maintained within the mucosa and set the stage for development of novel therapeutics to alleviate chronic inflammatory diseases such as inflammatory bowel disease.

Haemocytes control stem cell activity in the Drosophila intestine.

PubMed

Ayyaz, Arshad; Li, Hongjie; Jasper, Heinrich

2015-06-01

Coordination of stem cell activity with inflammatory responses is critical for regeneration and homeostasis of barrier epithelia. The temporal sequence of cell interactions during injury-induced regeneration is only beginning to be understood. Here we show that intestinal stem cells (ISCs) are regulated by macrophage-like haemocytes during the early phase of regenerative responses of the Drosophila intestinal epithelium. On tissue damage, haemocytes are recruited to the intestine and secrete the BMP homologue DPP, inducing ISC proliferation by activating the type I receptor Saxophone and the Smad homologue SMOX. Activated ISCs then switch their response to DPP by inducing expression of Thickveins, a second type I receptor that has previously been shown to re-establish ISC quiescence by activating MAD. The interaction between haemocytes and ISCs promotes infection resistance, but also contributes to the development of intestinal dysplasia in ageing flies. We propose that similar interactions influence pathologies such as inflammatory bowel disease and colorectal cancer in humans.

Hemocytes control stem cell activity in the Drosophila intestine

PubMed Central

Ayyaz, Arshad; Li, Hongjie; Jasper, Heinrich

2015-01-01

SUMMARY Coordination of stem cell activity with inflammatory responses is critical for regeneration and homeostasis of barrier epithelia. The temporal sequence of cell interactions during injury-induced regeneration is only beginning to be understood. Here we show that intestinal stem cells (ISCs) are regulated by macrophage-like hemocytes during the early phase of regenerative responses of the Drosophila intestinal epithelium. Upon tissue damage, hemocytes are recruited to the intestine and secrete the TGFβ/BMP homologue Dpp, inducing ISC proliferation by activating the Type I receptor Saxophone and the Smad homologue Smox. Activated ISCs then switch their response to Dpp by inducing expression of Thickveins, a second Type I receptor that has previously been shown to re-establish ISC quiescence by activating Mad. The interaction between hemocytes and ISCs promotes infection resistance, but also contributes to the development of intestinal dysplasia in aging flies. We propose that similar interactions influence pathologies like inflammatory bowel disease and colorectal cancer in humans. PMID:26005834

ACF7 regulates inflammatory colitis and intestinal wound response by orchestrating tight junction dynamics

PubMed Central

Ma, Yanlei; Yue, Jiping; Zhang, Yao; Shi, Chenzhang; Odenwald, Matt; Liang, Wenguang G.; Wei, Qing; Goel, Ajay; Gou, Xuewen; Zhang, Jamie; Chen, Shao-Yu; Tang, Wei-Jen; Turner, Jerrold R.; Yang, Feng; Liang, Hong; Qin, Huanlong; Wu, Xiaoyang

2017-01-01

In the intestinal epithelium, the aberrant regulation of cell/cell junctions leads to intestinal barrier defects, which may promote the onset and enhance the severity of inflammatory bowel disease (IBD). However, it remains unclear how the coordinated behaviour of cytoskeletal network may contribute to cell junctional dynamics. In this report, we identified ACF7, a crosslinker of microtubules and F-actin, as an essential player in this process. Loss of ACF7 leads to aberrant microtubule organization, tight junction stabilization and impaired wound closure in vitro. With the mouse genetics approach, we show that ablation of ACF7 inhibits intestinal wound healing and greatly increases susceptibility to experimental colitis in mice. ACF7 level is also correlated with development and progression of ulcerative colitis (UC) in human patients. Together, our results reveal an important molecular mechanism whereby coordinated cytoskeletal dynamics contributes to cell adhesion regulation during intestinal wound repair and the development of IBD. PMID:28541346

Histological damage and inflammatory response elicited by Monobothrium wageneri (Cestoda) in the intestine of Tinca tinca (Cyprinidae)

PubMed Central

2011-01-01

Background Among the European cyprinids, tench, Tinca tinca (L.), and the pathological effects their cestodes may effect, have received very little or no attention. Most literature relating to Monobothrium wageneri Nybelin, 1922, a common intestinal cestode of tench, for example, has focused on aspects of its morphology rather than on aspects of the host-parasite interaction. Results Immunopathological and ultrastructural studies were conducted on the intestines of 28 tench, collected from Lake Piediluco, of which 16 specimens harboured tight clusters of numerous M. wageneri attached to the intestinal wall. The infection was associated with the degeneration of the mucosal layer and the formation of raised inflammatory swelling surrounding the worms. At the site of infection, the number of granulocytes in the intestine of T. tinca was significantly higher than the number determined 1 cm away from the site of infection or the number found in uninfected fish. Using transmission electron microscopy, mast cells and neutrophils were frequently observed in close proximity to, and inside, the intestinal capillaries; often these cells were in contact with the cestode tegument. At the host-parasite interface, no secretion from the parasite's tegument was observed. Intense degranulation of the mast cells was seen within the submucosa and lamina muscularis, most noticeably at sites close to the tegument of the scolex. In some instances, rodlet cells were encountered in the submucosa. In histological sections, hyperplasia of the mucous cells, notably those giving an alcian blue positive reaction, were evident in the intestinal tissues close to the swelling surrounding the worms. Enhanced mucus secretion was recorded in the intestines of infected tench. Conclusions The pathological changes and the inflammatory cellular response induced by the caryophyllidean monozoic tapeworm M. wageneri within the intestinal tract of an Italian population of wild tench is reported for the first time. PMID:22152408

Intrauterine growth retardation promotes fetal intestinal autophagy in rats via the mechanistic target of rapamycin pathway

PubMed Central

WANG, Chao; ZHANG, Ruiming; ZHOU, Le; HE, Jintian; HUANG, Qiang; SIYAL, Farman A; ZHANG, Lili; ZHONG, Xiang; WANG, Tian

2017-01-01

Intrauterine growth retardation (IUGR) impairs fetal intestinal development, and is associated with high perinatal morbidity and mortality. However, the mechanism underlying this intestinal injury is largely unknown. We aimed to investigate this mechanism through analysis of intestinal autophagy and related signaling pathways in a rat model of IUGR. Normal weight (NW) and IUGR fetuses were obtained from primiparous rats via ad libitum food intake and 50% food restriction, respectively. Maternal serum parameters, fetal body weight, organ weights, and fetal blood glucose were determined. Intestinal apoptosis, autophagy, and the mechanistic target of rapamycin (mTOR) signaling pathway were analyzed. The results indicated that maternal 50% food restriction reduced maternal serum glucose, bilirubin, and total cholesterol and produced IUGR fetuses, which had decreased body weight; blood glucose; and weights of the small intestine, stomach, spleen, pancreas, and kidney. Decreased Bcl-2 and increased Casp9 mRNA expression was observed in IUGR fetal intestines. Analysis of intestinal autophagy showed that the mRNA expression of WIPI1, MAP1LC3B, Atg5, and Atg14 was also increased, while the protein levels of p62 were decreased in IUGR fetuses. Compared to NW fetuses, IUGR fetuses showed decreased mTOR protein levels and enhanced mRNA expression of ULK1 and Beclin1 in the small intestine. In summary, the results indicated that maternal 50% food restriction on gestational days 10–21 reduced maternal serum glucose, bilirubin, and total cholesterol contents, and produced IUGR fetuses that had low blood glucose and reduced small intestine weight. Intestinal injury of IUGR fetuses caused by maternal food restriction might be due to enhanced apoptosis and autophagy via the mTOR signaling pathway. PMID:28855439

Formula milk feeding does not increase the release of the inflammatory marker calprotectin, compared to human milk.

PubMed

Rosti, L; Braga, M; Fulcieri, C; Sammarco, G; Manenti, B; Costa, E

2011-01-01

Calprotectin is a protein released into stools, used as a marker of inflammation in inflammatory bowel diseases. We tested the hypothesis that cow's milk protein in formula milk may increase the intestinal release of calprotectin, as a consequence of a subclinical inflammatory reaction. At 12 weeks of age, we measured fecal calprotectin by an immunoenzyme assay (Calprest, Eurospital, Trieste, Italy), in 38 exclusively breastfed and in 32 exclusively formula-fed infants. Fecal calprotectin levels were not different in the two groups (p = 0.09), although a trend to higher values in infants with colic, or with family history of allergies was noted. This suggest that, in general, formula milk does not promote activation of an intestinal inflammatory reaction, compared to human milk, although a subclinical activation of the inflammatory response in infants at risk for allergic diseases may be present.

The effects of S-nitrosoglutathione on intestinal ischemia reperfusion injury and acute lung injury in rats: Roles of oxidative stress and NF-κB.

PubMed

Turan, Inci; Sayan Ozacmak, Hale; Ozacmak, V Haktan; Barut, Figen; Ozacmak, I Diler

2018-06-01

Intestinal ischemia and reperfusion (I/R) induces oxidative stress, inflammatory response, and acute lung injury. S-nitrosoglutathione (GSNO), a nitric oxide donor, has been documented to have protective effects on experimental ischemia models. The aim of this study was to examine the effect of GSNO on I/R-induced intestine and lung damage and detect the potential mechanisms emphasizing the protective role of GSNO. Intestinal I/R was induced by occluding the superior mesenteric artery for 30 min followed by reperfusion for 180 min. GSNO was administered intravenously before reperfusion period (0.25 mg/kg). The levels of lipid peroxidation, reduced glutathione, and myeloperoxidase (MPO), histopathological evaluation and immunohistochemical expressions of both nuclear factor KappaB (NF-κB) and inducible nitric oxide (iNOS) in intestine and lung tissues were assessed. Histolopathologic evaluation demonstrated that intestinal I/R induced severe damages in the intestine and the lung tissues. Histopathological scores decreased with GSNO treatment. GSNO treatment reduced lipid peroxidation and MPO levels and inhibited expression of NF-κB and iNOS in the intestine. Our results suggest that GSNO treatment may ameliorate the intestinal and lung injury in rats, at least in part, by inhibiting inflammatory response and oxidative stress. Copyright © 2018 Elsevier Ltd. All rights reserved.

[Descriptive analysis of the social, clinical, laboratorial and anthropometric profiles of inflammatory bowel disease inwards patients from the "Clementino Fraga Filho" University Hospital, Rio de Janeiro, RJ, Brazil].

PubMed

Elia, Paula Peruzzi; Fogaça, Homero Soares; Barros, Rodrigo G G Rego; Zaltman, Cyrla; Elia, Celeste Siqueira C

2007-01-01

The epidemiologic survey in Brazil is limited probably due to a diagnosis deficiency and a small number of population-based studies performed. The majority of the prevalence studies available have evaluated inflammatory bowel diseases outpatients, but the knowledge of the profile of inflammatory bowel diseases inpatients is important in order to detect predictive markers of disease severity that will allow earlier medical intervention decreasing the rate of hospitalization and reducing the Health System costs. To determine social, clinical, laboratorial and anthropometric profiles of hospitalized adults inflammatory bowel diseases patients of a tertiary university hospital. Prospective study was performed with 43 inflammatory bowel diseases inpatients from clinical and surgical wards and emergency section of university hospital. We characterized demographic data, presence of comorbidities, disease location and behavior, surgical past-history, extra intestinal manifestations using standardized definitions. Laboratory results were abstracted from medical records and anthropometric measures were performed during our visit. The vast majority of the inflammatory bowel diseases patients had Crohn's disease (72.1%), with ileocolic involvement (60%), with a penetrating disease behavior (77.4%) while ulcerative colitis group presented mostly pancolitis (50%). Articular pain was the most common (44.2%) extra intestinal manifestation of inflammatory bowel diseases patients and 97.7% of them had at least one type of complication related to disease. Although, the previous use of specific medical therapies to inflammatory bowel diseases before the hospitalization (more frequently corticosteroids) was done (79%), the majority of the patients were hospitalized because of inflammatory bowel diseases activity. Disease activity was present in 80.7% of Crohn's disease and 50% ulcerative colitis patients. Inflammatory bowel diseases mortality rate was 5.5% (2/36). Comorbidities presence occurred only in 30.2% of inflammatory bowel diseases patients. The predominant surgery performed was intestinal resection. The interval between the symptoms appearance and the definitive diagnosis was less than 1 year in more than 70% of inflammatory bowel diseases patients. Laboratory findings detected were a decreased serum albumin (85.7%) and anemia (69.8%). The majority of the patients had at least one anthropometric alteration. The social stratification of the inflammatory bowel diseases group was similar to the Brazilian population. The inflammatory bowel diseases inpatients from the university hospital wards had more severe evolution of these illnesses with an active and extensive disease with complications and frequent extra intestinal manifestations, despite the prolonged use of corticosteroids. The higher prevalence of Crohn's disease inpatients than ulcerative colitis could reflect a higher aggressive behavior of this disease. The reduced serum albumin, anemia and anthropometric alterations are common inflammatory bowel diseases inpatients and could be related to a major severity of inflammatory bowel diseases evolution.

Human Catestatin Alters Gut Microbiota Composition in Mice

PubMed Central

Rabbi, Mohammad F.; Munyaka, Peris M.; Eissa, Nour; Metz-Boutigue, Marie-Hélène; Khafipour, Ehsan; Ghia, Jean Eric

2017-01-01

The mammalian intestinal tract is heavily colonized with a dense, complex, and diversified microbial populations. In healthy individuals, an array of epithelial antimicrobial agents is secreted in the gut to aid intestinal homeostasis. Enterochromaffin cells (EC) in the intestinal epithelium are a major source of chromogranin A (CgA), which is a pro-hormone and can be cleaved into many bioactive peptides that include catestatin (CST). This study was carried out to evaluate the possible impact of CST on gut microbiota in vivo using a mouse model. The CST (Human CgA352−372) or normal saline was intrarectally administered in C57BL/6 male mice for 6 days and then sacrificed. Feces and colonic mucosa tissue samples were collected, DNA was extracted, the V4 region of bacterial 16S rRNA gene was amplified and subjected to MiSeq Illumina sequencing. The α-diversity was calculated using Chao 1 and β-diversity was determined using QIIME. Differences at the genus level were determined using partial least square discriminant analysis (PLS-DA). Phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) was used to predict functional capacity of bacterial community. CST treatment did not modify bacterial richness in fecal and colonic mucosa-associated microbiota; however, treatment significantly modified bacterial community composition between the groups. Also, CST-treated mice had a significantly lower relative abundance of Firmicutes and higher abundance of Bacteroidetes, observed only in fecal samples. However, at lower phylogenetic levels, PLS-DA analysis revealed that some bacterial taxa were significantly associated with the CST-treated mice in both fecal and colonic mucosa samples. In addition, differences in predicted microbial functional pathways in both fecal and colonic mucosa samples were detected. The results support the hypothesis that CST treatment modulates gut microbiota composition under non-pathophysiological conditions, however, the result of this study needs to be further validated in a larger experiment. The data may open new avenues for the development of a potential new line of antimicrobial peptides and their use as therapeutic agents to treat several inflammatory conditions of the gastrointestinal tract, such as inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), or other health conditions. PMID:28144234

Microbiota-host interplay at the gut epithelial level, health and nutrition.

