Cytokine production in vitro and in rat model of colitis in response to Lactobacillus plantarum LS/07.

PubMed

Štofilová, Jana; Langerholc, Tomaž; Botta, Cristian; Treven, Primož; Gradišnik, Lidija; Salaj, Rastislav; Šoltésová, Alena; Bertková, Izabela; Hertelyová, Zdenka; Bomba, Alojz

2017-10-01

Over the past decade, it has become clear that specific probiotic lactobacilli are valuable in the prevention and treatment of infectious and inflammatory diseases of gastrointestinal tract but their successful application would benefit greatly from a better understanding of the mechanisms of individual strains. Hence, each probiotic strain should be characterized for their immune activity before being proposed for clinical applications. The aim of the study was to characterize the immunomodulatory activity of the strain Lactobacillus (L.) plantarum LS/07 in vitro using functional gut model and to study its anti-inflammatory potential in dextran sulphate sodium (DSS)-induced colitis in rats. We showed that L. plantarum LS/07 induced production of IL-10 in macrophages derived from blood monocytes as well as monocyte/macrophages cell line stimulated indirectly via enterocytes in vitro. In rat model of colitis, L. plantarum LS/07 attenuated the DSS-induced signs of inflammatory process in colon such as weight loss, diarrhoea, infiltration of inflammatory cells associated with decreased colon weight/length ratio, inhibited gut mucosa destruction and depletion of goblet cells. Moreover, the strain increased the concentration of anti-inflammatory cytokine IL-10 in mucosal tissue. In conclusion, the protective effects of L. plantarum LS/07 in the DSS-induced colitis model seem to be related to the stimulation of IL-10 and the restoration of goblet cells and indicate it as a good candidate to prevent and treat diseases associated with inflammation. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Effects of curcumin plus Soy oligosaccharides on intestinal flora of rats with ulcerative colitis.

PubMed

Huang, G; Ye, L; Du, G; Huang, Y; Wu, Y; Ge, S; Yang, Z; Zhu, G

2017-08-15

To explore the therapeutic effect of curcumin (Cur) and soybean oligosaccharides (SBOS) on ulcerative colitis (UC) through testing the intestinal flora and ulcerative colitis (UC). 80 male SD rats were selected divided into four groups with 20 rats in each group: normal group, sulfasalazine (SASP) group, model group and group of curcumin plus soy oligosaccharide. All animals were treated for 4 weeks. In the fifth week rats were decapitated. Macroscopic damage scores of colonic mucosa were calculated. A 4mL blood sample was taken to detect the contents of serum tumor necrosis factor -α (TNF-α) and interleukin 8 (IL-8) by the double antibody sandwich ABC-ELISA method (enzyme-linked immunosorbent assay). Colonic tissues with the most obvious lesions were obtained using a surgical scissor. A routine hematoxylin-eosin (HE) staining method was used to stain pathological specimens and images of staining results were obtained. Histological injury scores of colonic mucosa were calculated. Ulcerative colitis model rats had the highest macroscopic damage scores and histological injury scores of colonic mucosa. After treatment the contents of TNF-α and IL-8 decreased significantly in the group of curcumin plus soy oligosaccharide compared with the model group with statistical significance (P <0.01) while the contents were close to those in the SASP group. There was no statistical significance (P> 0.05). The treatment could decrease TNF-α and IL- 8 expression and reduce colonic mucosa inflammation and tissue damage.

Xilei San Ameliorates Experimental Colitis in Rats by Selectively Degrading Proinflammatory Mediators and Promoting Mucosal Repair

PubMed Central

Hori, Kazutoshi; Wang, Shenglan; Kogure, Yoko; Fukunaga, Ken; Kashiwamura, Shinichiro; Yamamoto, Satoshi; Nakamura, Shiro; Li, Junxiang; Miwa, Hiroto; Noguchi, Koichi

2014-01-01

Xilei san (XLS), a herbal preparation widely used in China for erosive and ulcerative diseases, has been shown to be effective in ulcerative colitis (UC). The present experiments were conducted to assess its efficacy and determine its mechanism of action in a rat model that resembles human UC. The model was induced by adding 4% dextran sulfate sodium (DSS) to the rats' drinking water for 7 days. XLS was administered daily by retention enema from day 2 to day 7; the rats were sacrificed on day 8. The colon tissues were obtained for further experiments. A histological damage score and the activity of tissue myeloperoxidase were used to evaluate the severity of the colitis. The colonic cytokine levels were detected in a suspension array, and epithelial proliferation was assessed using Ki-67 immunohistochemistry. Intrarectal administration of XLS attenuated the DSS-induced colitis, as evidenced by a reduction in both the histological damage score and myeloperoxidase activity. It also decreased the levels of proinflammatory cytokines, but increased the mucosal repair-related cytokines. In addition, the epithelial Ki-67 expression was upregulated by XLS. These results suggest that XLS attenuates DSS-induced colitis by degrading proinflammatory mediators and promoting mucosal repair. XLS could be a potential topical treatment for human UC. PMID:25120575

Xilei san ameliorates experimental colitis in rats by selectively degrading proinflammatory mediators and promoting mucosal repair.

PubMed

Hao, Yongbiao; Nagase, Kazuko; Hori, Kazutoshi; Wang, Shenglan; Kogure, Yoko; Fukunaga, Ken; Kashiwamura, Shinichiro; Yamamoto, Satoshi; Nakamura, Shiro; Li, Junxiang; Miwa, Hiroto; Noguchi, Koichi; Dai, Yi

2014-01-01

Xilei san (XLS), a herbal preparation widely used in China for erosive and ulcerative diseases, has been shown to be effective in ulcerative colitis (UC). The present experiments were conducted to assess its efficacy and determine its mechanism of action in a rat model that resembles human UC. The model was induced by adding 4% dextran sulfate sodium (DSS) to the rats' drinking water for 7 days. XLS was administered daily by retention enema from day 2 to day 7; the rats were sacrificed on day 8. The colon tissues were obtained for further experiments. A histological damage score and the activity of tissue myeloperoxidase were used to evaluate the severity of the colitis. The colonic cytokine levels were detected in a suspension array, and epithelial proliferation was assessed using Ki-67 immunohistochemistry. Intrarectal administration of XLS attenuated the DSS-induced colitis, as evidenced by a reduction in both the histological damage score and myeloperoxidase activity. It also decreased the levels of proinflammatory cytokines, but increased the mucosal repair-related cytokines. In addition, the epithelial Ki-67 expression was upregulated by XLS. These results suggest that XLS attenuates DSS-induced colitis by degrading proinflammatory mediators and promoting mucosal repair. XLS could be a potential topical treatment for human UC.

Effects of Changtai granules, a traditional compound Chinese medicine, on chronic trinitrobenzene sulfonic acid-induced colitis in rats

PubMed Central

Cao, Yong-Bing; Zhang, Jun-Dong; Diao, Ya-Ying; Yan, Lan; Wang, De-Jun; Jia, Xin-Ming; Gao, Ping-Hui; Cheng, Ming-He; Xu, Zheng; Wang, Yan; Jiang, Yuan-Ying

2005-01-01

AIM: To study the effects of Changtai granules (CTG), a traditional compound Chinese medicine, on chronic trinitrobenzene sulfonic acid-induced colitis in rats. METHODS: Healthy adult Sprague-Dawley (SD) rats of both sexes, weighing 250-300 g, were employed in the present study. The rat colitis models were induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) enemas at a concentration of 100 mg/kg in 50% ethanol. The experimental animals were randomly divided into dexamethasone (DX) treatment, CTG treatment, and model control groups, which were intracolicly treated daily with DX (0.2 mg/kg), CTG at doses of 2.9, 5.7 and 11.4 g crude drug/kg, and the equal amount of saline respectively from 6 h following induction of the colitis in rats inflicted with TNBS to the end of study. A normal control group of rats treated without TNBS but saline enema was also included in the study. After 3 wk of treatment, the animals were assessed for colonal inflammatory and ulcerative responses with respect to mortality, frequency of diarrhea, histology and myeloperoxidase activity (MPO). RESULTS: The therapeutic effect of CTG on ulcerative colitis (UC) was better than DX. CTG effectively inhibited the activity of granulocytes, macrophages and monocytes in a dose-dependent manner. Also it reduced MPO and formation of inflammation in colonic mucosal tissue. Furthermore, administration of CTG significantly prevented body mass loss and death, and decreased frequency of diarrhea in UC rats, when compared with the model control group rats. CONCLUSION: CTG would prove to be an ideal drug for chronic UC, and is warranted to be studied further. PMID:15962370

Aronia melanocarpa fruit juice ameliorates the symptoms of inflammatory bowel disease in TNBS-induced colitis in rats.

PubMed

Valcheva-Kuzmanova, Stefka; Kuzmanov, Atanas; Kuzmanova, Vasilena; Tzaneva, Maria

2018-03-01

Trinitrobenzensulfonic acid (TNBS) is commonly used to induce an experimental inflammatory bowel disease (IBD) model. Oxidative stress and inflammation have been proposed as mechanisms underlying the pathophysiology of IBD. Aronia melanocarpa fruit juice (AMFJ) is extremely rich in polyphenolic substances, mainly proanthocyanidins, flavonoids and phenolic acids. The aim of this study was to evaluate the effect of AMFJ in a rat TNBSinduced colitis model and to compare the effect of the juice with that of sulfasalazine. Colitis was induced by TNBS in male Wistar rats. After the induction of colitis, AMFJ at three doses (2.5, 5 and 10 mL/kg) and sulfasalazine (400 mg/kg) were administered orally till the 14th experimental day. Severity of colitis was assessed by macroscopic and histopathological criteria. Oxidative stress was evaluated by the concentration of thiobarbituric acid reactive substances (TBARS). TNBS caused severe colonic damage. AMFJ dose-dependently ameliorated TNBS-induced colitis. It improved the macroscopic and microscopic signs of colitis, and prevented the increase of colonic TBARS concentrations. Regarding different indices, the effect of AMFJ was comparable or even higher than that of sulfasalazine. In conclusion, the ameliorative effects of AMFJ in the experimental TNBSinduced colitis might be the result of its potent antioxidant and antiinflammatory properties. Copyright © 2018 Elsevier Ltd. All rights reserved.

The protective effects of magnolol on acute trinitrobenzene sulfonic acid‑induced colitis in rats.

PubMed

Zhang, Yong; Fu, Li-Tang; Tang, Fang

2018-03-01

The present study aimed to investigate the protective effects of magnolol on acute 2,4,6-trinitrobenzene sulfonic acid (TNBS)‑induced colitis, and its underlying mechanisms. Experimental colitis was induced by intracolonic administration of TNBS/ethanol into rats. The model rats were randomly assigned into groups: TNBS, magnolol (high, medium and low doses), and salazosulfapyridine (positive control). All intervention regimens were administered by oral gavage, once a day for 7 consecutive days, 24 h after colitis induction. Histological and biochemical changes in colonic inflammation were evaluated by hematoxylin and eosin and immunohistochemistry, respectively. Rats treated with all doses of magnolol exhibited decreased colonic myeloperoxidase activity (P<0.05 vs. TNBS), reduced serum levels of proinflammatory cytokines [including interleukin (IL)‑6 and IL‑17], and downregulated Toll‑like receptor-4 (TLR‑4) mRNA expression. Histological analysis revealed that medium and high doses of magnolol conferred an anti‑inflammatory effect, which was indicated by a decrease in disease activity index, an increase in thymus index, and downregulation of nuclear factor (NF)‑κB p65 mRNA and TLR‑4 protein expression. However, only high‑dose magnolol significantly ameliorated the elevated colon weight/length ratio. The results of the present study indicate that magnolol exerts protective effects against acute TNBS‑induced colitis in rats, and the TLR‑4/NF‑κB signaling pathway‑mediated inhibitory effect on inflammatory cascades may contribute to the protective activity of magnolol.

Intervention effects of QRZSLXF, a Chinese medicinal herb recipe, on the DOR-β-arrestin1-Bcl2 signal transduction pathway in a rat model of ulcerative colitis.

PubMed

Fan, Heng; Liu, Xing-xing; Zhang, Li-juan; Hu, Hui; Tang, Qing; Duan, Xue-yun; Zhong, Min; Shou, Zhe-xing

2014-05-28

Qingre Zaoshi Liangxue Fang (QRZSLXF) is a Chinese medicinal herb recipe that is commonly prescribed for the treatment of ulcerative colitis. It includes 5 quality assured herbs: Sophora flavescens Aiton., Baphicacanthus cusia (Nees) Bremek., Bletilla striata Rchb.f., Glycyrrhiza uralensis Fisch. and Coptis chinensis Franch. The main phytochemical ingredient of QRZSLXF includes ammothamnine, sophocarpidine, liquiritin, berberine and indirubin. QRZSLXF has been clinically proven for use in the treatment of ulcerative colitis for over twenty years. In the past ten years, research has confirmed the therapeutic effect of QRZSLXF in ulcerative colitis and partially revealed its mechanism of action. Here, we further reveal the therapeutic mechanism of QRZSLXF in ulcerative colitis. To investigate the role of the DOR-β-arrestin1-Bcl-2 signal transduction pathway in ulcerative colitis and to determine the effects of QRZSLXF on this signal transduction pathway. Eighty-four Sprague-Dawley rats were randomly divided into six groups: normal control group, model group, mesalazine group, and QRZSLXF high-dose, medium-dose group and low-dose groups (n=14). Experimental colitis was induced by trinitrobenzenesulfonic acid (TNBS) in each group, except the normal control group. After modeling, bloody stool, mental state and diarrhea were observed and recorded. Two rats were randomly selected from the model groups adfnd sacrificed on day 3 to observe pathological changes in the colon tissue by microscopy. The rats in the QRZSLXF-treated groups received intramuscular injections of different concentrations of QRZSLXF for 15 days. The rats in the mesalazine group were treated with mesalazine solution (0.5 g/kg/day) by gastric lavage for 15 days. The rats in the normal control group and the model group were treated with 3 mL water by gastric lavage for 15 days. On the 16th day, after fasting for 24 h, the remaining rats were sacrificed and their colon tissues were used to detect the m

Antiinflammatory effects of Cordia myxa fruit on experimentally induced colitis in rats.

PubMed

Al-Awadi, F M; Srikumar, T S; Anim, J T; Khan, I

2001-05-01

Products of certain species of Cordia are reported to have antiinflammatory properties. In the present study we examined the effects of Cordia myxa fruit on experimentally induced colitis in rats. Colitis was induced by intrarectal administration of 4% acetic acid. Colitic, normal, and corresponding control animals were included. Body weight was recorded daily. All the animals were sacrificed 4 days after the fruit treatment. Colitis was monitored histologically and by activity of myeloperoxidase. Glutathione peroxidase, superoxide dismutase, as well as total antioxidant status and concentrations of zinc, copper, manganese, selenium, and iron were assayed in plasma, liver, and colon using standard methods. Histology of the colon of colitic rats showed acute colitis that was confirmed by a significant increase in the myeloperoxidase activity. Colitis was associated with significant decreases in the tissue activities of glutathione peroxidase and superoxide dismutase and lower concentrations of trace elements. Histologic examination and myeloperoxidase activity showed that the fruit treatment reversed the above findings in the inflamed colon, and in liver and plasma of colitic rats. The present results suggest that the observed antiinflammatory effect of the Cordia myxa may be attributed partly to its antioxidant property and to restoration of the levels of trace elements in the inflamed colon, liver, and plasma.

Protective Effect of Ocimum basilicum Essential Oil Against Acetic Acid-Induced Colitis in Rats.

PubMed

Rashidian, Amir; Roohi, Parnia; Mehrzadi, Saeed; Ghannadi, Ali Reza; Minaiyan, Mohsen

2016-10-01

Ocimum basilicum L has been traditionally used for the treatment of inflammatory bowel disease in Iran. This study investigates the ameliorative effect of Ocimum basilicum essential oil on an acetic acid-induced colitis model in rats. Ocimum basilicum essential oil with 2 doses (200 and 400 μL/kg) significantly ameliorated wet weight/length ratio of colonic tissue compared to the control group. Higher doses of essential oil (200 and 400 μL/kg) significantly reduced ulcer severity, ulcer area, and ulcer index. On the other hand, histological examination revealed the diminution of total colitis index as a marker for inflammatory cell infiltration in the colonic segments of rats treated with Ocimum basilicum essential oil (200 and 400 μL/kg). The increased level of myeloperoxidase was significantly decreased after the treatment with the essential oil (200 and 400 μL/kg). These results suggest that Ocimum basilicum exhibits protective effect against acetic acid-induced colitis. © The Author(s) 2015.

Protective effects of black cumin (Nigella sativa) oil on TNBS-induced experimental colitis in rats.

PubMed

Isik, F; Tunali Akbay, Tugba; Yarat, A; Genc, Z; Pisiriciler, R; Caliskan-Ak, E; Cetinel, S; Altıntas, A; Sener, G

2011-03-01

The pathogenesis and treatment of ulcerative colitis remain poorly understood. The aim of the present study is to investigate the effects of black cumin (Nigella sativa) oil on rats with colitis. Experimental colitis was induced with 1 mL trinitrobenzene sulfonic acid (TNBS) in 40% ethanol by intracolonic administration with 8-cm-long cannula under ether anesthesia to rats in colitis group and colitis + black cumin oil group. Rats in the control group were given saline at the same volume by intracolonic administration. Black cumin oil (BCO, Origo "100% natural Black Cumin Seed Oil," Turkey) was given to colitis + black cumin oil group by oral administration during 3 days, 5 min after colitis induction. Saline was given to control and colitis groups at the same volume by oral administration. At the end of the experiment, macroscopic lesions were scored and the degree of oxidant damage was evaluated by colonic total protein, sialic acid, malondialdehyde, and glutathione levels, collagen content, and tissue factor, superoxide dismutase, and myeloperoxidase activities. Tissues were also examined by histological and cytological analysis. Proinflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6], lactate dehydrogenase activity, and triglyceride and cholesterol levels were analyzed in blood samples. We found that black cumin oil decreased the proinflammatory cytokines, lactate dehydrogenase, triglyceride, and cholesterol, which were increased in colitis. BCO, by preventing inflammatory status in the blood, partly protected colonic tissue against experimental ulcerative colitis.

Nitric oxide released by Lactobacillus farciminis improves TNBS-induced colitis in rats.

PubMed

Lamine, F; Fioramonti, J; Bueno, L; Nepveu, F; Cauquil, E; Lobysheva, I; Eutamène, H; Théodorou, V

2004-01-01

Beneficial effects of lactobacilli have been reported in experimental colitis. On the other hand, despite the controversial role of nitric oxide (NO) in the inflammatory gut process, a protective action of exogenous NO in inflammation has been suggested. Consequently, this study aimed to determine the effect of (i) sodium nitroprusside (SNP), a NO donor and (ii) treatment with Lactobacillus farciminis, which produces NO in vitro, on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats and to evaluate the role of exogenous NO in this effect. Rats were divided into three groups receiving one of the following: (i) a continuous intracolonic (IC) infusion of SNP for 4 days, (ii) L. farciminis orally for 19 days, or (iii) saline. On day 1 and day 15, respectively, TNBS and saline were administrated IC, followed by a continuous IC infusion of saline or haemoglobin, a NO scavenger. At the end of treatments, the following parameters were evaluated: macroscopic damage of colonic mucosa, myeloperoxidase and nitric oxide synthase activities and colonic luminal NO production. In colitic rats, SNP and L. farciminis treatment significantly (P < 0.05) reduced macroscopic damage scores, myeloperoxidase and nitric oxide synthase activities compared to controls. Haemoglobin infusion abolished the anti-inflammatory effect of both NO donor treatments, but had no effect per se on colitis. NO released intraluminally by SNP infusion or by L. farciminis given orally improves TNBS-induced colitis in rats. These results indicate a protective role of NO donation in colonic inflammation and show for the first time a mechanism involving NO delivery by a bacterial strain reducing an experimental colitis.

The effect of stinging nettle (Urtica dioica) seed oil on experimental colitis in rats.

PubMed

Genc, Zeynep; Yarat, Aysen; Tunali-Akbay, Tugba; Sener, Goksel; Cetinel, Sule; Pisiriciler, Rabia; Caliskan-Ak, Esin; Altıntas, Ayhan; Demirci, Betul

2011-12-01

This study investigated the effect of Urtica dioica, known as stinging nettle, seed oil (UDO) treatment on colonic tissue and blood parameters of trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. Experimental colitis was induced with 1 mL of TNBS in 40% ethanol by intracolonic administration with a 8-cm-long cannula with rats under ether anesthesia, assigned to a colitis group and a colitis+UDO group. Rats in the control group were given saline at the same volume by intracolonic administration. UDO (2.5 mL/kg) was given to the colitis+UDO group by oral administration throughout a 3-day interval, 5 minutes later than colitis induction. Saline (2.5 mL/kg) was given to the control and colitis groups at the same volume by oral administration. At the end of the experiment macroscopic lesions were scored, and the degree of oxidant damage was evaluated by colonic total protein, sialic acid, malondialdehyde (MDA), and glutathione levels, collagen content, tissue factor activity, and superoxide dismutase and myeloperoxidase activities. Colonic tissues were also examined by histological and cytological analysis. Pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6), lactate dehydrogenase activity, and triglyceride and cholesterol levels were analyzed in blood samples. We found that UDO decreased levels of pro-inflammatory cytokines, lactate dehydrogenase, triglyceride, and cholesterol, which were increased in colitis. UDO administration ameliorated the TNBS-induced disturbances in colonic tissue except for MDA. In conclusion, UDO, through its anti-inflammatory and antioxidant actions, merits consideration as a potential agent in ameliorating colonic inflammation.

Preventative effects of a probiotic, Lactobacillus salivarius ssp. salivarius, in the TNBS model of rat colitis

PubMed Central

Peran, Laura; Camuesco, Desiree; Comalada, Monica; Nieto, Ana; Concha, Angel; Diaz-Ropero, Maria Paz; Olivares, Monica; Xaus, Jordi; Zarzuelo, Antonio; Galvez, Julio

2005-01-01

AIM: To investigate the intestinal anti-inflammatory effect and mechanism of a probiotic Lactobacillus salivarius ssp. salivarius CECT5713 in the TNBS model of rat colitis. METHODS: Female Wistar rats (180-200 g) were used in this study. A group of rats were administered orally the probiotic L. salivarius ssp. salivarius (5×108 CFU suspended in 0.5 mL of skimmed milk) daily for 3 wk. Two additional groups were used for reference, a non-colitic and a control colitic without probiotic treatment, which received orally the vehicle used to administer the probiotic. Two weeks after starting the experiment, the rats were rendered colitic by intracolonic administration of 10 mg of TNBS dissolved in 0.25 mL of 500 mL/L ethanol. One week after colitis induction, all animals were killed and colonic damage was evaluated both histologically and biochemically. The biochemical studies performed in colonic homogenates include determination of myeloperoxidase (MPO) activity, glutathione (GSH) content, leukotriene B4 (LTB4) and tumor necrosis factor α (TNF-α) levels, as well as inducible nitric oxide synthase (iNOS) expression. In addition, the luminal contents obtained from colonic samples were used for microbiological studies, in order to determine Lactobacilli and Bifidobacteria counts. RESULTS: Treatment of colitic rats with L. salivarius ssp. salivarius resulted in amelioration of the inflammatory response in colitic rats, when compared with the corresponding control group without probiotic treatment. This anti-inflammatory effect was evidenced macroscopically by a significant reduction in the extent of colonic necrosis and/or inflammation induced by the administration of TNBS/ethanol (2.3±0.4 cm vs 3.4±0.3 cm in control group, P<0.01) and histologically by improvement of the colonic architecture associated with a reduction in the neutrophil infiltrate in comparison with non-treated colitic rats. The latter was confirmed biochemically by a significant reduction of colonic

Adoptive transfer of nontransgenic mesenteric lymph node cells induces colitis in athymic HLA-B27 transgenic nude rats

PubMed Central

Hoentjen, F; Tonkonogy, S L; Liu, B; Sartor, R B; Taurog, J D; Dieleman, L A

2006-01-01

HLA-B27 transgenic (TG) rats develop spontaneous colitis when colonized with intestinal bacteria, whereas athymic nude (rnu/rnu) HLA-B27 TG rats remain disease free. The present study was designed to determine whether or not HLA-B27 expression on T cells is required for development of colitis after transfer of mesenteric lymph node (MLN) cells into rnu/rnu HLA-B27 recipients. Athymic nontransgenic (non-TG) and HLA-B27 TG recipients received MLN cells from either TG or non-TG rnu/+ heterozygous donor rats that contain T cells. HLA-B27 TG rnu/rnu recipients receiving either non-TG or TG MLN cells developed severe colitis and had higher caecal MPO and IL-1β levels, and their MLN cells produced more IFN-γ and less IL-10 after in vitro stimulation with caecal bacterial lysate compared to rnu/rnu non-TG recipients that remained disease free after receiving either TG or non-TG cells. Interestingly, proliferating donor TG T cells were detectable one week after adoptive transfer into rnu/rnu TG recipients but not after transfer into non-TG recipients. T cells from either non-TG or TG donors induce colitis in rnu/rnu TG but not in non-TG rats, suggesting that activation of effector T cells by other cell types that express HLA-B27 is pivotal for the pathogenesis of colitis in this model. PMID:16487247

Anti-inflammatory effects of nesfatin-1 in rats with acetic acid - induced colitis and underlying mechanisms.

PubMed

Ozturk, C C; Oktay, S; Yuksel, M; Akakin, D; Yarat, A; Kasimay Cakir, O

2015-10-01

Mucosal balance impairment, bacterial over-proliferation, cytokines, inflammatory mediators are known as responsible for inflammatory bowel disease. Besides known anorexigenic, neuroprotective, and anti-apoptotic effects, the major effect of nesfatin-1 on colitis is unknown. Our aim was to investigate the possible anti-inflammatory effects of nesfatin-1 in acetic acid induced colitis model and potential underlying mechanisms. Male Spraque-Dawley rats were anesthetized by intraperitoneal ketamine (100 mg/kg) and chlorpromazine (0.75 mg/kg). For nesfatin-1 and antagonist applications some of the rats were intracerebroventricularly (i.c.v.) cannulated. In colitis group, intrarectally (i.r.) 4% acetic acid solution (1 ml) and 10 minutes later i.c.v. nesfatin-1 (0.05 μg/5 μl) or vehicle (5 μl) were administered. Treatments continued for 3 days. In control group, physiological saline solution was used intrarectally. To identify the underlying effective mechanism of nesfatin-1, rats were divided into 3 subgroups, 5 minutes following colitis induction; i.c.v. atosiban (oxytocin receptor antagonist), SHU9119 (melanocortin receptor antagonist) or GHSR-1a antagonist (ghrelin receptor antagonist) were administered, 5 minutes later nesfatin-1 was administered for 3 days. On the fourth day, rats were decapitated, and colon tissues were sampled. Macroscopic and microscopic damage scores of distal colon, and colonic tissue malondialdehyde, glutathione, myeloperoxidase, superoxide dismutase, catalase, luminol and lucigenin chemiluminescence measurements were analysed. The increased myeloperoxidase activity, malondialdehyde levels, luminol and lucigenin chemiluminescence measurements, macroscopic and microscopic damage scores with colitis induction (P < 0.05 - 0.001) were decreased with nesfatin-1 treatment (P < 0.05 - 0.001). Nesfatin-1 may show this effect by inhibiting neutrophil infiltration through tissues and by decreasing formation of free oxygen radicals. Atosiban and

Supplemental calcium attenuates the colitis-related increase in diarrhea, intestinal permeability, and extracellular matrix breakdown in HLA-B27 transgenic rats.

PubMed

Schepens, Marloes A A; Schonewille, Arjan J; Vink, Carolien; van Schothorst, Evert M; Kramer, Evelien; Hendriks, Thijs; Brummer, Robert-Jan; Keijer, Jaap; van der Meer, Roelof; Bovee-Oudenhoven, Ingeborg M J

2009-08-01

We have shown in several controlled rat and human infection studies that dietary calcium improves intestinal resistance and strengthens the mucosal barrier. Reinforcement of gut barrier function may alleviate inflammatory bowel disease (IBD). Therefore, we investigated the effect of supplemental calcium on spontaneous colitis development in an experimental rat model of IBD. HLA-B27 transgenic rats were fed a purified high-fat diet containing either a low or high calcium concentration (30 and 120 mmol CaHPO4/kg diet, respectively) for almost 7 wk. Inert chromium EDTA (CrEDTA) was added to the diets to quantify intestinal permeability by measuring urinary CrEDTA excretion. Relative fecal wet weight was determined to quantify diarrhea. Colonic inflammation was determined histologically and by measuring mucosal interleukin (IL)-1beta. In addition, colonic mucosal gene expression of individual rats was analyzed using whole-genome microarrays. The calcium diet significantly inhibited the increase in intestinal permeability and diarrhea with time in HLA-B27 rats developing colitis compared with the control transgenic rats. Mucosal IL-1beta levels were lower in calcium-fed rats and histological colitis scores tended to be lower (P = 0.08). Supplemental calcium prevented the colitis-induced increase in the expression of extracellular matrix remodeling genes (e.g. matrix metalloproteinases, procollagens, and fibronectin), which was confirmed by quantitative real-time PCR and gelatin zymography. In conclusion, dietary calcium ameliorates several important aspects of colitis severity in HLA-B27 transgenic rats. Reduction of mucosal irritation by luminal components might be part of the mechanism. These results show promise for supplemental calcium as effective adjunct therapy for IBD.