PubMed

Lallès, Jean-Paul

2016-01-01

Growing evidence suggests the implication of the gut microbiota in various facets of health and disease. In this review, the focus is put on microbiota-host molecular cross-talk at the gut epithelial level with special emphasis on two defense systems: intestinal alkaline phosphatase (IAP) and inducible heat shock proteins (iHSPs). Both IAP and iHSPs are induced by various microbial structural components (e.g. lipopolysaccharide, flagellin, CpG DNA motifs), metabolites (e.g. n-butyrate) or secreted signal molecules (e.g., toxins, various peptides, polyphosphate). IAP is produced in the small intestine and secreted into the lumen and in the interior milieu. It detoxifies microbial components by dephosphorylation and, therefore, down-regulates microbe-induced inflammation mainly by inhibiting NF-κB pro-inflammatory pathway in enterocytes. IAP gene expression and enzyme activity are influenced by the gut microbiota. Conversely, IAP controls gut microbiota composition both directly, and indirectly though the detoxification of pro-inflammatory free luminal adenosine triphosphate and inflammation inhibition. Inducible HSPs are expressed by gut epithelial cells in proportion to the microbial load along the gastro-intestinal tract. They are also induced by various microbial components, metabolites and secreted molecules. Whether iHSPs contribute to shape the gut microbiota is presently unknown. Both systems display strong anti-inflammatory and anti-oxidant properties that are protective to the gut and the host. Importantly, epithelial gene expressions and protein concentrations of IAP and iHSPs can be stimulated by probiotics, prebiotics and a large variety of dietary components, including macronutrients (protein and amino acids, especially L-glutamine, fat, fiber), and specific minerals (e.g. calcium) and vitamins (e.g. vitamins K1 and K2). Some food components (e.g. lectins, soybean proteins, various polyphenols) may inhibit or disturb these systems. The general cellular and molecular mechanisms involved in the microbiota-host epithelial crosstalk and subsequent gut protection through IAP and iHSPs are reviewed along with their nutritional modulation. Special emphasis is also given to the pig, an economically important species and valuable biomedical model.

Fecal Microbiota Transplantation in Inflammatory Bowel Disease.

PubMed

Reinisch, Walter

2017-01-01

The etiology of inflammatory bowel disease (IBD) is unknown, but it is thought to arise from an aberrant immune response to a change in colonic environment in a genetically susceptible individual. The intestinal microbiota are located at the complex interface of the epithelial barrier and are sensitive to changes in environmental factors, such as diets, drugs or smoking and signals derived from the intestinal immune system and the gut-brain axis. In patients with IBD, an imbalance in the structural and/or functional configuration of the intestinal microbiota leading to the disruption of the host-microorganism homeostasis (dysbiosis) has been reproducibly reported. As animal models of IBD require gut bacteria to induce inflammation, it is hypothesized that the dysbiosis observed in patients is not only a surrogate of changes at the intestinal barrier but also a potential cause or at least enhancer of the mucosal inflammatory process. That burgeoning notion has stimulated thoughts to modify the intestinal microbiota and rekindled interest in previous work on the efficacy of antibiotics in patients with IBD. The feasibility and tremendous success of fecal microbiota transplantation (FMT) to treat antibiotic resistant Clostridium difficile has finally paved the way to embark into the unchartered territory of IBD using FMT. Different routes and number of administrations, choices of donors, disease status and permitted therapies might have contributed to mixed results, particularly from the so far published randomized controlled trials. However, microbiome analysis suggests that a durable transplantation of donor bacteria to the host appears feasible and might be associated with a higher likelihood of response. On the other hand, this raises the concern of transplanting not only anti-inflammatory active bacteria and their products, but also not-yet-known dispositions for other diseases including cancer. Attempts are being made to better characterize those components of the microbiome of healthy individuals, which might mediate anti-inflammatory functions and assemble 'synthetic stools' for more standardized treatment approaches. © 2017 S. Karger AG, Basel.

Triterpenoid herbal saponins enhance beneficial bacteria, decrease sulfate-reducing bacteria, modulate inflammatory intestinal microenvironment and exert cancer preventive effects in ApcMin/+ mice

PubMed Central

Chen, Lei; Brar, Manreetpal S.; Leung, Frederick C. C.; Hsiao, W. L. Wendy

2016-01-01

Saponins derived from medicinal plants have raised considerable interest for their preventive roles in various diseases. Here, we investigated the impacts of triterpenoid saponins isolated from Gynostemma pentaphyllum (GpS) on gut microbiome, mucosal environment, and the preventive effect on tumor growth. Six-week old ApcMin/+ mice and their wild-type littermates were fed either with vehicle or GpS daily for the duration of 8 weeks. The fecal microbiome was analyzed by enterobacterial repetitive intergenic consensus (ERIC)-PCR and 16S rRNA gene pyrosequencing. Study showed that GpS treatment significantly reduced the number of intestinal polyps in a preventive mode. More importantly, GpS feeding strikingly reduced the sulfate-reducing bacteria lineage, which are known to produce hydrogen sulfide and contribute to damage the intestinal epithelium or even promote cancer progression. Meanwhile, GpS also boosted the beneficial microbes. In the gut barrier of the ApcMin/+ mice, GpS treatment increased Paneth and goblet cells, up-regulated E-cadherin and down-regulated N-cadherin. In addition, GpS decreased the pro-oncogenic β-catenin, p-Src and the p-STAT3. Furthermore, GpS might also improve the inflamed gut epithelium of the ApcMin/+ mice by upregulating the anti-inflammatory cytokine IL-4, while downregulating pro-inflammatory cytokines TNF-β, IL-1β and IL-18. Intriguingly, GpS markedly stimulated M2 and suppressed M1 macrophage markers, indicating that GpS altered mucosal cytokine profile in favor of the M1 to M2 macrophages switching, facilitating intestinal tissue repair. In conclusion, GpS might reverse the host's inflammatory phenotype by increasing beneficial bacteria, decreasing sulfate-reducing bacteria, and alleviating intestinal inflammatory gut environment, which might contribute to its cancer preventive effects. PMID:27121311

Anti-inflammatory and antioxidant effects of infliximab on acute lung injury in a rat model of intestinal ischemia/reperfusion.

PubMed

Guzel, Ahmet; Kanter, Mehmet; Guzel, Aygul; Pergel, Ahmet; Erboga, Mustafa

2012-06-01

The purpose of this study was to investigate the role of infliximab on acute lung injury induced by intestinal ischemia/reperfusion (I/R). A total of 30 male Wistar albino rats were divided into three groups: sham, I/R and I/R+ infliximab; each group contain 10 animals. Sham group animals underwent laparotomy without I/R injury. After I/R groups animals underwent laparotomy, 1 h of superior mesenteric artery ligation were followed by 1 h of reperfusion. In the infliximab group, 3 days before I/R, infliximab (3 mg/kg) was administered by intravenously. All animals were sacrificed at the end of reperfusion and lung tissues samples were obtained for biochemical and histopathological investigation in all groups. To date, no more biochemical and histopathological changes on intestinal I/R injury in rats by infliximab treatment have been reported. Infliximab treatment significantly decreased the elevated tissue malondialdehyde levels and increased of reduced superoxide dismutase, and glutathione peroxidase enzyme activities in lung tissues samples. Intestinal I/R caused severe histopathological injury including edema, hemorrhage, increased thickness of the alveolar wall and a great number of inflammatory cells that infiltrated the interstitium and alveoli. Infliximab treatment significantly attenuated the severity of intestinal I/R injury. Furthermore, there is a significant reduction in the activity of inducible nitric oxide synthase and arise in the expression of surfactant protein D in lung tissue of acute lung injury induced by intestinal I/R with infliximab therapy. It was concluded that infliximab treatment might be beneficial in acute lung injury, therefore, shows potential for clinical use. Because of its anti-inflammatory and antioxidant effects, infliximab pretreatment may have protective effects in acute lung injury induced by intestinal I/R.

The effect of Saccharomyces boulardii on human colon cells and inflammation in rats with trinitrobenzene sulfonic acid-induced colitis.

PubMed

Lee, Sang Kil; Kim, Youn Wha; Chi, Sung-Gil; Joo, Yeong-Shil; Kim, Hyo Jong

2009-02-01

Saccharomyces boulardii (S. boulardii) has beneficial effects in the treatment of intestinal inflammation; however, little is known about the mechanisms by which these effects occur. We investigated the effects of S. boulardii on the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and interleukin-8 (IL-8), using human HT-29 colonocytes and a rat model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. The effect of S. boulardii on gene expression was assessed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), and Northern blot and Western blot assays. Pharmacological inhibitors for various signaling pathways were used to determine the signaling pathways implicated in the S. boulardii regulation of PPAR-gamma and IL-8. We found that S. boulardii up-regulated and down-regulated PPAR-gamma and IL-8 expression at the transcription level, both in vitro and in vivo (P < 0.05, respectively). Saccharomyces boulardii blocked tumor necrosis factor-alpha (TNF-alpha) regulation of PPAR-gamma and IL-8 through disruption of TNF-alpha-mediated nuclear factor kappa B (NF-kappaB) activation. Furthermore, S. boulardii suppressed colitis and expression of pro-inflammatory cytokine genes in vivo (P < 0.05, respectively). Our study demonstrated that S. boulardii reduces colonic inflammation and regulates inflammatory gene expression.

Intestinal Behçet and Crohn's disease: two sides of the same coin.

PubMed

Valenti, Simona; Gallizzi, Romina; De Vivo, Dominique; Romano, Claudio

2017-04-20

Behçet's disease (BD) and Crohn's disease (CD) are chronic immune-mediated, inflammatory disorders affecting many different systems (joints, skin, eyes, gastrointestinal and biliary tracts). Both disorders have fluctuating courses and when gastrointestinal symptoms are prevalent, differential diagnosis can be difficult. BD involves the gastrointestinal tract in 10-15% of cases with localized lesions in the ileocecal region. The clinical picture is heterogeneous with various clusters of disease expression. CD is a chronic inflammatory disorder, which can affect any part of the intestinal tract, as well as extra-intestinal tissue. Factors that contribute towards the pathogenesis of both disease include the host's genetic profile, and immune system, and environmental factors such as the gut microbiota. The aim of this manuscript is to provide a narrative review of clinical features of BD and CD, highlighting the importance of differential diagnosis and therapeutic approach, especially in the presence of gastrointestinal involvement. A comprehensive search of published literature using the Pubmed ( http://www.ncbi.nlm.nih.gov/pubmed/ ) database was carried out to identify all articles published in English from 1999 to October 2016, using 4 key terms: "Behçet Disease", "Intestinal Behçet's Disease", "Crohn's Disease" and" Inflammatory Bowel Disease".

MUC1-C ACTIVATES THE TAK1 INFLAMMATORY PATHWAY IN COLON CANCER

PubMed Central

Takahashi, Hidekazu; Jin, Caining; Rajabi, Hasan; Pitroda, Sean; Alam, Maroof; Ahmad, Rehan; Raina, Deepak; Hasegawa, Masanori; Suzuki, Yozo; Tagde, Ashujit; Bronson, Roderick T.; Weichselbaum, Ralph; Kufe, Donald

2015-01-01

The mucin 1 (MUC1) oncoprotein has been linked to the inflammatory response by promoting cytokine-mediated activation of the NF-κB pathway. The TGF-β-activated kinase 1 (TAK1) is an essential effector of proinflammatory NF-κB signaling that also regulates cancer cell survival. The present studies demonstrate that the MUC1-C transmembrane subunit induces TAK1 expression in colon cancer cells. MUC1 also induces TAK1 in a MUC1+/−/IL-10−/− mouse model of colitis and colon tumorigenesis. We show that MUC1-C promotes NF-κB-mediated activation of TAK1 transcription and, in a positive regulatory loop, MUC1-C contributes to TAK1-induced NF-κB signaling. In this way, MUC1-C binds directly to TAK1 and confers the association of TAK1 with TRAF6, which is necessary for TAK1-mediated activation of NF-κB. Targeting MUC1-C thus suppresses the TAK1→NF-κB pathway, downregulates BCL-XL, and in turn sensitizes colon cancer cells to MEK inhibition. Analysis of colon cancer databases further indicates that MUC1, TAK1 and TRAF6 are upregulated in tumors associated with decreased survival and that MUC1-C-induced gene expression patterns predict poor outcomes in patients. These results support a model in which MUC1-C-induced TAK1→NF-κB signaling contributes to intestinal inflammation and colon cancer progression. PMID:25659581

Helminths and the IBD hygiene hypothesis.

PubMed

Weinstock, Joel V; Elliott, David E

2009-01-01

Helminths are parasitic animals that have evolved over 100,000,000 years to live in the intestinal track or other locations of their hosts. Colonization of humans with these organisms was nearly universal until the early 20th century. More than 1,000,000,000 people in less developed countries carry helminths even today. Helminths must quell their host's immune system to successfully colonize. It is likely that helminths sense hostile changes in the local host environment and take action to control such responses. Inflammatory bowel disease (IBD) probably results from an inappropriately vigorous immune response to contents of the intestinal lumen. Environmental factors strongly affect the risk for IBD. People living in less developed countries are protected from IBD. The "IBD hygiene hypothesis" states that raising children in extremely hygienic environments negatively affects immune development, which predisposes them to immunological diseases like IBD later in life. Modern day absence of exposure to intestinal helminths appears to be an important environmental factor contributing to development of these illnesses. Helminths interact with both host innate and adoptive immunity to stimulate immune regulatory circuitry and to dampen effector pathways that drive aberrant inflammation. The first prototype worm therapies directed against immunological diseases are now under study in the United States and various countries around the world. Additional studies are in the advanced planning stage.

Placental growth factor enhances angiogenesis in human intestinal microvascular endothelial cells via PI3K/Akt pathway: Potential implications of inflammation bowel disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Yi, E-mail: mondayzy@126.com; Tu, Chuantao, E-mail: tu.chuantao@zs-hospital.sh.cn; Zhao, Yuan, E-mail: zhao.yuan@zs-hospital.sh.cn

Background: Angiogenesis plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Placental growth factor (PlGF) is a specific regulator of pathological angiogenesis and is upregulated in the sera of IBD patients. Therefore, the role of PlGF in IBD angiogenesis was investigated here using HIMECs. Methods: The expression of PlGF and its receptors in human intestinal microvascular endothelial cells (HIMECs) and inflamed mucosa of IBD patients were examined using quantitative PCR and western blot analysis and the role of PlGF in IBD HIMECs was further explored using small interfering RNA (siRNA). The induction of pro-inflammatory cytokine by PlGFmore » in HIMECs was confirmed by ELISA. The capacity of PlGF to induce angiogenesis in HIMECs was tested through proliferation, cell-migration, matrigel tubule-formation assays and its underlying signaling pathway were explored by western blot analysis of ERK1/2 and PI3K/Akt phosphorylation. Results: mRNA and protein expression of PlGF and its receptor NRP-1 were significantly increased in IBD HIMECs. Inflamed mucosa of IBD patients also displayed higher expression of PIGF. The production of IL-6 and TNF-α in culture supernatant of HIMECs treated with exogenous recombinant human PlGF-1 (rhPlGF-1) were increased. Furthermore, rhPlGF-1 significantly induced HIMECs migration and tube formation in a dose-dependent manner and knockdown of endogenous PlGF in IBD HIMECs using siRNA substantially reduced these angiogenesis activities. PlGF induced PI3K/Akt phosphorylation in HIMECs and pretreatment of PlGF-stimulated HIMECs with PI3K inhibitor (LY294002) significantly inhibited the PlGF-induced cell migration and tube formation. Conclusion: Our results demonstrated the pro-inflammatory and angiogenic effects of PlGF on HIMECs in IBD through activation of PI3K/Akt signaling pathway. PlGF/PI3K/Akt signaling may serve as a potential therapeutic target for IBD. - Highlights: • Expression of PlGF and its receptor NRP-1 were significantly increased in IBD HIMECs. • Exogenous rhPlGF-1 treatment significantly induced HIMECs migration and tube formation. • Knockdown of endogenous PlGF in IBD HIMECs using siRNA substantially reduced cell angiogenesis activities. • PlGF induced PI3K/Akt phosphorylation in HIMECs which is required for PIGF-induced cell migration and tube formation.« less

Anti-allergic effects of a nonameric peptide isolated from the intestine gastrointestinal digests of abalone (Haliotis discus hannai) in activated HMC-1 human mast cells.

PubMed

Ko, Seok-Chun; Lee, Dae-Sung; Park, Won Sun; Yoo, Jong Su; Yim, Mi-Jin; Qian, Zhong-Ji; Lee, Chang-Min; Oh, Junghwan; Jung, Won-Kyo; Choi, Il-Whan

2016-01-01

The aim of the present study was to examine whether the intestine gastrointestinal (GI) digests of abalone [Haliotis discus hannai (H. discus hannai)] modulate inflammatory responses and to elucidate the mechanisms involved. The GI digests of the abalone intestines were fractionated into fractions I (>10 kDa), II (5-10 kDa) and Ⅲ (<5 kDa). Of the abalone intestine GI digests (AIGIDs), fraction Ⅲ inhibited the passive cutaneous anaphylaxis (PCA) reaction in mice. Subsequently, a bioactive peptide [abalone intestine GI digest peptide (AIGIDP)] isolated from fraction Ⅲ was determined to be 1175.2 Da, and the amino acid sequence was found to be PFNQGTFAS. We noted that the purified nonameric peptide (AIGIDP) attenuated the phorbol‑12‑myristate 13-acetate plus calcium ionophore A23187 (PMACI)-induced histamine release and the production of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in human mast cells (HMC-1 cells). In addition, we also noted that AIGIDP inhibited the PMACI‑induced activation of nuclear factor‑κB (NF-κB) by suppressing IκBα phosphorylation and that it suppressed the production of cytokines by decreasing the phosphorylation of JNK. The findings of our study indicate that AIGIDP exerts a modulatory, anti-allergic effect on mast cell-mediated inflammatory diseases.

Anticoccidial activities of Chitosan on Eimeria papillata-infected mice.

PubMed

Abdel-Latif, Mahmoud; Abdel-Haleem, Heba M; Abdel-Baki, Abdel-Azeem S

2016-07-01

Eimeria spp. multiply within the intestinal tract causing severe inflammatory responses. Chitosan (CS), meanwhile, has been shown to exhibit anti-inflammatory activities in different experimental models. Here, we investigated the effect of CS on the outcome of inflammation caused by Eimeria papillata in the mouse intestine. Investigations were undertaken into the oocyst output in feces and developmental stages and goblet cells in intestinal tissue. Assays for lipid peroxidation, nitric oxide (NO), and myeloperoxidase (MPO) were also performed. T cells in intestinal tissue were counted using immunohistochemistry while total IgA in serum or intestinal wash was assayed using ELISA. In addition, mRNA expression of tumor necrosis factor alpha (TNF-α), transforming growth factor β (TGF-β), interleukin (IL)-10, and IL-4 were detected using real-time PCR. The data indicated a reduction in both oocyst output and in the number of parasite developmental stages following CS treatment, while the goblet cell hypoplasia in infected mice was also inhibited. CS decreased lipid peroxidation, NO, and MPO but did not alter the T cell count or IgA levels in comparison to the infected group. The expression of TNF-α and TGF-β decreased but IL-10 and IL-4 increased after CS treatment in comparison to the non-treated infected group. In conclusion, CS showed anti-inflammatory and protective effects against E. papillata infection.

Different tocopherol isoforms vary in capacity to scavenge free radicals, prevent inflammatory response, and induce apoptosis in both adult- and fetal-derived intestinal epithelial cells.

PubMed

Elisia, Ingrid; Kitts, David D

2013-01-01

Gamma-tocopherol (γ-Toc) and δ-Toc are two vitamin E isoforms for which biological activities are not well established, yet these isoforms are present in many different sources of vegetable oils and, therefore, contribute significantly to the total dietary intake of vitamin E. Infant formula also contains relatively high amounts of γ-Toc and δ-Toc, compared with that found in human milk. The efficacy of γ-Toc and δ-Toc to modulate cellular events that include oxidative stress, inflammatory response, and apoptosis-mediated cytotoxicity, relative to α-Toc, was determined using differentiated Caco-2 and primary FHs 74 Int cells intestinal epithelial cell lines. Antioxidant capacity of Toc-isoforms followed the order of δ-Toc > γ-Toc > α-Toc against peroxyl radical-induced membrane oxidation in both Caco-2 and FHs 74 Int cells, respectively. The different Toc-isoforms suppressed inflammatory response in interferon (IFN) γ/phorbol myristate acetate (PMA)-induced Caco-2 adult-derived intestinal epithelial cells, but exacerbated both IL8 and PGE2 secretion in fetal-derived FHs 74 Int intestinal epithelial cells. Lastly, Toc exhibited an isoform-dependent apoptosis-mediated cytotoxicity, whereby δ-Toc elicited the greatest apoptosis followed by γ-Toc, whereas α-Toc was not cytotoxic. Cellular uptake of non-α-Toc isoforms were greater (P < 0.05) than that observed for α-Toc in both intestinal epithelial cell lines which in part explains the superior bioactive function observed for both γ-Toc and δ-Toc, compared with α-Toc. We conclude that the non-α-Toc isoforms of vitamin E have distinct roles that influence oxidative stress and inflammatory responses in both adult and fetal-derived intestinal epithelial cell lines. © 2013 International Union of Biochemistry and Molecular Biology.

To observe the intensity of the inflammatory reaction caused by neonatal urine and meconium on the intestinal wall of rats in order to understand etiology of intestinal damage in gastroschisis

PubMed Central

Samala, Devdas S.; Parelkar, Sandesh V.; Sanghvi, Beejal V.; Vageriya, Natasha L.; Paradkar, Bhupesh A.; Kandalkar, Bhuvaneshwari M.; Sathe, Pragati A.

2014-01-01

Objectives: The aim of this experimental study was to observe the intensity of the inflammatory reaction caused by neonatal urine and meconium on the intestinal wall of rats to better understand etiology of intestinal damage in gastroschisis. Materials and Methods: A total of 24 adult Wistar rats were used as experimental models to simulate the effect of exposed bowel in cases of gastroschisis. The peritoneal cavity of the rats was injected with substances which constitute human amniotic fluid to study the effect on the bowel. Sterile urine and meconium were obtained from newborn humans. The rats were divided into four groups according to the material to be injected. In Group I (Control group) 3 mL of distilled water was injected, in Group II (Urine group) 3 mL of neonatal urine was injected, in Group III (Meconium group) 5% meconium suspension was injected, while in Group IV, a combination of 5% meconium suspension and urine was injected. A total of 3mL solution was injected into the right inferior quadrant twice a day for 5 days. The animals were sacrificed on the 6th day by a high dose of thiopentone sodium. A segment of small bowel specimen was excised, fixed in paraffin, and stained with hematoxylin-eosin for microscopic analysis for determination of the degree of inflammatory reaction in the intestinal wall. All pathology specimens were studied by the same pathologist. Results: The maximum bowel damage was seen in Group II (Urine group) in the form of serositis, severe enteritis, parietal necrosis, and peeling. A lesser degree of damage was observed in Group III (Meconium group) as mild enteritis (mild lymphoid hyperplasia). The least damage was seen in Group IV (Combination of meconium and urine) and Group I (Control group). Conclusion: The intraabdominal injection of neonatal human urine produces significant inflammatory reactions in the intestinal wall of rats. PMID:24604977

Cryptogenia multifocal ulcerous stenosing enteritis: an entity on its own as a cause of abdominal pain, iron deficiency anemia and protein-losing enteropathy.

PubMed

Guisado Vasco, P; Fraile Rodríguez, G

2014-01-01

We studied a patient with edema secondary to protein losing enteropathy, and recurrent bouts of bloating and abdominal pain secondary to intestinal subocclusion episodes. After the clinical study, the patient was diagnosed of cryptogenic multifocal ulcerous stenosing enteritis (CMUSE), that is a rare disease, probably caused by mutations in the gene PLA2G4A, and characterized by multiple short stenosis of the small bowel with superficial ulcers, which do not exceed the submucosa layer. Inflammatory bowel disease (Chron's disease), intestinal tuberculosis and intestinal ulcers secondary to non-steroidal anti-inflammatory drugs are the main differential diagnosis. To sum up, physicians should included CMUSE in the differential diagnosis of recurrent abdominal pain, iron deficiency anaemia, occult intestinal bleeding, edema and protein losing enteropathy. Copyright © 2013 Elsevier España, S.L. All rights reserved.

[Dual role for prostaglandin D2 in intestinal epithelial homeostasis].

PubMed

Le Loupp, Anne-Gaelle; Bach-Ngohou, Kalyane; Bettan, Armel; Denis, Marc; Masson, Damien

2015-01-01

Prostaglandin D2 (PGD2) and derivatives are lipid mediators involved in the control of the intestinal epithelial barrier homeostasis. Their involvement in the pathophysiology of chronic inflammatory bowel disease (IBD) is still debated. Several results highlight the duality of PGD2 as an anti- or pro-inflammatory mediator. This duality seems to be related to a differential expression of its receptors by intestinal epithelial cells and the surrounding immunocompetent cells. The enteric glial cells from the enteric nervous system (ENS) express the lipocalin-type-prostaglandin D synthase and secrete PGD2 and 15d-PGJ2. The protective role of the ENS in the homeostatic control of the epithelial intestinal barrier and its involvement in the pathogenesis of IBD have already been demonstrated. Thus, these lipid mediators seem to be new actors of the neuro-glio-epithelial unit and could play a crucial role maintaining gut barrier integrity. © 2015 médecine/sciences – Inserm.

The role of the intestinal microvasculature in inflammatory bowel disease: studies with a modified Caco-2 model including endothelial cells resembling the intestinal barrier in vitro.

PubMed

Kasper, Jennifer Y; Hermanns, Maria Iris; Cavelius, Christian; Kraegeloh, Annette; Jung, Thomas; Danzebrink, Rolf; Unger, Ronald E; Kirkpatrick, Charles James

The microvascular endothelium of the gut barrier plays a crucial role during inflammation in inflammatory bowel disease. We have modified a commonly used intestinal cell model based on the Caco-2 cells by adding microvascular endothelial cells (ISO-HAS-1). Transwell filters were used with intestinal barrier-forming Caco-2 cells on top and the ISO-HAS-1 on the bottom of the filter. The goal was to determine whether this coculture mimics the in vivo situation more closely, and whether the model is suitable to evaluate interactions of, for example, prospective nanosized drug vehicles or contrast agents with this coculture in a physiological and inflamed state as it would occur in inflammatory bowel disease. We monitored the inflammatory responsiveness of the cells (release of IL-8, soluble intercellular adhesion molecule 1, and soluble E-selectin) after exposure to inflammatory stimuli (lipopolysaccharide, TNF-α, INF-γ, IL1-β) and a nanoparticle (Ba/Gd: coprecipitated BaSO 4 and Gd(OH) 3 ), generally used as contrast agents. The barrier integrity of the coculture was evaluated via the determination of transepithelial electrical resistance and the apparent permeability coefficient (P app ) of NaFITC. The behavior of the coculture Caco-1/ISO-HAS-1 was compared to the respective monocultures Caco-2 and ISO-HAS-1. Based on transepithelial electrical resistance, the epithelial barrier integrity of the coculture remained stable during incubation with all stimuli, whereas the P app decreased after exposure to the cytokine mixture (TNF-α, INF-γ, IL1-β, and Ba/Gd). Both the endothelial and epithelial monocultures showed a high inflammatory response in both the upper and lower transwell-compartments. However, in the coculture, inflammatory mediators were only detected on the epithelial side and not on the endothelial side. Thus in the coculture, based on the P app , the epithelial barrier appears to prevent a potential inflammatory overreaction in the underlying endothelial cells. In summary, this coculture model exhibits in vivo-like features, which cannot be observed in conventional monocultures, making the former more suitable to study interactions with external stimuli.

Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability.

PubMed

Cani, P D; Possemiers, S; Van de Wiele, T; Guiot, Y; Everard, A; Rottier, O; Geurts, L; Naslain, D; Neyrinck, A; Lambert, D M; Muccioli, G G; Delzenne, N M

2009-08-01

Obese and diabetic mice display enhanced intestinal permeability and metabolic endotoxaemia that participate in the occurrence of metabolic disorders. Our recent data support the idea that a selective increase of Bifidobacterium spp. reduces the impact of high-fat diet-induced metabolic endotoxaemia and inflammatory disorders. Here, we hypothesised that prebiotic modulation of gut microbiota lowers intestinal permeability, by a mechanism involving glucagon-like peptide-2 (GLP-2) thereby improving inflammation and metabolic disorders during obesity and diabetes. Study 1: ob/ob mice (Ob-CT) were treated with either prebiotic (Ob-Pre) or non-prebiotic carbohydrates as control (Ob-Cell). Study 2: Ob-CT and Ob-Pre mice were treated with GLP-2 antagonist or saline. Study 3: Ob-CT mice were treated with a GLP-2 agonist or saline. We assessed changes in the gut microbiota, intestinal permeability, gut peptides, intestinal epithelial tight-junction proteins ZO-1 and occludin (qPCR and immunohistochemistry), hepatic and systemic inflammation. Prebiotic-treated mice exhibited a lower plasma lipopolysaccharide (LPS) and cytokines, and a decreased hepatic expression of inflammatory and oxidative stress markers. This decreased inflammatory tone was associated with a lower intestinal permeability and improved tight-junction integrity compared to controls. Prebiotic increased the endogenous intestinotrophic proglucagon-derived peptide (GLP-2) production whereas the GLP-2 antagonist abolished most of the prebiotic effects. Finally, pharmacological GLP-2 treatment decreased gut permeability, systemic and hepatic inflammatory phenotype associated with obesity to a similar extent as that observed following prebiotic-induced changes in gut microbiota. We found that a selective gut microbiota change controls and increases endogenous GLP-2 production, and consequently improves gut barrier functions by a GLP-2-dependent mechanism, contributing to the improvement of gut barrier functions during obesity and diabetes.