BTZO-15, an ARE-Activator, Ameliorates DSS- and TNBS-Induced Colitis in Rats

PubMed Central

Yukitake, Hiroshi; Kimura, Haruhide; Suzuki, Hirobumi; Tajima, Yasukazu; Sato, Yoshimi; Imaeda, Toshihiro; Kajino, Masahiro; Takizawa, Masayuki

2011-01-01

Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders that are primarily represented by ulcerative colitis and Crohn's disease. The etiology of IBD is not well understood; however, oxidative stress is considered a potential etiological and/or triggering factor for IBD. We have recently reported the identification of BTZO-1, an activator of antioxidant response element (ARE)-mediated gene expression, which protects cardiomyocytes from oxidative stress-induced insults. Here we describe the potential of BTZO-15, an active BTZO-1 derivative for ARE-activation with a favorable ADME-Tox profile, for the treatment of IBD. BTZO-15 induced expression of heme oxygenase-1 (HO-1), an ARE-regulated cytoprotective protein, and inhibited NO-induced cell death in IEC-18 cells. Large intestine shortening, rectum weight gain, diarrhea, intestinal bleeding, and an increase in rectal myeloperoxidase (MPO) activity were observed in a dextran sulfate sodium (DSS)-induced colitis rat model. Oral administration of BTZO-15 induced HO-1 expression in the rectum and attenuated DSS-induced changes. Furthermore BTZO-15 reduced the ulcerated area and rectal MPO activity in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rats without affecting rectal TNF-α levels. These results suggest that BTZO-15 is a promising compound for a novel IBD therapeutic drug with ARE activation properties. PMID:21853095

Pharmacokinetic alterations of rhubarb anthraquinones in experimental colitis induced by dextran sulfate sodium in the rat.

PubMed

Wu, Wen-Jin; Yan, Ru; Li, Ting; Li, Ya-Ping; Zhou, Rui-Na; Wang, Yi-Tao

2017-02-23

Rhubarb (Rhei Rhizoma et Radix) is used for the treatment of digestive diseases in traditional medicinal practice in China. Recent studies also support its beneficial activities in alleviating ulcerative colitis (UC). This study aimed to characterize the oral pharmacokinetics of rhubarb anthraquinones, the main bioactive components of this herb, in the experimental chronic colitis rat model induced by dextran sulfate sodium (DSS) and to identify the factors causing the pharmacokinetic alterations. Rats received drinking water (normal group) or 5% DSS for the first 7 days and 3% DSS for additional 14 days (UC group). On day 21 both groups received an oral dose of the rhubarb extract (equivalent to 5.0g crude drug/kg body weight). Plasma anthraquinone aglycones levels were determined directly by an LC-MS/MS method and the total of each anthraquinone (aglycone+conjugates) was quantified after β-glucuronidases hydrolysis. Rhubarb anthraquinones predominantly existed as conjugates in plasma samples from both groups and only free aloe-emodin, rhein and emodin were detected. Compared to the normal rats, both C max and AUC of the three free anthraquinones were increased, while the systemic exposure (AUC) of the total (aglycone+conjugates) of most anthraquinones decreased by UC accompanied by the disappearance of multiple-peak phenomenon in the plasma concentration-time profiles. Gut bacteria from UC rats exhibited a decreased activity in hydrolyzing anthraquinone glycosides to form respective aglycone and there were significant decreases in microbial β-glucosidases and β-glucuronidases activities. Moreover, the intestinal microsomes from UC rats catalyzed glucuronidation of free anthraquinones with higher activities, while the activities of hepatic microsomes were comparable to normal rats. The decreases of β-glucuronidases activity in DSS-induced chronic rat colitis should mainly account for the decreases in systemic exposure and abrogation of enterohepatic

Granisetron ameliorates acetic acid-induced colitis in rats.

PubMed

Fakhfouri, Gohar; Rahimian, Reza; Daneshmand, Ali; Bahremand, Arash; Rasouli, Mohammad Reza; Dehpour, Ahmad Reza; Mehr, Shahram Ejtemaei; Mousavizadeh, Kazem

2010-04-01

Inflammatory bowel disease (IBD) is a chronically relapsing inflammation of the gastrointestinal tract, of which the definite etiology remains ambiguous. Considering the adverse effects and incomplete efficacy of currently administered drugs, it is indispensable to explore new candidates with more desirable therapeutic profiles. 5-HT( 3) receptor antagonists have shown analgesic and anti-inflammatory properties in vitro and in vivo. This study aims to investigate granisetron, a 5-HT( 3) receptor antagonist, in acetic acid-induced rat colitis and probable involvement of 5-HT(3) receptors. Colitis was rendered by instillation of 1 mL of 4% acetic acid (vol/vol) and after 1 hour, granisetron (2 mg/kg), dexamethasone (1 mg/kg), meta-chlorophenylbiguanide (mCPBG, 5 mg/kg), a 5-HT( 3) receptor agonist, or granisetron + mCPBG was given intraperitoneally. Twenty-four hours following colitis induction, animals were sacrificed and distal colons were assessed macroscopically, histologically and biochemically (malondialdehyde, myeloperoxidase, tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6). Granisetron or dexamethasone significantly (p < .05) improved macroscopic and histologic scores, curtailed myeloperoxidase activity and diminished colonic levels of inflammatory cytokines and malondialdehyde. The protective effects of granisetron were reversed by concurrent administration of mCPBG. Our data suggests that the salutary effects of granisetron in acetic acid colitis could be mediated by 5-HT(3) receptors.

The dual anti-inflammatory and antioxidant activities of natural honey promote cell proliferation and neural regeneration in a rat model of colitis.

PubMed

Nooh, Hanaa Z; Nour-Eldien, Nermeen M

2016-07-01

A decreased antioxidant capacity and excessive inflammation are well-known features in the pathogenesis of ulcerative colitis (UC). Recent evidence has suggested a role of honey in reducing colitis-induced inflammatory and oxidative stress markers. In this study, we examined whether the anti-inflammatory and anti-oxidative properties of honey have a beneficial effect on the enteric innervation and cellular proliferation of UC in rat. The colitis was induced in rats by dextran sodium sulphate (DSS). The effect of natural honey on induced colitis was assessed by the following parameters in colonic samples: tissue injury, inflammatory infiltration, interleukin-1β and -6, superoxide dismutase and reduced glutathione. In addition, the expression of tumour necrosis factor-α, inducible NO synthase, caspase-3, CD34, Ki67, S100, c-kit, and neuron-specific enolase were examined by immunohistochemistry. Compared to the DSS-induced colitis group, the honey-treated group had significantly improved macroscopic and microscopic scores and exhibited the down-regulation of oxidative, inflammatory, and apoptotic markers. In addition, up-regulation of intrinsic muscular innervation and epithelial cellular proliferation markers was detected. These results provide new insight into the beneficial role of natural honey in the treatment of DSS-induced colitis via the inhibition of colonic motor dysfunction and the inflammatory-oxidative-apoptotic cascade. In addition, the role of honey in epithelial regeneration was clarified. Copyright © 2016 Elsevier GmbH. All rights reserved.

Sodium selenite ameliorates both intestinal and extra-intestinal changes in acetic acid-induced colitis in rats.

PubMed

Soliman, Samar M; Wadie, Walaa; Shouman, Samia A; Ainshoka, Afaf A

2018-06-01

Selenium and its derivatives including sodium selenite (sod sel) belong to the group of essential trace elements needed for proper health and nutrition. They are fairly safe and possess antioxidant and anti-inflammatory properties. The aim of present investigation was to elucidate the effect of sod sel on experimental colitis model in rats. Colitis was induced by intrarectal instillation of 4% (v/v) acetic acid. Two hours later, sod sel was given to rats on a daily basis for 15 consecutive days. Clinical symptoms, colon mass index, spleen weight inflammatory markers, hematological, biochemical, macroscopic, and histological changes were determined. Sod sel markedly ameliorated colitis as evidenced by a significant decrease in macroscopic and microscopic score, disease activity index, colon mass index, and spleen weight. Treatment with sod sel attenuated oxidative stress in the colon by normalizing the colonic content of nitric oxide, malondialdehyde, and reduced glutathione, as well as the activities of catalase, superoxide dismutase, and junctional adhesion molecule (JAM-a). In addition, it significantly reduced colonic myeloperoxidase content, the intercellular adhesion molecule (ICAM-1), and the proinflammatory cytokines; TNF-α, IL-1β. Moreover, sod sel normalized hematological parameters, serum transaminases, and kidney and liver function enzymes. The current study indicates that sod sel was effective in ameliorating the intestinal and extra-intestinal manifestation in acetic acid-induced colitis through its antioxidant, anti-inflammatory, and immunomodulatory effects.

Effect of royal jelly on experimental colitis induced by acetic acid and alteration of mast cell distribution in the colon of rats

PubMed Central

Karaca, T.; Bayiroglu, F.; Yoruk, M.; Kaya, M.S.; Uslu, S.; Comba, B.; Mis, L.

2010-01-01

This study investigated the effects of royal jelly (RJ) on acetic acid-induced colitis in rats. Twenty adult female Wistar albino rats were divided into four treatment groups of 5 animals each, including a control group (Group I); Group II was treated orally with RJ (150 mg kg−1 body weight); Group III had acetic acid-induced colitis; and Group IV had acetic acid-induced colitis treated orally with RJ (150 mg kg−1 body weight) for 4 weeks. Colitis was induced by intracolonic instillation of 4% acetic acid; the control group received physiological saline (10 mL kg−1). Colon samples were obtained under deep anaesthesia from animals in all groups. Tissues were fixed in 10% formalin neutral buffer solution for 24 h and embedded in paraffin. Six-micrometre-thick sections were stained with Mallory’s triple stain and toluidine blue in 1% aqueous solution at pH 1.0 for 5 min (for Mast Cells). RJ was shown to protect the colonic mucosa against the injurious effect of acetic acid. Colitis (colonic damage) was confirmed histomorphometrically as significant increases in the number of mast cells (MC) and colonic erosions in rats with acetic acid-induced colitis. The RJ treatment significantly decreased the number of MC and reduced the area of colonic erosion in the colon of RJ-treated rats compared with rats with untreated colitis. The results suggest that oral treatment with RJ could be used to treat colitis. PMID:21263740

TRPV1 receptors on unmyelinated C-fibres mediate colitis-induced sensitization of pelvic afferent nerve fibres in rats

PubMed Central

De Schepper, H U; De Winter, B Y; Van Nassauw, L; Timmermans, J-P; Herman, A G; Pelckmans, P A; De Man, J G

2008-01-01

Patients with inflammatory bowel disease often suffer from gastrointestinal motility and sensitivity disorders. The aim of the current study was to investigate the role of transient receptor potential of the vanilloid type 1 (TRPV1) receptors in the pathophysiology of colitis-induced pelvic afferent nerve sensitization. Trinitrobenzene sulphate (TNBS) colitis (7.5 mg, 30% ethanol) was induced in Wistar rats 72 h prior to the experiment. Single-fibre recordings were made from pelvic nerve afferents in the decentralized S1 dorsal root. Fibres responding to colorectal distension (CRD) were identified in controls and rats with TNBS colitis. The effect of the TRPV1 antagonist N-(4-tertiarybutylphenyl)-4-(3-chlorophyridin-2-yl)tetrahydropyrazine-1(2H)carboxamide (BCTC; 0.25–5 mg kg−1) or its vehicle (hydroxypropyl-β-cyclodextrin) was tested on the afferent response to repetitive distensions (60 mmHg). Immunocytochemical staining of TRPV1 and NF200, a marker for A-fibre neurons, was performed in the dorsal root ganglia L6–S1. TNBS colitis significantly increased the response to colorectal distension of pelvic afferent C-fibres. BCTC did not significantly affect the C-fibre response in controls, but normalized the sensitized response in rats with colitis. TNBS colitis increased the spontaneous activity of C-fibres, an effect which was insensitive to administration of BCTC. TNBS colitis had no effect on Aδ-fibres, nor was their activity modulated by BCTC. TNBS colitis caused an immunocytochemical up-regulation of TRPV1 receptors in the cell bodies of pelvic afferent NF200 negative neurons. TRPV1 signalling mediates the colitis-induced sensitization of pelvic afferent C-fibres to CRD, while Aδ-fibres are neither sensitized by colitis nor affected by TRPV1 inhibition. PMID:18755744

Intestinal anti-inflammatory activity of apigenin K in two rat colitis models induced by trinitrobenzenesulfonic acid and dextran sulphate sodium.

PubMed

Mascaraque, Cristina; González, Raquel; Suárez, María Dolores; Zarzuelo, Antonio; Sánchez de Medina, Fermín; Martínez-Augustin, Olga

2015-02-28

Flavonoids are polyphenolic compounds that are widespread in nature, and consumed as part of the human diet in significant amounts. The aim of the present study was to test the intestinal anti-inflammatory activity of apigenin K, a soluble form of apigenin, in two models of rat colitis, namely the trinitrobenzenesulfonic acid (TNBS) model and the dextran sulphate sodium (DSS) model. Apigenin K (1, 3 and 10 mg/kg; by the oral route; n 4-6 per group) was administered as a pre-treatment to rats with TNBS and DSS colitis, and colonic status was checked by macroscopic and biochemical examination. Apigenin K pre-treatment resulted in the amelioration of morphological signs and biochemical markers in the TNBS model. The results demonstrated a reduction in the inflamed area, as well as lower values of score and colonic weight:length ratio compared with the TNBS group. Myeloperoxidase (MPO) activity was reduced by 30 % (P< 0·05). Moreover, apigenin K pre-treatment ameliorated morphological signs and biochemical markers in the DSS model. Thus, macroscopic damage was significantly reduced and the colonic weight:length ratio was lowered by approximately 10 %, while colonic MPO and alkaline phosphatase activities were decreased by 35 and 21 %, respectively (P< 0·05). Apigenin K pre-treatment also tended to normalise the expression of a number of colonic inflammatory markers (e.g. TNF-α, transforming growth factor-β, IL-6, intercellular adhesion molecule 1 or chemokine (C-C motif) ligand 2). In conclusion, apigenin K is found to have anti-inflammatory effects in two preclinical models of inflammatory bowel disease.

Anti-inflammatory effect of Helichrysum oligocephalum DC extract on acetic acid — Induced acute colitis in rats

PubMed Central

Minaiyan, Mohsen; Ghassemi-Dehkordi, Nasrollah; Mahzouni, Parvin; Ahmadi, Najme-Sadat

2014-01-01

Background: Helichrysum oligocephalum DC. from Asteraceae family is an endemic plant growing wild in Iran. This study was carried out to investigate the effect of H. oligocephalum hydroalcoholic extract (HOHE) on ulcerative colitis (UC) induced by acetic acid (AA) in rats. Materials and Methods: Rats were grouped (n = 6) and fasted for 24 h before colitis induction. Treatments were started 2 h before the induction of colitis and continued for two consecutive days with different doses of HOHE (100, 200, and 400 mg/kg) orally (p.o.) and intraperitoneally (i.p.). The colon tissue was removed and tissue damages were scored after macroscopic and histopathologic assessments. Results: Among the examined doses of HOHE, 100 mg/kg was the most effective dose that reduced the extent of UC lesions and resulted in significant alleviation. Weight/length ratio as an index of tissue inflammation and extravasation was also diminished in the treatment group administered HOHE at a dose of 100 mg/kg, and the results showed correlation with macroscopic and histopathologic evaluations. These data suggest that HOHE (100 mg/kg) administered either p.o. or i.p. was effective in diminishing inflammation and ulcer indices in this murine model of acute colitis in a non–dose-related manner. Conclusions: H. oligocephalum could be considered as a suitable anticolitis alternative; however, further studies are needed to support this hypothesis for clinical setting. PMID:24761395

The probiotic mixture IRT5 ameliorates age-dependent colitis in rats.

PubMed

Jeong, Jin-Ju; Woo, Jae-Yeon; Ahn, Young-Tae; Shim, Jae-Hun; Huh, Chul-Sung; Im, Sin-Heog; Han, Myung Joo; Kim, Dong-Hyun

2015-06-01

To investigate the anti-inflammatory effect of probiotics, we orally administered IRT5 (1×10(9)CFU/rat) for 8 weeks to aged (16 months-old) Fischer 344 rats, and measured parameters of colitis. The expression levels of the inflammatory markers' inducible NO synthase (iNOS), cyclooxygenase-2 (COX2), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β were higher in the colons of normal aged rats (18 months-old) than in the colons of normal young rats (6 months-old). Treatment with IRT5 suppressed the age-associated increased expression of iNOS, COX2, TNF-α, and IL-1β, and activation of NF-κB and mitogen-activated protein kinases. In a similar manner, the expression of tight junction proteins in the colon of normal aged rats was suppressed more potently than in normal young rats, and treatment of aged rats with IRT5 decreased the age-dependent suppression of tight junction proteins ZO-1, occludin, and claudin-1. Treatment with IRT5 suppressed age-associated increases in expressions of senescence markers p16 and p53 in the colon of aged rats, but increased age-suppressed expression of SIRT1. However, treatment with IRT5 inhibited age-associated increased myeloperoxidase activity in the colon. In addition, treatment with IRT5 lowered the levels of LPS in intestinal fluid and blood of aged rats, as well as the reduced concentrations of reactive oxygen species, malondialdehyde, and C-reactive protein in the blood. These findings suggest that IRT5 treatment may suppress age-dependent colitis by inhibiting gut microbiota LPS production. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of humanin on experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid in rats.

PubMed

Gultekin, Fatma A; Emre, Ali U; Celik, Sevim K; Barut, Figen; Tali, Ufuk; Sumer, Demet; Turkcu, Ummuhani O

2017-01-01

The excessive apoptosis of intestinal epithelial cells (IECs) partly accounts for the development of colonic inflammation and eventually results in ulcerative colitis (UC). Humanin, an endogenous anti-apoptotic peptide, has previously been shown to protect against Alzheimer's disease and a variety of cellular insults. The present study aimed to investigate the effects of glysin variant of humanin (HNG) on 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. Rats were divided into four groups as follows: Group 1 (n = 8): control; isotonic saline solution 0.1 ml/rat rectally, Group 2 (n = 8): TNBS colitis; 0.1 ml of a 2.5% (w/v) TNBS solution in 50% ethanol rectally, Group 3 (n = 8): 10 μM HNG, and Group 4 (n = 8): 20 μM HNG intraperitoneal (ip) on day 2 and 6 after rectal TNBS administration. Rats were sacrificed 7 days after the induction of colitis. Blood and tissue samples were harvested for biochemical and histopathological analysis. HNG treatment significantly ameliorated weight loss and macroscopic and microscopic scores. TNBS-induced colitis significantly increased the colonic mRNA expression of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and caspase-3 activities in group II in comparison to the group I. HNG treatment was associated with an inhibition of mRNA expression of TNF-α and IL-1β, and a decrease in caspase-3 activities in colon tissues in group III and IV when compared to group II. The results of this study indicate that HNG treatment may exert beneficial effects in UC by decreasing inflammatory reactions and apoptosis.

Resistant starch modulates in vivo colonic butyrate uptake and its oxidation in rats with dextran sulfate sodium-induced colitis.

PubMed

Moreau, Noëlle M; Champ, Martine M; Goupry, Stéphane M; Le Bizec, Bruno J; Krempf, Michel; Nguyen, Patrick G; Dumon, Henri J; Martin, Lucile J

2004-03-01

We previously demonstrated improvements of colonic lesions due to dextran sulfate sodium (DSS) in rats after 7 d of supplementation with resistant starch (RS) type 3, a substrate yielding high levels of butyrate (C(4)), a colonic cell fuel source. In the present study, we hypothesized that if inflammation is related to decreased C(4) utilization by the colonic mucosa, RS supplementation should restore C(4) use simultaneously with an increase in the amount of C(4) present in the digestive tract. Hence, we compared, in vivo, the cecocolonic uptake of C(4) and its oxidation into CO(2) and ketone bodies in control and DSS-treated rats fed a fiber-free basal diet (BD) or a RS-supplemented diet. Sprague-Dawley rats (n = 60) were used. DSS treatment was performed to induce acute colitis and then to maintain chronic colitis. After cecal infusion of [1-(13)C]-C(4) (20 micro mol in 1 h), concentrations and (13)C-enrichment of C(4), ketone bodies, and CO(2) were quantified in the abdominal aorta and portal vein. Portal blood flow was recorded. During acute colitis, (13)C(4) uptake and (13)CO(2) production were lower in DSS rats than in controls. During chronic colitis, DSS rats did not differ from controls. After 7 d of chronic colitis, RS-DSS rats exhibited the same C(4) uptake as BD-DSS rats in spite of higher C(4) cecocolonic disposal. After 14 d, C(4) uptake was higher in RS-DSS than in BD-DSS rats. Thus, the increased utilization of C(4) by the mucosa is subsequent to evidence of healing and appears to be a consequence rather than a cause of this RS healing effect.

The effect of chemically induced colitis, psychological stress and their combination on visceral pain in female Wistar rats.

PubMed

Deiteren, Annemie; Vermeulen, Wim; Moreels, Tom G; Pelckmans, Paul A; De Man, Joris G; De Winter, Benedicte Y

2014-09-01

Visceral sensitivity is of pathophysiological importance in abdominal pain disorders and can be modulated by inflammation and stress. However, it is unclear whether inflammation and stress alter visceral perception independently of each other or in conjunction through neuroendocrine interactions. Therefore, we compared the short- and long-term effects of experimental colitis and water avoidance stress (WAS), alone or in combination, on visceral sensitivity in female Wistar rats. Colitis was induced by trinitrobenzene sulfonic acid (TNBS) and colonoscopically confirmed. During WAS, rats were placed on a platform surrounded by water for 1 h. Visceral sensitivity was assessed by quantifying the visceromotor responses (VMRs) to colorectal distension. Activation of the hypothalamic-pituitary-adrenal axis was determined by measuring serum corticosterone in a separate protocol. TNBS instillation resulted in overt colitis, associated with significant visceral hypersensitivity during the acute inflammatory phase (3 days post-TNBS; n = 8/group); after colitis had subsided (28 days post-TNBS), hypersensitivity was resolved (n = 4-8/group). Single WAS was associated with increased VMRs of a magnitude comparable to acute TNBS-induced hypersensitivity (n = 8/group). However, after repetitive WAS no significant hypersensitivity was present (n = 8/group). No additive effect of colitis and stress was seen on visceral pain perception (n = 6-8/group). Corticosterone levels were only increased in acute TNBS-colitis, acute WAS and their combination. To conclude, both colitis and stress successfully induced short-term visceral hypersensitivity and activated the hypothalamic-pituitary-adrenal axis, but long-term effects were absent. In addition, our current findings do not support an additive effect of colitis and stress on visceral sensitivity in female Wistar rats.

Comparative protective effect of hawthorn berry hydroalcoholic extract, atorvastatin, and mesalamine on experimentally induced colitis in rats.

PubMed

Malekinejad, Hassan; Shafie-Irannejad, Vahid; Hobbenaghi, Rahim; Tabatabaie, Seyed Hamed; Moshtaghion, Seyed-Mehdi

2013-07-01

The protective effect of hydroalcoholic extract of hawthorn berries (HBE) on acetic acid (AA)-induced colitis in rats was investigated. Forty-two Wistar rats were divided into seven groups, including control and test groups (n=6). The control animals received saline, and the test animals were treated with saline (sham group), mesalamine (50 mg/kg; M group), atorvastatin (20 mg/kg; A group), HBE (100 mg/kg; H group), mesalamine and HBE (HM group), or atorvastatin plus HBE (HA group), 3 days before and a week after colitis induction. Colitis was induced by administration of 1 mL AA (4%) via a polyethylene catheter intrarectally. High-performance liquid chromatography analyses showed that HBE contained 0.13% and 0.5% oleanolic acid and ursolic acid, respectively. Elevated myeloperoxidase activity and lipid peroxidation were attenuated in the HA group. The H and HM groups showed marked reductions in colitis-induced decreases in total thiol molecules and body weight. The histopathological studies revealed that HBE decreased colitis-induced edema and infiltration of neutrophils. Our data suggest the anti-inflammatory and antioxidant effects of HBE and atorvastatin protect against AA-induced colitis. The anti-inflammatory effect of HBE may be attributable to its ability to decrease myeloperoxidase activity as a biomarker of neutrophil infiltration.

Therapeutic efficacy of osthole against dinitrobenzene sulphonic acid induced-colitis in rats.

PubMed

Khairy, Hanan; Saleh, Hanan; Badr, Abeer M; Marie, Mohamed-Assem S

2018-04-01

Several mediators were associated with the pathogenesis of inflammatory bowel disease such as oxidative stress through the production of reactive oxygen metabolites, neutrophils infiltration and release of pro-inflammatory cytokines. This study was designed to investigate the therapeutic efficacy of osthole against dinitrobenzene sulfonic acid (DNBS) induced-colitis in rats through its anti-oxidant and anti-inflammatory properties. Colitis was induced in rats by single intracolonic instillation of (250 μl DNBS-25 mg/rat). Then 4 days later, rats were received oral administration of either (osthole 50 mg/kg), (sulfasalazine 500 mg/kg) or both in combination for 7 consecutive days. Body weight, some hematological parameters, colonic malondialdehyde (MDA) and myeloperoxidase activity (MPO), antioxidant parameters, colon injury and mucosa architectures were assessed. T helper (Th1)-related cytokines [Tumor necrosis factor alpha (TNF-α) and interferon-gamma (INF-γ)], Th2-relarted cytokines (interleukin-4 [IL-4 and IL-10], and Th-17 related cytokines [IL-17] were determined by ELISA. Osthole significantly improved the loss in body weight. That was accompanied with a remarkable amelioration of the disruption of the colonic architecture as well as a significant improvement in the antioxidant defense system. A reduction in MPO and MDA was observed in flamed colon. Treatment with either osthole or combination therapy showed suppressive activities on pro-inflammatory Th2-related cytokines and upregulation of anti-inflammatory Th2-related cytokines The results of this study suggest that osthole exert beneficial therapeutic effect in experimental colitis and improved the efficacy of the synthetized drugs such as sulfasalazine. Therefore, osthole may have a valuable sound in the treatment of inflammatory bowel disease. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Submucosal neurons and enteric glial cells expressing the P2X7 receptor in rat experimental colitis.

PubMed

da Silva, Marcos Vinícius; Marosti, Aline Rosa; Mendes, Cristina Eusébio; Palombit, Kelly; Castelucci, Patricia

2017-06-01

The aim of this study was to evaluate the effect of ulcerative colitis on the submucosal neurons and glial cells of the submucosal ganglia of rats. 2,4,6-Trinitrobenzene sulfonic acid (TNBS; colitis group) was administered in the colon to induce ulcerative colitis, and distal colons were collected after 24h. The colitis rats were compared with those in the sham and control groups. Double labelling of the P2X7 receptor with calbindin (marker for intrinsic primary afferent neurons, IPANs, submucosal plexus), calretinin (marker for secretory and vasodilator neurons of the submucosal plexus), HuC/D and S100β was performed in the submucosal plexus. The density (neurons per area) of submucosal neurons positive for the P2X7 receptor, calbindin, calretinin and HuC/D decreased by 21%, 34%, 8.2% and 28%, respectively, in the treated group. In addition, the density of enteric glial cells in the submucosal plexus decreased by 33%. The profile areas of calbindin-immunoreactive neurons decreased by 25%. Histological analysis revealed increased lamina propria and decreased collagen in the colitis group. This study demonstrated that ulcerative colitis affected secretory and vasodilatory neurons, IPANs and enteric glia of the submucosal plexus expressing the P2X7 receptor. Copyright © 2017 Elsevier GmbH. All rights reserved.

Comparative Protective Effect of Hawthorn Berry Hydroalcoholic Extract, Atorvastatin, and Mesalamine on Experimentally Induced Colitis in Rats

PubMed Central

Shafie-Irannejad, Vahid; Hobbenaghi, Rahim; Tabatabaie, Seyed Hamed; Moshtaghion, Seyed-Mehdi

2013-01-01

Abstract The protective effect of hydroalcoholic extract of hawthorn berries (HBE) on acetic acid (AA)–induced colitis in rats was investigated. Forty-two Wistar rats were divided into seven groups, including control and test groups (n=6). The control animals received saline, and the test animals were treated with saline (sham group), mesalamine (50 mg/kg; M group), atorvastatin (20 mg/kg; A group), HBE (100 mg/kg; H group), mesalamine and HBE (HM group), or atorvastatin plus HBE (HA group), 3 days before and a week after colitis induction. Colitis was induced by administration of 1 mL AA (4%) via a polyethylene catheter intrarectally. High-performance liquid chromatography analyses showed that HBE contained 0.13% and 0.5% oleanolic acid and ursolic acid, respectively. Elevated myeloperoxidase activity and lipid peroxidation were attenuated in the HA group. The H and HM groups showed marked reductions in colitis-induced decreases in total thiol molecules and body weight. The histopathological studies revealed that HBE decreased colitis-induced edema and infiltration of neutrophils. Our data suggest the anti-inflammatory and antioxidant effects of HBE and atorvastatin protect against AA-induced colitis. The anti-inflammatory effect of HBE may be attributable to its ability to decrease myeloperoxidase activity as a biomarker of neutrophil infiltration. PMID:23875899

Anti-inflammatory and immunomodulatory effects of Spirulina platensis in comparison to Dunaliella salina in acetic acid-induced rat experimental colitis.