Altered Th1/Th2 cytokine profiles in the intestinal mucosa of patients with inflammatory bowel disease as assessed by quantitative reversed transcribed polymerase chain reaction (RT-PCR).

PubMed Central

Niessner, M; Volk, B A

1995-01-01

Cytokines serve a central function as key factors in the regulation of the intestinal immune response and mediation of tissue damage in inflammatory bowel disease (IBD). Abnormalities in the expression of immunoregulatory cytokines such as IL-2, IL-4, IL-10 and interferon-gamma (IFN-gamma) may indicate a dysregulation of intestinal immunity probably associated with pathogenic events. Therefore, cytokine mRNA concentrations were determined in the mucosa of patients with IBD at sites of active (n = 13) and inactive (n = 12) ulcerative colitis (UC), active (n = 11) and inactive (n = 11) Crohn's disease (CD) and in control patients (n = 14) using quantitative RT-PCR. IL-10 mRNA concentrations were significantly increased in patients with both active UC (P < 0.001) and active CD (P < 0.005) compared with control patients. IFN-gamma mRNA concentrations were also significantly increased both in patients with active UC (P < 0.02) and active CD (P < 0.05) compared with control patients, whereas IL-2 mRNA levels were significantly (P < 0.02) increased only in active CD. IL-4 mRNA expression in the intestinal mucosa was frequently below the detection limit. Our results demonstrate that chronic intestinal inflammation in patients with CD is characterized by an increase of Th1-like cytokines. Furthermore, the increased IL-10 mRNA expression at sites of active IBD suggests that IL-10 is an important regulatory component involved in the control of the inflammatory response in inflammatory bowel disease. Images Fig. 1 Fig. 4 PMID:7664489

Neurokinin NK1 and NK3 receptors as targets for drugs to treat gastrointestinal motility disorders and pain.

PubMed

Sanger, Gareth J

2004-04-01

NK1 and NK3 receptors do not appear to play significant roles in normal GI functions, but both may be involved in defensive or pathological processes. NK1 receptor antagonists are antiemetic, operating via vagal sensory and motor systems, so there is a need to study their effects on other gastro-vagal functions thought to play roles in functional bowel disorders. Interactions between NK1 receptors and enteric nonadrenergic, noncholinergic motorneurones suggest a need to explore the role of this receptor in disrupted colonic motility. NK1 receptor antagonism does not exert consistent analgesic activity in humans, but similar studies have not been carried out against pain of GI origin, where NK1 receptors may have additional influences on mucosal inflammatory or "irritant" processes. NK3 receptors mediate certain disruptions of intestinal motility. The activity may be driven by tachykinins released from intrinsic primary afferent neurones (IPANs), which induce slow EPSP activity in connecting IPANs and hence, a degree of hypersensitivity within the enteric nervous system. The same process is also proposed to increase C-fibre sensitivity, either indirectly or directly. Thus, NK3 receptor antagonists inhibit intestinal nociception via a "peripheral" mechanism that may be intestine-specific. Studies with talnetant and other selective NK3 receptor antagonists are, therefore, revealing an exciting and novel pathway by which pathological changes in intestinal motility and nociception can be induced, suggesting a role for NK3 receptor antagonism in irritable bowel syndrome.

A unique role for autophagy and Atg16L1 in Paneth cells in murine and human intestine

PubMed Central

Cadwell, Ken; Liu, John; Brown, Sarah L.; Miyoshi, Hiroyuki; Loh, Joy; Lennerz, Jochen; Kishi, Chieko; KC, Wumesh; Carrero, Javier A.; Hunt, Steven; Stone, Christian; Brunt, Elizabeth M.; Xavier, Ramnik J.; Sleckman, Barry P.; Li, Ellen; Mizushima, Noboru; Stappenbeck, Thaddeus S.; Virgin, Herbert W.

2008-01-01

Susceptibility to Crohn's disease (CD), a complex inflammatory disease involving the small intestine, is controlled by up to 32 loci1. One CD risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG162. It is not known how Atg16L1 or autophagy contributes to intestinal biology or CD pathogenesis. To address these questions we generated and characterized mice that are hypomorphic for Atg16L1 protein expression, and validated conclusions based on studies in these mice by analyzing intestinal tissues that we collected from CD patients carrying the CD risk allele of ATG16L1. We show that Atg16L1 is a bona fide autophagy protein. Within the ileal epithelium, both Atg16L1 and a second essential autophagy protein Atg5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell which functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment3. Atg16L1 and Atg5-deficient Paneth cells exhibited striking abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to Atg16L1-deficient Paneth cells including increased expression of genes involved in PPAR signaling and lipid metabolism, acute phase reactants, as well as two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, CD patients homozygous for the ATG16L1 CD risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy protein-deficient mice and expressed increased levels of leptin protein. Thus, Atg16L1, and likely the process of autophagy, play their role within the intestinal epithelium of mice and CD patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells. PMID:18849966

NOD1 downregulates intestinal serotonin transporter and interacts with other pattern recognition receptors.

PubMed

Layunta, Elena; Latorre, Eva; Forcén, Raquel; Grasa, Laura; Plaza, Miguel A; Arias, Maykel; Alcalde, Ana I; Mesonero, José E

2018-05-01

Serotonin (5-HT) is an essential gastrointestinal modulator whose effects regulate the intestinal physiology. 5-HT effects depend on extracellular 5-HT bioavailability, which is controlled by the serotonin transporter (SERT) expressed in both the apical and basolateral membranes of enterocytes. SERT is a critical target for regulating 5-HT levels and consequently, modulating the intestinal physiology. The deregulation of innate immune receptors has been extensively studied in inflammatory bowel diseases (IBD), where an exacerbated defense response to commensal microbiota is observed. Interestingly, many innate immune receptors seem to affect the serotonergic system, demonstrating a new way in which microbiota could modulate the intestinal physiology. Therefore, our aim was to analyze the effects of NOD1 activation on SERT function, as well as NOD1's interaction with other immune receptors such as TLR2 and TLR4. Our results showed that NOD1 activation inhibits SERT activity and expression in Caco-2/TC7 cells through the extracellular signal-regulated kinase (ERK) signaling pathway. A negative feedback between 5-HT and NOD1 expression was also described. The results showed that TLR2 and TLR4 activation seems to regulate NOD1 expression in Caco-2/TC7 cells. To assess the extend of cross-talk between NOD1 and TLRs, NOD1 expression was measured in the intestinal tract (ileum and colon) of wild type mice and mice with individual knockouts of TLR2, and TLR4 as well as double knockout TLR2/TLR4 mice. Hence, we demonstrate that NOD1 acts on the serotonergic system decreasing SERT activity and molecular expression. Additionally, NOD1 expression seems to be modulated by 5-HT and other immune receptors as TLR2 and TLR4. This study could clarify the relation between both the intestinal serotonergic system and innate immune system, and their implications in intestinal inflammation. © 2017 Wiley Periodicals, Inc.

Sodium Butyrate Attenuates Diarrhea in Weaned Piglets and Promotes Tight Junction Protein Expression in Colon in a GPR109A-Dependent Manner.

PubMed

Feng, Wenqian; Wu, Yancheng; Chen, Guangxin; Fu, Shoupeng; Li, Bai; Huang, Bingxu; Wang, Dali; Wang, Wei; Liu, Juxiong

2018-06-27

Butyric acid plays an important role in maintaining intestinal health. Butyric acid has received special attention as a short-chain fatty acid, but its role in protecting the intestinal barrier is poorly characterized. Butyric acid not only provides energy for epithelial cells but also acts as a histone deacetylase inhibitor; it is also a natural ligand for G protein-coupled receptor 109A (GPR109A). A GPR109A analog was expressed in Sus scrofa and mediated the anti-inflammatory effects of beta-hydroxybutyric acid. This study investigated the effects of butyrate on growth performance, diarrhea symptoms, and tight junction protein levels in 21-day-old weaned piglets. We also studied the mechanism by which butyric acid regulates intestinal permeability. Twenty-four piglets that had been weaned at an age of 21 days were divided randomly into 2 equal groups: basal diet group and sodium butyrate + basal diet group. Diarrhea rate, growth performance during 3 weeks of feeding on these diets were observed, the lactulose-mannitol ratio in urine were detected by High Performance Liquid Chromatography, the expression levels of tight junction proteins in the intestinal tract and related signaling molecules, such as GPR109A and Akt, in the colon were examined by quantitative real-time PCR or western blot analyses on day 21. Caco-2 cells were used as a colon cell model and cultured with or without sodium butyrate to assess the expression of tight junction proteins and the activation of related signaling molecules. GPR109A-short hairpin RNA (shRNA) and specific antagonists of Akt and ERK1/2 were used as signaling pathway inhibitors to elucidate the mechanism by which butyric acid regulates the expression of tight junction proteins and the colonic epithelial barrier. The sodium butyrate diet alleviated diarrhea symptoms and decreased intestinal permeability without affecting the growth of early weaned piglets. The expression levels of the tight junction proteins Claudin-3, Occludin, and zonula occludens 1 were up-regulated by sodium butyrate in the colon and Caco-2 cells. GPR109A knockdown using shRNA or blockade of the Akt signaling pathway in Caco-2 cells suppressed sodium butyrate-induced Claudin-3 expression. Sodium butyrate acts on the Akt signaling pathway to facilitate Claudin-3 expression in the colon in a GPR109A-dependent manner. © 2018 The Author(s). Published by S. Karger AG, Basel.

Cross sectional evaluation of the gut-microbiome metabolome axis in an Italian cohort of IBD patients.

PubMed

Santoru, Maria Laura; Piras, Cristina; Murgia, Antonio; Palmas, Vanessa; Camboni, Tania; Liggi, Sonia; Ibba, Ivan; Lai, Maria Antonia; Orrù, Sandro; Blois, Sylvain; Loizedda, Anna Lisa; Griffin, Julian Leether; Usai, Paolo; Caboni, Pierluigi; Atzori, Luigi; Manzin, Aldo

2017-08-25

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract of uncertain origin, which includes ulcerative colitis (UC) and Crohn's disease (CD). The composition of gut microbiota may change in IBD affected individuals, but whether dysbiosis is the cause or the consequence of inflammatory processes in the intestinal tissue is still unclear. Here, the composition of the microbiota and the metabolites in stool of 183 subjects (82 UC, 50 CD, and 51 healthy controls) were determined. The metabolites content and the microbiological profiles were significantly different between IBD and healthy subjects. In the IBD group, Firmicutes, Proteobacteria, Verrucomicrobia, and Fusobacteria were significantly increased, whereas Bacteroidetes and Cyanobacteria were decreased. At genus level Escherichia, Faecalibacterium, Streptococcus, Sutterella and Veillonella were increased, whereas Bacteroides, Flavobacterium, and Oscillospira decreased. Various metabolites including biogenic amines, amino acids, lipids, were significantly increased in IBD, while others, such as two B group vitamins, were decreased in IBD compared to healthy subjects. This study underlines the potential role of an inter-omics approach in understanding the metabolic pathways involved in IBD. The combined evaluation of metabolites and fecal microbiome can be useful to discriminate between healthy subjects and patients with IBD.

Fecal Microbiota in Pediatric Inflammatory Bowel Disease and Its Relation to Inflammation.

PubMed

Kolho, Kaija-Leena; Korpela, Katri; Jaakkola, Tytti; Pichai, Madharasi V A; Zoetendal, Erwin G; Salonen, Anne; de Vos, Willem M

2015-06-01

Inflammatory bowel disease (IBD) is considered to result from interplay between host and intestinal microbiota. While IBD in adults has shown to be associated with marked changes in the intestinal microbiota, there are only a few studies in children, and particularly studies focusing on therapeutic responses are lacking. Hence, this prospective study addressed the intestinal microbiota in pediatric IBD especially related to the level of inflammation. In total, 68 pediatric patients with IBD and 26 controls provided stool and blood samples in a tertiary care hospital and 32 received anti-tumor necrosis factor-α (anti-TNF-α). Blood inflammatory markers and fecal calprotectin levels were determined. The intestinal microbiota was characterized by phylogenetic microarray and qPCR analysis. The microbiota varied along a gradient of increasing intestinal inflammation (indicated by calprotectin levels), which was associated with reduced microbial richness, abundance of butyrate producers, and relative abundance of Gram-positive bacteria (especially Clostridium clusters IV and XIVa). A significant association between microbiota composition and inflammation was indicated by a set of bacterial groups predicting the calprotectin levels (area under curve (AUC) of 0.85). During the induction of anti-TNF-α, the microbial diversity and similarity to the microbiota of controls increased in the responder group by week 6, but not in the non-responders (P<0.01; response related to calprotectin levels). The abundance of six groups of bacteria including those related to Eubacterium rectale and Bifidobacterium spp. predicted the response to anti-TNF-α medication. Intestinal microbiota represents a potential biomarker for correlating the level of inflammation and therapeutic responses to be further validated.

The Hippo pathway in intestinal regeneration and disease.

PubMed

Hong, Audrey W; Meng, Zhipeng; Guan, Kun-Liang

2016-06-01

The Hippo pathway is a signalling cascade conserved from Drosophila melanogaster to mammals. The mammalian core kinase components comprise MST1 and MST2, SAV1, LATS1 and LATS2 and MOB1A and MOB1B. The transcriptional co-activators YAP1 and TAZ are the downstream effectors of the Hippo pathway and regulate target gene expression. Hippo signalling has crucial roles in the control of organ size, tissue homeostasis and regeneration, and dysregulation of the Hippo pathway can lead to uncontrolled cell growth and malignant transformation. Mammalian intestine consists of a stem cell compartment as well as differentiated cells, and its ability to regenerate rapidly after injury makes it an excellent model system to study tissue homeostasis, regeneration and tumorigenesis. Several studies have established the important role of the Hippo pathway in these processes. In addition, crosstalk between Hippo and other signalling pathways provides tight, yet versatile, regulation of tissue homeostasis. In this Review, we summarize studies on the role of the Hippo pathway in the intestine on these physiological processes and the underlying mechanisms responsible, and discuss future research directions and potential therapeutic strategies targeting Hippo signalling in intestinal disease.

The Hippo pathway in intestinal regeneration and disease

PubMed Central

Hong, Audrey W.; Meng, Zhipeng; Guan, Kun-Liang

2017-01-01

The Hippo pathway is a signalling cascade conserved from Drosophila melanogaster to mammals. The mammalian core kinase components comprise MST1 and MST2, SAV1, LATS1 and LATS2 and MOB1A and MOB1B. The transcriptional co-activators YAP1 and TAZ are the downstream effectors of the Hippo pathway and regulate target gene expression. Hippo signalling has crucial roles in the control of organ size, tissue homeostasis and regeneration, and dysregulation of the Hippo pathway can lead to uncontrolled cell growth and malignant transformation. Mammalian intestine consists of a stem cell compartment as well as differentiated cells, and its ability to regenerate rapidly after injury makes it an excellent model system to study tissue homeostasis, regeneration and tumorigenesis. Several studies have established the important role of the Hippo pathway in these processes. In addition, crosstalk between Hippo and other signalling pathways provides tight, yet versatile, regulation of tissue homeostasis. In this Review, we summarize studies on the role of the Hippo pathway in the intestine on these physiological processes and the underlying mechanisms responsible, and discuss future research directions and potential therapeutic strategies targeting Hippo signalling in intestinal disease. PMID:27147489

Indoleacrylic Acid Produced by Commensal Peptostreptococcus Species Suppresses Inflammation.

PubMed

Wlodarska, Marta; Luo, Chengwei; Kolde, Raivo; d'Hennezel, Eva; Annand, John W; Heim, Cortney E; Krastel, Philipp; Schmitt, Esther K; Omar, Abdifatah S; Creasey, Elizabeth A; Garner, Ashley L; Mohammadi, Sina; O'Connell, Daniel J; Abubucker, Sahar; Arthur, Timothy D; Franzosa, Eric A; Huttenhower, Curtis; Murphy, Leon O; Haiser, Henry J; Vlamakis, Hera; Porter, Jeffrey A; Xavier, Ramnik J

2017-07-12

Host factors in the intestine help select for bacteria that promote health. Certain commensals can utilize mucins as an energy source, thus promoting their colonization. However, health conditions such as inflammatory bowel disease (IBD) are associated with a reduced mucus layer, potentially leading to dysbiosis associated with this disease. We characterize the capability of commensal species to cleave and transport mucin-associated monosaccharides and identify several Clostridiales members that utilize intestinal mucins. One such mucin utilizer, Peptostreptococcus russellii, reduces susceptibility to epithelial injury in mice. Several Peptostreptococcus species contain a gene cluster enabling production of the tryptophan metabolite indoleacrylic acid (IA), which promotes intestinal epithelial barrier function and mitigates inflammatory responses. Furthermore, metagenomic analysis of human stool samples reveals that the genetic capability of microbes to utilize mucins and metabolize tryptophan is diminished in IBD patients. Our data suggest that stimulating IA production could promote anti-inflammatory responses and have therapeutic benefits. Copyright © 2017 Elsevier Inc. All rights reserved.

The new insight on the regulatory role of the vitamin D3 in metabolic pathways characteristic for cancerogenesis and neurodegenerative diseases.

PubMed

Kubis, Adriana Maria; Piwowar, Agnieszka

2015-11-01

Apart from the classical function of regulating intestinal, bone and kidney calcium and phosphorus absorption as well as bone mineralization, there is growing evidence for the neuroprotective function of vitamin D3 through neuronal calcium regulation, the antioxidative pathway, immunomodulation and detoxification. Vitamin D3 and its derivates influence directly or indirectly almost all metabolic processes such as proliferation, differentiation, apoptosis, inflammatory processes and mutagenesis. Such multifactorial effects of vitamin D3 can be a profitable source of new therapeutic solutions for two radically divergent diseases, cancer and neurodegeneration. Interestingly, an unusual association seems to exist between the occurrence of these two pathological states, called "inverse comorbidity". Patients with cognitive dysfunctions or dementia have considerably lower risk of cancer, whereas survivors of cancer have lower prevalence of central nervous system (CNS) disorders. To our knowledge, there are few publications analyzing the role of vitamin D3 in biological pathways existing in carcinogenic and neuropathological disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

Anti-inflammatory and anti-allergic properties of donkey's and goat's milk.

PubMed

Jirillo, Felicita; Magrone, Thea

2014-03-01

Nowadays, donkey's and goat's milk consumption has been reevaluated for its potential benefits to human health. For example, in infants with intolerance to cow's milk, donkey's milk represents a good alternative due to its chemical characteristics similar to those of human milk. On the other hand, goat's milk in virtue of its higher content in short chain, medium chain, mono and polyunsaturated fatty acids than that of cow's milk, is more digestible than the bovine counterpart. From an immunological point of view, donkey's milk is able to induce release of inflammatory and anti-inflammatory cytokines from normal human peripheral blood lymphomononuclear cells, thus maintaining a condition of immune homeostasis. Similarly, goat's milk has been shown to trigger innate and adaptive immune responses in an in vitro human system, also inhibiting the endotoxin-induced activation of monocytes. Finally, in these milks the presence of their own microbiota may normalize the human intestinal microbiota with a cascade of protective effects at intestinal mucosal sites, even including triggering of intestinal T regulatory cells. In the light of the above considerations, donkey's and goat's milk should be recommended as a dietary supplement in individuals with inflammatory and allergic conditions, even including elderly people.

Old and New Lymphocyte Players in Inflammatory Bowel Disease.

PubMed

Giuffrida, Paolo; Corazza, Gino Roberto; Di Sabatino, Antonio

2018-02-01

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic intestinal inflammatory disorder characterized by diffuse accumulation of lymphocytes in the gut mucosa as a consequence of over-expression of endothelial adhesion molecules. The infiltrating lymphocytes have been identified as subsets of T cells, including T helper (Th)1 cells, Th17 cells, and regulatory T cells. The function of these lymphocyte subpopulations in the development of IBD is well-known, since they produce a number of pro-inflammatory cytokines, such as interferon-γ and interleukin-17A, which in turn activate mucosal proteases, thus leading to the development of intestinal lesions, i.e., ulcers, fistulas, abscesses, and strictures. However, the immune mechanisms underlying IBD are not yet fully understood, and knowledge about the function of newly discovered lymphocytes, including Th9 cells, innate lymphoid cells, mucosal-associated invariant T cells, and natural killer T cells, might add new pieces to the complex puzzle of IBD pathogenesis. This review summarizes the recent advances in the understanding of the role of mucosal lymphocytes in chronic intestinal inflammation and deals with the therapeutic potential of lymphocyte-targeting drugs in IBD patients.

Potential of Lactobacillus plantarum CCFM639 in Protecting against Aluminum Toxicity Mediated by Intestinal Barrier Function and Oxidative Stress

PubMed Central

Yu, Leilei; Zhai, Qixiao; Tian, Fengwei; Liu, Xiaoming; Wang, Gang; Zhao, Jianxin; Zhang, Hao; Narbad, Arjan; Chen, Wei

2016-01-01

Aluminum (Al) is a ubiquitous metal that can seriously harm the health of animals and humans. In our previous study, we demonstrated that Lactobacillus plantarum CCFM639 can decrease Al burden in the tissues of mice by inhibiting intestinal Al absorption. The main aim of the present research was to investigate whether the protection by the strain is also associated with enhancement of the intestinal barrier, alleviation of oxidative stress and modulation of the inflammatory response. In an in vitro cell model, two protection modes (intervention and therapy) were examined and the results indicated that L. plantarum CCFM639 alleviated Al-induced cytotoxicity. In a mouse model, L. plantarum CCFM639 treatment was found to significantly alleviate oxidative stress in the intestinal tract, regulate the function of the intestinal mucosal immune system, restore the integrity of tight junction proteins and maintain intestinal permeability. These results suggest that in addition to Al sequestration, L. plantarum CCFM639 can also inhibit Al absorption by protecting the intestinal barrier, alleviating Al-induced oxidative stress and inflammatory response. Therefore, L. plantarum CCFM639 has the potential to be a dietary supplement ingredient that provides protection against Al-induced gut injury. PMID:27918411

Inflammation-associated alterations to the intestinal microbiota reduce colonization resistance against non-typhoidal Salmonella during concurrent malaria parasite infection.

PubMed

Mooney, Jason P; Lokken, Kristen L; Byndloss, Mariana X; George, Michael D; Velazquez, Eric M; Faber, Franziska; Butler, Brian P; Walker, Gregory T; Ali, Mohamed M; Potts, Rashaun; Tiffany, Caitlin; Ahmer, Brian M M; Luckhart, Shirley; Tsolis, Renée M

2015-10-05

Childhood malaria is a risk factor for disseminated infections with non-typhoidal Salmonella (NTS) in sub-Saharan Africa. While hemolytic anemia and an altered cytokine environment have been implicated in increased susceptibility to NTS, it is not known whether malaria affects resistance to intestinal colonization with NTS. To address this question, we utilized a murine model of co-infection. Infection of mice with Plasmodium yoelii elicited infiltration of inflammatory macrophages and T cells into the intestinal mucosa and increased expression of inflammatory cytokines. These mucosal responses were also observed in germ-free mice, showing that they are independent of the resident microbiota. Remarkably, P. yoelii infection reduced colonization resistance of mice against S. enterica serotype Typhimurium. Further, 16S rRNA sequence analysis of the intestinal microbiota revealed marked changes in the community structure. Shifts in the microbiota increased susceptibility to intestinal colonization by S. Typhimurium, as demonstrated by microbiota reconstitution of germ-free mice. These results show that P. yoelii infection, via alterations to the microbial community in the intestine, decreases resistance to intestinal colonization with NTS. Further they raise the possibility that decreased colonization resistance may synergize with effects of malaria on systemic immunity to increase susceptibility to disseminated NTS infections.

Inflammation-associated alterations to the intestinal microbiota reduce colonization resistance against non-typhoidal Salmonella during concurrent malaria parasite infection

PubMed Central

Mooney, Jason P.; Lokken, Kristen L.; Byndloss, Mariana X.; George, Michael D.; Velazquez, Eric M.; Faber, Franziska; Butler, Brian P.; Walker, Gregory T.; Ali, Mohamed M.; Potts, Rashaun; Tiffany, Caitlin; Ahmer, Brian M. M.; Luckhart, Shirley; Tsolis, Renée M.

2015-01-01

Childhood malaria is a risk factor for disseminated infections with non-typhoidal Salmonella (NTS) in sub-Saharan Africa. While hemolytic anemia and an altered cytokine environment have been implicated in increased susceptibility to NTS, it is not known whether malaria affects resistance to intestinal colonization with NTS. To address this question, we utilized a murine model of co-infection. Infection of mice with Plasmodium yoelii elicited infiltration of inflammatory macrophages and T cells into the intestinal mucosa and increased expression of inflammatory cytokines. These mucosal responses were also observed in germ-free mice, showing that they are independent of the resident microbiota. Remarkably, P. yoelii infection reduced colonization resistance of mice against S. enterica serotype Typhimurium. Further, 16S rRNA sequence analysis of the intestinal microbiota revealed marked changes in the community structure. Shifts in the microbiota increased susceptibility to intestinal colonization by S. Typhimurium, as demonstrated by microbiota reconstitution of germ-free mice. These results show that P. yoelii infection, via alterations to the microbial community in the intestine, decreases resistance to intestinal colonization with NTS. Further they raise the possibility that decreased colonization resistance may synergize with effects of malaria on systemic immunity to increase susceptibility to disseminated NTS infections. PMID:26434367

T-cell selection and intestinal homeostasis

PubMed Central

Ai, Teresa L.; Solomon, Benjamin D.; Hsieh, Chyi-Song

2014-01-01

Summary Although intestinal bacteria live deep within the body, they are topographically on the exterior surface and thus outside the host. According to the classic notion that the immune system targets non-self rather than self, these intestinal bacteria should be considered foreign and therefore attacked and eliminated. While this appears to be true for some commensal bacterial species, recent data suggests that the immune system actively becomes tolerant to many bacterial organisms. The induction or activation of regulatory T (Treg) cells that inhibit, rather than promote, inflammatory responses to commensal bacteria appears to be a central component of mucosal tolerance. Loss of this mechanism can lead to inappropriate immune reactivity toward commensal organisms, perhaps contributing to mucosal inflammation characteristic of disorders such as inflammatory bowel disease. PMID:24712459

TUNING IMMUNE TOLERANCE WITH VASOACTIVE INTESTINAL PEPTIDE: A NEW THERAPEUTIC APPROACH FOR IMMUNE DISORDERS

PubMed Central

POZO, DAVID; GONZALEZ-REY, ELENA; CHORNY, ALEJO; ANDERSON, PER; VARELA, NIEVES; DELGADO, MARIO

2007-01-01

The induction of immune tolerance is essential for the maintenance of immune homeostasis and to limit the occurrence of exacerbated inflammatory and autoimmune conditions. Multiple mechanisms act together to ensure self-tolerance, including central clonal deletion, cytokine deviation and induction of regulatory T cells. Identifying the factors that regulate these processes is crucial for the development of new therapies of autoimmune diseases and transplantation. The vasoactive intestinal peptide (VIP) is a well-characterized endogenous anti-inflammatory neuropeptide with therapeutic potential for a variety of immune disorders. Here we examine the latest research findings, which indicate that VIP participates in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T-cell effectors. PMID:17521775

An endogenous aryl hydrocarbon receptor (AhR) ligand, ITE induces regulatory T cells (Tregs) and ameliorates experimental colitis.

PubMed

Abron, Jessicca D; Singh, Narendra P; Mishra, Manoj K; Price, Robert L; Nagarkatti, Mitzi; Nagarkatti, Prakash S; Singh, Udai P

2018-04-19

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that affects millions of people with high morbidity and health-care cost. The precise etiology of IBD is unknown, but clear evidence suggests that intestinal inflammation is caused by an excessive immune response to mucosal antigens. Recent studies have shown that activation of the aryl hydrocarbon receptor (AhR) induces regulatory T cells (Tregs) and suppresses autoimmune diseases. In the current study, we investigated if nontoxic ligand of AhR, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), can attenuate dextran sodium sulphate (DSS)-induced colitis. Our studies demonstrated that in mice that received ITE treatment, in-vivo colitis pathogenesis, including a decrease in body weight, was significantly reversed along with the systemic and intestinal inflammatory cytokines. ITE increased the expression of Tregs in spleen, mesenteric lymph nodes (MLNs) and colon lamina propria lymphocytes (cLPL) of mice with colitis when compared to controls. This induction of Tregs was reversed by AhR antagonist treatment in-vitro. ITE treatment also increased dendritic cells (DCs; CD11c+) and decreased F4/80+ (macrophage) from the spleen, MLNs and cLPL in mice with colitis. ITE also reversed the systemic and intestinal frequency of CD4+T cells during colitis and suppressed inflammatory cytokines including IFN-γ, TNF-α, IL-17, IL-6 and IL-1 as well as induced IL-10 levels. These findings suggest that ITE attenuates colitis through induction of Tregs and reduction in inflammatory CD4+ T cells and cytokines. Thus, our work demonstrates that the nontoxic endogenous AhR ligand ITE, may serve as a therapeutic modality to treat IBD.

Effects of Bifidobacterium breve on inflammatory gene expression in neonatal and weaning rat intestine.

PubMed

Ohtsuka, Yoshikazu; Ikegami, Takako; Izumi, Hirohisa; Namura, Mariko; Ikeda, Tomomi; Ikuse, Tamaki; Baba, Yosuke; Kudo, Takahiro; Suzuki, Ryuyo; Shimizu, Toshiaki

2012-01-01

To examine the immune-modulatory effects of probiotics during early infancy, Bifidobacterium breve M-16V (B. breve) was administered to rat pups during the newborn or weaning period, and the expression of inflammatory genes was investigated using a cDNA microarray and real-time PCR. After B. breve administration, significant increases in the numbers of Bifidobacterium in both the cecum and colon were confirmed during the newborn period. The numbers of upregulated and downregulated genes were greater during the weaning period than in the newborn period and were greatest in the colon, with fewer genes altered in the small intestine and the fewest in the spleen. The expression of inflammation-related genes, including lipoprotein lipase (Lpl), glutathione peroxidase 2 (Gpx2), and lipopolysaccharide-binding protein (Lbp), was significantly reduced in the colon during the newborn period. In weaning rat pups, the expression of CD3d, a cell surface receptor-linked signaling molecule, was significantly enhanced in the colon; however, the expression of co-stimulatory molecules was not enhanced. Our findings support a possible role for B. breve in mediating anti-inflammatory and antiallergic reactions by modulating the expression of inflammatory molecules during the newborn period and by regulating the expression of co-stimulatory molecules during the weaning period. Gene expression in the intestine was investigated after feeding 5 × 10(8) cfu of B. breve every day to the F344/Du rat from days 1 to 14 (newborn group) and from days 21 to 34 (weaning group). mRNA was extracted from intestine, and the expression of inflammatory gene was analyzed by microarray and real-time PCR.