PubMed

Abdel-Daim, Mohamed M; Farouk, Sameh M; Madkour, Fedekar F; Azab, Samar S

2015-04-01

Spirulina platensis (SP) is used as a source of protein and vitamin supplement in humans without any significant side-effects. Dunaliella salina (DS) is also regarded as one of the richest natural producers of carotenoid, thus used as a source of antioxidants to protect cells from oxidative damage. The aim of the present study is to compare the ameliorative effect of Spirulina and Dunaliella in experimental colitis. Spirulina and Dunaliella were investigated at the same dose of 500 mg/kg body weight for their modulatory effect against acetic-acid induced ulcerative colitis (UC) in rats. The colonic lesion was analyzed by examining macroscopic damage, bloody diarrhea scores, colon weight/length and change in body weight of tested rats. Colon lipid peroxidation and oxidative stress markers were examined by evaluating malondialdehyde (MDA), protein carbonyl (PCO), catalase (CAT), reduced glutathione (GSH) and superoxide dismutase (SOD). Colon inflammatory markers; myeloperoxidase (MPO) and prostaglandin (PGE2) as well as proinflammatory cytokines; tumor necrosis factor (TNF-α) and interleukins (IL-1β, IL-6) were also studied. The colonic mucosal injury, biochemical and histopathologic results suggest that both SP and DS exhibit significant modulatory effect on acetic acid-induced colitis in rats, which may be due to a significant increase of antioxidant enzymes activity and significant inhibition of lipid peroxidation and inflammation markers. Results showed that in comparison to Sulfasalazine, SP exhibited better therapeutic and safety profile than DS against acetic acid-induced UC. This study suggests potential benefits of SP and DS in an experimental model of colitis.

Anti-inflammatory effect of Prunus armeniaca L. (Apricot) extracts ameliorates TNBS-induced ulcerative colitis in rats

PubMed Central

Minaiyan, M.; Ghannadi, A.; Asadi, M.; Etemad, M.; Mahzouni, P.

2014-01-01

Prunus armeniaca L. (Apricot) is a tree cultivated in different parts of the world. Apricot kernel as a good dietary supplement has shown antioxidant, anti-inflammatory and other pharmacologic properties which suggest that it may be functional as an anticolitis agent. In this study we evaluated the effects of apricot kernel extract and oil on ulcerative colitis in rats. Rats were fasted for 36 h before the experiment. Colitis was induced by intra-rectal instillation of 50 mg/kg trinitrobenzene sulfonic acid in male Wistar rats. Treatments were started 6 h after colitis induction and continued every 24 h for 5 days. Apricot kernel extract (100, 200, 400 mg/kg p.o. and 100, 400 mg/kg i.p.) and apricot kernel extract/oil (100, 200, 400 mg/kg p.o.) were used as experimental treatments and prednisolone (4 mg/kg p.o. or i.p.) was used as reference drug. On the day 6, colon tissue was removed and macroscopic and pathologic parameters were evaluated. Ulcer index and total colitis index as representative of macroscopic and histologic parameters respectively showed ameliorating effects in experimental groups especially those treated by intraperitoneal administration route. Results also demonstrated that oil fraction was not able to potentiate the effects of extract. These data suggest that apricot kernel extracts (with or without oil) can be introduced for further mechanistic and clinical studies as a complementary medicine for inflammatory bowel disorders. PMID:25657793

Hydroalcoholic extract of Brazilian red propolis exerts protective effects on acetic acid-induced ulcerative colitis in a rodent model.

PubMed

Barbosa Bezerra, Gislaine; de Menezes de Souza, Luana; Dos Santos, Adailma Santana; de Almeida, Grace Kelly Melo; Souza, Marília Trindade Santana; Santos, Sandra Lauton; Aparecido Camargo, Enilton; Dos Santos Lima, Bruno; de Souza Araújo, Adriano Antunes; Cardoso, Juliana Cordeiro; Gomes, Silvana Vieira Floresta; Gomes, Margarete Zanardo; de Albuquerque, Ricardo Luiz Cavalcanti

2017-01-01

Ulcerative colitis (UC) is a common intestinal inflammatory disease with an etiology that is not well understood. Although the anti-inflammatory and anti-oxidant effects of the hydroalcoholic extract of Brazilian red propolis (HERP) have been reported in various experimental models, its protective effect in models of UC have not been evaluated. The purpose of this study was to investigate the chemopreventive effect of hydroalcoholic extract of Brazilian red propolis (HERP) in acetic acid-induced colitis (AAIC) using a rodent model. The HERP was chemically characterised by HPLC/DAD analyses. Male rats were randomly assigned into four groups: sham, vehicle (with AAIC, treated with vehicle), P10 (with AAIC, treated with 10mg/kg HERP), and P100 (with AAIC, treated with 100mg/kg HERP). Treatments were performed for 7days, and colitis was induced on day seven. Animals were euthanized 24h after colitis induction and body weight, colon length, gross and histological scores, malondialdehyde (MDA) and myeloperoxidase (MPO) concentrations in colon tissue, and the immunohistochemical expression of inducible nitric oxide synthase (iNOS) were assessed. The major compounds found in HERP were liquiritigenin (68.8mg/g), formononetin (54.29mg/g), biochanin A (30.97mg/g), and daidzein (19.90mg/g). Rats treated with 10mg/kg HERP demonstrated significant decreases in MPO concentrations, gross and histological scores of tissue damage, and iNOS expression (p<0.05). Similarly, rats treated with 100mg/kg HERP demonstrated significant decreases in MPO levels (p<0.05) and histological scores of tissue damage (p<0.05). The results of this study indicate that oral administration of HERP attenuates AAIC in rats, which may be due to anti-inflammatory effects related to iNOS inhibition. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

The impact of mangiferin from Belamcanda chinensis on experimental colitis in rats.

PubMed

Szandruk, Marta; Merwid-Ląd, Anna; Szeląg, Adam

2018-04-01

Inflammatory bowel disease (IBD) [including Crohn's disease (CD) and ulcerative colitis (UC)] constitutes an important clinical problem. The pathogenesis of IBD remains unclear. It is believed that immune dysfunction, inflammatory mediators and oxidative damage play crucial roles in development of IBD. The condition is clinically associated with symptoms ranging from mild to severe during relapses, depending on the affected segment of the gastrointestinal tract. Bloody diarrhea with mucus, abdominal pain, weight loss and anemia are initial symptoms of both CD and UC. Differences between diseases become more evident in time, along with the development of intestinal and extraintestinal complications. Mangiferin (1,3,6,7-tetrahydroxyxanthone-C-2-β-D-glucoside), a natural polyphenol in plants, exerts antioxidant and anti-inflammatory effects making it an interesting option for the treatment of inflammatory pathologies associated with oxidative stress in humans, such as IBD. The aim of the current study was to elucidate the impact of mangiferin on colon tissues in 2,4,6-trinitrobenzensulfonic acid (TNBS)-induced colitis in rats. Mangiferin was obtained from Belamcanda chinensis rhizomes by a multistage process. Groups of rats were pre-treated with 10, 30 or 100 mg/kg of mangiferin, or with distilled water administered intragastrically for 16 days. An ethanol solution of TNBS or saline was given rectally on the day 15 of the experiment. The experiment was terminated on the day 17. The colon was removed, cleaned, weighed and examined macro- and microscopically. Determination of tumor necrosis factor α (TNF-α), interleukin 17 (IL-17), malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were performed spectrophotometrically in homogenates of colon tissues. Rats in the TNBS group developed symptoms of colitis, including: body weight loss, colon mass index increase and damage of intestinal tissues with concomitant increase in TNF-α, IL-17, MDA levels

Anti-inflammatory Effect of Amitriptyline on Ulcerative Colitis in Normal and Reserpine-Induced Depressed Rats

PubMed Central

Fattahian, Ehsan; Hajhashemi, Valiollah; Rabbani, Mohammad; Minaiyan, Mohsen; Mahzouni, Parvin

2016-01-01

Depressive disorders are more common among persons with chronic diseases such as inflammatory bowel disease and anti-inflammatory effect of some antidepressants such as amitriptyline has been reported. Acetic acid colitis was induced in both reserpinised (depressed) and non-reserpinised (normal) rats. Reserpinised groups received reserpine (6 mg/kg, i.p.) one hour prior to colitis induction. Then Amitriptyline (5, 10, 20 mg/kg, i.p.) was administered to separate groups of male Wistar rats. All treatments were carried out two hours after colitis induction and continued daily for four days. Dexamethasone (1 mg/kg) and normal saline (1 mL/kg) were used in reference and control groups, respectively. At day five, animals were euthanized and colonic tissue injuries were assessed macroscopically and pathologically. Myeloperoxidase activity as a marker of neutrophil infiltration was also measured in colonic tissues. Results showed that reserpine (6 mg/kg, i.p.) intensified colitic condition. Compared to control, amitriptyline (10, 20 mg/kg) and dexamethasone significantly decreased weight of colon and ulcer index in normal and reserpine-induced depressed rats. Myeloperoxidase activity and pathological assessments also proved anti-inflammatory effect of amitriptyline. Our results suggest that amitriptyline, a tricyclic antidepressant, could reduce inflammatory and ulcerative injuries of colon both in normal and depressed rats. So among the wide spread anti-depressant drugs, amitriptyline is a good choice to treat depression comorbidities in patients with IBD. PMID:28228811

Cape Gooseberry [Physalis peruviana L.] Calyces Ameliorate TNBS Acid-induced Colitis in Rats.

PubMed

Castro, Jenny; Ocampo, Yanet; Franco, Luis

2015-11-01

Physalis peruviana [cape gooseberry] is highly appreciated for its commercial value. The Colombian ecotype is in great demand in the international market, particularly for the unique morphological characteristics of the calyx, which has extended use as a traditional herbal remedy in Colombia because of its anti-inflammatory properties. In this work, the anti-inflammatory activity of the total ethereal extract of Physalis peruviana calyces was evaluated in preventive and therapeutic protocols in a TNBS acid-induced colitis rat model. Colitis was induced by intrarectal administration of TNBS. An evaluation of macroscopic and histopathological parameters in colonic tissue was performed, along with the determination of myeloperoxidase enzyme activity, cytokine levels and gene expression. Additionally, effects on nitric oxide release by lipopolysaccharide [LPS]-stimulated RAW264.7 macrophages and the scavenging activity of DPPH and ABTS free radicals were determined. The treatment with the Physalis peruviana extract produced a significant improvement in the colonic tissue at both macroscopic and histological levels. IL-1β and TNF-α production was reduced by the extract in both experimental approaches. The groups treated with Physalis peruviana showed a tendency to MUC2 up-regulation and down-regulation of COX-2, iNOS, NLRP3, IL-1β, IL-6 and IL-10 expression. Nitric oxide release in RAW264.7 macrophages was significantly inhibited. The Physalis peruviana extract showed intestinal anti-inflammatory activity in the TNBS-induced colitis model, placing this species' calyx, a natural derivative, as a promising source of metabolites that could be used in treatment for inflammatory bowel disease. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Effect of intracolonic benzalkonium chloride on trinitrobenzene sulphonic acid-induced colitis in the rat.

PubMed

Miampamba, M; Parr, E J; McCafferty, D M; Wallace, J L; Sharkey, K A

1998-03-01

We investigated the effects of benzalkonium chloride (BAC) on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. TNBS was administered intrarectally before and/or after BAC treatment. In the first study, the effects of treatment with BAC 6, 12 or 24 h after TNBS were examined. In the second study, animals were treated with BAC before, after or before and after TNBS, and were examined 7 days later. The severity of colitis was assessed by macroscopic and histological scoring of the colonic damage and by determination of colonic myeloperoxidase (MPO) activity. Macrophages and CD4+ and CD8+ T cells were examined by immunohistochemistry. When BAC was instilled into the colon 6, 12 or 24 h after TNBS, weight loss and macroscopic and histological features of the colon were similar to that of controls (TNBS alone). In contrast, MPO activity was significantly reduced in all three groups post-treated with BAC. In the groups examined 7 days after TNBS treatment, rats post-treated with BAC exhibited increased weight gain and significantly reduced macroscopic damage and MPO activity compared to the TNBS control group. Rats pre-treated with BAC exhibited less macroscopic damage of the colon than rats receiving only TNBS, but histological damage, MPO and weight gain were unchanged from TNBS controls. Immunohistochemistry revealed that BAC pre-treatment increased the numbers of macrophages and T cells in the colon. After TNBS treatment, macrophage accumulation was evident in the colon, but T cells were scarce. However, these cells were preserved or enhanced in the colonic mucosa in TNBS-treated rats that had been pre-treated with BAC. Treatment with BAC, particularly after induction of colitis, produces a significant reduction in the severity of tissue injury and inflammation through mechanisms that are not fully understood.

The Influence of Ghrelin on the Development of Dextran Sodium Sulfate-Induced Colitis in Rats

PubMed Central

Matuszyk, Aleksandra; Ceranowicz, Dagmara; Warzecha, Zygmunt; Ceranowicz, Piotr; Fyderek, Krzysztof; Gałązka, Krystyna; Cieszkowski, Jakub; Bonior, Joanna; Jaworek, Jolanta; Pihut, Małgorzata; Dembiński, Artur

2015-01-01

Ghrelin has protective and therapeutic effects in the gut. The aim of present studies was to investigate the effect of treatment with ghrelin on the development of colitis evoked by dextran sodium sulfate (DSS). Methods. Studies have been performed on rats. Colitis was induced by adding 5% DSS to the drinking water for 5 days. During this period animals were treated intraperitoneally twice a day with saline or ghrelin given at the dose of 8 nmol/kg/dose. On the sixth day, animals were anesthetized and the severity of colitis was assessed. Results. Treatment with ghrelin during administration of DSS reduced the development of colitis. Morphological features of colonic mucosa exhibited a reduction in the area and deep of mucosal damage. Ghrelin reversed the colitis-induced decrease in blood flow, DNA synthesis, and superoxide dismutase activity in colonic mucosa. These effects were accompanied by a decrease in the colitis-evoked increase in mucosal concentration of interleukin-1β and malondialdehyde. Treatment with ghrelin reversed the DSS-induced reduction in body weight gain. Conclusions. Administration of ghrelin exhibits the preventive effect against the development of DSS-induced colitis. This effect seems to be related to ghrelin's anti-inflammatory and antioxidative properties. PMID:26713317

Baicalin attenuates TNBS-induced colitis in rats by modulating the Th17/Treg paradigm.

PubMed

Zou, Ying; Dai, Shi-Xue; Chi, Hong-Gang; Li, Tao; He, Zhi-Wei; Wang, Jian; Ye, Cai-Guo; Huang, Guo-Liang; Zhao, Bing; Li, Wen-Yang; Wan, Zheng; Feng, Jin-Shan; Zheng, Xue-Bao

2015-10-01

Baicalin, a flavonoid, has a wide range of pharmacological properties, including immunomodulation. The objective of this study was to investigate the effect of baicalin on the balance of T helper 17 (Th17) and regulatory T (Treg) cells in a colitis model. The rat colitis model was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Baicalin (10 ml/kg, each) or mesalazine (positive control) was then administered orally for 7 days. Inflammatory and immunological responses were evaluated by pathology, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, western blot analysis, and flow cytometry. Our study showed that baicalin not only significantly attenuated TNBS-induced colitis by reducing the disease activity index as well as macroscopic and microscopic scores, but it also improved the weight loss and shortening of the colon. Baicalin treatment also induced a significant decrease in the levels of inflammatory mediators, including the myeloperoxidase activity, the levels of tumor necrosis factor α, IL-1β, and Th1-related cytokines IL-12 and IFN-γ. Furthermore, the beneficial effects of baicalin seem to be associated with regulation of the Th17 and Treg paradigm. We found that administration of baicalin significantly downregulated the number of Th17 cells and the levels of Th17-related cytokines (IL-17 and IL-6) and retinoic acid receptor-related orphan receptor γt. In contrast, there was an increase in Treg cells numbers, Treg-related cytokines transforming growth factor-β and IL-10, and forkhead box P3. Our results suggest that the anti-inflammatory effect of baicalin may be linked to modulation of the balance between Th17 and Treg cells in TNBS-induced ulcerative colitis.

Involvement of PPARγ in the protective action of tropisetron in an experimental model of ulcerative colitis.

PubMed

Rahimian, Reza; Zirak, Mohammad Reza; Keshavarz, Mojtaba; Fakhraei, Nahid; Mohammadi-Farani, Ahmad; Hamdi, Hanan; Mousavizadeh, Kazem

2016-09-20

Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal (GI) tract. Tropisetron, a selective 5-HT 3 receptor antagonist, is highly used to counteract chemotherapy-induced emesis. Previous studies revealed the anti-inflammatory properties of this drug. The aim of this study was to evaluate the role of peroxisome proliferator-activated receptor gamma (PPARγ) receptor in the protective effect of tropisetron in an animal model of ulcerative colitis. Experimental colitis was induced by a single intra-colonic instillation of 4% (V/V) acetic acid in male rats. Tropisetron (3 mg/kg) and GW9662 (PPARγ antagonist) (5 mg/kg) were given twice daily for 2 days after colitis induction. Forty-eight hours after induction of colitis, colon was removed and macroscopic and microscopic features were given. Moreover, colonic concentrations of malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) levels, myeloperoxidase (MPO), and PPARγ activity were assessed. Both macroscopic and histopathological features of colonic injury were markedly ameliorated by tropisetron. Likewise, levels of NO, MDA, TNF-α, and IL-1β diminished significantly (p < .05). GW9662 reversed the effect of tropisetron on these markers partially or completely. In addition, tropisetron increased the PPARγ and decreased the MPO activity (p < .05). Tropisetron exerts notable anti-inflammatory effects in acetic acid-induced colitis in rats, which is probably mediated through PPARγ receptors.

Dietary protocatechuic acid ameliorates dextran sulphate sodium-induced ulcerative colitis and hepatotoxicity in rats.

PubMed

Farombi, Ebenezer O; Adedara, Isaac A; Awoyemi, Omolola V; Njoku, Chinonye R; Micah, Gabriel O; Esogwa, Cynthia U; Owumi, Solomon E; Olopade, James O

2016-02-01

The present study investigated the antioxidant and anti-inflammatory effects of dietary protocatechuic acid (PCA), a simple hydrophilic phenolic compound commonly found in many edible vegetables, on dextran sulphate sodium (DSS)-induced ulcerative colitis and its associated hepatotoxicity in rats. PCA was administered orally at 10 mg kg(-1) to dextran sulphate sodium exposed rats for five days. The result revealed that administration of PCA significantly (p < 0.05) prevented the incidence of diarrhea and bleeding, the decrease in the body weight gain, shortening of colon length and the increase in colon mass index in DSS-treated rats. Furthermore, PCA prevented the increase in the plasma levels of pro-inflammatory cytokines, markers of liver toxicity and markedly suppressed the DSS-mediated elevation in colonic nitric oxide concentration and myeloperoxidase activity in the treated rats. Administration of PCA significantly protected against colonic and hepatic oxidative damage by increasing the antioxidant status and concomitantly decreased hydrogen peroxide and lipid peroxidation levels in the DSS-treated rats. Moreover, histological examinations confirmed PCA chemoprotection against colon and liver damage. Immunohistochemical analysis showed that PCA significantly inhibited cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein expression in the colon of DSS-treated rats. In conclusion, the effective chemoprotective role of PCA in colitis and the associated hepatotoxicity is related to its intrinsic anti-inflammatory and anti-oxidative properties.

MAG-EPA reduces severity of DSS-induced colitis in rats.

PubMed

Morin, Caroline; Blier, Pierre U; Fortin, Samuel

2016-05-15

Ulcerative colitis (UC) is a chronic disease characterized by diffuse inflammation of the intestinal mucosa of the large bowel. Omega-3 (ω3) fatty acid supplementation has been associated with a decreased production of inflammatory cytokines involved in UC pathogenesis. The aim of this study was to determine the preventive and therapeutic potential of eicosapentaenoic acid monoglyceride (MAG-EPA) in an in vivo rats model of UC induced by dextran sulfate sodium (DSS). DSS rats were untreated or treated per os with MAG-EPA. Morphological, histological, and biochemical analyses were performed following MAG-EPA administrations. Morphological and histological analyses revealed that MAG-EPA pretreatment (12 days pre-DSS) and treatment (6 days post-DSS) exhibited strong activity in reducing severity of disease in DSS rats. Following MAG-EPA administrations, tissue levels of the proinflammatory cytokines TNF-α, IL-1β, and IL-6 were markedly lower compared with rats treated only with DSS. MAG-EPA per os administration decrease neutrophil infiltration in colon tissues, as depicted by myelohyperoxidase activity. Results also revealed a reduced activation of NF-κB pathways correlated with a decreased expression of COX-2 in colon homogenates derived from MAG-EPA-pretreated and treated rats. Tension measurements performed on colon tissues revealed that contractile responses to methacholine and relaxing effect induced by sodium nitroprusside were largely increased following MAG-EPA treatment. The combined treatment of MAG-EPA and vitamin E displayed an antagonistic effect on anti-inflammatory properties of MAG-EPA in DSS rats. Copyright © 2016 the American Physiological Society.

Short-chain inulin-like fructans reduce endotoxin and bacterial translocations and attenuate development of TNBS-induced colitis in rats.

PubMed

Ito, Hiroyuki; Tanabe, Hiroki; Kawagishi, Hirokazu; Tadashi, Wada; Yasuhiko, Tomono; Sugiyama, Kimio; Kiriyama, Shuhachi; Morita, Tatsuya

2009-10-01

Anti-inflammatory effects of short-chain inulin-like fructans (SCF) on trinitrobenzene sulfonic acid (TNBS)-induced colitis were investigated in rats, focusing specifically on endotoxin and bacterial translocations. SCF with degrees of polymerization (DP) of 4 and 8 were used. Rats were fed either control diet or diets including 60 g DP4 or DP8 per kilogram for 7 days, and then received intracolonic TNBS and were fed the respective diets for a further 10 days. DP4 and DP8 significantly reduced colonic injuries as assessed by damage score, but the reduction of colonic myeloperoxidase activity was manifest solely with DP8. At 3 days after colitis induction, bacterial translocation to the mesenteric lymph node was significantly lower in the DP4 and DP8 groups, but significant reduction in the portal endotoxin concentration was achieved solely in the DP8 group. Immediately prior to colitis induction, cecal immunoglobulin A and mucin concentrations were higher in the DP4 and DP8 groups, but these changes were abolished at 10 days post colitis induction. The data suggest that SCF exert prophylactic effects against TNBS colitis, presumably as a result of inhibitory effects on endotoxin and bacterial translocations.

Ameliorative effects of bombesin and neurotensin on trinitrobenzene sulphonic acid-induced colitis, oxidative damage and apoptosis in rats.

PubMed

Akcan, Alper; Muhtaroglu, Sebahattin; Akgun, Hulya; Akyildiz, Hizir; Kucuk, Can; Sozuer, Erdogan; Yurci, Alper; Yilmaz, Namik

2008-02-28

To investigate the effects of bombesin (BBS) and neurotensin (NTS) on apoptosis and colitis in an ulcerative colitis model. In this study, a total of 50 rats were divided equally into 5 groups. In the control group, no colitis induction or drug administration was performed. Colitis was induced in all other groups. Following the induction of colitis, BBS, NTS or both were applied to three groups of rats. The remaining group (colitis group) received no treatment. On the 11th d after induction of colitis and drug treatment, blood samples were collected for TNF-alpha and IL-6 level studies. Malondialdehyde (MDA), carbonyl, myeloperoxidase (MPO) and caspase-3 activities, as well as histopathological findings, evaluated in colonic tissues. According to the macroscopic and microscopic findings, the study groups treated with BBS, NTS and BBS + NTS showed significantly lower damage and inflammation compared with the colitis group (macroscopic score, 2.1 +/- 0.87, 3.7 +/- 0.94 and 2.1 +/- 0.87 vs 7.3 +/- 0.94; microscopic score, 2.0 +/- 0.66, 3.3 +/- 0.82 and 1.8 +/- 0.63 vs 5.2 +/- 0.78, P < 0.01). TNF-alpha and IL-6 levels were increased significantly in all groups compared with the control group. These increases were significantly smaller in the BBS, NTS and BBS + NTS groups compared with the colitis group (TNF-alpha levels, 169.69 +/- 53.56, 245.86 +/- 64.85 and 175.54 +/- 42.19 vs 556.44 +/- 49.82; IL-6 levels, 443.30 +/- 53.99, 612.80 +/- 70.39 and 396.80 +/- 78.43 vs 1505.90 +/- 222.23, P < 0.05). The colonic MPO and MDA levels were significantly lower in control, BBS, NTS and BBS + NTS groups than in the colitis group (MPO levels, 24.36 +/- 8.10, 40.51 +/- 8.67 and 25.83 +/- 6.43 vs 161.47 +/- 38.24; MDA levels, 4.70 +/- 1.41, 6.55 +/- 1.12 and 4.51 +/- 0.54 vs 15.60 +/- 1.88, P < 0.05). Carbonyl content and caspase-3 levels were higher in the colitis and NTS groups than in control, BBS and BBS + NTS groups (carbonyl levels, 553.99 +/- 59.58 and 336.26 +/- 35.72 vs

Effects of dexpanthenol on acetic acid-induced colitis in rats

PubMed Central

Cagin, Yasir Furkan; Parlakpinar, Hakan; Vardi, Nigar; Polat, Alaadin; Atayan, Yahya; Erdogan, Mehmet Ali; Tanbek, Kevser

2016-01-01

While the pathogenesis of acetic acid (AA)-induced colitis is unclear, reactive oxygen species are considered to have a significant effect. The aim of the present study was to elucidate the therapeutic potential of dexpanthenol (Dxp) on the amelioration of colitis in rats. Group I (n=8; control group) was intrarectally administered 1 ml saline solution (0.9%); group II [n=8; AA] was administered 4% AA into the colon via the rectum as a single dose for three consecutive days; group III (n=8; AA + Dxp) was administered AA at the same dosage as group II from day 4, and a single dose of Dxp was administered intraperitoneally; and group IV (n=8; Dxp) was administered Dxp similarly to Group III. Oxidative stress and colonic damage were assessed via biochemical and histologic examination methods. AA treatment led to an increase in oxidative parameters and a decrease in antioxidant systems. Histopathological examination showed that AA treatment caused tissue injury and increased caspase-3 activity in the distal colon and triggered apoptosis. Dxp treatment caused biochemical and histopathological improvements, indicating that Dxp may have an anti-oxidant effect in colitis; therefore, Dxp may be a potential therapeutic agent for the amelioration of IBD. PMID:27882101

Effects of dexpanthenol on acetic acid-induced colitis in rats.

PubMed

Cagin, Yasir Furkan; Parlakpinar, Hakan; Vardi, Nigar; Polat, Alaadin; Atayan, Yahya; Erdogan, Mehmet Ali; Tanbek, Kevser

2016-11-01

While the pathogenesis of acetic acid (AA)-induced colitis is unclear, reactive oxygen species are considered to have a significant effect. The aim of the present study was to elucidate the therapeutic potential of dexpanthenol (Dxp) on the amelioration of colitis in rats. Group I (n=8; control group) was intrarectally administered 1 ml saline solution (0.9%); group II [n=8; AA] was administered 4% AA into the colon via the rectum as a single dose for three consecutive days; group III (n=8; AA + Dxp) was administered AA at the same dosage as group II from day 4, and a single dose of Dxp was administered intraperitoneally; and group IV (n=8; Dxp) was administered Dxp similarly to Group III. Oxidative stress and colonic damage were assessed via biochemical and histologic examination methods. AA treatment led to an increase in oxidative parameters and a decrease in antioxidant systems. Histopathological examination showed that AA treatment caused tissue injury and increased caspase-3 activity in the distal colon and triggered apoptosis. Dxp treatment caused biochemical and histopathological improvements, indicating that Dxp may have an anti-oxidant effect in colitis; therefore, Dxp may be a potential therapeutic agent for the amelioration of IBD.

Sulfhydryl blocker-induced colitis in the rat: immunological changes in thymus gland and colonic mucosa.