Is the use of AGILE patency capsule prior to videocapsule endoscopy useful in all patients with spondyloarthritis?

PubMed

Gheorghe, Andrada; Zahiu, Denise Carmen Mihaela; Voiosu, Theodor Alexandru; Mateescu, Bogdan Radu; Voiosu, Mihail Radu; Rimbaş, Mihai

2017-06-01

As already known, spondyloarthritis patients present a striking resemblance in intestinal inflammation with early Crohn's disease. Moreover, the frequent use of nonsteroidal anti-inflammatory drugs is an important part of their treatment. Both conditions could lead to intestinal stenoses. Therefore we proposed to investigate the usefulness of the patency capsule test in patients with spondyloarthritis. 64 consecutive patients (33 males; mean age 38 ± 11 years) that fulfilled the AMOR criteria for seronegative spondyloarthropathy (59.4% ankylosing spondylitis) lacking symptoms or signs of intestinal stenosis were enrolled and submitted to an AGILE™ capsule patency test followed by a video capsule endoscopy (PillCam SB2™), as part of a protocol investigating the presence of intestinal inflammatory lesions. After reviewing the VCE recordings, the Lewis score (of small bowel inflammatory involvement) was computed. In only 5 patients (7.8%) of the study group, the luminal patency test was negative. However, there was no retention of the videocapsule in any of the patients. From the 59 patients with a positive patency test, 3 patients presented single small bowel stenoses (two with ulcerated overlying inflamed mucosa, one cicatricial), all being traversed by the videocapsule along the length of the recording. None of the patients with a negative test had bowel stenoses. There was no correlation between the patency test and the Lewis score, the C reactive protein value, diagnosis of inflammatory bowel disease, or the family history of spondyloarthritis, psoriasis or inflammatory bowel disease. The AGILE patency capsule does not seem to be a useful tool for all patients with spondyloarthritis prior to small bowel videocapsule endoscopy (ClinicalTrial.gov ID NCT 00768950).

Diaphragm disease of the small intestine: an interesting case report.

PubMed

Ullah, Sana; Ajab, Shereen; Rao, Rajashekhar; Raghunathan, Girish; DaCosta, Philip

2015-06-01

Diaphragm disease of small intestine usually presents with nonspecific clinical features. Radiological investigations often fail to differentiate it from small intestinal tumors and inflammatory bowel disease. It is therefore diagnosed on final histology after surgical resection. We hereby report an interesting case of a suspected small bowel tumor later diagnosed as diaphragm disease on histology. © The Author(s) 2014.

Dietary Bacillus subtilis-based direct-fed microbials alleviate LPS-induced intestinal immunological stress and improve intestinal barrier gene expression in commercial broiler chickens

USDA-ARS?s Scientific Manuscript database

The present study investigated the effects of B. subtilis-based probiotics on performance, modulation of host inflammatory responses and intestinal barrier integrity of broilers subjected to LPS challenge. Birds at day 0 of age were randomly allocated to one of the 3 dietary treatments - controls, ...

The Anti-Inflammatory Effect of Spray-Dried Plasma Is Mediated by a Reduction in Mucosal Lymphocyte Activation and Infiltration in a Mouse Model of Intestinal Inflammation.

PubMed

Pérez-Bosque, Anna; Miró, Lluïsa; Amat, Concepció; Polo, Javier; Moretó, Miquel

2016-10-22

Spray-dried preparations from porcine and bovine plasma can alleviate mucosal inflammation in experimental models and improve symptoms in patients with enteropathy. In rodents, dietary supplementation with porcine spray-dried plasma (SDP) attenuates intestinal inflammation and improves the epithelial barrier function during intestinal inflammation induced by Staphylococcus aureus enterotoxin B (SEB). The aim of this study was to discern the molecular mechanisms involved in the anti-inflammatory effects of SDP. Male C57BL/6 mice were fed with 8% SDP or control diet (based on milk proteins) for two weeks, from weaning until day 33. On day 32, the mice were given a SEB dose (i.p., 25 µg/mouse) or vehicle. SEB administration increased cell recruitment to mesenteric lymph nodes and the percentage of activated Th lymphocytes and SDP prevented these effects). SDP supplementation increased the expression of interleukin 10 (IL-10) or transforming growth factor- β (TGF-β) compared to the SEB group. The SEB challenge increased six-fold the expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) and intercellular adhesion molecule 1 (ICAM-1); and these effects were attenuated by SDP supplementation. SEB also augmented NF-κB phosphorylation, an effect that was prevented by dietary SDP. Our results indicate that the anti-inflammatory effects of SDP involve the regulation of transcription factors and adhesion molecules that reduce intestinal cell infiltration and the degree of the inflammatory response.

Metabolic inflammation in inflammatory bowel disease: crosstalk between adipose tissue and bowel.

PubMed

Gonçalves, Pedro; Magro, Fernando; Martel, Fátima

2015-02-01

Epidemiological studies show that both the incidence of inflammatory bowel disease (IBD) and the proportion of people with obesity and/or obesity-associated metabolic syndrome increased markedly in developed countries during the past half century. Obesity is also associated with the development of more active IBD and requirement for hospitalization and with a decrease in the time span between diagnosis and surgery. Patients with IBD, especially Crohn's disease, present fat-wrapping or "creeping fat," which corresponds to ectopic adipose tissue extending from the mesenteric attachment and covering the majority of the small and large intestinal surface. Mesenteric adipose tissue in patients with IBD presents several morphological and functional alterations, e.g., it is more infiltrated with immune cells such as macrophages and T cells. All these lines of evidence clearly show an association between obesity, adipose tissue, and functional bowel disorders. In this review, we will show that the mesenteric adipose tissue and creeping fat are not innocent by standers but actively contribute to the intestinal and systemic inflammatory responses in patients with IBD. More specifically, we will review evidence showing that adipose tissue in IBD is associated with major alterations in the secretion of cytokines and adipokines involved in inflammatory process, in adipose tissue mesenchymal stem cells and adipogenesis, and in the interaction between adipose tissue and other intestinal components (immune, lymphatic, neuroendocrine, and intestinal epithelial systems). Collectively, these studies underline the importance of adipose tissue for the identification of novel therapeutic approaches for IBD.

Inflammatory response in multiple organs in a mouse model of acute alcohol intoxication and burn injury*

PubMed Central

Li, Xiaoling; Akhtar, Suhail; Kovacs, Elizabeth J.; Gamelli, Richard L.; Choudhry, Mashkoor A.

2011-01-01

The present study characterized the inflammatory response following burn injury and determined whether ethanol (EtOH) intoxication at the time of burn injury influences this response. To accomplish this, male mice were gavaged with EtOH (2.9 g/Kg) 4 hours prior to 12–15% total body surface area sham or burn injury. Mice were sacrificed on day one after injury; blood, small intestine, lung and liver were collected to measure IL-6, IL-10, IL-18 and MCP-1 levels. In addition, neutrophil infiltration, MPO activity and edema formation were also measured in the small intestine, lung and liver. There was no difference in the inflammatory markers in the small intestine, lung and liver in mice receiving either sham or burn injury alone except IL-6 which was increased in all 4 tissue compartments following burn injury alone. However, as compared to EtOH or burn injury alone, EtOH combined with burn injury resulted in a significant increase in cytokines, neutrophil infiltration, MPO activity and edema in the small intestine, liver and lung tissue. Furthermore, a significant increase in IL-6 and MCP-1 was observed in circulation following EtOH and burn injury compared to either EtOH intoxication or burn injury alone, no other cytokines were detected in circulation. These findings suggest that acute EtOH intoxication exacerbates the inflammatory response following burn injury. PMID:21593683

Intestinal helminth infection drives carcinogenesis in colitis-associated colon cancer

PubMed Central

Pastille, Eva; Frede, Annika; McSorley, Henry J.; Gräb, Jessica; Adamczyk, Alexandra; Hansen, Wiebke; Buer, Jan; Maizels, Rick M.

2017-01-01

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract, strongly associated with an increased risk of colorectal cancer development. Parasitic infections caused by helminths have been shown to modulate the host’s immune response by releasing immunomodulatory molecules and inducing regulatory T cells (Tregs). This immunosuppressive state provoked in the host has been considered as a novel and promising approach to treat IBD patients and alleviate acute intestinal inflammation. On the contrary, specific parasite infections are well known to be directly linked to carcinogenesis. Whether a helminth infection interferes with the development of colitis-associated colon cancer (CAC) is not yet known. In the present study, we demonstrate that the treatment of mice with the intestinal helminth Heligmosomoides polygyrus at the onset of tumor progression in a mouse model of CAC does not alter tumor growth and distribution. In contrast, H. polygyrus infection in the early inflammatory phase of CAC strengthens the inflammatory response and significantly boosts tumor development. Here, H. polygyrus infection was accompanied by long-lasting alterations in the colonic immune cell compartment, with reduced frequencies of colonic CD8+ effector T cells. Moreover, H. polygyrus infection in the course of dextran sulfate sodium (DSS) mediated colitis significantly exacerbates intestinal inflammation by amplifying the release of colonic IL-6 and CXCL1. Thus, our findings indicate that the therapeutic application of helminths during CAC might have tumor-promoting effects and therefore should be well-considered. PMID:28938014

TLR2 mediates gap junctional intercellular communication through connexin-43 in intestinal epithelial barrier injury.

PubMed

Ey, Birgit; Eyking, Annette; Gerken, Guido; Podolsky, Daniel K; Cario, Elke

2009-08-14

Gap junctional intercellular communication (GJIC) coordinates cellular functions essential for sustaining tissue homeostasis; yet its regulation in the intestine is not well understood. Here, we identify a novel physiological link between Toll-like receptor (TLR) 2 and GJIC through modulation of Connexin-43 (Cx43) during acute and chronic inflammatory injury of the intestinal epithelial cell (IEC) barrier. Data from in vitro studies reveal that TLR2 activation modulates Cx43 synthesis and increases GJIC via Cx43 during IEC injury. The ulcerative colitis-associated TLR2-R753Q mutant targets Cx43 for increased proteasomal degradation, impairing TLR2-mediated GJIC during intestinal epithelial wounding. In vivo studies using mucosal RNA interference show that TLR2-mediated mucosal healing depends functionally on intestinal epithelial Cx43 during acute inflammatory stress-induced damage. Mice deficient in TLR2 exhibit IEC-specific alterations in Cx43, whereas administration of a TLR2 agonist protects GJIC by blocking accumulation of Cx43 and its hyperphosphorylation at Ser368 to prevent spontaneous chronic colitis in MDR1alpha-deficient mice. Finally, adding the TLR2 agonist to three-dimensional intestinal mucosa-like cultures of human biopsies preserves intestinal epithelial Cx43 integrity and polarization ex vivo. In conclusion, Cx43 plays an important role in innate immune control of commensal-mediated intestinal epithelial wound repair.

TLR2 Mediates Gap Junctional Intercellular Communication through Connexin-43 in Intestinal Epithelial Barrier Injury*

PubMed Central

Ey, Birgit; Eyking, Annette; Gerken, Guido; Podolsky, Daniel K.; Cario, Elke

2009-01-01

Gap junctional intercellular communication (GJIC) coordinates cellular functions essential for sustaining tissue homeostasis; yet its regulation in the intestine is not well understood. Here, we identify a novel physiological link between Toll-like receptor (TLR) 2 and GJIC through modulation of Connexin-43 (Cx43) during acute and chronic inflammatory injury of the intestinal epithelial cell (IEC) barrier. Data from in vitro studies reveal that TLR2 activation modulates Cx43 synthesis and increases GJIC via Cx43 during IEC injury. The ulcerative colitis-associated TLR2-R753Q mutant targets Cx43 for increased proteasomal degradation, impairing TLR2-mediated GJIC during intestinal epithelial wounding. In vivo studies using mucosal RNA interference show that TLR2-mediated mucosal healing depends functionally on intestinal epithelial Cx43 during acute inflammatory stress-induced damage. Mice deficient in TLR2 exhibit IEC-specific alterations in Cx43, whereas administration of a TLR2 agonist protects GJIC by blocking accumulation of Cx43 and its hyperphosphorylation at Ser368 to prevent spontaneous chronic colitis in MDR1α-deficient mice. Finally, adding the TLR2 agonist to three-dimensional intestinal mucosa-like cultures of human biopsies preserves intestinal epithelial Cx43 integrity and polarization ex vivo. In conclusion, Cx43 plays an important role in innate immune control of commensal-mediated intestinal epithelial wound repair. PMID:19528242

Lactobacillus rhamnosus GG and its SpaC pilus adhesin modulate inflammatory responsiveness and TLR-related gene expression in the fetal human gut

PubMed Central

Ganguli, Kriston; Collado, Maria Carmen; Rautava, Jaana; Lu, Lei; Satokari, Reetta; von Ossowski, Ingemar; Reunanen, Justus; de Vos, Willem M.; Palva, Airi; Isolauri, Erika; Salminen, Seppo; Walker, W. Allan; Rautava, Samuli

2015-01-01

Background Bacterial contact in utero modulates fetal and neonatal immune responses. Maternal probiotic supplementation reduces the risk of immune-mediated disease in the infant. We investigated the immunomodulatory properties of live Lactobacillus rhamnosus GG and its SpaC pilus adhesin in human fetal intestinal models. Methods TNF-α mRNA expression was measured by qPCR in a human fetal intestinal organ culture model exposed to live L. rhamnosus GG and proinflammatory stimuli. Binding of recombinant SpaC pilus protein to intestinal epithelial cells was assessed in human fetal intestinal organ culture and the human fetal intestinal epithelial cell line H4 by immunohistochemistry and immunofluorescence, respectively. TLR-related gene expression in fetal ileal organ culture after exposure to recombinant SpaC was assessed by qPCR. Results Live L. rhamnosus GG significantly attenuates pathogen-induced TNF-α mRNA expression in the human fetal gut. Recombinant SpaC protein was found to adhere to the fetal gut and to modulate varying levels of TLR-related gene expression. Conclusion The human fetal gut is responsive to luminal microbes. L. rhamnosus GG significantly attenuates fetal intestinal inflammatory responses to pathogenic bacteria. The L. rhamnosus GG pilus adhesin SpaC binds to immature human intestinal epithelial cells and directly modulates intestinal epithelial cell innate immune gene expression. PMID:25580735

Lactobacillus paracasei CNCM I-4034 and its culture supernatant modulate Salmonella-induced inflammation in a novel transwell co-culture of human intestinal-like dendritic and Caco-2 cells.