PubMed

Suzuki, H; Hibi, T; Oda, M; Hosoda, Y; Mori, M; Miura, S; Tanaka, S; Watanabe, M; Tsuchiya, M

1994-01-01

The study was designed to examine the changes of thymus in sulfhydryl blocker-induced colitis. We used N-ethylmaleimide (NEM) as sulfhydryl blockers. Fasted male Sprague-Dawley rats were given 3% NEM in 1% methyl cellulose into the colon. N-ethylmaleimide treatment caused severe diarrhoea with bleeding for the first 7 days. At autopsy, adhesions, colon dilatation, and single or multiple erosions and ulcers were observed. Time-course studies revealed that the lesions were most extensive and severe 3 or 7 days after the administration of NEM. Histological examination of colon on the 3rd day after NEM treatment demonstrated mucosal erosion, oedema and extensive infiltration of neutrophils. The mucosal lesions extended into the submucosa and muscle on the 7th day after NEM treatment. Immunohistochemical studies showed that T cells and macrophages were markedly increased in the lamina propria of colonic mucosa. After 3 weeks, the infiltration of chronic inflammatory cells was observed and regeneration of the mucosa was noticed. The thymus gland was significantly decreased in weight and size on the 3rd day after NEM treatment, but the weight loss of thymus gland was regained in 3 weeks. Transient atrophy of thymus gland was noticed in this colitis model. The phenotypes of thymocytes were not influenced by NEM treatment. It is concluded that the thymus abnormalities in human ulcerative colitis are not induced in this animal model and that other chronic models are necessary for the elucidation of the immunological abnormalities, including thymus abnormalities.

The effects of Delta-tetrahydrocannabinol and cannabidiol alone and in combination on damage, inflammation and in vitro motility disturbances in rat colitis.

PubMed

Jamontt, J M; Molleman, A; Pertwee, R G; Parsons, M E

2010-06-01

Cannabis is taken as self-medication by patients with inflammatory bowel disease for symptomatic relief. Cannabinoid receptor agonists decrease inflammation in animal models of colitis, but their effects on the disturbed motility is not known. (-)-Cannabidiol (CBD) has been shown to interact with Delta(9)-tetrahydrocannabinol (THC) in behavioural studies, but it remains to be established if these cannabinoids interact in vivo in inflammatory disorders. Therefore the effects of CBD and THC alone and in combination were investigated in a model of colitis. The 2,4,6-trinitrobenzene sulphonic acid (TNBS) model of acute colitis in rats was used to assess damage, inflammation (myeloperoxidase activity) and in vitro colonic motility. Sulphasalazine was used as an active control drug. Sulphasalazine, THC and CBD proved beneficial in this model of colitis with the dose-response relationship for the phytocannabinoids showing a bell-shaped pattern on the majority of parameters (optimal THC and CBD dose, 10 mg.kg(-1)). THC was the most effective drug. The effects of these phytocannabinoids were additive, and CBD increased some effects of an ineffective THC dose to the level of an effective one. THC alone and in combination with CBD protected cholinergic nerves whereas sulphasalazine did not. In this model of colitis, THC and CBD not only reduced inflammation but also lowered the occurrence of functional disturbances. Moreover the combination of CBD and THC could be beneficial therapeutically, via additive or potentiating effects.

Dietary intervention with narrow-leaved cattail rhizome flour (Typha angustifolia L.) prevents intestinal inflammation in the trinitrobenzenesulphonic acid model of rat colitis

PubMed Central

2012-01-01

Background Inflammatory bowel disease (IBD) is a chronic inflammation of the intestinal epithelium that is driven by the intestinal immune system, oxidative stress and the loss of tolerance to the luminal microbiota. The use of dietary products containing ingredients such as fibres and carbohydrates and/or antioxidant compounds have been used as a therapeutic strategy for intestinal diseases because these products are considered effective in the modulation of the immune system and colonic microbiota. We investigated the beneficial effects of cattail rhizome flour (Typha angustifolia L.) in the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. In addition, we investigated the effects of cattail rhizome flour on the intestinal anti-inflammatory activity of prednisolone, which is a reference drug that is used for treatment of human IBD. Methods The present study included the preparation of flour from rhizomes of cattail (Typha angustifolia L.); an evaluation of the qualitative phytochemical profile of cattail rhizomes; an evaluation of the efficacy of cattail rhizome flour in TNBS-induced rat colitis; an evaluation of the synergistic effects of cattail rhizome flour on the intestinal anti-inflammatory activity of prednisolone; and macroscopic, clinical, biochemical, histopathological and microbiological studies to assess the healing effects of cattail rhizome flour and its synergistic effects in TNBS-induced rat colitis. The data were analysed by ANOVA, Kruskal-Wallis and χ2 tests. Results We tested several concentrations of cattail rhizome flour and found that dietary supplementation with 10% cattail rhizome flour showed the best effects at reducing the extension of the lesion, the colon weight ratio, adherences to adjacent organs and diarrhoea. These effects were related to inhibition of myeloperoxidase (MPO) and alkaline phosphatase (AP) activities and an attenuation of glutathione (GSH) depletion. The 10% cattail rhizome flour was as effective as

Dietary intervention with narrow-leaved cattail rhizome flour (Typha angustifolia L.) prevents intestinal inflammation in the trinitrobenzenesulphonic acid model of rat colitis.

PubMed

Fruet, Andréa Costa; Seito, Leonardo Noboru; Rall, Vera Lúcia Mores; Di Stasi, Luiz Claudio

2012-05-04

Inflammatory bowel disease (IBD) is a chronic inflammation of the intestinal epithelium that is driven by the intestinal immune system, oxidative stress and the loss of tolerance to the luminal microbiota. The use of dietary products containing ingredients such as fibres and carbohydrates and/or antioxidant compounds have been used as a therapeutic strategy for intestinal diseases because these products are considered effective in the modulation of the immune system and colonic microbiota. We investigated the beneficial effects of cattail rhizome flour (Typha angustifolia L.) in the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. In addition, we investigated the effects of cattail rhizome flour on the intestinal anti-inflammatory activity of prednisolone, which is a reference drug that is used for treatment of human IBD. The present study included the preparation of flour from rhizomes of cattail (Typha angustifolia L.); an evaluation of the qualitative phytochemical profile of cattail rhizomes; an evaluation of the efficacy of cattail rhizome flour in TNBS-induced rat colitis; an evaluation of the synergistic effects of cattail rhizome flour on the intestinal anti-inflammatory activity of prednisolone; and macroscopic, clinical, biochemical, histopathological and microbiological studies to assess the healing effects of cattail rhizome flour and its synergistic effects in TNBS-induced rat colitis. The data were analysed by ANOVA, Kruskal-Wallis and χ(2) tests. We tested several concentrations of cattail rhizome flour and found that dietary supplementation with 10% cattail rhizome flour showed the best effects at reducing the extension of the lesion, the colon weight ratio, adherences to adjacent organs and diarrhoea. These effects were related to inhibition of myeloperoxidase (MPO) and alkaline phosphatase (AP) activities and an attenuation of glutathione (GSH) depletion. The 10% cattail rhizome flour was as effective as prednisolone, and no synergistic

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

Ameliorative effects of bombesin and neurotensin on trinitrobenzene sulphonic acid-induced colitis, oxidative damage and apoptosis in rats

PubMed Central

Akcan, Alper; Muhtaroglu, Sebahattin; Akgun, Hulya; Akyildiz, Hizir; Kucuk, Can; Sozuer, Erdogan; Yurci, Alper; Yilmaz, Namik

2008-01-01

AIM: To investigate the effects of bombesin (BBS) and neurotensin (NTS) on apoptosis and colitis in an ulcerative colitis model. METHODS: In this study, a total of 50 rats were divided equally into 5 groups. In the control group, no colitis induction or drug administration was performed. Colitis was induced in all other groups. Following the induction of colitis, BBS, NTS or both were applied to three groups of rats. The remaining group (colitis group) received no treatment. On the 11th d after induction of colitis and drug treatment, blood samples were collected for TNF-α and IL-6 level studies. Malondialdehyde (MDA), carbonyl, myeloperoxidase (MPO) and caspase-3 activities, as well as histopathological findings, evaluated in colonic tissues. RESULTS: According to the macroscopic and microscopic findings, the study groups treated with BBS, NTS and BBS + NTS showed significantly lower damage and inflammation compared with the colitis group (macroscopic score, 2.1 ± 0.87, 3.7 ± 0.94 and 2.1 ± 0.87 vs 7.3 ± 0.94; microscopic score, 2.0 ± 0.66, 3.3 ± 0.82 and 1.8 ± 0.63 vs 5.2 ± 0.78, P < 0.01). TNF-α and IL-6 levels were increased significantly in all groups compared with the control group. These increases were significantly smaller in the BBS, NTS and BBS + NTS groups compared with the colitis group (TNF-α levels, 169.69 ± 53.56, 245.86 ± 64.85 and 175.54 ± 42.19 vs 556.44 ± 49.82; IL-6 levels, 443.30 ± 53.99, 612.80 ± 70.39 and 396.80 ± 78.43 vs 1505.90 ± 222.23, P < 0.05). The colonic MPO and MDA levels were significantly lower in control, BBS, NTS and BBS + NTS groups than in the colitis group (MPO levels, 24.36 ± 8.10, 40.51 ± 8.67 and 25.83 ± 6.43 vs 161.47 ± 38.24; MDA levels, 4.70 ± 1.41, 6.55 ± 1.12 and 4.51 ± 0.54 vs 15.60 ± 1.88, P < 0.05). Carbonyl content and caspase-3 levels were higher in the colitis and NTS groups than in control, BBS and BBS + NTS groups (carbonyl levels, 553.99 ± 59.58 and 336.26 ± 35.72 vs 209.76 ± 30

Dietary medium-chain triglycerides prevent chemically induced experimental colitis in rats.

PubMed

Kono, Hiroshi; Fujii, Hideki; Ishii, Kenichi; Hosomura, Naohiro; Ogiku, Masahito

2010-03-01

The effects of dietary medium-chain triglycerides (MCTs) on experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid (TNBS) were investigated in rats. Male Wistar rats were given an intracolonic injection of TNBS and were then fed liquid diets containing MCTs or corn oil (AIN93) as controls. Serum and tissue samples were collected 1 week after TNBS enema. The severity of colitis was evaluated pathologically, and tissue myeloperoxidase (MPO) activity was measured. Furthermore, messenger RNA (mRNA) and protein levels for inflammatory cytokines and a chemokine were assessed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. In another set of experiments, the protein expression of Toll-like receptor (TLR)-4 in the colon was measured 1 week after feeding of liquid diets. To investigate the effects of MCTs on macrophages, RAW246.7 macrophages were incubated with media containing albumin conjugated with MCT or linoleic acid, which is the major component of corn oil. Then, the production of tumor necrosis factor-alpha (TNF-alpha) was measured. Dietary MCTs blunted significantly the protein levels of TLR-4 in the colon. Furthermore, the expression of TLR-4 was significantly blunted in RAW264.7 cells incubated with MCTs compared with cells incubated with linoleic acid. Induction of interleukin 1beta (IL-1beta), TNF-alpha, and macrophage inflammatory protein-2 (MIP-2) in the colon was attenuated by dietary MCT. Furthermore, MPO activities in the colonic tissue were significantly blunted in animals fed the MCT diets compared with those fed the control diets. As a result, dietary MCTs improved chemically induced colitis significantly. MCTs most likely are useful for the therapy of inflammatory bowel disease as an anti-inflammatory immunomodulating nutrient. Copyright 2010 Mosby, Inc. All rights reserved.

SPECT-computed tomography in rats with TNBS-induced colitis: A first step toward functional imaging

PubMed Central

Marion-Letellier, Rachel; Bohn, Pierre; Modzelewski, Romain; Vera, Pierre; Aziz, Moutaz; Guérin, Charlène; Savoye, Guillaume; Savoye-Collet, Céline

2017-01-01

AIM To assess the feasibility of SPECT-computed tomography (CT) in rats with trinitrobenzene sulfonic acid (TNBS)-induced acute colitis and confront it with model inflammatory characteristics. METHODS Colitis was induced in Sprague-Dawley rats by intrarectal injection of TNBS (n = 10) while controls received vehicle (n = 10). SPECT-CT with intravenous injection of 10 MBq of 67Ga-Citrate was performed at day 2. SPECT-CT criteria were colon wall thickness and maximal wall signal intensity. Laboratory parameters were assessed: colon weight:length ratio, colon cyclooxygenase-2 expression by western blot and histological inflammatory score. RESULTS Colon weight/length ratio, colon COX-2 expression and histological inflammatory score were significantly higher in the TNBS group than in the control group (P = 0.0296, P < 0.0001, P = 0.0007 respectively). Pixel max tend to be higher in the TNBS group than in the control group but did not reach statistical significance (P = 0.0662). Maximal thickness is significantly increased in the TNBS group compared to the control group (P = 0.0016) while colon diameter is not (P = 0.1904). Maximal thickness and colon diameter were correlated to colon COX-2 expression (P = 0.0093, P = 0.009 respectively) while pixel max was not (P = 0.22). Maximal thickness was significantly increased when inflammation was histologically observed (P = 0.0043) while pixel max and colon diameter did not (P = 0.2452, P = 0.3541, respectively). CONCLUSION SPECT-CT is feasible and easily distinguished control from colitic rats. PMID:28127195

Synergic Interaction of Rifaximin and Mutaflor (Escherichia coli Nissle 1917) in the Treatment of Acetic Acid-Induced Colitis in Rats.

PubMed

Dembiński, Artur; Warzecha, Zygmunt; Ceranowicz, Piotr; Dembiński, Marcin; Cieszkowski, Jakub; Gosiewski, Tomasz; Bulanda, Małgorzata; Kuśnierz-Cabala, Beata; Gałązka, Krystyna; Konturek, Peter Christopher

2016-01-01

Background. Inflammatory bowel disease results from the dysregulation of immune response to environmental and microbial agents in genetically susceptible individuals. The aim of the present study was to examine the effect of rifaximin and/or Mutaflor (Escherichia coli Nissle 1917, EcN) administration on the healing of acetic acid-induced colitis. Methods. Colitis was induced in male Wistar rats by rectal enema with 3.5% acetic acid solution. Rifaximin (50 mg/kg/dose) and/or Mutaflor (10(9) CFU/dose) were given intragastrically once a day. The severity of colitis was assessed at the 8th day after induction of inflammation. Results. Treatment with rifaximin significantly accelerated the healing of colonic damage. This effect was associated with significant reversion of the acetic acid-evoked decrease in mucosal blood flow and DNA synthesis. Moreover, administration of rifaximin significantly reduced concentration of proinflammatory TNF-α and activity of myeloperoxidase in colonic mucosa. Mutaflor given alone was without significant effect on activity of colitis. In contrast, Mutaflor given in combination with rifaximin significantly enhanced therapeutic effect of rifaximin. Moreover, Mutaflor led to settle of the colon by EcN and this effect was augmented by pretreatment with rifaximin. Conclusion. Rifaximin and Mutaflor exhibit synergic anti-inflammatory and therapeutic effect in acetic acid-induced colitis in rats.

Brain endothelial adhesion molecule expression in experimental colitis.

PubMed

Sans, M; Kawachi, S; Soriano, A; Palacín, A; Morise, Z; Granger, D N; Piqué, J M; Grisham, M B; Panés, J

2001-04-01

1) To determine if endothelial expression of adhesion molecules involved in leukocyte recruitment is increased in the brain and other organs in four different models of experimental colitis, and 2) to investigate whether leukocyte infiltration occurs in the brain of colitic animals. Endothelial vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression was quantified, using the dual radiolabeled antibody technique in rats with trinitrobenzenesulfonic acid (TNBS)-induced colitis, in mice with dextran sulfate sodium (DSS)-induced colitis, in SCID mice reconstituted with CD45RBhigh T-cells, and in IL-10-/- mice. Leukocyte infiltration in the brain of TNBS-induced colitic rats was assessed by myeloperoxidase activity and immunohistochemical staining with anti-CD45 monoclonal antibody. Marked upregulation of brain endothelial VCAM-1 (2- to 5.5-fold) was consistently found in colitic animals in the four models studied. Brain VCAM-1 strongly correlated with colon VCAM-1 and colon weight. By contrast, upregulation of brain ICAM-1 in colitic animals was only observed in the CD45RBhigh transfer (3-fold) and the TNBS-induced (1.5-fold models). Heart and muscle VCAM-1 and ICAM-1 were not upregulated in colitic animals in the majority of models studied. There was no leukocyte infiltration into the brain of TNBS-induced colitic rats. Our study demonstrates a marked and specific upregulation of endothelial VCAM-1 in the brain of colitic animals. This activation of cerebral endothelial cells was not associated with an infiltration of leukocytes into brain tissue.

Ficus carica aqueous extract alleviates delayed gastric emptying and recovers ulcerative colitis-enhanced acute functional gastrointestinal disorders in rats.

PubMed

Rtibi, Kaïs; Grami, Dhekra; Wannes, Dalanda; Selmi, Slimen; Amri, Mohamed; Sebai, Hichem; Marzouki, Lamjed

2018-06-02

Ficus carica fruit, a source of bioactive functional ingredients, have been traditionally long time used for its medicinal benefits as they improve the digestive system, treating constipation and used as a natural laxative. The recent study was investigated the ameliorative effect of Ficus carica L. aqueous extract (FCAE) on delayed gastric emptying and ulcerative colitis-improved motility disturbances in dextran sulfate sodium (DSS)-induced acute colitis in rats. Wistar rats were assigned randomly and received 5% DSS for seven days. Ulcerative colitis diagnosis was confirmed by clinical signs, visible fecal blood and histopatological evaluation. The estimation of the action of colitis on TGI and constipation as well as the protective effect of extract, the intestinal biochemical and physiological parameters were measured using the charcoal meal test, loperamide (Lop)-induced constipation as well as spectrophotometric assays. FCAE (150 and 300 mg kg -1 ) was administered orally once per day for seven days 1 h after the loperamide treatment. Phenol-red colorimetric method was used to explore the action of FCAE on gastric emptying process. Ulcerative colitis caused a significantly gastrointestinal motility inhibition in normal rats and notably aggravated the constipation in LOP group. Oppositely, FCAE oral intake significantly increased levels of the gastrointestinal transit ratio and gastric emptying by accelerating of their times. Moreover, constipation severity induced by colitis was remarkably reduced in the FCAE treatment group, as demonstrated by a marked management of fecal parameters, water content, oxidative stress indicators, lipid metabolism, and intracellular mediators. Phytochemical analysis of FCAE revealed the presence of carbohydrates, polysaccharides, phenolic acids as gallic acid, chlorogenic acid, syringic acid and ellagic acid, and flavonoids (e.g. rutin, catechin, epicatechin and apeginine). The obtained results indicated that FCAE exhibits

Protective effect of Averrhoa bilimbi L. fruit extract on ulcerative colitis in wistar rats via regulation of inflammatory mediators and cytokines.

PubMed

Suluvoy, Jagadish Kumar; Sakthivel, K M; Guruvayoorappan, C; Berlin Grace, V M

2017-07-01

Ulcerative Colitis (UC) is a lingering type of Inflammatory Bowel Disease (IBD) which affects the colon mucosa. Ulcerative colitis is majorly associated with oxidative stress and inflammation in colon tissue leading to damage. Averrhoa bilimbi L. fruit is rich in antioxidant phytochemicals including Vitamin C. In the current research, we have evaluated the defence mechanism of Averrhoa bilimbi L. on Ulcerative Colitis (UC). Male wistar rats were treated with Averrhoa bilimbi L. fruit extract (50mg/kg/bwt and 100mg/kg/bwt) and a standard drug Sulfasalazine (100mg/kg/bwt) for 6 consecutive days via intra peritoneally. After one day fasting, rats were given single dose of 3% 2ml of acetic acid through anal (intra-anal) region to induce Ulcerative Colitis. The protective and therapeutic effect of fruit extract on UC was assessed by comparing the relevant changes observed in the normal and treated group. In treated group the level of mucosal injury was decreased (ulcer score - 2) when compared to the control group (ulcer score - 9). The abnormal increase observed in the inflammation mediator cytokines in control rats, i.e IL-1β, IL-6, TNF-α levels were decreased significantly (**p<0.01) in the Averrhoa bilimbi L. fruit extract treated groups. The increase in weights of the colon tissue and spleen of the control rats were found to be reduced in treated groups. The levels of inflammatory markers iNOS and COX-2 were also decreased in treated group significantly (**p<0.01) when compared with the control. Furthermore, the treatment with Averrhoa bilimbi L. fruit extract has shown a significant antioxidant activity in the UC condition by reducing the levels of NO and enhancing the levels of SOD and GSH in the colon tissue. These results demonstrate the effective anti-ulcerative colitis activity of the Averrhoa bilimbi L. fruit extract in experimental wistar rats. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Efficacy of thalidomide on trinitrobenzene sulfonate-induced colitis in young rats and its mechanism.

PubMed

Xu, Jiahua; Zheng, Cuifang; Huang, Ying; Liang, Yingjie

2014-01-01

Thalidomide could relieve clinical symptoms and intestinal mucosal lesions effectively in children with refractory inflammatory bowel disease (IBD) from the pre-clinical study. This study aimed to observe the therapeutic effect of thalidomide by the established animal model of IBD model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in Sprague-Dawley (SD) rats and to investigate the possible mechanism of action. A total of 82 SD rats of about 4-5 weeks were randomly divided into three groups: the control group (25 rats), TNBS-treated group (29 rats), and thalidomide treatment group (28 rats). Daily activities were recorded. At least eight rats from each group were killed on the 4th, 7th, and 14th days. Morphological and histological changes in the colon were individually assessed. Serum was collected and the levels of TNF-α and interleukins (IL-1β and IL-10) were assayed by ELISA method. The expression of colonic mucosal nuclear factor (NF)-κB was assayed with the immunohistochemical method. (1) In the control group, diarrhea and rectal bleeding recovered rapidly and no death was recorded. In the TNBS-treated group, diarrhea and rectal bleeding persisted for a longer time. The mortality rate was 10.34% during the observation period. In the thalidomide treatment group, diarrhea and rectal bleeding persisted for a significantly shorter time than the TNBS-treated group (P < 0.01). The rats of this group also exhibited faster weight gain on day 7 compared with the TNBS-treated group but still lower than that of the control group. The mortality rate of the thalidomide treatment group was 3.57%. (2) Macroscopic and microscopic scores of the thalidomide-treated group were significantly lower than those of the TNBS model group on the 14th day (P < 0.01). These results suggested faster and better colonic recovery in the thalidomide-treated group. (3) NF-κB expression in the colonic mucosa of the control group was lower than in the others, mainly

Colitis-induced oxidative damage of the colon and skeletal muscle is ameliorated by regular exercise in rats: the anxiolytic role of exercise.

PubMed

Kasimay, Ozgür; Güzel, Esra; Gemici, Ali; Abdyli, Asead; Sulovari, Admir; Ercan, Feriha; Yeğen, Berrak C

2006-09-01

Epidemiological studies have shown that exercise protects the gastrointestinal tract, reducing the risk of diverticulosis, gastrointestinal haemorrhage and inflammatory bowel disease, while many digestive complaints occurring during exercise are attributed to the adverse effects of exercise on the colon. In order to assess the effects of regular exercise on the pathogenesis of colitis, Sprague-Dawley rats of both sexes were either kept sedentary or given exercise on a running wheel (0.4 km h(-1), 30 min for 3 days week(-1)). At the end of 6 weeks, under anaesthesia, either saline or acetic acid (4%, 1 ml) was given intracolonically. Holeboard tests were performed for the evaluation of anxiety at 24 h before and 48 h after induction of colitis. Increased 'freezing time' in the colitis-induced sedentary group, representing increased anxiety, was reduced in the exercised colitis group (P < 0.05). On the third day following the colonic instillation, the rats were decapitated under brief ether anesthesia and the distal 8 cm of the colons were removed. In the sedentary colitis group, macroscopic and microscopic damage scores, malondialdehyde level and myeloperoxidase activity were increased when compared to the control group (P < 0.01-0.001), while exercise prior to colitis reduced all the measurements with respect to sedentary colitis group (P < 0.05-0.001). The results demonstrate that low-intensity, repetitive exercise protects against oxidative colonic injury, and that this appears to involve the anxiolytic effect of exercise, suggesting that exercise may have a therapeutic value in reducing stress-related exacerbation of colitis.

Dextran-5-(4-ethoxycarbonylphenylazo)salicylic acid ester, a polymeric colon-specific prodrug releasing 5-aminosalicylic acid and benzocaine, ameliorates TNBS-induced rat colitis.

PubMed

Nam, Joon; Kim, Wooseong; Lee, Sunyoung; Jeong, Seongkeun; Yoo, Jin-Wook; Kim, Min-Soo; Jung, Yunjin

2016-01-01

Local anesthetics have beneficial effects on colitis. Dextran-5-(4-ethoxycarbonylphenylazo)salicylic acid ester (Dex-5-ESA), designed as a polymeric colon-specific prodrug liberating 5-ASA and benzocaine in the large intestine, was prepared and its therapeutic activity against colitis was evaluated using a TNBS-induced rat colitis model. Dex-5-ESA liberated 5-ASA and benzocaine in the cecal contents while (bio)chemically stable in the small intestinal contents and mucosa. Oral administration of Dex-5-ESA (equivalent to 10 mg 5-ASA/kg, twice a day) alleviated colonic injury and reduced MPO activity in the inflamed colon. In parallel, pro-inflammatory mediators, COX-2, iNOS and CINC-3, elevated by TNBS-induced colitis, were substantially diminished in the inflamed colon. Dex-5-ESA was much more effective for the treatment of colitis than 5-(4-ethoxycarbonylphenylazo)salicylic acid (5-ESA) that may not deliver benzocaine to the large intestine. Our data suggest that Dex-5-ESA is a polymeric colon-specific prodrug, liberating 5-ASA and benzocaine in the target site (large intestine), probably exerting anti-colitic effects by combined action of 5-ASA and benzocaine.

Effect of Coriandrum sativum hydroalcoholic extract and its essential oil on acetic acid- induced acute colitis in rats

PubMed Central

Heidari, Bahareh; Sajjadi, Seyed Ebrahim; Minaiyan, Mohsen

2016-01-01

Objective: The aim of this study was to determine the protective effects of Coriandrum sativum on acetic acid-inducedcolitis in rats. C. sativum (Coriander) has long been used in Iranian traditional medicine and its use as an anti-inflammatory agent is still common in some herbal formulations. Materials and Methods: Colitis was induced by intra-rectal administration of 2ml acetic acid 4% in fasted male Wistar rats. Treatment was carried out using three increasing doses of extract (250, 500, 1000 mg/kg) and essential oil (0.25, 0.5, 1 ml/kg) of coriander started 2 h before colitis induction and continued for a five-day period. Colon biopsies were taken for weighting, macroscopic scoring of injured tissue, histopathological examination and measuring myeloperoxidase (MPO) activity. Results: Colon weight was decreased in the groups treated with extract (500 and 1000 mg/kg) and essential oil (0.5 ml/kg) compared to the control group. Regarding MPO levels, ulcer severity and area as well as the total colitis index, same results indicating meaningful alleviation of colitis was achieved after treatment with oral extract and essential oil. Conclusion: Since the present experiment was made by oral fractions of coriander thus the resulting effects could be due to both the absorption of the active ingredients and/or the effect of non-absorbable materials on colitis after reaching the colon. In this regard, we propose more toxicological and clinical experiments to warranty its beneficial application in human inflammatory bowel diseases. PMID:27222834

Swimming attenuates inflammation, oxidative stress, and apoptosis in a rat model of dextran sulfate sodium-induced chronic colitis

PubMed Central

Zhu, Xiao-shan; Liu, Qin-qin; Wang, Li-feng; Yang, An-gang; Gao, Chun-fang; Li, Jun-tang

2017-01-01

Increasing evidence suggests that regular physical exercise suppresses chronic inflammation. However, the potential inhibitory effects of swimming on dextran sulfate sodium (DSS)-induced chronic colitis, and its underlying mechanisms, remain unclear. In this study, rats were orally administered DSS to induce chronic colitis, and subsequently treated with or without swimming exercise. A 7-week swimming program (1 or 1.5 hours per day, 5 days per week) ameliorated DSS-caused colon shortening, colon barrier disruption, spleen enlargement, serum LDH release, and reduction of body weight gain. Swimming for 1.5 hours per day afforded greater protection than 1 hour per day. Swimming ameliorated DSS-induced decrease in crypt depth, and increases in myeloperoxidase activity, infiltration of Ly6G+ neutrophils and TNF-a- and IFN-?-expressing CD3+ T cells, as well as fecal calprotectin and lactoferrin. Swimming inhibited pro-inflammatory cytokine and chemokine production and decreased the protein expression of phosphorylated nuclear factor-?B p65 and cyclooxygenase 2, whereas it elevated interleukin-10 levels. Swimming impeded the generation of reactive oxygen species, malondialdehyde, and nitric oxide; however, it boosted glutathione levels, total antioxidant capacity, and superoxide dismutase and glutathione peroxidase activities. Additionally, swimming decreased caspase-3 activity and expression of apoptosis-inducing factor, cytochrome c, Bax, and cleaved-caspase-3, but increased Bcl-2 levels. Overall, these results suggest that swimming exerts beneficial effects on DSS-induced chronic colitis by modulating inflammation, oxidative stress, and apoptosis. PMID:28030847

Swimming attenuates inflammation, oxidative stress, and apoptosis in a rat model of dextran sulfate sodium-induced chronic colitis.