PubMed

Bermudez-Brito, Miriam; Muñoz-Quezada, Sergio; Gómez-Llorente, Carolina; Matencio, Esther; Romero, Fernando; Gil, Angel

2015-04-01

The action of probiotics has been studied in vitro in cells isolated from both mice and humans, particularly enterocytes (IECs), dendritic cells (DCs) and co-cultures of peripheral DCs and IECs. Peripheral DCs and murine DCs differ from human gut DCs, and to date there are no data on the action of any probiotic on co-cultured human IECs and human intestinal DCs. To address this issue, a novel transwell model was used. Human IECs (Caco-2 cells) grown in the upper chamber of transwell filters were co-cultured with intestinal-like human DCs grown in the basolateral compartment of the transwells. The system was apically exposed for 4 h to live probiotic L. paracasei CNCM I-4034 obtained from the faeces of breastfed infants or to its cell-free culture supernatant (CFS) and challenged with Salmonella typhi. The secretion of pro- and anti-inflammatory cytokines in the basolateral compartment was determined by immunoassay, and the DC expression pattern of 20 TLR signaling pathway genes was analysed by PCR array. The presence of the live probiotic alone significantly increased IL-1β, IL-6, IL-8, TGF-β2, RANTES and IP-10 levels and decreased IL-12p40, IL-10, TGF- β1 and MIP-1α levels. This release was correlated with a significant increase in the expression of almost all TLR signaling genes. By contrast, incubation of the co-culture with CFS increased IL-1β, IL-6, TGF-β2 and IP-10 production only when Salmonella was present. This induction was correlated with an overall decrease in the expression of all TLR genes except TLR9, which was strongly up-regulated. The data presented here clearly indicate that L. paracasei CNCM I-4034 significantly increases the release of pro-inflammatory cytokines, enhances TLR signaling pathway activation and stimulates rather than suppresses the innate immune system. Furthermore, our findings provide evidence that the effects of probiotics in the presence of IECs and DCs differ from the effects of probiotics on cultures of each cell type alone, as reported by us earlier. Thus, co-culture systems such as the one described here are needed to characterise the effects of probiotics in vitro, highlighting the potential utility of such co-cultures as a model system.

Intestinal Lymphatic Transport: an Overlooked Pathway for Understanding Absorption of Plant Secondary Compounds in Vertebrate Herbivores.

PubMed

Kohl, Kevin D; Dearing, M Denise

2017-03-01

Herbivores employ numerous strategies to reduce their exposure to toxic plant secondary chemicals (PSCs). However, the physiological mechanisms of PSC absorption have not been extensively explored. In particular, the absorption of PSCs via intestinal lymphatic absorption has been largely overlooked in herbivores, even though this pathway is well recognized for pharmaceutical uptake. Here, we investigated for the first time whether PSCs might be absorbed by lymphatic transport. We fed woodrats (Neotoma albigula) diets with increasing concentrations of terpene-rich juniper (Juniperus monosperma) either with or without a compound that blocks intestinal lymphatic absorption (Pluronic L-81). Woodrats consuming diets that contained the intestinal lymphatic absorption blocker exhibited increased food intakes and maintained higher body masses on juniper diets. Our study represents the first demonstration that PSCs may be absorbed by intestinal lymphatic absorption. This absorption pathway has numerous implications for the metabolism and distribution of PSCs in the systemic circulation, given that compounds absorbed via lymphatic transport bypass first-pass hepatic metabolism. The area of lymphatic transport of PSCs represents an understudied physiological pathway in plant-herbivore interactions.

Polysaccharide of Hericium erinaceus attenuates colitis in C57BL/6 mice via regulation of oxidative stress, inflammation-related signaling pathways and modulating the composition of the gut microbiota.

PubMed

Ren, Yilin; Geng, Yan; Du, Yan; Li, Wang; Lu, Zhen-Ming; Xu, Hong-Yu; Xu, Guo-Hua; Shi, Jin-Song; Xu, Zheng-Hong

2018-03-16

Inflammatory bowel disease (IBD) is a disease caused by a dysregulated immune with unknown etiology. Hericium erinaceus (H. erinaceus) is a Chinese medicinal fungus, with the effect of prevention and treatment of gastrointestinal disorders. In this study, we have tested the anti-inflammatory effect of polysaccharide of H. erinaceus (HECP, Mw: 86.67 kDa) in the model of dextran sulfate sodium (DSS)-induced colitis in C57BL/6 mice. Our data indicated that HECP could improve clinical symptoms and down-regulate key markers of oxidative stresses, including nitric oxide (NO), malondialdehyde (MDA), total superoxide dismutase (T-SOD), and myeloperoxidase (MPO). HECP also suppressed the secretion of interleukin (IL)-6, interleukin (IL)-1β, tumor necrosis factor (TNF)-α and the expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and decreased the expression of related mRNA. Meanwhile, HECP blocked phosphorylation of nuclear factor-κB (NF-κB) p65, NF-κB inhibitor alpha (IκB-α), mitogen-activated protein kinases (MAPK) and Protein kinase B (Akt) in DSS-treated mice. Moreover, HECP reversed DSS-induced gut dysbiosis and maintained intestinal barrier integrity. In conclusion, HECP ameliorates DSS-induced intestinal injury in mice, which suggests that HECP can serve as a protective dietary nutrient against IBD. Copyright © 2018. Published by Elsevier Inc.

A non-inflammatory form of immune competence prevails in acute pre-pubescent malnutrition: new evidence based on critical mRNA transcripts in the mouse.

PubMed

Monk, Jennifer M; Richard, Cynthia L; Woodward, Bill

2012-05-01

The declining inflammatory immune competence of acute (i.e. wasting) pre-pubescent protein-energy malnutrition has been regarded as reflecting an unregulated immunological disintegration. Recent evidence, however, suggests that malnutrition stimulates a regulated immunological reconfiguration to achieve a non-inflammatory form of competence, perhaps offering protection against autoimmune reactions - the 'Tolerance Model'. Our objective was to determine the influence of acute pre-pubescent malnutrition on the expression of genes critical to tolerogenic regulation. Male and female C57BL/6J mice, initially 19 d old, consumed a complete purified diet either ad libitum (age-matched controls) or in restricted daily quantities (mimicking marasmus), or consumed an isoenergetic low-protein diet ad libitum (mimicking incipient kwashiorkor) for 14 d (six animals per dietary group). Gene expression in the spleen, typically an inflammatory organ, and in the small intestine, a site designed for non-inflammatory defence, was assessed by real-time quantitative RT-PCR, and normalised to β-actin. In the spleen of the malnourished groups, both IL-10 and transforming growth factor-β1 mRNA expression increased compared with controls (P < 0.05), whereas mRNA expression of IL-12p40 decreased (P < 0.05). Conversely, malnutrition exerted no influence on the expression of mRNA for these cytokines in the small intestine (P>0.05). Moreover, forkhead box P3 mRNA expression, indicative of cell-based tolerogenic potential, was sustained in both the spleen and intestine of the malnourished groups (P>0.05). Thus, despite limited supplies of energy and substrates, the spleen shifted towards a non-inflammatory character and the intestine was sustained in this mode in advanced pre-pubescent weight loss. These findings provide the first support for the Tolerance Model at the level of mRNA transcript expression.

R-Spondins Are Expressed by the Intestinal Stroma and are Differentially Regulated during Citrobacter rodentium- and DSS-Induced Colitis in Mice

PubMed Central

Kang, Eugene; Yousefi, Mitra; Gruenheid, Samantha

2016-01-01

The R-spondin family of proteins has recently been described as secreted enhancers of β-catenin activation through the canonical Wnt signaling pathway. We previously reported that Rspo2 is a major determinant of susceptibility to Citrobacter rodentium-mediated colitis in mice and recent genome-wide association studies have revealed RSPO3 as a candidate Crohn’s disease-specific inflammatory bowel disease susceptibility gene in humans. However, there is little information on the endogenous expression and cellular source of R-spondins in the colon at steady state and during intestinal inflammation. RNA sequencing and qRT-PCR were used to assess the expression of R-spondins at steady state and in two mouse models of colonic inflammation. The cellular source of R-spondins was assessed in specific colonic cell populations isolated by cell sorting. Data mining from publicly available datasets was used to assess the expression of R-spondins in the human colon. At steady state, colonic expression of R-spondins was found to be exclusive to non-epithelial CD45- lamina propria cells, and Rspo3/RSPO3 was the most highly expressed R-spondin in both mouse and human colon. R-spondin expression was found to be highly dynamic and differentially regulated during C. rodentium infection and dextran sodium sulfate (DSS) colitis, with notably high levels of Rspo3 expression during DSS colitis, and high levels of Rspo2 expression during C. rodentium infection, specifically in susceptible mice. Our data are consistent with the hypothesis that in the colon, R-spondins are expressed by subepithelial stromal cells, and that Rspo3/RSPO3 is the family member most implicated in colonic homeostasis. The differential regulation of the R-spondins in different models of intestinal inflammation indicate they respond to specific pathogenic and inflammatory signals that differ in the two models and provides further evidence that this family of proteins plays a key role in linking intestinal inflammation and homeostasis. PMID:27046199

Barrier-protective function of intestinal epithelial Toll-like receptor 2.

PubMed

Cario, E

2008-11-01

The intestinal epithelial cell (IEC) barrier plays an important role in maintaining mucosal immune homeostasis. Dysregulated IEC barrier function appears to trigger and perpetuate inflammation in inflammatory bowel diseases (IBD). Novel risk variants in the Toll-like receptor 2 (TLR2) gene have previously been associated with a more severe disease phenotype in a subgroup of IBD patients. Recent studies have provided important insights of the commensal and host defense mechanisms to maintain functional barrier integrity of the intestinal epithelium through TLR2. Deficient TLR2 signaling may imbalance commensal-dependent intestinal epithelial barrier defense, facilitating mucosal injury and leading to increased susceptibility of colitis. Treatment with a synthetic TLR2 ligand significantly suppresses mucosal inflammation by efficiently protecting tight junction-associated integrity of the intestinal epithelium in vivo. These beneficial effects may be supplemented by TLR2-induced anti-inflammatory immune responses (such as interleukin-10 production) in lamina propria mononuclear cells. Thus, cell-specific TLR2 targeting may offer a novel therapeutic approach to human IBD therapy by protecting IEC barrier function.

Mesenchymal stem cells increase antioxidant capacity in intestinal ischemia/reperfusion damage.

PubMed

Inan, M; Bakar, E; Cerkezkayabekir, A; Sanal, F; Ulucam, E; Subaşı, C; Karaöz, E

2017-07-01

Mesenchymal stem cells (MSCs) may have beneficial effects in reversing intestinal damage resulting from circulatory disorders. The hypothesis of this study is that MSCs increase antioxidant capacity of small bowel tissue following intestinal ischemia reperfusion (I/R) damage. A total of 100 rats were used for the control group and three experimental groups, as follows: the sham control, local MSC, and systemic MSC groups. Each group consisted of 10 animals on days 1, 4, and 7 of the experiment. Ischemia was established by clamping the superior mesenteric artery (SMA) for 45min; following this, reperfusion was carried out for 1, 4, and 7days in all groups. In the local and systemic groups, MSCs were administered intravenously and locally just after the ischemia, and they were investigated after 1, 4, and 7days. The superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (Gpx) activities, as well as malondialdehyde (MDA) and total protein levels, were measured. Histopathological analysis was performed using light and electron microscopy. The indicators of proliferation from the effects of anti- and pro-inflammatory cytokines were evaluated using immunohistochemistry. MDA was increased (P<0.05) in the sham control group and decreased (P<0.05) in the MSC groups. SOD, CAT, and Gpx were decreased in the local MSC group (P<0.05). The highest level of amelioration was observed on day 7 in the local MSC group via light and electron microscopy. It was found that the MSCs arrived at the damaged intestinal wall in the MSC groups immediately after injection. Pro-inflammatory cytokines interleukin-1β (IL1β), transforming growth factor-β1 (TGFβ1), tumor necrosis factor-α (TNFα), IL6, MIP2, and MPO decreased (P<0.05), while anti-inflammatory cytokines EP3 and IL1ra increased (p<0.05) in the local and systemic MSC groups. In addition, proliferation indicators, such as PCNA and KI67, increased (P<0.05) in the local and systemic MSC groups. Parallel to our hypothesis, MSC increases the antioxidant capacity of small bowel tissue after intestinal I/R damage. The MSCs migrated to the reperfused small intestine by homing and reduced oxidative stress via the effects of SOD, CAT, and Gpx, as well as reducing the MDA level; thus, they could increase antioxidant capacity of intestine and have a therapeutic effect on the damaged tissue. We think that this effect was achieved via scavenging of oxygen radicals, suppression of pro-inflammatory cytokines, and increasing the expression of anti-inflammatory cytokines. Copyright © 2017 Elsevier Inc. All rights reserved.

Time-dependent LXR/RXR pathway modulation characterizes capillary remodeling in inflammatory corneal neovascularization.

PubMed

Mukwaya, Anthony; Lennikov, Anton; Xeroudaki, Maria; Mirabelli, Pierfrancesco; Lachota, Mieszko; Jensen, Lasse; Peebo, Beatrice; Lagali, Neil

2018-05-01

Inflammation in the normally immune-privileged cornea can initiate a pathologic angiogenic response causing vision-threatening corneal neovascularization. Inflammatory pathways, however, are numerous, complex and are activated in a time-dependent manner. Effective resolution of inflammation and associated angiogenesis in the cornea requires knowledge of these pathways and their time dependence, which has, to date, remained largely unexplored. Here, using a model of endogenous resolution of inflammation-induced corneal angiogenesis, we investigate the time dependence of inflammatory genes in effecting capillary regression and the return of corneal transparency. Endogenous capillary regression was characterized by a progressive thinning and remodeling of angiogenic capillaries and inflammatory cell retreat in vivo in the rat cornea. By whole-genome longitudinal microarray analysis, early suppression of VEGF ligand-receptor signaling and inflammatory pathways preceded an unexpected later-phase preferential activation of LXR/RXR, PPARα/RXRα and STAT3 canonical pathways, with a concurrent attenuation of LPS/IL-1 inhibition of RXR function and Wnt/β-catenin signaling pathways. Potent downstream inflammatory cytokines such as Cxcl5, IL-1β, IL-6 and Ccl2 were concomitantly downregulated during the remodeling phase. Upstream regulators of the inflammatory pathways included Socs3, Sparc and ApoE. A complex and coordinated time-dependent interplay between pro- and anti-inflammatory signaling pathways highlights a potential anti-inflammatory role of LXR/RXR, PPARα/RXRα and STAT3 signaling pathways in resolving inflammatory corneal angiogenesis.

Evidence for the existence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with and without abdominal discomfort (irritable bowel) syndrome.