PubMed

Qin, Ling; Yao, Zhi-Qiang; Chang, Qi; Zhao, Ya-Li; Liu, Ning-Ning; Zhu, Xiao-Shan; Liu, Qin-Qin; Wang, Li-Feng; Yang, An-Gang; Gao, Chun-Fang; Li, Jun-Tang

2017-01-31

Increasing evidence suggests that regular physical exercise suppresses chronic inflammation. However, the potential inhibitory effects of swimming on dextran sulfate sodium (DSS)-induced chronic colitis, and its underlying mechanisms, remain unclear. In this study, rats were orally administered DSS to induce chronic colitis, and subsequently treated with or without swimming exercise. A 7-week swimming program (1 or 1.5 hours per day, 5 days per week) ameliorated DSS-caused colon shortening, colon barrier disruption, spleen enlargement, serum LDH release, and reduction of body weight gain. Swimming for 1.5 hours per day afforded greater protection than 1 hour per day. Swimming ameliorated DSS-induced decrease in crypt depth, and increases in myeloperoxidase activity, infiltration of Ly6G+ neutrophils and TNF-α- and IFN-γ-expressing CD3+ T cells, as well as fecal calprotectin and lactoferrin. Swimming inhibited pro-inflammatory cytokine and chemokine production and decreased the protein expression of phosphorylated nuclear factor-κB p65 and cyclooxygenase 2, whereas it elevated interleukin-10 levels. Swimming impeded the generation of reactive oxygen species, malondialdehyde, and nitric oxide; however, it boosted glutathione levels, total antioxidant capacity, and superoxide dismutase and glutathione peroxidase activities. Additionally, swimming decreased caspase-3 activity and expression of apoptosis-inducing factor, cytochrome c, Bax, and cleaved-caspase-3, but increased Bcl-2 levels. Overall, these results suggest that swimming exerts beneficial effects on DSS-induced chronic colitis by modulating inflammation, oxidative stress, and apoptosis.

Dietary Propolis Ameliorates Dextran Sulfate Sodium-Induced Colitis and Modulates the Gut Microbiota in Rats Fed a Western Diet.

PubMed

Wang, Kai; Jin, Xiaolu; You, Mengmeng; Tian, Wenli; Le Leu, Richard K; Topping, David L; Conlon, Michael A; Wu, Liming; Hu, Fuliang

2017-08-14

Propolis is an important hive product and considered beneficial to health. However, evidence of its potential for improving gut health is still lacking. Here we use rats to examine whether dietary supplementation with propolis could be used as a therapy for ulcerative colitis. Rats were fed with a Western style diet alone (controls) or supplemented with different amounts of Chinese propolis (0.1%, 0.2%, and 0.3%) to examine effects on acute colitis induced by 3% dextran sulphate sodium (DSS) in drinking water. Propolis at 0.3%, but not lower levels, significantly improved colitis symptoms compared with the control group, with a less pronounced disease activity index (DAI) ( p < 0.001), a significant increase in colon length/weight ratio ( p < 0.05) and an improved distal colon tissue structure as assessed by histology. Although short chain fatty acid levels in digesta were not altered by propolis supplementation, 16S rRNA phylogenetic sequencing revealed a significant increase in gut microbial diversity after 21 days of 0.3% propolis supplementation compared with controls including a significant increase in bacteria belonging to the Proteobacteria and Acidobacteria phyla. This is the first study to demonstrate that propolis can attenuate DSS-induced colitis and provides new insight into diet-microbiota interactions during inflammatory bowel disease.

Protective effect of natural honey against acetic acid-induced colitis in rats.

PubMed

Mahgoub, A A; el-Medany, A H; Hagar, H H; Sabah, D M

2002-01-01

The protective effects of natural honey against acetic acid-induced colitis were investigated in rats. Honey and glucose, fructose, sucrose, maltose mixture were administered, orally and rectally, daily for a period of 4 days. Induction of colitis was done on the third day using 3% acetic acid. Animals were killed on day 4 two hours after administration of the dose and colonic biopsies were taken for macroscopic scoring, histopathological and biochemical studies. Honey dose-dependently afforded protection against acetic acid-induced colonic damage. There was almost 100% protection with the highest dose (5 g/kg) used while glucose, fructose, sucrose, maltose mixture produced no significant protective effect. Also, honey prevented the depletion of the antioxidant enzymes reduced glutathione and catalase and restored the lipid peroxide malondialdehyde towards normal levels. Further studies are required to explore the active ingredients responsible for the antioxidant effect of honey and its therapeutic potential in humans.

Stable gastric pentadecapeptide BPC 157 in the treatment of colitis and ischemia and reperfusion in rats: New insights.

PubMed

Duzel, Antonija; Vlainic, Josipa; Antunovic, Marko; Malekinusic, Dominik; Vrdoljak, Borna; Samara, Mariam; Gojkovic, Slaven; Krezic, Ivan; Vidovic, Tinka; Bilic, Zdenko; Knezevic, Mario; Sever, Marko; Lojo, Nermin; Kokot, Antonio; Kolovrat, Marijan; Drmic, Domagoj; Vukojevic, Jaksa; Kralj, Tamara; Kasnik, Katarina; Siroglavic, Marko; Seiwerth, Sven; Sikiric, Predrag

2017-12-28

To provide new insights in treatment of colitis and ischemia and reperfusion in rats using stable gastric pentadecapeptide BPC 157. Medication [BPC 157, L-NAME, L-arginine (alone/combined), saline] was bath at the blood deprived colon segment. During reperfusion, medication was BPC 157 or saline. We recorded (USB microscope camera) vessel presentation through next 15 min of ischemic colitis (IC-rats) or reperfusion (removed ligations) (IC + RL-rats); oxidative stress as MDA (increased (IC- and IC + RL-rats)) and NO levels (decreased (IC-rats); increased (IC + RL-rats)) in colon tissue. IC + OB-rats [IC-rats had additional colon obstruction (OB)] for 3 d (IC + OB-rats), then received BPC 157 bath. Commonly, in colon segment (25 mm, 2 ligations on left colic artery and vein, 3 arcade vessels within ligated segment), in IC-, IC + RL-, IC + OB-rats, BPC 157 (10 μg/kg) bath (1 mL/rat) increased vessel presentation, inside/outside arcade interconnections quickly reappeared, mucosal folds were preserved and the pale areas were small and markedly reduced. BPC 157 counteracted worsening effects induced by L-NAME (5 mg) and L-arginine (100 mg). MDA- and NO-levels were normal in BPC 157 treated IC-rats and IC + RL-rats. In addition, on day 10, BPC 157-treated IC + OB-rats presented almost completely spared mucosa with very small pale areas and no gross mucosal defects; the treated colon segment was of normal diameter, and only small adhesions were present. BPC 157 is a fundamental treatment that quickly restores blood supply to the ischemically injured area and rapidly activates collaterals. This effect involves the NO system.

Stable gastric pentadecapeptide BPC 157 in the treatment of colitis and ischemia and reperfusion in rats: New insights

PubMed Central

Duzel, Antonija; Vlainic, Josipa; Antunovic, Marko; Malekinusic, Dominik; Vrdoljak, Borna; Samara, Mariam; Gojkovic, Slaven; Krezic, Ivan; Vidovic, Tinka; Bilic, Zdenko; Knezevic, Mario; Sever, Marko; Lojo, Nermin; Kokot, Antonio; Kolovrat, Marijan; Drmic, Domagoj; Vukojevic, Jaksa; Kralj, Tamara; Kasnik, Katarina; Siroglavic, Marko; Seiwerth, Sven; Sikiric, Predrag

2017-01-01

AIM To provide new insights in treatment of colitis and ischemia and reperfusion in rats using stable gastric pentadecapeptide BPC 157. METHODS Medication [BPC 157, L-NAME, L-arginine (alone/combined), saline] was bath at the blood deprived colon segment. During reperfusion, medication was BPC 157 or saline. We recorded (USB microscope camera) vessel presentation through next 15 min of ischemic colitis (IC-rats) or reperfusion (removed ligations) (IC + RL-rats); oxidative stress as MDA (increased (IC- and IC + RL-rats)) and NO levels (decreased (IC-rats); increased (IC + RL-rats)) in colon tissue. IC + OB-rats [IC-rats had additional colon obstruction (OB)] for 3 d (IC + OB-rats), then received BPC 157 bath. RESULTS Commonly, in colon segment (25 mm, 2 ligations on left colic artery and vein, 3 arcade vessels within ligated segment), in IC-, IC + RL-, IC + OB-rats, BPC 157 (10 μg/kg) bath (1 mL/rat) increased vessel presentation, inside/outside arcade interconnections quickly reappeared, mucosal folds were preserved and the pale areas were small and markedly reduced. BPC 157 counteracted worsening effects induced by L-NAME (5 mg) and L-arginine (100 mg). MDA- and NO-levels were normal in BPC 157 treated IC-rats and IC + RL-rats. In addition, on day 10, BPC 157-treated IC + OB-rats presented almost completely spared mucosa with very small pale areas and no gross mucosal defects; the treated colon segment was of normal diameter, and only small adhesions were present. CONCLUSION BPC 157 is a fundamental treatment that quickly restores blood supply to the ischemically injured area and rapidly activates collaterals. This effect involves the NO system. PMID:29358856

Anti-inflammatory Efficiency of Ankaferd Blood Stopper in Experimental Distal Colitis Model

PubMed Central

Koçak, Erdem; Akbal, Erdem; Taş, Adnan; Köklü, Seyfettin; Karaca, Gökhan; Can, Murat; Kösem, Bahadır; Üstün, Hüseyin

2013-01-01

Background/Aim: Ankaferd blood stopper (ABS) is a herbal extract that enhances mucosal healing. In this study, we aimed to investigate the efficiency of ABS in the treatment of experimental distal colitis. Materials and Methods: Twenty one male albino rats were divided into three groups: Sham control (Group 1), colitis induced by acetic acid and treated with saline (Group 2), colitis induced by acetic acid and treated with ABS (Group 3). At end of the 7th day of induction, all the rats were lightly anesthetized with intramuscular ketamine (8 mg/kg) and thereafter laparotomy and total colectomy were performed. The distal colon segment was assessed macroscopically and microscopically. In addition malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide (NO) levels of the colonic tissue and changes in body weight were measured. Results: The MDA and NO levels of the colonic tissues and weight loss were significantly higher in Group 2 compared to Group 1 and Group 3. Microscopic and macroscopic damage scores were significantly higher in Group 2 and Group 3 than Group 1 (P: 0.001, P: 0.004, respectively). Although the microscopic and macroscopic damage scores in Group 3 were slightly lower than Group 2, the difference was not statistically significant. The SOD levels of the colonic tissues were not different between the three groups. Conclusion: Weight alterations and high-levels of the colonic tissue MDA and NO suggested that ABS might have anti-inflammatory effects on experimental distal colitis. However, this suggestion was not supported by histopathological findings. PMID:23680710

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

[The specificity between "fei and dachang" in the lung injury of rats with ulcerative colitis].

PubMed

Zhu, Li; Wang, Xin-yue; Yang, Xue; Jing, Shan; Zhou, Bo; Huang, Xiu-xia; Jia, Xu

2013-03-01

To observe the features of bronchopulmonary lesions in ulcerative colitis (UC) rats and the specificity with Fei and Dachang, thus providing reliance for the theory of "intestinal diseases involved Fei". The UC rat model was duplicated by using rabbit intestine mucosa tissue allergenic model and TNBS-ethanol model. A normal rat group was set up as the control. The pulmonary functions [including inspiratory resistance (Ri), expiratory resistance (Re), forced vital capacity (FVC); FEV. 2/FVC, maximal voluntary ventilation (MVV), forced expiratory flow rate (FEF25% - 75%)], and indicators of liver and kidney functions [serum alanine aminotransferase (ALT), aspartate amino transferase (AST), blood urea nitrogen (BUN), and creatinine (Cr)] were detected in the two groups. The pathological changes of colon, lung, liver, and kidney were observed in the two groups. Rats in the model group in both acute and chronic stages had weight loss, mucus and loose stool. Partial rats had such symptoms as dyspnea, shortness of breath, and wheezing. Compared with the normal group, the MW, FVC, FEV0.2 and FEF25% -75% in the acute stage; Ri, Re, MVV, FVC, and FEF25% - 75% in the chronic stage all significantly decreased (P <0.05, P <0.01), and FEV0.2/FVC significantly increased in the model group (P <0.05). The pathological results showed interstitial pneumonia and pulmonary interstitial fibrosis in the model group. But the indicators of liver and kidney functions were all in the normal range. No obvious pathological change was seen in the renal and liver tissues in the two groups. UC could specifically induce bronchopulmonary lesions. Lung injury was one of UC's intestinal manifestations. The theory of "Fei and Dachang being interior-exteriorly correlated" was demonstrated from the theory of "intestinal diseases involved Fei".

Costus root granules improve ulcerative colitis through regulation of TGF-β mediation of the PI3K/AKT signaling pathway

PubMed Central

Wang, Xiaohong; Li, Dan; Zhang, Yong; Wu, Shuang; Tang, Fang

2018-01-01

Ulcerative colitis is a chronic nonspecific inflammatory disease that occurs in the colon and rectum. Costus root is a type of traditional Chinese medicine that exhibits antibacterial properties and serves an inhibitory role in the regeneration of gut bacteria. However, the molecular mechanisms underlying Costus root-mediated improvements in ulcerative colitis remain unclear. A complex formula of Costus root granules was created and investigated in the present study for its therapeutic effects in a rat model of ulcerative colitis. Ingredient dissolution into a traditional water decoction was used as a control. The potential mechanism mediated by Costus root granules was also analyzed in colonic epithelial cells isolated from the experimental rats. The results of the present study demonstrated that Costus root granule treatment inhibited inflammation in colonic tissue. Costus root granule treatment also suppressed the apoptosis of colonic epithelial cells isolated from the rat model of ulcerative colitis. Analyses of the underlying mechanisms of these effects indicated that the administration of Costus root granules increased transforming growth factor β expression, which activated the phosphoinositide 3-kinase/RAC-α serine/threonine-protein kinase signaling pathway in colonic epithelial cells. Notably, the administration of Costus root granules improved stomachache, diarrhea and hematochezia in and increased the body weight of, the ulcerative colitis rats. In conclusion, these results indicate that Costus root granules markedly ameliorate inflammation of the colonic epithelium, decrease the apoptosis of colonic epithelial cells and improve colonic function, which suggests that Costus root granules are an efficient agent for the treatment of ulcerative colitis. PMID:29731832

Medium-chain triglyceride-rich enteral nutrition is more effective than low-fat enteral nutrition in rat colitis, but is equal in enteritis.

PubMed

Tsujikawa, T; Ohta, N; Nakamura, T; Yasuoka, T; Satoh, J; Fukunaga, T; Itohi, A; Uda, K; Ihara, T; Andoh, A; Sasaki, M; Fujiyama, Y; Bamba, T

2001-10-01

Although enteral nutrition (EN) therapy for Crohn's disease has been confirmed to be as effective as steroid therapy, the precise mechanism responsible for the effects of EN remains unclear, although some of the therapeutic effects of EN are believed to be due to a low dietary fat content. In order to elucidate the influence of fat in EN, it is important to investigate not only the quantity of fat, but also the source of the fat. We compared two enteral nutritional formulae: Elental (Ajinomoto) (elemental diet; ED), which contains only 1.5% fat, provided as long-chain triglycerides (LCT), versus Twinline (Snow Brand Milk Products) (TL), which contains a high percentage of fat (20.4%), provided mainly as medium-chain triglycerides (MCT). These formulae were tested on rat enteritis and rat colitis induced by trinitrobenzene sulfonic acid (TNBS). Both ED and TL reduced the manifestations of enteritis. TL had a stronger anti-inflammatory effect than ED for colitis. TL also had nutritional advantages as compared with ED, as shown by the total serum protein in the TL group being significantly higher than that in the ED group. The results indicate that intraluminal MCT is suitable as a fat energy source during intestinal inflammation in rats. We suggest that Twinline may be more useful to improve nutritional status and to reduce the mucosal inflammation in rat colitis, but that Twinline is equal in effect to Elental for rat enteritis.

Sequential changes in luminal microflora and mucosal cytokine expression during developing of colitis in HLA-B27/beta2-microglobulin transgenic rats.

PubMed

Hata, K; Andoh, A; Sato, H; Araki, Y; Tanaka, M; Tsujikawa, T; Fujiyama, Y; Bamba, T

2001-11-01

Transgenic rats expressing HLA-B27 and human beta2-microglobulin (HLA-B27 rats) spontaneously develop chronic colitis resembling human inflammatory bowel disease. We investigated the sequential changes in the luminal bacterial flora and mucosal cytokine mRNA expression in this model. HLA-B27 rats were maintained in a specific pathogen-free environment, and luminal microflora was evaluated by standard bacterial culture technique. The expression of mucosal cytokine mRNA was analysed by RT-PCR methods. Clinical symptoms of colitis appeared at 8 weeks of age. The total number of obligate anaerobes was higher than those of facultative anaerobes during the experimental period. At 6 weeks of age, the colonization of Bacteroides spp., Bifidobacterium spp. and Lactobacillus spp. was already detectable at high concentrations, whereas Clostridium spp. and Eubacterium spp. were not detected. The expression of proinflammatory cytokines (IL-Ibeta, IL-8 and TNF-alpha) appeared at 8 weeks of age, and these were detectable until 17 weeks. A similar pattern was observed in the expression of Th1 cytokines (IL-2, IL-12 and IFN-gamma). On the other hand, the expression of Th2 cytokines (IL-4, IL-10 and TGF-beta) was weak. IL-4 mRNA expression was weakly detectable only at 6 and 8 weeks of age. The expression of IL-10 and TGF-beta mRNA was scarcely detectable throughout the experimental period. The development of colitis may be mediated by both the predominant expression of Th1 cytokines and the weakness of Th2 cytokine expression in the mucosa. The colonization of anaerobic bacteria, especially Bacteroides spp., may be initiating and promoting these cytokine responses.

Novel mouse model of colitis characterized by hapten-protein visualization.

PubMed

Ishiguro, Kazuhiro; Ando, Takafumi; Maeda, Osamu; Watanabe, Osamu; Goto, Hidemi

2010-09-01

Trinitrobenzene sulfonic acid (TNBS) and oxazolone are used to induce colitis for the investigation of inflammatory reactions in the colon. Although these chemicals are presumed to bind proteins in the colonic mucosa and then induce colitis as haptens, hapten-protein formation has not yet been confirmed in the colonic mucosa. We developed a mouse model of colitis characterized by hapten-protein visualization, using 4-chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl), which emits fluorescence after binding to proteins. The enema of 1 mg/mL NBD-Cl induced severe diarrhea, rectal bleeding, and body weight reductions in BALB/c mice. Mucosal signs indicative of colitis, such as redness and swelling observed under stereomicroscopy or inflammatory cell infiltration and crypt-epithelium destruction under microscopy, were manifested around NBD-proteins visualized with fluorescence. Fluorescence microscopy showed the infiltration of F4/80+ cells around areas of NBD-proteins, and flow cytometry indicated the uptake of NBD-proteins by CD11b+ cells. We also found critical roles for T cells and interleukin-6 in colitis induction with NBD-proteins. NBD-Cl-induced colitis presents a unique model to study the relevance between hapten-protein formation and inflammatory reactions and offers a method to assess experimental interventions on colitis induction in the mucosa, where hapten-protein formation is confirmed.

Camellia Oil ( Camellia oleifera Abel.) Modifies the Composition of the Gut Microbiota and Alleviates Acetic Acid-induced Colitis in Rats.

PubMed

Lee, Wei-Ting; Tung, Yu-Tang; Wu, Chun-Ching; Tu, Pang-Shuo; Yen, Gow-Chin

2018-06-13

Ulcerative colitis (UC), one type of chronic inflammatory bowel disease (IBD), is a chronic and recurrent disorder of the gastrointestinal (GI) tract. As camellia oil (CO) is traditionally used to treat GI disorders, this study investigated the role of CO on acetic acid-induced colitis in the rat. The composition of the gut microbial community is related to many diseases, thus, this study also investigated the effects of CO on the composition of the gut microbiota. The rats were fed a dose of 2 mL/kg body weight CO, olive oil (OO), or soybean oil (SO) once a day for 20 days, and the gut microbiota was analyzed using 16S rRNA gene sequencing. Results of the gut microbiota examination showed significant clustering of feces after treatment with CO and OO; however, individual differences with OO varied considerably. Compared to SO and OO, the intake of CO increased the ratio of Firmicutes/Bacteroidetes, the α-diversity, relative abundance of the Bifidobacterium, and reduced Prevotella of the gut microbiota. On day 21, colitis was induced by a single transrectal administration of 2 mL of 4% acetic acid. However, pretreatment of rats with CO or OO for 24 days slightly enhanced antioxidant and antioxidant enzyme activities, and significantly reduced inflammatory damage and lipid peroxidation, thus ameliorating acetic acid-induced colitis. These results indicated that CO was better able to ameliorate impairment of the antioxidant system induced by acetic acid compared to OO and SO, which may have been due to CO modifying the composition of the gut microbiota or CO being a rich source of phytochemicals.

New insights on the modulatory roles of metformin or alpha-lipoic acid versus their combination in dextran sulfate sodium-induced chronic colitis in rats.

PubMed

Samman, Fatma S; Elaidy, Samah M; Essawy, Soha S; Hassan, Mohammad S

2017-11-24

Dextran sulfate sodium (DSS)-induced colitis is the most widely used model that resembles ulcerative colitis (UC) in human with challenging chronic mechanistic oxidative stress-inflammatory/immunological cascades. In models of acute colitis, reduction of oxidative stress and inflammatory burdens beside manipulation of many transcriptional factors were achieved by metformin or alpha-lipoic acid (α-LA). Currently, in vivo DSS-induced chronic colitis was conducted and the possible therapeutic roles of metformin and/or α-LA were explored. Chronic UC was induced by adding 5% DSS orally in drinking water for 7 days followed by 3% DSS in drinking water for 14 days in adult male albino Wistar rats. Intraperitoneal administration of α-LA (25 mg/kg, twice/day) and/or metformin (100 mg/kg/day) were set at day 7 of DSS administration and continued for 14 days. Body weights, survival rates, disease activity index (DAI), colonic oxidative stress markers, tumor necrosis factor (TNF)-α levels, colonic nuclear factor-kappa-B (NF-κB) immunohistochemical expression, and the colonic histopathological changes were observed. Metformin or/and α-LA attenuated the severity of the DSS-induced colitis through improving the reductions in body weights, the DAI, the colonic oxidative stress markers, TNF-α, and NF-κB levels, and the morphological mucosal damage scores. Significant synergetic therapeutic effects were observed with combined therapeutic regimens. Therapeutically, metformin and α-LA could be administered in chronic colitis. The combination of currently used pharmaceutics with natural and synthetic potent antioxidant compounds will become a therapeutic strategy of choice for UC to improve the quality of life if sufficient clinical trials are available. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

Changes in the Expression and Distribution of Claudins, Increased Epithelial Apoptosis, and a Mannan-Binding Lectin-Associated Immune Response Lead to Barrier Dysfunction in Dextran Sodium Sulfate-Induced Rat Colitis

PubMed Central

Yuan, Bosi; Zhou, Shuping; Lu, Youke; Liu, Jiong; Jin, Xinxin; Wan, Haijun; Wang, Fangyu

2015-01-01

Background/Aims This animal study aimed to define the underlying cellular mechanisms of intestinal barrier dysfunction. Methods Rats were fed 4% with dextran sodium sulfate (DSS) to induce experimental colitis. We analyzed the sugars in 24-hour urine output by high pressure liquid chromatography. The expression of claudins, mannan-binding lectin (MBL), and MBL-associated serine proteases 2 (MASP-2) were detected in the colonic mucosa by immunohistochemistry; and apoptotic cells in the colonic epithelium were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method assay. Results The lactulose and sucralose excretion levels in the urine of rats with DSS-induced colitis were significantly higher than those in the control rats. Mannitol excretion was lower and lactulose/mannitol ratios and sucralose/mannitol ratios were significantly increased compared with those in the control group (p<0.05). Compared with the controls, the expression of sealing claudins (claudin 3, claudin 5, and claudin 8) was significantly decreased, but that of claudin 1 was increased. The expression of pore-forming claudin 2 was upregulated and claudin 7 was downregulated in DSS-induced colitis. The epithelial apoptotic ratio was 2.8%±1.2% in controls and was significantly increased to 7.2%±1.2% in DSS-induced colitis. The expression of MBL and MASP-2 in the intestinal mucosa showed intense staining in controls, whereas there was weak staining in the rats with colitis. Conclusions There was increased intestinal permeability in DSS-induced colitis. Changes in the expression and distribution of claudins, increased epithelial apoptosis, and the MASP-2-induced immune response impaired the intestinal epithelium and contributed to high intestinal permeability. PMID:25717051

Changes in the Expression and Distribution of Claudins, Increased Epithelial Apoptosis, and a Mannan-Binding Lectin-Associated Immune Response Lead to Barrier Dysfunction in Dextran Sodium Sulfate-Induced Rat Colitis.

PubMed

Yuan, Bosi; Zhou, Shuping; Lu, Youke; Liu, Jiong; Jin, Xinxin; Wan, Haijun; Wang, Fangyu

2015-11-23

This animal study aimed to define the underlying cellular mechanisms of intestinal barrier dysfunction. Rats were fed 4% with dextran sodium sulfate (DSS) to induce experimental colitis. We analyzed the sugars in 24-hour urine output by high pressure liquid chromatography. The expression of claudins, mannan-binding lectin (MBL), and MBL-associated serine proteases 2 (MASP-2) were detected in the colonic mucosa by immunohistochemistry; and apoptotic cells in the colonic epithelium were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method assay. The lactulose and sucralose excretion levels in the urine of rats with DSS-induced colitis were significantly higher than those in the control rats. Mannitol excretion was lower and lactulose/mannitol ratios and sucralose/mannitol ratios were significantly increased compared with those in the control group (p<0.05). Compared with the controls, the expression of sealing claudins (claudin 3, claudin 5, and claudin 8) was significantly decreased, but that of claudin 1 was increased. The expression of pore-forming claudin 2 was upregulated and claudin 7 was downregulated in DSS-induced colitis. The epithelial apoptotic ratio was 2.8%±1.2% in controls and was significantly increased to 7.2%±1.2% in DSS-induced colitis. The expression of MBL and MASP-2 in the intestinal mucosa showed intense staining in controls, whereas there was weak staining in the rats with colitis. There was increased intestinal permeability in DSS-induced colitis. Changes in the expression and distribution of claudins, increased epithelial apoptosis, and the MASP-2-induced immune response impaired the intestinal epithelium and contributed to high intestinal permeability.

In utero and postnatal exposure to a phytoestrogen-enriched diet increases parameters of acute inflammation in a rat model of TNBS-induced colitis.

PubMed

Seibel, Jan; Molzberger, Almut F; Hertrampf, Torsten; Laudenbach-Leschowski, Ute; Degen, Gisela H; Diel, Patrick

2008-12-01

Inflammatory bowel disease (IBD) is very common in Europe and USA. Its incidence in East Asia has been traditionally low, albeit the risk of IBD increases in Asian immigrants adopting western lifestyles, suggesting a strong role of environmental/dietary factors in IBD. A lifelong exposure to phytoestrogen-rich diets has been associated with a decreased risk of developing breast cancer and might also be protective against IBD. We studied the influence of in utero and postnatal exposure to a phytoestrogen (PE)-rich diet on acute inflammation in an animal model of TNBS-induced colitis. Wistar rats were exposed in utero and postnatally to high (genistein: 240 microg/g feed; daidzein: 232 microg/g feed) or very low levels (genistein and daidzein <10 microg/g feed) of phytoestrogen isoflavones fed to pregnant dams with the diet and throughout nursing. After weaning, the offspring had free access to these diets. At the age of 11 weeks, colitis was induced with an enema of TNBS. After 3 days, animals were sacrificed and tissues were collected for histological evaluation and analysis of molecular markers of inflammation. Animals kept on a PE-rich diet (PRD) had higher colon weights than animals on low PE-levels (PDD), suggesting enhanced acute inflammation by phytoestrogens. This result was supported by histological findings and by analysis of myeloperoxidase activity. Interestingly, relative mRNA and protein expression of cyclooxygenase-2 (COX-2) were modulated in rats on PRD, providing evidence that COX-2, the inducible isoform of the enzyme, is involved in the management of colonic inflammation. Our results suggest that early-in-life exposure to PE might not protect against the development of IBD but enhances the extent of acute inflammation.

Comparison of two models of inflammatory bowel disease in rats.