PubMed

Maes, Michael; Leunis, Jean-Claude; Geffard, Michel; Berk, Michael

2014-01-01

There is evidence that Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is accompanied by gastro-intestinal symptoms; and IgA and IgM responses directed against lipopolysaccharides (LPS) of commensal bacteria, indicating bacterial translocation. This study was carried out to examine gastro-intestinal symptoms in subjects with ME/CFS versus those with chronic fatigue (CF). The two groups were dissected by dichotomizing those fulfilling and not fulfilling Fukuda's critera. In these groups, we examined the association between gastro-intestinal symptoms and the IgA and IgM responses directed against commensal bacteria. Using cluster analysis performed on gastro-intestinal symptoms we delineated that the cluster analysis-generated diagnosis of abdominal discomfort syndrome (ADS) was significantly higher in subjects with ME/CFS (59.6%) than in those with CF (17.7%). The diagnosis of ADS was strongly associated with the diagnosis of irritable bowel syndrome (IBS). There is evidence that ME/CFS consists of two subgroups, i.e. ME/CFS with and without ADS. Factor analysis showed four factors, i.e. 1) inflammation-hyperalgesia; 2) fatigue-malaise; 3) gastro-intestinal symptoms/ADS; and 4) neurocognitive symptoms. The IgA and IgM responses to LPS of commensal bacteria were significantly higher in ME/CFS patients with ADS than in those without ADS. The findings show that ADS is a characteristic of a subset of patients with ME/CFS and that increased bacterial translocation (leaky gut) is associated with ADS symptoms. This study has defined a pathway phenotype, i.e bacterial translocation, that is related to ME/CFS and ADS/IBS and that may drive systemic inflammatory processes.

Endotoxaemia resulting from decreased serotonin tranporter (5-HTT) function: a reciprocal risk factor for depression and insulin resistance?

PubMed

Pomytkin, Igor A; Cline, Brandon H; Anthony, Daniel C; Steinbusch, Harry W; Lesch, Klaus-Peter; Strekalova, Tatyana

2015-01-01

Depression and diabetes are serious diseases with an increasing global prevalence. Intriguingly, recent meta-analyses have highlighted an asymmetrical relationship between the two conditions as depressed patients were found to display a higher risk of developing type 2 diabetes than those individuals suffering from diabetes are to become depressed. Based on recent findings, we favor a hypothesis where by decreased peripheral serotonin (5-HT) transporter (5-HTT) function is a reciprocal risk factor for the co-morbidity of depression and diabetes, as it can trigger inflammatory pathogenetic mechanisms of both conditions. Higher intestinal levels of 5-HT and 5-HT3 receptor stimulation lead to increased intestinal permeability in 5-HTT deficient mice, which is viewed one of the most relevant animal models of depression. We hypothesize that this leakage of bacterial endotoxins can activate both central and peripheral Toll-like receptor 4 (TLR4), which inhibits insulin signaling and IRS1/PI3K/Akt and thus, contribute to the pathogenesis of diabetes and depression that are associated with this pathway. Antidepressant therapies, which also suppress intestinal 5-HTT, may have potentiating effects on the association between depression and diabetes. It is also of interest that high carbohydrate and fat intake ("cafeteria-type diet") increases intestinal 5-HT leading to TLR4 activation. Thus, endotoxaemia and inflammation owing to increased intestinal 5-HT may underpin the depression and diabetes association, where the risk of the latter pathology becomes particularly preeminent after the onset of depression and not vice versa. The evidence presented here shows the further investigation into peripheral mechanisms that linked diabetes to depression is clearly warranted. Copyright © 2014. Published by Elsevier B.V.

Matrix Stiffness Corresponding to Strictured Bowel Induces a Fibrogenic Response in Human Colonic Fibroblasts

PubMed Central

Johnson, Laura A.; Rodansky, Eva S.; Sauder, Kay L.; Horowitz, Jeffrey C.; Mih, Justin D.; Tschumperlin, Daniel J.; Higgins, Peter D.

2013-01-01

Background Crohn’s disease is characterized by repeated cycles of inflammation and mucosal healing which ultimately progress to intestinal fibrosis. This inexorable progression towards fibrosis suggests that fibrosis becomes inflammation-independent and auto-propagative. We hypothesized that matrix stiffness regulates this auto-propagation of intestinal fibrosis. Methods The stiffness of fresh ex vivo samples from normal human small intestine, Crohn’s disease strictures, and the unaffected margin were measured with a microelastometer. Normal human colonic fibroblasts were cultured on physiologically normal or pathologically stiff matrices corresponding to the physiological stiffness of normal or fibrotic bowel. Cellular response was assayed for changes in cell morphology, α-smooth muscle actin (αSMA) staining, and gene expression. Results Microelastometer measurements revealed a significant increase in colonic tissue stiffness between normal human colon and Crohn’s strictures as well as between the stricture and adjacent tissue margin. In Ccd-18co cells grown on stiff matrices corresponding to Crohn’s strictures, cellular proliferation increased. Pathologic stiffness induced a marked change in cell morphology and increased αSMA protein expression. Growth on a stiff matrix induced fibrogenic gene expression, decreased matrix metalloproteinase and pro-inflammatory gene expression, and was associated with nuclear localization of the transcriptional cofactor MRTF-A. Conclusions Matrix stiffness, representative of the pathological stiffness of Crohn’s strictures, activates human colonic fibroblasts to a fibrogenic phenotype. Matrix stiffness affects multiple pathways suggesting the mechanical properties of the cellular environment are critical to fibroblast function and may contribute to autopropagation of intestinal fibrosis in the absence of inflammation, thereby contributing to the intractable intestinal fibrosis characteristic of Crohn’s disease. PMID:23502354

Multi-Drug Resistance Transporter 2 Regulates Mucosal Inflammation by Facilitating the Synthesis of Hepoxilin A3

PubMed Central

Pazos, Michael; Siccardi, Dario; Mumy, Karen L.; Bien, Jeffrey D.; Louie, Steve; Shi, Hai Ning; Gronert, Karsten; Mrsny, Randall J.; McCormick, Beth A.

2008-01-01

Neutrophil transmigration across mucosal surfaces contributes to dysfunction of epithelial barrier properties, a characteristic underlying many mucosal inflammatory diseases. Thus, insight into the directional movement of neutrophils across epithelial barriers will provide important information relating to the mechanisms of such inflammatory disorders. The eicosanoid hepoxilin A3, an endogenous product of 12-lipoxygenase activity, is secreted from the apical surface of the epithelial barrier and establishes a chemotatic gradient to guide neutrophils from the submucosa, across epithelia to the luminal site of an inflammatory stimulus - the final step in neutrophil recruitment. Currently, little is known regarding how hepoxilin A3 is secreted from the intestinal epithelium during an inflammatory insult. In this study we reveal that hepoxilin A3 is a substrate for the apical efflux ABC transporter, multi-drug resistance protein 2 (MRP2). Moreover, using multiple in vitro and in vivo models we show that induction of intestinal inflammation profoundly up-regulates apical expression of MRP2, and that interfering with hepoxilin A3 synthesis and/or inhibition of MRP2 function results in a marked reduction in inflammation and severity of disease. Lastly, examination of inflamed intestinal epithelia in human biopsies revealed up-regulation of MRP2. Thus, blocking hepoxilin A3 synthesis and/or inhibiting MRP2 may lead to the development of new therapeutic strategies for the treatment of epithelial-associated inflammatory conditions. PMID:19017997

[New knowledge of the pathogenesis of Crohn's disease].

PubMed

Ambrůzová, B; Rédová, M; Michálek, J; Sachlová, M; Slabý, O

2012-04-01

Crohns disease is a complex chronic inflammatory disease of the gastrointestinal tract with multifactorial pathogenesis. Over the recent years, there has been rather a sharp increase in the incidence of Crohn's disease and, even though this disease had been known for some time, the cause remains unknown. Studies exploring genetic basis of Crohn's disease have provided new knowledge of the pathogenesis of this disease, suggesting that this may be associated with a failure of mechanisms behind symbiosis of gut microflora and intestinal mucosal immune system. Crohn's disease seems to be caused by inadequate immune response to intestinal flora in genetically predisposed individuals. Crohn's disease has been linked to a number of genes. Many of them are related to the modulation of non-specific immune response, defects of which are considered to be key in Crohn's disease pathogenesis. The aim of this review paper is to summarize the new knowledge on the pathogenesis of Crohn's disease at the level of polymorphisms of the NOD2, ATG16L1 genes and the IL23-Th17-lymfocytes signalling pathway genes and to consider further research directions in this disease.

Emerging roles for antigen presentation in establishing host-microbiome symbiosis

PubMed Central

Bessman, Nicholas J.; Sonnenberg, Gregory F.

2016-01-01

Trillions of beneficial bacteria inhabit the intestinal tract of healthy mammals from birth. Accordingly, mammalian hosts have evolved a series of complementary and redundant pathways to limit pathologic immune responses against these bacteria, while simultaneously protecting against enteric pathogen invasion. These pathways can be generically responsive to the presence of any commensal bacteria and innate in nature, as for IL-22-related pathways. Alternatively, specific bacterial antigens can drive a distinct set of adaptive immune cell responses, including IgA affinity maturation and secretion, and a recently described pathway of intestinal selection whereby MHCII+ ILC3 deletes commensal bacteria-reactive CD4 T cells. These pathways can either promote or inhibit colonization by specific subsets of commensal bacteria, and cooperatively maintain intestinal homeostasis. In this review, we will highlight recent developments in understanding how these diverse pathways complement each other to cooperatively shape the symbiotic relationship between commensal bacteria and mammalian hosts. PMID:27319348

Prevention and management of non-steroidal anti-inflammatory drugs-induced small intestinal injury

PubMed Central

Park, Sung Chul; Chun, Hoon Jai; Kang, Chang Don; Sul, Donggeun

2011-01-01

Non-steroidal anti-inflammatory drug (NSAID)-induced small bowel injury is a topic that deserves attention since the advent of capsule endoscopy and balloon enteroscopy. NSAID enteropathy is common and is mostly asymptomatic. However, massive bleeding, stricture, or perforation may occur. The pathogenesis of small intestine injury by NSAIDs is complex and different from that of the upper gastrointestinal tract. No drug has yet been developed that can completely prevent or treat NSAID enteropathy. Therefore, a long-term randomized study in chronic NSAID users is needed. PMID:22180706

Activity of inflammatory bowel disease influences the expression of cytokines in gingival tissue.

PubMed

Figueredo, C M; Martins, A P; Lira-Junior, R; Menegat, J B; Carvalho, A T; Fischer, R G; Gustafsson, A

2017-07-01

This study assessed the cytokine expression in gingival and intestinal tissues from periodontitis patients with inflammatory bowel disease (IBD) and evaluated if IBD activity is a covariate to the amount of gingival cytokines. Paired gingival and intestinal tissues were collected from 21 patients and homogenised using a cell disruptor. Cytokine expression (IL-1β, IL-4, IL-6, IL-10, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IL-17A, IL-17F, IFN-γ, sCD40L, and TNF-α) was evaluated using bead-based multiplex technology. An inflammation score was developed using the intestinal cytokines that showed good accuracy to discriminate IBD active patients from those in remission and then a similar score was applied to gingival tissue. IL-4, IL-10 and IL-21 expressions were significantly increased in gingival tissue from patients with an active disease as compared to those with a disease in remission. The inflammation score (mean value of IL-1β, IL-6, IL-21, and sCD40L) was significantly higher in gingival tissue from patients with IBD activity. There was a significant correlation between gingival and intestinal inflammation scores (rho=0.548; P=0.01). Significantly higher IL-23 and IFN-γ levels and lower IL-31 and TNF-α levels were observed in gingival tissues than in intestinal ones. Activity of inflammatory bowel disease influenced the cytokine expression in gingival tissue. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dietary intervention with green dwarf banana flour (Musa sp AAA) prevents intestinal inflammation in a trinitrobenzenesulfonic acid model of rat colitis.

PubMed

Scarminio, Viviane; Fruet, Andrea C; Witaicenis, Aline; Rall, Vera L M; Di Stasi, Luiz C

2012-03-01

Dietary products are among the therapeutic approaches used to modify intestinal microflora and to promote protective effects during the intestinal inflammatory process. Because the banana plant is rich in resistant starch, which is used by colonic microbiota for the anaerobic production of the short-chain fatty acids that serve as a major fuel source for colonocytes: first, green dwarf banana flour produces protective effects on the intestinal inflammation acting as a prebiotic and, second, combination of this dietary supplementation with prednisolone presents synergistic effects. For this, we used the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. Our results revealed that the protective effect produced by a combination of 10% green dwarf banana flour with prednisolone was more pronounced than those promoted by a single administration of prednisolone or a diet containing 10% or 20% banana flour. This beneficial effect was associated with an improvement in the colonic oxidative status because the banana flour diet prevented the glutathione depletion and inhibited myeloperoxidase activity and lipid peroxidation. In addition, the intestinal anti-inflammatory activity was associated with an inhibition of alkaline phosphatase activity, a reduction in macroscopic and microscopic scores, and an extension of the lesions. In conclusion, the dietary use of the green dwarf banana flour constitutes an important dietary supplement and complementary medicine product to prevention and treatment of human inflammatory bowel disease. Copyright © 2012 Elsevier Inc. All rights reserved.

Differential intestinal anti-inflammatory effects of Lactobacillus fermentum and Lactobacillus salivarius in DSS mouse colitis: impact on microRNAs expression and microbiota composition.

PubMed

Rodríguez-Nogales, Alba; Algieri, Francesca; Garrido-Mesa, Jose; Vezza, Teresa; Utrilla, M Pilar; Chueca, Natalia; Garcia, Federico; Olivares, Mónica; Rodríguez-Cabezas, M Elena; Gálvez, Julio

2017-11-01

To compare the intestinal anti-inflammatory effects of two probiotics Lactobacillus fermentum and Lactobacillus salivarius in mouse colitis, focusing on their impact on selected miRNAs and microbiota composition. Male C57BL/6J mice were randomly assigned to four groups (n = 10): non-colitic, DSS colitic and two colitic groups treated with probiotics (5 × 10 8 CFU/mouse/day). Both probiotics ameliorated macroscopic colonic damage. They improved the colonic expression of markers involved in the immune response, and the expression of miR-155 and miR-223. L. fermentum also restored miR-150 and miR-143 expression, also linked to the preservation of the intestinal barrier function. Besides, these beneficial effects were associated with the amelioration of the microbiota dysbiosis and a recovery of the SCFAs- and lactic acid-producing bacterial populations, although only L. fermentum improved Chao richness, Pielou evenness and Shannon diversity. Moreover, L. fermentum also restored the Treg cell population in MLNs and the Th1/Th2 cytokine balance. Both probiotics exerted intestinal anti-inflammatory effects in DSS-mouse colitis, maybe due to their ability to restore the intestinal microbiota homeostasis and modulate the immune response. L. fermentum showed a greater beneficial effect compared to L. salivarius, which makes it more interesting for future studies. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Helminths and Intestinal Flora Team Up to Improve Gut Health.

PubMed

Giacomin, Paul; Agha, Zainab; Loukas, Alex

2016-09-01

Inflammatory bowel diseases (IBD) are associated with impaired intestinal barrier function, chronic inflammation, and microbial dysbiosis. In a recent publication in Science, Ramanan et al. used murine and human studies to demonstrate that infections with gastrointestinal helminths can protect against IBD by provoking immune responses that alter the balance of commensal and pathogenic bacteria in the intestine. Copyright © 2016 Elsevier Ltd. All rights reserved.