PubMed

Catana, Cristina Sorina; Magdas, Cristian; Tabaran, Flaviu Alexandru; Crăciun, Elena Cristina; Deak, Georgiana; Magdaş, Virginia Ana; Cozma, Vasile; Gherman, Călin Mircea; Berindan-Neagoe, Ioana; Dumitraşcu, Dan Lucian

2018-03-26

There is a need for experimental animal models for inflammatory bowel diseases (IBD), but no proposed model has been unanimously accepted. The aim of this study was to develop 2 affordable models of IBD in rats and to compare them. We produced IBD in rats using either dextran sodium sulfate (DSS) or 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). The requirements for experimental models were: a predictable clinical course, histopathology and inflammation similar to human ulcerative colitis (UC) and Crohn's disease (CD). The effect of acute administration of DSS and TNBS on oxidative stress (as measured by the assessment of glutathione peroxidase - GPx) was verified. The activity of whole blood GPx was measured using a commercially available Randox kit (Crumlin, UK). The administration of DSS increased GPx activity compared to the control and TNBS-treated groups, but not to a statistically significant degree. Histological examination of the colonic mucosa following the administration of DSS showed multifocal erosions with minimal to mild inflammatory infiltrate, mainly by polymorphonuclear cells (PMN), lymphocytes and plasma cells. For TNBS-induced colitis, the histological changes manifested as multifocal areas of ulcerative colitis with mild to severe inflammatory infiltrate. Whole blood GPx values displayed a direct dependence on the chemical agent used. Our results show a correlation between histopathology, proinflammatory state and oxidative stress. The experimental DSSor TNBS-induced bowel inflammation used in this study corresponds to human IBD and is reproducible with characteristics indicative of acute inflammation in the case of the protocols mentioned.

Intestinal anti-inflammatory activity of combined quercitrin and dietary olive oil supplemented with fish oil, rich in EPA and DHA (n-3) polyunsaturated fatty acids, in rats with DSS-induced colitis.

PubMed

Camuesco, D; Comalada, M; Concha, A; Nieto, A; Sierra, S; Xaus, J; Zarzuelo, A; Gálvez, J

2006-06-01

Previous studies have described the intestinal anti-inflammatory effects exerted by the bioflavonoid quercitrin (QR) and by an n-3 polyunsaturated fatty acids (PUFA)-enriched diet in experimental models of rat colitis. The aim of the present study was to test if the combination of both treatments would result in an improvement in the intestinal anti-inflammatory effect achieved separately. Colitis was induced in female Wistar rats by incorporating dextran sodium sulfate (DSS) in drinking water at 5% (w/v) for 5 days and at 2% (w/v) for the following 10 days. Five groups of rats (n=10) were used: two of them received an olive-oil-based diet with fish oil, rich in n-3 PUFA (FO diet) for 2 weeks before colitis induction and until the end of the experiment, and one of those also was administered daily QR (1mg/kg, PO), starting when DSS concentration was changed. DSS colitis was induced in other two groups fed with standard rat diet, one of them being administered QR as before. A non-colitic group fed standard diet was also included. After that period, the rats were sacrificed and colonic damage was assessed both histologically and biochemically. The concurrent administration of FO diet and QR exhibited an intestinal anti-inflammatory effect, as evidenced by a significant improvement of all biochemical parameters of colonic inflammation assayed in comparison with non-treated colitic rats. Thus, both colonic myeloperoxidase (MPO) and alkaline phosphatase (AP) activities were significantly reduced compared with untreated colitic rats. In addition, a complete restoration of colonic glutathione content, which was depleted as a consequence of the colonic insult, was obtained in rats treated with QR plus FO diet; this content was even higher than that obtained when colitic rats were treated with FO diet alone. When compared with the control colitic group, the combined treatment was also associated with a lower colonic nitric oxide synthase and cyclooxygenase-2 expression as

Anti-inflammatory effects of Mangifera indica L. extract in a model of colitis.

PubMed

Márquez, Lucía; Pérez-Nievas, Beatriz G; Gárate, Icíar; García-Bueno, Borja; Madrigal, José Lm; Menchén, Luis; Garrido, Gabino; Leza, Juan C

2010-10-21

To investigate the effect of aqueous extract from Mangifera indica L. (MIE) on dextran sulfate sodium (DSS)-induced colitis in rats. MIE (150 mg/kg) was administered in two different protocols: (1) rectally, over 7 d at the same time as DSS administration; and (2) once daily over 14 d (by oral gavage, 7 d before starting DSS, and rectally for 7 d during DSS administration). General observations of clinical signs were performed. Anti-inflammatory activity of MIE was assessed by myeloperoxidase (MPO) activity. Colonic lipid peroxidation was determined by measuring the levels of thiobarbituric acid reactive substances (TBARS). Reduced glutathione (GSH) levels, expression of inflammatory related mediators [inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, respectively] and cytokines [tumor necrosis factor (TNF)-α and TNF receptors 1 and 2] in colonic tissue were also assessed. Interleukin (IL)-6 and TNF-α serum levels were also measured. The results demonstrated that MIE has anti-inflammatory properties by improvement of clinical signs, reduction of ulceration and reduced MPO activity when administered before DSS. In addition, administration of MIE for 14 d resulted in an increase in GSH and reduction of TBARS levels and iNOS, COX-2, TNF-α and TNF R-2 expression in colonic tissue, and a decrease in IL-6 and TNF-α serum levels. MIE has anti-inflammatory activity in a DSS-induced rat colitis model and preventive administration (prior to DSS) seems to be a more effective protocol.

Investigation of mitigating effect of colon-specific prodrugs of boswellic acid on 2,4,6-trinitrobenzene sulfonic acid-induced colitis in Wistar rats: Design, kinetics and biological evaluation

PubMed Central

Sarkate, Ajinkya; Dhaneshwar, Suneela S

2017-01-01

AIM To develop a colon-targeting bioreversible delivery system for β-boswellic acid (BBA) and explore utility of its prodrugs in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. METHODS Synthesis of 4 co-drugs of BBA with essential amino acids was achieved by CDI coupling, followed by their spectral characterization. In vitro kinetics were studied by HPLC in aqueous buffers, homogenates of gastrointestinal tract and fecal matter. In vivo kinetic studies were performed in Wistar rat plasma, urine and feces. The prodrugs were screened in TNBS-induced colitis modeled Wistar rats. Statistical significance was assumed at P < 0.05, P < 0.01, P < 0.001 when compared with disease controls using one-way and two-way ANOVAs. RESULTS Prodrugs were stable in 0.05 mol/L HCl buffer (pH 1.2) and stomach homogenates. Negligible hydrolysis was observed in phosphate buffer and intestinal homogenates. Substantial release (55%-72% and 68%-86%) of BBA was achieved in rat fecal matter and homogenates of colon. In vivo studies of BBA with L-tryptophan (BT) authenticated colon-specific release of BBA. But, surprisingly substantial concentration of BBA was seen to reach the systemic circulation due to probable absorption through colonic mucosa. Site-specifically enhanced bioavailability of BBA could be achieved in colon, which resulted in demonstration of significant mitigating effect on TNBS-induced colitis in rats without inducing any adverse effects on stomach, liver and pancreas. Prodrug of BT was found to be 1.7% (P < 0.001) superior than sulfasalazine in reducing the inflammation to colon among all prodrugs tested. CONCLUSION The outcome of this study strongly suggests that these prodrugs might have dual applicability to inflammatory bowel disease and chronotherapy of rheumatoid arthritis. PMID:28275295

Oral administration of d-limonene controls inflammation in rat colitis and displays anti-inflammatory properties as diet supplementation in humans.

PubMed

d'Alessio, Patrizia A; Ostan, Rita; Bisson, Jean-François; Schulzke, Joerg D; Ursini, Matilde V; Béné, Marie C

2013-07-10

To further explore the anti-inflammatory properties of d-Limonene. A rat model was used to compare evolution of TNBS (2,5,6-trinitrobenzene sulfonic acid)-induced colitis after oral feeding with d-Limonene compared to ibuprofen. Peripheral levels of TNF-α (Tumor Necrosis Factor alpha) were assessed in all animals. Cell cultures of fibroblasts and enterocytes were used to test the effect of d-Limonene respectively on TNFα-induced NF-κB (nuclear factor-kappa B) translocation and epithelial resistance. Finally, plasmatic inflammatory markers were examined in an observational study of diet supplementation with d-Limonene-containing orange peel extract (OPE) in humans. Administered per os at a dose of 10mg/kg p.o., d-Limonene induced a significant reduction of intestinal inflammatory scores, comparable to that induced by ibuprofen. Moreover, d-Limonene-fed rats had significantly lowered serum concentrations of TNF-α compared to untreated TNBS-colitis rats. The anti-inflammatory effect of d-Limonene also involved inhibition of TNFα-induced NF-κB translocation in fibroblast cultures. The application of d-Limonene on colonic HT-29/B6 cell monolayers increased epithelial resistance. Finally, inflammatory markers, especially peripheral IL-6, markedly decreased upon OPE supplementation of elderly healthy subjects submitted or not to 56 days of dietary supplementation with OPE. In conclusion, d-Limonene indeed demonstrates significant anti-inflammatory effects both in vivo and in vitro. Protective effects on the epithelial barrier and decreased cytokines are involved, suggesting a beneficial role of d-Limonene as diet supplement in reducing inflammation. Copyright © 2013 Elsevier Inc. All rights reserved.

Diphenyl diselenide attenuates oxidative stress and inflammatory parameters in ulcerative colitis: A comparison with ebselen.

PubMed

Petronilho, Fabricia; Michels, Monique; Danielski, Lucinéia G; Goldim, Mariana Pereira; Florentino, Drielly; Vieira, Andriele; Mendonça, Mariana G; Tournier, Moema; Piacentini, Bárbara; Giustina, Amanda Della; Leffa, Daniela D; Pereira, Gregório W; Pereira, Volnei D; Rocha, João Batista Teixeira Da

2016-09-01

The aim of this study was to evaluate the effects of diphenyl diselenide (PhSe)2 and ebselen (EB) in ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) in rats. The effects of (PhSe)2 and EB in rats submitted to DSS-induced colitis were determined by measurement of oxidative stress parameters, inflammatory response and bowel histopathological alterations. Animals developed moderate to severe neutrophil infiltration in histopathology assay in DSS rats and (PhSe)2 improved this response. Moreover, the treatment with (PhSe)2 decreased the oxidative damage in lipids and proteins, as well as reversed the superoxide dismutase (SOD) and catalase (CAT) levels in rats treated with DSS. EB was able only to reverse damage in lipids and the low levels of SOD in this animal model. The organoselenium compounds tested demonstrated an anti-inflammatory and antioxidant activity reducing the colon damage, being (PhSe)2 more effective than EB. Copyright © 2016 Elsevier GmbH. All rights reserved.

Anti-inflammatory effects of Mangifera indica L. extract in a model of colitis

PubMed Central

Márquez, Lucía; Pérez-Nievas, Beatriz G; Gárate, Icíar; García-Bueno, Borja; Madrigal, José LM; Menchén, Luis; Garrido, Gabino; Leza, Juan C

2010-01-01

AIM: To investigate the effect of aqueous extract from Mangifera indica L. (MIE) on dextran sulfate sodium (DSS)-induced colitis in rats. METHODS: MIE (150 mg/kg) was administered in two different protocols: (1) rectally, over 7 d at the same time as DSS administration; and (2) once daily over 14 d (by oral gavage, 7 d before starting DSS, and rectally for 7 d during DSS administration). General observations of clinical signs were performed. Anti-inflammatory activity of MIE was assessed by myeloperoxidase (MPO) activity. Colonic lipid peroxidation was determined by measuring the levels of thiobarbituric acid reactive substances (TBARS). Reduced glutathione (GSH) levels, expression of inflammatory related mediators [inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, respectively] and cytokines [tumor necrosis factor (TNF)-α and TNF receptors 1 and 2] in colonic tissue were also assessed. Interleukin (IL)-6 and TNF-α serum levels were also measured. RESULTS: The results demonstrated that MIE has anti-inflammatory properties by improvement of clinical signs, reduction of ulceration and reduced MPO activity when administered before DSS. In addition, administration of MIE for 14 d resulted in an increase in GSH and reduction of TBARS levels and iNOS, COX-2, TNF-α and TNF R-2 expression in colonic tissue, and a decrease in IL-6 and TNF-α serum levels. CONCLUSION: MIE has anti-inflammatory activity in a DSS-induced rat colitis model and preventive administration (prior to DSS) seems to be a more effective protocol. PMID:20954278

AOM/DSS Model of Colitis-Associated Cancer

PubMed Central

Parang, Bobak; Barret, Caitlyn W.; Williams, Christopher S.

2016-01-01

Summary Our understanding of colitis-associated carcinoma (CAC) has benefited substantially from mouse models that faithfully recapitulate human CAC. Chemical models, in particular, have enabled fast and efficient analysis of genetic and environmental modulators of CAC without the added requirement of time-intensive genetic crossings. Here we describe the Azoxymethane (AOM)/Dextran Sodium Sulfate (DSS) mouse model of inflammatory colorectal cancer. PMID:27246042

Changes of the peptide YY levels in the intestinal tissue of rats with experimental colitis following oral administration of mesalazine and prednisolone.

PubMed

Hirotani, Yoshihiko; Mikajiri, Kyoko; Ikeda, Kenji; Myotoku, Michiaki; Kurokawa, Nobuo

2008-09-01

Few studies have reported the changes in the peptide YY (PYY) levels in the intestinal tissue of rats with ulcerative colitis (UC) following oral administration of mesalazine and prednisolone. We investigated the effects of these drugs on the intestinal mucosal PYY levels in a rat model of UC. We confirmed that the PYY levels in the rat intestinal mucosal tissue were high in the lower intestinal tract. The leukocyte count and hemoglobin levels approached the normal values after administering mesalazine or prednisolone to rats treated with 3% dextran sulfate sodium (DSS). The PYY levels in the caecum and colon decreased significantly after administering DSS but increased when mesalazine was administered in a tissue-specific manner. Unlike mesalazine, the PYY levels increased in the ileum in addition to the colon and rectum after administering prednisolone. However, neither of the drugs induced any changes in the plasma PYY levels. These findings indicate that changes in the intestinal tissue PYY levels may be partially involved in the improvement of DSS-induced UC in rats following the administration of these drugs.

Diagnostic imaging advances in murine models of colitis.

PubMed

Brückner, Markus; Lenz, Philipp; Mücke, Marcus M; Gohar, Faekah; Willeke, Peter; Domagk, Dirk; Bettenworth, Dominik

2016-01-21

Inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis are chronic-remittent inflammatory disorders of the gastrointestinal tract still evoking challenging clinical diagnostic and therapeutic situations. Murine models of experimental colitis are a vital component of research into human IBD concerning questions of its complex pathogenesis or the evaluation of potential new drugs. To monitor the course of colitis, to the present day, classical parameters like histological tissue alterations or analysis of mucosal cytokine/chemokine expression often require euthanasia of animals. Recent advances mean revolutionary non-invasive imaging techniques for in vivo murine colitis diagnostics are increasingly available. These novel and emerging imaging techniques not only allow direct visualization of intestinal inflammation, but also enable molecular imaging and targeting of specific alterations of the inflamed murine mucosa. For the first time, in vivo imaging techniques allow for longitudinal examinations and evaluation of intra-individual therapeutic response. This review discusses the latest developments in the different fields of ultrasound, molecularly targeted contrast agent ultrasound, fluorescence endoscopy, confocal laser endomicroscopy as well as tomographic imaging with magnetic resonance imaging, computed tomography and fluorescence-mediated tomography, discussing their individual limitations and potential future diagnostic applications in the management of human patients with IBD.

Therapeutic Effects of 6-Gingerol, 8-Gingerol, and 10-Gingerol on Dextran Sulfate Sodium-Induced Acute Ulcerative Colitis in Rats.

PubMed

Zhang, Feng; Ma, Na; Gao, Yong-Feng; Sun, Li-Li; Zhang, Ji-Guo

2017-09-01

Ulcerative colitis is one of the most common types of inflammatory bowel disease and is multifactorial and relapsing. 6-Gingerol, a component of gingerols extracted from ginger (Zingiber officinale), has been reported to improve ulcerative colitis. The present study aims to investigate the therapeutic efficacy of two analogous forms of 6-gingerol, 8-gingerol, and 10-gingerol, on ulcerative colitis. Colitis was induced in rats through consumption of 5% (w/v) dextran sulfate sodium drinking water for 7 consecutive days. 6-Gingerol, 8-gingerol, and 10-gingerol were then given intraperitoneally at doses of 30 mg kg -1  d -1 for another 7 days, respectively. Body weight change, disease activity index, inflammatory cytokines, and oxidative stress indices were measured, and the colonic tissue injuries were assessed macroscopically and histopathologically. Results showed that all three gingerols attenuated colitic symptoms evoked by dextran sulfate sodium, significantly elevated superoxide dismutase activity, decreased malondialdehyde levels and myeloperoxidase activity in the colon tissue, and markedly reduced the content of tumor necrosis factor alpha and Interleukin 1 beta in the serum. Histological observations showed that all three gingerols obviously accelerated mucosal damage healing. It is concluded that 6-gingerol, 8-gingerol, and 10-gingerol, the three analogues, have a strong and relatively equal efficacy in the treatment of colitis. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

The Anti-Inflammatory Activity of a Novel Fused-Cyclopentenone Phosphonate and Its Potential in the Local Treatment of Experimental Colitis

PubMed Central

Shifrin, Helena; Harel, Efrat; Nadler-Milbauer, Mirela; Weinstock, Marta; Srebnik, Morris

2015-01-01

A novel fused-cyclopentenone phosphonate compound, namely, diethyl 3-nonyl-5-oxo-3,5,6,6a-tetrahydro-1H-cyclopenta[c]furan-4-ylphosphonate (P-5), was prepared and tested in vitro (LPS-activated macrophages) for its cytotoxicity and anti-inflammatory activity and in vivo (DNBS induced rat model) for its potential to ameliorate induced colitis. Specifically, the competence of P-5 to reduce TNFα, IL-6, INFγ, MCP-1, IL-1α, MIP-1α, and RANTES in LPS-activated macrophages was measured. Experimental colitis was quantified in the rat model, macroscopically and by measuring the activity of tissue MPO and iNOS and levels of TNFα and IL-1β. It was found that P-5 decreased the levels of TNFα and the tested proinflammatory cytokines and chemokines in LPS-activated macrophages. In the colitis-induced rat model, P-5 was effective locally in reducing mucosal inflammation. This activity was equal to the activity of local treatment with 5-aminosalicylic acid. It is speculated that P-5 may be used for the local treatment of IBD (e.g., with the aid of colon-specific drug platforms). Its mode of action involves inhibition of the phosphorylation of MAPK ERK but not of p38 and had no effect on IκBα. PMID:25949237

Increase in neurokinin-1 receptor-mediated colonic motor response in a rat model of irritable bowel syndrome.

PubMed

La, Jun-Ho; Kim, Tae-Wan; Sung, Tae-Sik; Kim, Hyn-Ju; Kim, Jeom-Yong; Yang, Il-Suk

2005-01-14

Irritable bowel syndrome (IBS) is a functional bowel disorder. Its major symptom is bowel dysmotility, yet the mechanism of the symptom is poorly understood. Since the neurokinin-1 receptor (NK1R)-mediated signaling in the gut is important in the control of normal bowel motor function, we aimed to investigate whether the NK1R-mediated bowel motor function was altered in IBS, using a rat IBS model that was previously reported to show colonic dysmotility in response to restraint stress. IBS symptoms were produced in male Sprague-Dawley rats by inducing colitis with acetic acid. Rats were left to recover from colitis for 6 d, and used for experiments 7 d post-induction of colitis. Motor activities of distal colon were recorded in vitro. The contractile sensitivity of isolated colon to a NK1R agonist (Sar9,Met(O2)11)-substance P (1-30 nmol/L) was higher in IBS rats than that in normal rats. After the enteric neurotransmission was blocked by tetrodotoxin (TTX, 1 micromol/L), the contractile sensitivity to the NK1R agonist was increased in normal colon but not in IBS rat colon. The NK1R agonist-induced contraction was not different between the two groups when the agonist was challenged to the TTX-treated colon or the isolated colonic myocytes. A nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 micromol/L) augmented the NK1R agonist-induced contraction only in normal rat colon. These results suggest that the NK1R-meidated colonic motor response is increased in IBS rats, due to the decrease in the nitrergic inhibitory neural component.

Enteral diets enriched with medium-chain triglycerides and N-3 fatty acids prevent chemically induced experimental colitis in rats.

PubMed

Kono, Hiroshi; Fujii, Hideki; Ogiku, Masahito; Tsuchiya, Masato; Ishii, Kenichi; Hara, Michio

2010-11-01

The specific purpose of this study was to evaluate the significant effects of medium-chain triglycerides (MCTs) and N-3 fatty acids on chemically induced experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid (TNBS) in rats. Male Wistar rats were fed liquid diets enriched with N-6 fatty acid (control diets), N-3 fatty acid (MCT- diets), and N-3 fatty acid and MCT (MCT+ diets) for 2 weeks and then were given an intracolonic injection of TNBS. Serum and tissue samples were collected 5 days after ethanol or TNBS enema. The severity of colitis was evaluated pathologically, and tissue myeloperoxidase activity was measured in colonic tissues. Furthermore, protein levels for inflammatory cytokines and a chemokine were assessed by an enzyme-linked immunosorbent assay in colonic tissues. Induction of proinflammatory cytokines tumor necrosis factor-α and interleukin-1β in the colon by TNBS enema was markedly attenuated by the MCT+ diet among the 3 diets studied. Furthermore, the induction of chemokines macrophage inflammatory protein-2 and monocyte chemotactic protein-1 also was blunted significantly in animals fed the MCT+ diets. As a result, MPO activities in the colonic tissue also were blunted significantly in animals fed the MCT+ diets compared with those fed the control diets or the MCT- diets. Furthermore, the MCT+ diet improved chemically induced colitis significantly among the 3 diets studied. Diets enriched with both MCTs and N-3 fatty acids may be effective for the therapy of inflammatory bowel disease as antiinflammatory immunomodulating nutrients. Copyright © 2010 Mosby, Inc. All rights reserved.

Reduction of experimental colitis in the rat by inhibitors of glycogen synthase kinase-3beta.

PubMed

Whittle, Brendan J R; Varga, Csaba; Pósa, Anikó; Molnár, Andor; Collin, Marika; Thiemermann, Christoph

2006-03-01

The effects of the inhibitors of glycogen synthase kinase-3beta (GSK-3beta), TDZD-8 and SB 415286, which can substantially reduce the systemic inflammation associated with endotoxic shock in vivo, have now been investigated on the acute colitis provoked by trinitrobenzene sulphonic acid (TNBS) in the rat. Administration of the GSK-3beta inhibitor TDZD-8 (0.1, 0.33 or 1.0 mg kg-1, s.c., b.i.d., for 3 days) caused a dose-dependent reduction in the colonic inflammation induced by intracolonic TNBS assessed after 3 days, both as the area of macroscopic involvement and as a score using 0-10 scale. Likewise, following administration of the GSK-3beta inhibitor SB 415286 (0.1, 0.33 or 1.0 mg kg-1, s.c., b.i.d., for 3 days), the extent and degree of the TNBS-provoked colonic inflammation was reduced. Administration of either TDZD-8 or SB 415286 reduced the fall in body weight following challenge with TNBS at each dose level studied. The increase in myeloperoxidase activity, an index of neutrophil infiltration into the TNBS-induced inflamed colon, was significantly inhibited by both TDZD-8 and SB 415286 at each dose level. The increase in the levels of the proinflammatory cytokine, TNF-alpha, in the inflamed colon was also significantly inhibited by either compound at the highest doses evaluated. The elevated levels of the transcription factor NF-kappaB subunit p65, as determined by Western blot in the nuclear extracts from the TNBS-provoked inflamed colonic tissue, were dose-dependently reduced by TDZD-8 or SB 415286 treatment. These findings demonstrate that two chemically distinct selective inhibitors of the activity of GSK-3beta reduce the inflammation and tissue injury in a rat model of acute colitis. The mechanisms underlying this anti-inflammatory action may be related to downregulation of NF-kappaB activity, involved in the generation of proinflammatory mediators.

Essential Role of Growth Hormone and IGF-1 in Therapeutic Effect of Ghrelin in the Course of Acetic Acid-Induced Colitis.

PubMed

Ceranowicz, Piotr; Warzecha, Zygmunt; Cieszkowski, Jakub; Ceranowicz, Dagmara; Kuśnierz-Cabala, Beata; Bonior, Joanna; Jaworek, Jolanta; Ambroży, Tadeusz; Gil, Krzysztof; Olszanecki, Rafał; Pihut, Małgorzata; Dembiński, Artur

2017-05-24

Previous studies have shown that ghrelin exhibits a protective and therapeutic effect in the gut. The aim of the present study was to examine whether administration of ghrelin affects the course of acetic acid-induced colitis and to determine what is the role of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in this effect. In sham-operated or hypophysectomized male Wistar rats, colitis was induced by enema with 1 mL of 3% solution of acetic acid. Saline or ghrelin (given at the dose of 8 nmol/kg/dose) was administered intraperitoneally twice a day. Seven days after colitis induction, rats were anesthetized and the severity of the colitis was assessed. Treatment with ghrelin reduced the area of colonic mucosa damage in pituitary-intact rat. This effect was associated with increase in serum levels of GH and IGF-1. Moreover, administration of ghrelin improved blood flow in colonic mucosa and mucosal cell proliferation, as well as reduced mucosal concentration of proinflammatory interleukin-1β (IL-1β) and activity of myeloperoxidase. Hypophysectomy reduced serum levels of GH and IGF-1 and increased the area of colonic damage in rats with colitis. These effects were associated with additional reduction in mucosal blood follow and DNA synthesis when compared to pituitary-intact rats. Mucosal concentration of IL-1β and mucosal activity of myeloperoxidase were maximally increased. Moreover, in hypophysectomized rats, administration of ghrelin failed to affect serum levels of GH or IGF-1, as well as the healing rate of colitis, mucosal cell proliferation, and mucosal concentration of IL-1β, or activity of myeloperoxidase. We conclude that administration of ghrelin accelerates the healing of the acetic acid-induced colitis. Therapeutic effect of ghrelin in experimental colitis is mainly mediated by the release of endogenous growth hormone and IGF-1.

Effect of hydroalcoholic extract of Hibiscus rosa sinensis Linn. leaves in experimental colitis in rats

PubMed Central

Kandhare, Amit D; Raygude, Kiran S; Ghosh, Pinaki; Ghule, Arvindkumar E; Gosavi, Tejas P; Badole, Sachin L; Bodhankar, Subhash L

2012-01-01

Objective To elucidate the ameliorative effect of hydroalcoholic extract of leaves of Hibiscus rosa sinensis (HRS) in acetic acid induced experimental colitis in male wistar rats. Methods The animals were administered with 2 mL acetic acid (4%) via intra rectal. The animals were divided into various treatment groups (n=6). Prednisolone was used as standard drug and HRS was administered at a dose of 50, 100 and 200 mg/kg p.o. The control group of animals received 1 mL of vehicle (distilled water). Ulcer area, ulcer index, spleen weight, colon weight to length ratio, macroscopic score, haematological parameters, colonic superoxide dismutase (SOD), glutathione (GSH), myeloperoxidase (MPO), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), nitric oxide (NO) and histological changes were recorded after the treatment regimen of 11 days. Results Intrarectal instillation of acetic acid caused enhanced ulcer area, ulcer index, spleen weight, colon weight to length ratio, colonic MPO, MDA, NO and TNF-α It caused significant decreased level of SOD and GSH. Pretreatment with HRS for 7 days exhibited significant effect in lowering of oxidative stress, colonic NO, TNF-α and elevation of SOD and GSH at a dose of 100 and 200 mg/kg in acetic acid induced colitis. Conclusions The present investigation demonstrates HRS is of potent therapeutic value in the amelioration of experimental colitis in laboratory animals by inhibiting the proinflammatory mediator like NO and TNF-α. PMID:23569927

Anti-inflammatory intestinal activity of Arctium lappa L. (Asteraceae) in TNBS colitis model.

PubMed

de Almeida, Ana Beatriz Albino; Sánchez-Hidalgo, Marina; Martín, Antonio Ramón; Luiz-Ferreira, Anderson; Trigo, José Roberto; Vilegas, Wagner; dos Santos, Lourdes Campaner; Souza-Brito, Alba Regina Monteiro; de la Lastra, Catalina Alarcón

2013-03-07

In Brazilian traditional medicine, Arctium lappa (Asteraceae), has been reported to relieve gastrointestinal symptoms. In the present study, we investigated the effects of the lactone sesquiterpene onopordopicrin enriched fraction (ONP fraction) from Arctium lappa in an experimental colitis model induced by 2,4,6 trinitrobenzene sulfonic acid and performed experiments to elucidate the underlying action mechanisms involved in that effect. ONP fraction (25 and 50 mg/kg/day) was orally administered 48, 24 and 1 h prior to the induction of colitis and 24 h after. The inflammatory response was assessed by gross appearance, myeloperoxidase (MPO) activity, tumor necrosis factor alpha (TNF-α) levels and a histological study of the lesions. We determined cyclooxygenase (COX)-1 and -2 protein expressions by western blotting and immunohistochemistry assays. TNBS group was characterized by increased colonic wall thickness, edema, diffuse inflammatory cell infiltration, increased MPO activity and TNF-α levels. On the contrary, ONP fraction (25 and 50 mg/kg) treatment significantly reduced the macroscopic inflammation scores (p<0.05 and p<0.01, respectively) and morphological alterations associated with an increase in the mucus secretion. Similarly, the degree of neutrophil infiltration and the cytokine levels were significantly ameliorated. Moreover, COX-2 expression was up regulated in TNBS-treated rats. In contrast, ONP fraction (50 mg/kg) administration reduced COX-2 overexpression. We have shown that the ONP fraction obtained from Arctium lappa exert marked protective effects in acute experimental colitis, confirming and justifying, at least in part, the popular use of this plant to treat gastrointestinal diseases. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Ferulic acid ameliorates TNBS-induced ulcerative colitis through modulation of cytokines, oxidative stress, iNOs, COX-2, and apoptosis in laboratory rats

PubMed Central

Sadar, Smeeta S.; Vyawahare, Niraj S.; Bodhankar, Subhash L.

2016-01-01

Ulcerative colitis (UC) is a chronic immune-inflammatory disorder characterized by oxido-nitrosative stress, the release of pro-inflammatory cytokines and apoptosis. Ferulic acid (FA), a phenolic compound is considered to possess potent antioxidant, anti-apoptotic and anti-inflammatory activities. The aim is to evaluate possible mechanism of action of FA against trinitrobenzensulfonic acid (TNBS) induced ulcerative colitis (UC) in rats. UC was induced in Sprague-Dawley rats (150-200 g) by intrarectal administration of TNBS (100 mg/kg). FA was administered (10, 20 and 40 mg/kg, p.o.) for 14 days after colitis was induced. Various biochemical, molecular and histological changes were assessed in the colon. Intrarectal administration of TNBS caused significant induction of ulcer in the colon with an elevation of oxido-nitrosative stress, myeloperoxidase and hydroxyproline activity in the colon. Administration of FA (20 and 40 mg/kg) significantly decrease oxido-nitrosative stress, myeloperoxidase, and hydroxyproline activities. Up-regulated mRNA expression of TNF-α, IL-1β, IL-6, COX-2, and iNOs, as well as down-regulated IL-10 mRNA expressions after TNBS administration, were significantly inhibited by FA (20 and 40 mg/kg) treatment. Flow cytometric analysis revealed that intrarectal administration of TNBS-induced significantly enhanced the colonic apoptosis whereas administration of FA (20 and 40 mg/kg) significantly restored the elevated apoptosis. FA administration also significantly restored the histopathological aberration induced by TNBS. The findings of the present study demonstrated that FA ameliorates TNBS-induced colitis via inhibition of oxido-nitrosative stress, apoptosis, proinflammatory cytokines production, and down- regulation of COX-2 synthesis. Graphical Abstract: TNBS caused activation of T cells which interact with CD40 on antigen presenting cells i.e. dendritic cells (DC) that induce the key Interleukin 12 (IL-12)-mediated Th1 T cell immune

Use of a balanced dual cyclooxygenase-1/2 and 5-lypoxygenase inhibitor in experimental colitis.

PubMed

Pallio, Giovanni; Bitto, Alessandra; Pizzino, Gabriele; Galfo, Federica; Irrera, Natasha; Minutoli, Letteria; Arcoraci, Vincenzo; Squadrito, Giovanni; Macrì, Antonio; Squadrito, Francesco; Altavilla, Domenica

2016-10-15

Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) play an important role in inflammatory bowel diseases (IBDs). We investigated the effects of flavocoxid, a dual COX/LOX inhibitor, in experimental colitis induced with either dinitrobenzenesulfonic acid (DNBS) or dextrane sulphate sodium (DSS) In the first model, colitis was induced in rats by a single intra-colonic instillation (25mg in 0.8ml 50% ethanol) of DNBS; after 24h animals were randomized to receive orally twice a day, flavocoxid (10mg/kg), zileuton (50mg/kg), or celecoxib (5mg/kg). Sham animals received 0.8ml of saline by a single intra-colonic instillation. Rats were killed 4 days after induction and samples were collected for analysis. In the second model, colitis was induced in rats by the administration of 8% DSS dissolved in drinking water; after 24h animals were randomized to the same above reported treatments. Sham animals received standard drinking water. Rats were killed 5 days after induction and samples were collected for analysis. Flavocoxid, zileuton and celecoxib improved weight loss, reduced colonic myeloperoxydase activity, macroscopic and microscopic damage, and TNF-α serum levels. Flavocoxid and celecoxib also reduced malondialdheyde, 6-keto PGF1α and PGE-2 levels while flavocoxid and zileuton decreased LTB-4 levels. In addition, flavocoxid treatment improved histological features and apoptosis as compared to zileuton and celecoxib; moreover only flavocoxid reduced TXB2, thus avoiding an imbalance in eicosanoids production. Our results show that flavocoxid has protective effect in IBDs and may represents a future safe treatment for inflammatory bowel diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

Enzyme-linked immunosorbent assay for S100A9 in the stool of rats with dextran sulfate sodium-induced colitis.

PubMed

Sekiya, Shunsuke; Murata, Makoto; Arai, Satoshi; Murayama, Hiroshi; Kawasaki, Atushi; Ashida, Noriyuki; Okada, Kohki; Ikemoto, Masaki

2016-12-01

Calprotectin, a heterodimer of S100A8 and S100A9, has been reported to be a useful biomarker in inflammatory bowel disease (IBD); however, the relationship between the fecal level of S100A9 and the extent of inflammation in IBD remains unclear. Our aim was to develop a new enzyme-linked immunosorbent assay (ELISA) for rat S100A9, and to investigate whether changes in fecal S100A9 levels reflect the inflammatory conditions in the intestinal tracts of rats with dextran sulfate sodium (DSS)-induced colitis. Anti-rat S100A9 monoclonal antibodies were raised in mice and used for the development of a novel ELISA for rat S100A9. The performance of our ELISA was assessed by dilution and recovery tests, and the detection range was 3.75-240ng/mL. The dilution test showed good linearity. The recovery of fecal S100A9 was 95.1% (mean), with a range of 86.1%-108.8%. Colitis was induced in rats by oral administration of 3% DSS/drinking water (DW) for 11days (D group), while DW alone was provided to rats of the control group (C group) during the same period. The extent of inflammation was evaluated with the disease activity index (DAI), and the concentration of fecal S100A9 was determined by ELISA. Both the DAI scores and the fecal S100A9 levels were significantly higher in the D group than in the C group. Microscopic observation revealed that S100A9 was dominantly produced in many immune cells of myeloid origin in rat rectal tissues. These results indicate that the novel ELISA may be applied to clinically evaluate IBD in rats with high sensitivity. In conclusion, our ELISA is useful in toxicological and pharmacological evaluations. Copyright © 2016 Elsevier B.V. All rights reserved.

A budesonide prodrug accelerates treatment of colitis in rats.

PubMed Central

Cui, N; Friend, D R; Fedorak, R N

1994-01-01

Although oral glucocorticoids are the treatment of choice for moderate to severe ulcerative pancolitis, their systemic side effects and adrenal suppression account for considerable morbidity. An oral glucocorticoid-conjugate (prodrug), budesonide-beta-D-glucuronide, which is not absorbed in the small intestine but is hydrolysed by colonic bacterial and mucosal beta-glucuronidase to release free budesonide into the colon was synthesised. The objective of this study was to compare treatment with budesonide-beta-D-glucuronide with treatment with free budesonide by examining: (1) the healing of experimental colitis and (2) the extent of adrenal suppression. Pancolitis was induced with 4% acetic acid. Animals were then randomised to receive oral therapy for 72 hours with (1) budesonide-beta-D-glucuronide, (2) free budesonide, or (3) vehicle. Drug efficacy and colitic healing was determined by measuring gross colonic ulceration, myeloperoxidase activity, and in vivo colonic fluid absorption. Adrenal suppression was determined by measuring plasma adrenocorticotrophic hormone and serum corticosterone. Vehicle-treated colitis animals had gross ulceration, increased myeloperoxidase activity, and net colonic fluid secretion. Treatment with oral budesonide-beta-D-glucuronide accelerated all measures of colitis healing at a fourfold lower dose than did free budesonide. Furthermore, treatment with budesonide-beta-D-glucuronide did not result in adrenal suppression whereas free budesonide treatment did. A newly synthesised orally administered glucocorticoid-conjugate accelerates colitis healing with limited adrenal suppression. Development of an orally administered colon-specific steroid delivery system represents a novel approach to inflammatory bowel disease treatment. PMID:7959202

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.

T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade.

PubMed

Ostanin, Dmitry V; Bao, Jianxiong; Koboziev, Iurii; Gray, Laura; Robinson-Jackson, Sherry A; Kosloski-Davidson, Melissa; Price, V Hugh; Grisham, Matthew B

2009-02-01

The inflammatory bowel diseases (Crohn's disease; ulcerative colitis) are idiopathic chronic inflammatory disorders of the intestine and/or colon. A major advancement in our understanding of the pathogenesis of these diseases has been the development of mouse models of chronic gut inflammation. One model that has been instrumental in delineating the immunological mechanisms responsible for the induction as well as regulation of intestinal inflammation is the T cell transfer model of chronic colitis. This paper presents a detailed protocol describing the methods used to induce chronic colitis in mice. Special attention is given to the immunological concepts that explain disease pathogenesis in this model, considerations and potential pitfalls in using this model, and finally different "tricks" that we have learned over the past 12 years that have allowed us to develop a more simplified version of this model of experimental IBD.

Polyphenol-rich extract of Ocimum gratissimum leaves ameliorates colitis via attenuating colonic mucosa injury and regulating pro-inflammatory cytokines production and oxidative stress.

PubMed

Alabi, Quadri K; Akomolafe, Rufus O; Omole, Joseph G; Adefisayo, Modinat A; Ogundipe, Olaofe L; Aturamu, Ayodeji; Sanya, Joseph O

2018-04-20

Colitis is a chronic inflammation and ulcer on the inner lining of the large intestine. For many centuries Ocimum gratissimum (OG) leaves have been used in folk medicine in Nigeria to treat inflammatory bowel diseases, however, to date, the anti-colitis effects of OG have not been scientifically proven. In this study we investigated the effects of polyphenol rich extract of Ocimum gratissimum (PREOG) leaf on colonic mucosa injury in colitis, its mechanisms, initial administration time and dosage. Dextran sodium sulfate (DSS)-induced rat colitis models was used. PREOG administration was initiated at 3 and 7 d after the model was established at doses of 200, 400 and 800 mg/kg for 7 d. 5-aminosalicylic acid (5-ASA) was used as a reference drug. The disease activity index (DAI), vascular permeability, markers of oxidative stress, granulocyte infiltration, inflammation and histopathological alteration were evaluated. Obvious colonic inflammation and mucosa injuries were observed in DSS-induced colitis groups. PREOG administration promoted repair of colonic mucosa injuries, attenuated inflammation, and decreased DAI scores in rats with colitis. PREOG also decreased the plasma concentrations of Interleukin-(IL)-6 and tumor necrosis factor (TNF)-α, and concentrations of myeloperoxidase, nitric oxide, cyclooxygenase-2 and malondialdehyde in the colon, and increased the plasma concentrations of IL-4 and IL-10 as well as the concentration of superoxide dismutase, catalase and reduced glutathione in the colon. The efficacy of PREOG was dosage dependent. In conclusion, OG repairs colonic mucosa injury in experimental colitis through its ant-inflammatory and ant-oxidant. Its efficacy related to initial administration time and dose. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis.

PubMed

Shailubhai, Kunwar; Palejwala, Vaseem; Arjunan, Krishna Priya; Saykhedkar, Sayali; Nefsky, Bradley; Foss, John A; Comiskey, Stephen; Jacob, Gary S; Plevy, Scott E

2015-11-06

To evaluate the effect of orally administered plecanatide or dolcanatide, analogs of uroguanylin, on amelioration of colitis in murine models. The cyclic guanosine monophosphate (cGMP) stimulatory potency of plecanatide and dolcanatide was measured using a human colon carcinoma T84 cell-based assay. For animal studies all test agents were formulated in phosphate buffered saline. Sulfasalazine or 5-amino salicylic acid (5-ASA) served as positive controls. Effect of oral treatment with test agents on amelioration of acute colitis induced either by dextran sulfate sodium (DSS) in drinking water or by rectal instillation of trinitrobenzene sulfonic (TNBS) acid, was examined in BALB/c and/or BDF1 mice. Additionally, the effect of orally administered plecanatide on the spontaneous colitis in T-cell receptor alpha knockout (TCRα(-/-)) mice was also examined. Amelioration of colitis was assessed by monitoring severity of colitis, disease activity index and by histopathology. Frozen colon tissues were used to measure myeloperoxidase activity. Plecanatide and dolcanatide are structurally related analogs of uroguanylin, which is an endogenous ligand of guanylate cyclase-C (GC-C). As expected from the agonists of GC-C, both plecanatide and dolcanatide exhibited potent cGMP-stimulatory activity in T84 cells. Once-daily treatment by oral gavage with either of these analogs (0.05-0.5 mg/kg) ameliorated colitis in both DSS and TNBS-induced models of acute colitis, as assessed by body weight, reduction in colitis severity (P < 0.05) and disease activity index (P < 0.05). Amelioration of colitis by either of the drug candidates was comparable to that achieved by orally administered sulfasalazine or 5-ASA. Plecanatide also effectively ameliorated colitis in TCRα(-/-) mice, a model of spontaneous colitis. As dolcanatide exhibited higher resistance to proteolysis in simulated gastric and intestinal juices, it was selected for further studies. This is the first-ever study reporting

Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis

PubMed Central

Shailubhai, Kunwar; Palejwala, Vaseem; Arjunan, Krishna Priya; Saykhedkar, Sayali; Nefsky, Bradley; Foss, John A; Comiskey, Stephen; Jacob, Gary S; Plevy, Scott E

2015-01-01

AIM: To evaluate the effect of orally administered plecanatide or dolcanatide, analogs of uroguanylin, on amelioration of colitis in murine models. METHODS: The cyclic guanosine monophosphate (cGMP) stimulatory potency of plecanatide and dolcanatide was measured using a human colon carcinoma T84 cell-based assay. For animal studies all test agents were formulated in phosphate buffered saline. Sulfasalazine or 5-amino salicylic acid (5-ASA) served as positive controls. Effect of oral treatment with test agents on amelioration of acute colitis induced either by dextran sulfate sodium (DSS) in drinking water or by rectal instillation of trinitrobenzene sulfonic (TNBS) acid, was examined in BALB/c and/or BDF1 mice. Additionally, the effect of orally administered plecanatide on the spontaneous colitis in T-cell receptor alpha knockout (TCRα-/-) mice was also examined. Amelioration of colitis was assessed by monitoring severity of colitis, disease activity index and by histopathology. Frozen colon tissues were used to measure myeloperoxidase activity. RESULTS: Plecanatide and dolcanatide are structurally related analogs of uroguanylin, which is an endogenous ligand of guanylate cyclase-C (GC-C). As expected from the agonists of GC-C, both plecanatide and dolcanatide exhibited potent cGMP-stimulatory activity in T84 cells. Once-daily treatment by oral gavage with either of these analogs (0.05-0.5 mg/kg) ameliorated colitis in both DSS and TNBS-induced models of acute colitis, as assessed by body weight, reduction in colitis severity (P < 0.05) and disease activity index (P < 0.05). Amelioration of colitis by either of the drug candidates was comparable to that achieved by orally administered sulfasalazine or 5-ASA. Plecanatide also effectively ameliorated colitis in TCRα-/- mice, a model of spontaneous colitis. As dolcanatide exhibited higher resistance to proteolysis in simulated gastric and intestinal juices, it was selected for further studies. CONCLUSION: This is

Ulcerative Colitis

MedlinePlus

... Ulcerative colitis care at Mayo Clinic Symptoms Ulcerative colitis symptoms can vary, depending on the severity of inflammation ... children, failure to grow Most people with ulcerative colitis have mild to moderate symptoms. The course of ulcerative colitis may vary, with ...

Use of Propolis Hydroalcoholic Extract to Treat Colitis Experimentally Induced in Rats by 2,4,6-Trinitrobenzenesulfonic Acid

PubMed Central

Gonçalves, Cely Cristina Martins; Hernandes, Luzmarina; Bersani-Amado, Ciomar Aparecida; Franco, Selma Lucy; Silva, Joaquim Felipe de Souza

2013-01-01

This study focused on the therapeutic effect of a propolis SLNC 106PI extract on experimental colitis. Wistar adult rats received 0.8 mL rectal dose of one of the following solutions: saline (group S), 20 mg TNBS in 50% ethanol (group TNBS), 20 mg TNBS in 50% ethanol and propolis extract in saline (group TNBS-P), propolis extract in saline (group SP), and 20 mg TNBS in 50% ethanol and 50 mg/kg mesalazine (group TNBS-M). The animals were euthanized 7 or 14 days after the colitis induction. Samples of the distal colon were harvested for the analysis of myeloperoxidase (MPO) enzyme activity and for morphometric analysis in paraffin-embedded histological sections with hematoxylin-eosin or histochemical staining. The animals treated with TNBS exhibited the typical clinical signs of colitis. Increased MPO activity confirmed the presence of inflammation. TNBS induced the development of megacolon, ulceration, transmural inflammatory infiltrate, and thickened bowel walls. Treatment with propolis moderately reduced the inflammatory response, decreased the number of cysts and abscesses, inhibited epithelial proliferation, and increased the number of goblet cells. The anti-inflammatory activity of the propolis SLNC 106 extract was confirmed by the reductions in both the inflammatory infiltrate and the number of cysts and abscesses in the colon mucosa. PMID:24101941

Oral Delivery of Nanoparticles Loaded With Ginger Active Compound, 6-Shogaol, Attenuates Ulcerative Colitis and Promotes Wound Healing in a Murine Model of Ulcerative Colitis.

PubMed

Zhang, Mingzhen; Xu, Changlong; Liu, Dandan; Han, Moon Kwon; Wang, Lixin; Merlin, Didier

2018-01-24

Oral drug delivery is the most attractive pathway for ulcerative colitis [UC] therapy, since it has many advantages. However, this strategy has encountered many challenges, including the instability of drugs in the gastrointestinal tract [GT], low targeting of disease tissues, and severe adverse effects. Nanoparticles capable of colitis tissue-targeted delivery and site-specific drug release may offer a unique and therapeutically effective system that addresses these formidable challenges. We used a versatile single-step surface-functionalising technique to prepare PLGA/PLA-PEG-FA nanoparticles loaded with the ginger active compound, 6-shogaol [NPs-PEG-FA/6-shogaol]. The therapeutic efficacy of NPs-PEG-FA/6-shogaol was evaluated in the well-established mouse model of dextran sulphate sodium [DSS]-induced colitis. NPs-PEG-FA exhibited very good biocompatibility both in vitro and in vivo. Subsequent cellular uptake experiments demonstrated that NPs-PEG-FA could undergo efficient receptor-mediated uptake by colon-26 cells and activated Raw 264.7 macrophage cells. In vivo, oral administration of NPs-PEG-FA/6-shogaol encapsulated in a hydrogel system [chitosan/alginate] significantly alleviated colitis symptoms and accelerated colitis wound repair in DSS-treated mice by regulating the expression levels of pro-inflammatory [TNF-α, IL-6, IL-1β, and iNOS] and anti-inflammatory [Nrf-2 and HO-1] factors. Our study demonstrates a convenient, orally administered 6-shogaol drug delivery system that effectively targets colitis tissue, alleviates colitis symptoms, and accelerates colitis wound repair. This system may represent a promising therapeutic approach for treating inflammatory bowel disease [IBD]. 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

Effects of indigo naturalis on colonic mucosal injuries and inflammation in rats with dextran sodium sulphate-induced ulcerative colitis.

PubMed

Wang, Yunliang; Liu, Lijuan; Guo, Yi; Mao, Tangyou; Shi, Rui; Li, Junxiang

2017-08-01

The effects of indigo naturalis (IN), which is a traditional Chinese herbal formulation, have been clinically demonstrated in treating refractory ulcerative colitis (UC). The present study aimed to verify the effects and mechanisms of IN in experimental UC rats. A total of 48 male Sprague-Dawley rats were randomly divided into six groups: Chow, model, high-dose IN, medium-dose IN, low-dose IN and mesalazine (a bowel-specific aminosalicylate drug) groups. The models were administered 3.5% dextran sodium sulphate solution for 7 days. The treatment groups were administered IN or mesalazine and then sacrificed and sampled on day 8. Disease activity index (DAI), histological damage score (HDS) and myeloperoxidase (MPO) activity were used to evaluate the severity of UC. Colon and serum cytokines were detected using liquid-phase chip technology and the expression of occludin protein in colonic mucosa was assessed by immunohistochemistry and western blot analysis. The results indicated that the oral administration of IN may reduce DAI, HDS and MPO activity. IN also reduced the expression of inflammatory cytokines and increased the expression of colonic mucosal repair-related cytokines and occludin protein. These results highlight the potential of IN as a therapeutic agent for treating UC through its action of inflammation control and colonic mucosal damage repair.

Effects of indigo naturalis on colonic mucosal injuries and inflammation in rats with dextran sodium sulphate-induced ulcerative colitis

PubMed Central

Wang, Yunliang; Liu, Lijuan; Guo, Yi; Mao, Tangyou; Shi, Rui; Li, Junxiang

2017-01-01

The effects of indigo naturalis (IN), which is a traditional Chinese herbal formulation, have been clinically demonstrated in treating refractory ulcerative colitis (UC). The present study aimed to verify the effects and mechanisms of IN in experimental UC rats. A total of 48 male Sprague-Dawley rats were randomly divided into six groups: Chow, model, high-dose IN, medium-dose IN, low-dose IN and mesalazine (a bowel-specific aminosalicylate drug) groups. The models were administered 3.5% dextran sodium sulphate solution for 7 days. The treatment groups were administered IN or mesalazine and then sacrificed and sampled on day 8. Disease activity index (DAI), histological damage score (HDS) and myeloperoxidase (MPO) activity were used to evaluate the severity of UC. Colon and serum cytokines were detected using liquid-phase chip technology and the expression of occludin protein in colonic mucosa was assessed by immunohistochemistry and western blot analysis. The results indicated that the oral administration of IN may reduce DAI, HDS and MPO activity. IN also reduced the expression of inflammatory cytokines and increased the expression of colonic mucosal repair-related cytokines and occludin protein. These results highlight the potential of IN as a therapeutic agent for treating UC through its action of inflammation control and colonic mucosal damage repair. PMID:28781623

Therapeutic action of ghrelin in a mouse model of colitis.

PubMed

Gonzalez-Rey, Elena; Chorny, Alejo; Delgado, Mario

2006-05-01

Ghrelin is a novel growth hormone-releasing peptide with potential endogenous anti-inflammatory activities ameliorating some pathologic inflammatory conditions. Crohn's disease is a chronic debilitating disease characterized by severe T helper cell (Th)1-driven inflammation of the colon. The aim of this study was to investigate the therapeutic effect of ghrelin in a murine model of colitis. We examined the anti-inflammatory action of ghrelin in the colitis induced by intracolonic administration of trinitrobenzene sulfonic acid. Diverse clinical signs of the disease were evaluated, including weight loss, diarrhea, colitis, and histopathology. We also investigated the mechanisms involved in the potential therapeutic effect of ghrelin, such as inflammatory cytokines and chemokines, Th1-type response, and regulatory factors. Ghrelin ameliorated significantly the clinical and histopathologic severity of the trinitrobenzene sulfonic acid-induced colitis; abrogating body weight loss, diarrhea, and inflammation; and increasing survival. The therapeutic effect was associated with down-regulation of both inflammatory and Th1-driven autoimmune response through the regulation of a wide spectrum of inflammatory mediators. In addition, a partial involvement of interluekin-10/transforming growth factor-beta1-secreting regulatory T cells in this therapeutic effect was demonstrated. Importantly, the ghrelin treatment was therapeutically effective in established colitis and avoided the recurrence of the disease. Our data demonstrate novel anti-inflammatory actions for ghrelin in the gastrointestinal tract, ie, the capacity to deactivate the intestinal inflammatory response and to restore mucosal immune tolerance at multiple levels. Consequently, ghrelin administration represents a novel possible therapeutic approach for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis.

Impact of dextran sulphate sodium-induced colitis on the intestinal transport of the colon carcinogen PhIP.

PubMed

Nicken, Petra; von Keutz, Anne; Willenberg, Ina; Ostermann, Annika I; Schebb, Nils Helge; Giovannini, Samoa; Kershaw, Olivia; Breves, Gerhard; Steinberg, Pablo

2016-05-01

Colorectal cancer is one of the most frequent cancers in Western countries. Chronic intestinal diseases such as Crohn's disease and ulcerative colitis, in which the intestinal barrier is massively disturbed, significantly raise the risk of developing a colorectal tumour. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a genotoxic heterocyclic aromatic amine that is formed after strongly heating fish and meat. In this study, the hypothesis that PhIP uptake in the gut is increased during chronic colitis was tested. Chronic colitis was induced by oral administration of dextran sulphate sodium (DSS) to Fischer 344 rats. The transport of PhIP in eight different rat intestinal segments was examined in Ussing chambers. The tissues were incubated with 10 µM PhIP for 90 min, and the concentration of PhIP was determined in the mucosal and serosal compartments of the Ussing chambers as well as in the clamped tissues by LC-MS. Although chronic colitis was clearly induced in the rats, no differences in the intestinal transport of PhIP were observed between control and DSS-treated animals. The hypothesis that in the course of chronic colitis more PhIP is taken up by the intestinal epithelium, thereby increasing the risk of developing colorectal cancer, could not be confirmed in the present report.

Enhanced therapeutic efficacy of budesonide in experimental colitis with enzyme/pH dual-sensitive polymeric nanoparticles.

PubMed

Naeem, Muhammad; Cao, Jiafu; Choi, Moonjeong; Kim, Woo Seong; Moon, Hyung Ryong; Lee, Bok Luel; Kim, Min-Soo; Jung, Yunjin; Yoo, Jin-Wook

2015-01-01

Current colon-targeted drug-delivery approaches for colitis therapy often utilize single pH-triggered systems, which are less reliable due to the variation of gut pH in individuals and in disease conditions. Herein, we prepared budesonide-loaded dual-sensitive nanoparticles using enzyme-sensitive azo-polyurethane and pH-sensitive methacrylate copolymer for the treatment of colitis. The therapeutic potential of the enzyme/pH dual-sensitive nanoparticles was evaluated using a rat colitis model and compared to single pH-triggered nanoparticles. Clinical activity scores, colon/body weight ratios, myeloperoxidase activity, and proinflammatory cytokine levels were markedly decreased by dual-sensitive nanoparticles compared to single pH-triggered nanoparticles and budesonide solution. Moreover, dual-sensitive nanoparticles accumulated selectively in inflamed segments of the colon. In addition, dual-sensitive nanoparticle plasma concentrations were lower than single pH-triggered nanoparticles, and no noticeable in vitro or in vivo toxicity was observed. Our results demonstrate that enzyme/pH dual-sensitive nanoparticles are an effective and safe colon-targeted delivery system for colitis therapy.

Enhanced therapeutic efficacy of budesonide in experimental colitis with enzyme/pH dual-sensitive polymeric nanoparticles

PubMed Central

Naeem, Muhammad; Cao, Jiafu; Choi, Moonjeong; Kim, Woo Seong; Moon, Hyung Ryong; Lee, Bok Luel; Kim, Min-Soo; Jung, Yunjin; Yoo, Jin-Wook

2015-01-01

Current colon-targeted drug-delivery approaches for colitis therapy often utilize single pH-triggered systems, which are less reliable due to the variation of gut pH in individuals and in disease conditions. Herein, we prepared budesonide-loaded dual-sensitive nanoparticles using enzyme-sensitive azo-polyurethane and pH-sensitive methacrylate copolymer for the treatment of colitis. The therapeutic potential of the enzyme/pH dual-sensitive nanoparticles was evaluated using a rat colitis model and compared to single pH-triggered nanoparticles. Clinical activity scores, colon/body weight ratios, myeloperoxidase activity, and proinflammatory cytokine levels were markedly decreased by dual-sensitive nanoparticles compared to single pH-triggered nanoparticles and budesonide solution. Moreover, dual-sensitive nanoparticles accumulated selectively in inflamed segments of the colon. In addition, dual-sensitive nanoparticle plasma concentrations were lower than single pH-triggered nanoparticles, and no noticeable in vitro or in vivo toxicity was observed. Our results demonstrate that enzyme/pH dual-sensitive nanoparticles are an effective and safe colon-targeted delivery system for colitis therapy. PMID:26213469

Propolis from Different Geographic Origins Suppress Intestinal Inflammation in a Model of DSS-Induced Colitis is Associated with Decreased Bacteroides spp. in the Gut.

PubMed

Wang, Kai; Jin, Xiaolu; Li, Qiangqiang; Sawaya, Alexandra Christine Helena Frankland; Leu, Richard K Le; Conlon, Michael A; Wu, Liming; Hu, Fuliang

2018-06-11

Dietary supplementation with polyphenol-rich propolis can protect against experimentally-induced colitis. We examined whether different polyphenol compositions of Chinese propolis (CP) and Brazilian propolis (BP) influences their ability to protect against dextran sulfate sodium (DSS)-induced colitis in rats. HPLC-DAD/Q-TOF-MS analysis confirmed that polyphenol compositions of CP and BP were dissimilar. Rats were given CP or BP by gavage (300 mg/kg body weight) throughout the study, starting 1 week prior to DSS treatment for 1 week followed by 3 d without DSS. CP and BP significantly reduced the colitis disease activity index relative to controls not receiving propolis, prevented significant DSS-induced colonic tissue damage and increased resistance to DSS-induced colonic oxidative stress as shown by reduced malonaldehyde levels and increased T-AOC levels. CP and BP significantly reduced DSS-induced colonic apoptosis. Colonic inflammatory markers IL-1β, IL-6 and MCP-1 were suppressed by CP and BP, whereas only BP induced expression of TGF-β. CP, not BP, increased the diversity and richness of gut microbiota populations. Both forms of propolis significantly reduced populations of Bacteroides spp. Despite the dissimilar polyphenol compositions of CP and BP, their ability to protect against DSS-induced colitis is similar. Nevertheless, some different physiological impacts were observed. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Effects of n-3 polyunsaturated fatty acids and vitamin E on colonic mucosal leukotriene generation, lipid peroxidation, and microcirculation in rats with experimental colitis.

PubMed

Shimizu, T; Igarashi, J; Ohtuka, Y; Oguchi, S; Kaneko, K; Yamashiro, Y

2001-01-01

We investigated the effect of n-3 polyunsaturated fatty acids (PUFAs) on mucosal levels of leukotrienes (LTs) and lipid peroxide (LPO), and on mucosal microcirculation, in rats with experimental colitis induced by dextran sulfate sodium (DSS). We fed Wistar rats a perilla oil-enriched diet containing alpha-linolenic acid (63.2% of total fatty acids) with various doses of vitamin E for 4 weeks, with 4% DSS added to the drinking water during the last week. Control rats were fed a diet produced from soybean oil containing alpha-linolenic acid (5.1% of total fatty acids). Colonic mucosal blood flow was measured with a laser Doppler flowmeter. The mucosal level of arachidonic acid was significantly lower and that of eicosapentaenoic acid was significantly higher in the experimental group. The mucosal level of LPO in the experimental group fed a trace or ordinary dose of vitamin E was significantly higher than that of the controls. The production of LTB(4) and LTC(4) from the colonic mucosa in the experimental group was significantly lower than that in controls. However, only the experimental group fed a vitamin E dose 4-fold higher than that given to the controls showed a significant increase in mucosal blood flow. These results suggest that n-3 PUFAs increase mucosal blood flow by inhibiting LT production when there is sufficient vitamin E to inhibit lipid peroxidation in rats with experimental colitis. Copyright 2001 S. Karger AG, Basel

Anti-inflammatory effect of diosmectite in hapten-induced colitis in the rat

PubMed Central

González, Raquel; Sánchez de Medina, Fermin; Martínez-Augustin, Olga; Nieto, Ana; Gálvez, Julio; Risco, Severiano; Zarzuelo, Antonio

2004-01-01

Diosmectite is a natural silicate effectively used in the treatment of infectious diarrhoea. Its antidiarrhoeal properties involve adsorption of toxins and bacteria and modifications of the rheological characteristics of gastrointestinal mucus. Hence, the aim of this study was to test the intestinal anti-inflammatory activity of diosmectite. Diosmectite (500 mg kg−1 day−1, p.o.) was administered as a post-treatment to rats with chronic trinitrobenzene sulphonic acid colitis. Colonic status was checked 1 and 2 weeks after colitis induction by macroscopic, histological and biochemical examination. Diosmectite post-treatment resulted in amelioration of the morphological signs (intestinal weight, macroscopic damage, necrosed area, histology) and biochemical markers (myeloperoxidase activity, glutathione levels, MUC2 expression, inducible nitric oxide synthase and interleukin-1β (IL-1β) and leukotriene B4 synthesis), as well as in the reduction of the severity of diarrhoea. The effect of the clay was comparable to that of sulphasalazine (50 mg kg−1 day−1). Diosmectite exhibited a dose-dependent capacity to adsorb proteins in vitro as well as a dose-dependent inhibitory effect on the basolateral secretion of IL-8 by lipopolysaccharide (LPS)-stimulated HT29 cells. Diosmectite had a dose-dependent inhibitory effect on IL-1β production by LPS-stimulated THP-1 cells. The effect of diosmectite on MUC2 was post-transcriptional, since mRNA levels were unaffected. However, diosmectite is able to upregulate MUC2 mRNA levels in HT29-MTX cells. Diosmectite has anti-inflammatory activity administered as a post-treatment. Possible mechanisms include adsorption of luminal antigens, increase of colonic mucin levels and possibly a direct modulatory action of cytokine production by mucosal cells. PMID:14993105

Pseudomembranous colitis

MedlinePlus

... colitis URL of this page: //medlineplus.gov/ency/article/000259.htm Pseudomembranous colitis To use the sharing features on this page, please enable JavaScript. Pseudomembranous colitis refers to swelling or inflammation of ...

Diverticular colitis of the ascending colon preceding the onset of ulcerative colitis.

PubMed

Maeshiro, Tatsuji; Hokama, Akira; Kinjo, Tetsu; Fujita, Jiro

2014-06-30

We present a case of diverticular colitis of the ascending colon preceding the onset of ulcerative colitis. A 58-year-old man presented with positive faecal occult blood test. Colonoscopy disclosed diverticular colitis of the ascending colon. After a year's follow-up, typical ulcerative colitis developed and diverticular colitis improved. Diverticular colitis is a newly established disorder of chronic segmental mucosal inflammation affected by diverticular disease. There is increasing recognition of such cases with diverticular colitis preceding ulcerative colitis. There may be a possible pathogenic relationship between the two diseases. 2014 BMJ Publishing Group Ltd.

Immunological studies in ulcerative colitis. IV. Origin of autoantibodies.

PubMed

Lagercrantz, R; Hammarström, S; Perlmann, P; Gustafsson, B E

1968-12-01

The incidence and height of antibody titers to colon, assayed by indirect hemagglutination with a heat stable colon extract from germ free rats, is significantly higher in sera from patients with ulcerative colitis than in those from healthy controls or from patients with amebic liver abscess or dysentery. While sera from ulcerative colitis patients and controls are indistinguishable in regard to incidence and height of antibody titers to Forsman antigen, Staphylococcus aureus S 209, Clostridium difficile, and several common strains of E. coli, they have elevated titers and increased incidence of antibodies to a heat stable antigen of E. coli O14. Patients with amebic dysentery have normal titers of such antibodies. Absorption of patients' sera with E. coli O14 antigen inhibits the colon directed hemagglutination reaction in approximately 30% of the cases tested. Likewise, the anti-E. coli O14 reaction can sometimes be inhibited with the colon extract. Other E. coli strains and other bacteria are inactive or have only weak inhibitory activity. Hemagglutination inhibition experiments show that germ free rat colon and E. coli O14 contain common structures, depicted by antibodies in the patients' sera. This pattern of reactivity closely resembles that seen in rats made autoimmune to colon by injection of newborn rabbit colon. E. coli O14 is known to carry a heterogenetic antigen present in lower concentration (or activity) in most Enterobacteriaceae. Hemagglutination inhibition experiments with rabbit antisera to E. coli O14 suggest that the antigen common for E. coli O14 and colon is related to this heterogenetic antigen. The findings imply that this antigen, which is constantly present in low concentrations in the human colon, may give rise to anticolon antibody formation in ulcerative colitis through breakage of tolerance. Since this antigen is present in healthy individuals as well, additional factors are required to explain the induction of anti

Partial replacement of dietary linoleic acid with long chain n-3 polyunsaturated fatty acids protects against dextran sulfate sodium-induced colitis in rats.

PubMed

Tyagi, Anupama; Kumar, Uday; Santosh, Vadakattu Sai; Reddy, Suryam; Mohammed, Saazida Bhanu; Ibrahim, Ahamed

2014-12-01

Imbalances in the dietary n-6 and n-3 polyunsaturated fatty acids have been implicated in the increased prevalence of inflammatory bowel disease. This study investigated the effects of substitution of linoleic acid with long chain n-3 polyunsaturated fatty acids and hence decreasing n-6:n-3 fatty acid ratio on inflammatory response in dextran sulfate sodium induced colitis. Male weanling Sprague Dawley rats were fed diets with n-6:n-3 fatty acid in the ratios of 215,50,10 or 5 for 3 months and colitis was induced by administration of dextran sulfate sodium in drinking water during last 11 days. Decreasing the dietary n-6:n-3 fatty acid ratio to 10 and 5 significantly attenuated the severity of colitis as evidenced by improvements in clinical symptoms, reversal of shortening of colon length, reduced severity of anemia, preservation of colonic architecture as well as reduced colonic mucosal myeloperoxidase activity. This protection was associated with suppression of colonic mucosal proinflammatory mediators such as TNFα, IL-1β and nitric oxide. These findings suggest that long chain n-3 polyunsaturated fatty acids at a level of 3.0 g/kg diet (n-6:n-3 ratio of 10) prevents dextran sulfate sodium induced colitis by suppressing the proinflammatory mediators. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Saccharomyces boulardii reduced intestinal inflammation in mice model of 2,4,6-trinitrobencene sulfonic acid induced colitis: based on microarray].

PubMed

Lee, Sang Kil; Kim, Hyo Jong; Chi, Sung Gil

2010-01-01

Saccharomyces boulardii has been reported to be beneficial in the treatment of inflammatory bowel disease. The aim of this work was to evaluate the effect of S. boulardii in a mice model of 2,4,6-trinitrobencene sulfonic acid (TNBS) induced colitis and analyze the expression of genes in S. boulardii treated mice by microarray. BALB/c mice received TNBS or TNBS and S. boulardii treatment for 4 days. Microarray was performed on total mRNA form colon, and histologic evaluation was also performed. In mice treated with S. boulardii, the histological appearance and mortality rate were significantly restored compared with rats receiving only TNBS. Among 330 genes which were altered by both S. boulardii and TNBS (>2 folds), 193 genes were down-regulated by S. boulardii in microarray. Most of genes which were down-regulated by S. bouardii were functionally classified as inflammatory and immune response related genes. S. boulardii may reduce colonic inflammation along with regulation of inflammatory and immune responsive genes in TNBS-induced colitis.

Role of moxibustion in inflammatory responses during treatment of rat ulcerative colitis

PubMed Central

Han, Yang; Ma, Tie-Ming; Lu, Mao-Lin; Ren, Lu; Ma, Xian-De; Bai, Zeng-Hua

2014-01-01

AIM: To investigate the efficacy of moxibustion in ulcerative colitis (UC) rats from morphological, immunological and molecular biological perspectives. METHODS: Thirty-two Sprague-Dawley rats were randomly assigned to a blank control group (normal rats, n = 6) and a model replication (MR) group (UC rats, n = 26). A UC model was established by 2,4,6-trinitrobenzenesulfonic acid/dextran sulfate sodium enema. Rats in the MR group were further randomly assigned to a 9-min moxibustion (9M) group (9 moxa-cone, n = 6), 6-min moxibustion (6M) group (6 moxa-cone, n = 6), 3-min moxibustion (3M) group (3 moxa-cone, n = 6), and a waiting list control (WLC) group (no moxibustion treatment, n = 6). Rats in the moxibustion treatment group were treated in 14 sessions over 28 d. Disease activity, local tissue morphology, serum level of interleukin (IL)-8 and IL-10, and expression of Toll-like receptor (TLR)9 as well as nuclear factor (NF)-κB p65 in colonic tissue were determined by disease activity index (DAI), hematoxylin and eosin staining, electron microscopy, enzyme-linked immunosorbent assay and Western blotting, respectively. RESULTS: DAI was lowest in the 9M group and highest in the WLC group. The differences in DAI between the moxibustion treatment (3M, 6M, 9M) and no treatment groups were significant for all one-to-one comparisons (0.60 ± 0.54 vs 1.20 ± 0.44, 0.60 ± 0.54 vs 1.80 ± 0.45, 0.60 ± 0.54 vs 3.0 ± 0.45, respectively, P < 0.05). Light and electron microscopy showed that the neatness of the glandular arrangement in colonic mucosal epithelia gradually increased in the WLC, 3M, 6M to 9M groups. IL-8 level successively decreased while IL-10 level increased from the WLC to 3M, 6M and 9M groups. The differences among these groups were significant for all comparisons (105.46 ± 8.75 vs 76.61 ± 3.58, 105.46 ± 8.75 vs 69.78 ± 1.87, 105.46 ± 8.75 vs 67.41 ± 1.84, respectively, P < 0.01 for IL-8; and 30.83 ± 1.29 vs 75.64 ± 1.90, 30.83 ± 1.29 vs 80.90 ± 3

Role of moxibustion in inflammatory responses during treatment of rat ulcerative colitis.

PubMed

Han, Yang; Ma, Tie-Ming; Lu, Mao-Lin; Ren, Lu; Ma, Xian-De; Bai, Zeng-Hua

2014-08-28

To investigate the efficacy of moxibustion in ulcerative colitis (UC) rats from morphological, immunological and molecular biological perspectives. Thirty-two Sprague-Dawley rats were randomly assigned to a blank control group (normal rats, n = 6) and a model replication (MR) group (UC rats, n = 26). A UC model was established by 2,4,6-trinitrobenzenesulfonic acid/dextran sulfate sodium enema. Rats in the MR group were further randomly assigned to a 9-min moxibustion (9M) group (9 moxa-cone, n = 6), 6-min moxibustion (6M) group (6 moxa-cone, n = 6), 3-min moxibustion (3M) group (3 moxa-cone, n = 6), and a waiting list control (WLC) group (no moxibustion treatment, n = 6). Rats in the moxibustion treatment group were treated in 14 sessions over 28 d. Disease activity, local tissue morphology, serum level of interleukin (IL)-8 and IL-10, and expression of Toll-like receptor (TLR)9 as well as nuclear factor (NF)-κB p65 in colonic tissue were determined by disease activity index (DAI), hematoxylin and eosin staining, electron microscopy, enzyme-linked immunosorbent assay and Western blotting, respectively. DAI was lowest in the 9M group and highest in the WLC group. The differences in DAI between the moxibustion treatment (3M, 6M, 9M) and no treatment groups were significant for all one-to-one comparisons (0.60 ± 0.54 vs 1.20 ± 0.44, 0.60 ± 0.54 vs 1.80 ± 0.45, 0.60 ± 0.54 vs 3.0 ± 0.45, respectively, P < 0.05). Light and electron microscopy showed that the neatness of the glandular arrangement in colonic mucosal epithelia gradually increased in the WLC, 3M, 6M to 9M groups. IL-8 level successively decreased while IL-10 level increased from the WLC to 3M, 6M and 9M groups. The differences among these groups were significant for all comparisons (105.46 ± 8.75 vs 76.61 ± 3.58, 105.46 ± 8.75 vs 69.78 ± 1.87, 105.46 ± 8.75 vs 67.41 ± 1.84, respectively, P < 0.01 for IL-8; and 30.83 ± 1.29 vs 75.64 ± 1.90, 30.83 ± 1.29 vs 80.90 ± 3.16, 30.83 ± 1.29 vs 83

Dysregulated luminal bacterial antigen-specific T-cell responses and antigen-presenting cell function in HLA-B27 transgenic rats with chronic colitis

PubMed Central

Qian, Bi-Feng; Tonkonogy, Susan L; Hoentjen, Frank; Dieleman, Levinus A; Sartor, R Balfour

2005-01-01

HLA-B27/β2 microglobulin transgenic (TG) rats spontaneously develop T-cell-mediated colitis when colonized with normal commensal bacteria, but remain disease-free under germ-free conditions. We investigated regulation of in vitro T-cell responses to enteric bacterial components. Bacterial lysates prepared from the caecal contents of specific pathogen-free (SPF) rats stimulated interferon-γ (IFN-γ) production by TG but not non-TG mesenteric lymph node (MLN) cells. In contrast, essentially equivalent amounts of interleukin-10 (IL-10) were produced by TG and non-TG cells. However, when cells from MLNs of non-TG rats were cocultured with TG MLN cells, no suppression of IFN-γ production was noted. Both non-TG and TG antigen-presenting cells (APC) pulsed with caecal bacterial lysate were able to induce IFN-γ production by TG CD4+ cells, although non-TG APC were more efficient than TG APC. Interestingly, the addition of exogenous IL-10 inhibited non-TG APC but not TG APC stimulation of IFN-γ production by cocultured TG CD4+ lymphocytes. Conversely, in the presence of exogenous IFN-γ, production of IL-10 was significantly lower in the supernatants of TG compared to non-TG APC cultures. We conclude that commensal luminal bacterial components induce exaggerated in vitro IFN-γ responses in HLA-B27 TG T cells, which may in turn inhibit the production of regulatory molecules, such as IL-10. Alterations in the production of IFN-γ, and in responses to this cytokine, as well as possible resistance of TG cells to suppressive regulation could together contribute to the development of chronic colitis in TG rats. PMID:16108823

Colonic responses to Lactobacillus farciminis treatment in trinitrobenzene sulphonic acid-induced colitis in rats.

PubMed

Lamine, F; Eutamène, H; Fioramonti, J; Buéno, L; Théodorou, V

2004-12-01

It has recently been shown that Lactobacillus farciminis treatment exerts an anti-inflammatory effect in trinitrobenzene sulphonic acid (TNBS)-induced colitis partly through a nitric oxide release by this strain. The aim of this study was to evaluate whether L. farciminis treatment shares also the general mechanisms of action involved in the beneficial effect of probiotics in the colonic inflammatory process. Rats received L. farciminis for 15 days before and 4 days after intracolonic administration of TNBS or vehicle. The following parameters were evaluated: macroscopic damage of colonic mucosa, myeloperoxidase activity, cytokine mucosal levels, bacterial profile in colonic content and mucosa, bacterial translocation and colonic paracellular permeability. In the absence of TNBS, L. farciminis treatment reduced colonic paracellular permeability and increased the IL-10 level in the colonic wall. TNBS administration induced colonic macroscopic damage, associated with an increase of myeloperoxidase activity, bacterial translocation, colonic paracellular permeability and IL-1beta mucosal level, and a decrease in IL-10 mucosal level. Moreover, the bacterial profile of colonic content and mucosa was modified. All these alterations were abolished or significantly reduced by L. farciminis treatment. As previously shown, L. farciminis treatment improves TNBS-induced colitis. This study indicates that, in addition to the nitric oxide released by this bacterial strain, the anti-inflammatory action of L. farciminis involves also normalization of colonic microflora, prevention of bacterial translocation, enhancement of barrier integrity and a decrease in the IL-1beta mucosal level.

Embelin lipid nanospheres for enhanced treatment of ulcerative colitis - Preparation, characterization and in vivo evaluation.

PubMed

Badamaranahalli, Shivaram Shivakumar; Kopparam, Manjunath; Bhagawati, Siddalingappa Tippanna; Durg, Sharanbasappa

2015-08-30

Aim of the present study is to develop embelin lipid nanospheres (LNE) for better treatment of ulcerative colitis. Embelin LNs were developed using soya bean oil/virgin coconut oil as liquid lipid carrier and soya/egg lecithin as stabilizer by hot homogenization followed by ultrasonication technique. The particle size of LNEs ranged from 196.1±3.57 to 269.2±1.05nm with narrow polydispersity index values whereas zeta potential was from -36.6 to -62.0mV. Embelin was successfully incorporated into lipid nanospheres with entrapment efficiency about 99%. There was no interaction between embelin and selected liquid lipids which was confirmed by FTIR studies. In vitro drug release studies performed using Franz diffusion cell and results showed sustained release of embelin. Embelin LNs were stabilized with egg and soya lecithin, embelin release from these LNs followed Higuchi model and first order model, respectively, however mechanism of drug release in both LNs was non-Fickian. In vivo studies were carried out using acetic acid induced ulcerative colitis rat model and results revealed that treatment with embelin LNs significantly reduced clinical activity and macroscopic scores compared to embelin conventional suspension. Treatment with embelin LNs decreased MPO, LDH and LPO levels, increased reduced GSH levels which indicated better treatment of ulcerative colitis was achieved. This was also confirmed by improved histopathological conditions. Thus embelin LNs could be favourably used for treatment of ulcerative colitis. Copyright © 2015 Elsevier B.V. All rights reserved.

Omega 3 fatty acids supplementation has an ameliorative effect in experimental ulcerative colitis despite increased colonic neutrophil infiltration.

PubMed

Varnalidis, Ioannis; Ioannidis, Orestis; Karamanavi, Elisavet; Ampas, Zafeiris; Poutahidis, Theofilos; Taitzoglou, Ioannis; Paraskevas, George; Botsios, Dimitrios

2011-10-01

omega 3 polyunsaturated fatty acids have anti-inflammatory properties and can be beneficial in the treatment of inflammatory diseases, such as ulcerative colitis. Dextran sodium sulphate (DSS) colitis in rats appears to mimic nearly all of the morphological characteristics and lesion distributions of ulcerative colitis. The purpose of the current study was to investigate the efficacy of omega 3 fatty acids in the treatment of experimental ulcerative colitis. thirty-six Wistar rats were randomly assigned to group A or group B receiving 5% dextran sulfate sodium (DSS) in their drinking water for eight days. For the next eight days post-DSS, group A animals received tap-water, and group B animals were fed a nutritional solution containing high levels of omega 3 polyunsaturated fatty acids (ProSure®, Abbott Laboratories, Zwolle, Netherlands) once per day, administrated with a orogastric feeding tube. animals fed an omega 3 rich diet exhibited a statistically significant increase in hematocrit and hemoglobin levels, compared to animals drinking tap water, and a trend towards histopathological and clinical improvement, with the administration of omega 3 fatty acids ameliorating epithelial erosion by day 8 post-DSS, but no statistically significant difference was observed between group A and group B animals at 4 or 8 days post-DSS. Also, a statistically significant increase in neutrophil infiltration was observed, as depicted by myelohyperoxidase activity. our findings support a positive role of omega 3 polyunsaturated fatty acids supplementation in an experimental model of ulcerative colitis despite the increased colonic neutrophil infiltration. Further studies are needed in order to investigate the role of increased neutrophils in colonic mucosa.

Walnut phenolic extract inhibits nuclear factor kappaB signaling in intestinal epithelial cells, and ameliorates experimental colitis and colitis-associated colon cancer in mice.

PubMed

Koh, Seong-Joon; Choi, Youn-I; Kim, Yuri; Kim, Yoo-Sun; Choi, Sang Woon; Kim, Ji Won; Kim, Byeong Gwan; Lee, Kook Lae

2018-05-09

Walnuts (Juglans regia) are known to have anti-cancer and immunomodulatory effects. However, little information is available on the effects of walnut phenolic extract (WPE) on intestinal inflammation and colitis-associated colon cancer. COLO205 cells were pretreated with WPE and then stimulated with tumor necrosis factor (TNF)-α. In the acute colitis model, wild type mice (C57BL/6) were administered 4% dextran sulfate sodium (DSS) for 5 days. In the chronic colitis model, interleukin (IL)-10 -/- mice were administered with either the vehicle or WPE (20 mg/kg) by oral gavage daily for 2 weeks. In an inflammation-associated tumor model, wild type mice were administered a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption. WPE significantly inhibited IL-8 and IL-1α expression in COLO205 cells. WPE attenuated both the TNF-α-induced IκB phosphorylation/degradation and NF-κB DNA binding activity. The administration of oral WPE significantly reduced the severity of colitis in both acute and chronic colitis models, including the IL-10 -/- mice. In immunohistochemical staining, WPE attenuated NF-κB signaling in the colons of both colitis models. Finally, WPE also significantly reduced tumor development in a murine model of colitis-associated colon cancer (CAC). WPE ameliorates acute and chronic colitis and CAC in mice, suggesting that WPE may have potentials for the treatment of inflammatory bowel disease.

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.

Fucoidan Extracts Ameliorate Acute Colitis

PubMed Central

Lean, Qi Ying; Eri, Rajaraman D.; Fitton, J. Helen; Patel, Rahul P.; Gueven, Nuri

2015-01-01

Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn’s disease, are an important cause of morbidity and impact significantly on quality of life. Overall, current treatments do not sustain a long-term clinical remission and are associated with adverse effects, which highlight the need for new treatment options. Fucoidans are complex sulphated, fucose-rich polysaccharides, found in edible brown algae and are described as having multiple bioactivities including potent anti-inflammatory effects. Therefore, the therapeutic potential of two different fucoidan preparations, fucoidan-polyphenol complex (Maritech Synergy) and depyrogenated fucoidan (DPF) was evaluated in the dextran sulphate sodium (DSS) mouse model of acute colitis. Mice were treated once daily over 7 days with fucoidans via oral (Synergy or DPF) or intraperitoneal administration (DPF). Signs and severity of colitis were monitored daily before colons and spleens were collected for macroscopic evaluation, cytokine measurements and histology. Orally administered Synergy and DPF, but not intraperitoneal DPF treatment, significantly ameliorated symptoms of colitis based on retention of body weight, as well as reduced diarrhoea and faecal blood loss, compared to the untreated colitis group. Colon and spleen weight in mice treated with oral fucoidan was also significantly lower, indicating reduced inflammation and oedema. Histological examination of untreated colitis mice confirmed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and oedema, while all aspects of this pathology were alleviated by oral fucoidan. Importantly, in this model, the macroscopic changes induced by oral fucoidan correlated significantly with substantially decreased production of at least 15 pro-inflammatory cytokines by the colon tissue. Overall, oral fucoidan preparations significantly reduce the inflammatory pathology associated with DSS-induced colitis and could therefore

Daikenchuto, a Kampo medicine, regulates intestinal fibrosis associated with decreasing expression of heat shock protein 47 and collagen content in a rat colitis model.

PubMed

Inoue, Ken; Naito, Yuji; Takagi, Tomohisa; Hayashi, Natsuko; Hirai, Yasuko; Mizushima, Katsura; Horie, Ryusuke; Fukumoto, Kohei; Yamada, Shinya; Harusato, Akihito; Hirata, Ikuhiro; Omatsu, Tatsushi; Yoshida, Naohisa; Uchiyama, Kazuhiko; Ishikawa, Takeshi; Handa, Osamu; Konishi, Hideyuki; Wakabayashi, Naoki; Yagi, Nobuaki; Ichikawa, Hiroshi; Kokura, Satoshi; Yoshikawa, Toshikazu

2011-01-01

Heat shock protein (HSP) 47 may play an important role in the pathogenesis of intestinal fibrosis. Daikenchuto (DKT), a traditional Japanese herbal (Kampo) medicine, has been reported to ameliorate intestinal inflammation. The aims of this study were to determine time-course profiles of several parameters of fibrosis in a rat model, to confirm the HSP47-expressing cells in the colon, and finally to evaluate DKT's effects on intestinal fibrosis. Colitis was induced in male Wistar rats weighing 200 g using an enema of trinitrobenzene sulfonic acid (TNBS). HSP47 localization was determined by immunohistochemistry. Colonic inflammation and fibrosis were assessed by macroscopic, histological, morphometric, and immunohistochemical analyses. Colonic mRNA expression of transforming growth factor β1 (TGF-β1), HSP47, and collagen type I were assessed by real time-polymerase chain reaction (PCR). DKT was administered orally once a day from 8 to 14 d after TNBS administration. The colon was removed on the 15th day. HSP47 immunoreactivity was coexpressed with α-smooth muscle actin-positive cells located in the subepithelial space. Intracolonic administration of TNBS resulted in grossly visible ulcers. Colonic inflammation persisted for 6 weeks, and fibrosis persisted for 4 weeks after cessation of TNBS treatment. The expression levels of mRNA and proteins for TGF-β1, HSP47, and collagen I were elevated in colonic mucosa treated with TNBS. These fibrosis markers indicated that DKT treatment significantly inhibited TNBS-induced fibrosis. These findings suggest that DKT reduces intestinal fibrosis associated with decreasing expression of HSP47 and collagen content in the intestine.

Healing Acceleration of Acetic Acid-induced Colitis by Marigold (Calendula officinalis) in Male Rats

PubMed Central

Tanideh, Nader; Jamshidzadeh, Akram; Sepehrimanesh, Masood; Hosseinzadeh, Masood; Koohi-Hosseinabadi, Omid; Najibi, Asma; Raam, Mozhdeh; Daneshi, Sajad; Asadi-Yousefabad, Seyedeh-Leili

2016-01-01

Background/Aim: Ulcerative colitis (UC) is a type of chronic inflammatory bowel disease with unknown etiology. Several therapeutic strategies such as consumption of medicinal plants have been used for its treatment. The aim of this study was to evaluate healing effects of Calendula officinalis hydroalcoholic extract in experimentally induced UC in rat. Materials and Methods: Ninety-six rats, weighing 200 ± 20 g, were randomly divided into eight equal groups. UC induced by 3% acetic acid and oral doses of C. officinalis extract, 1500 and 3000 mg/kg, and enema (gel 10% and 20%) were given. Two groups as positive controls were given asacol (enema) and oral mesalamine. Negative control groups were given normal saline and base gel. On days 3 and 7, intestinal histopathology and weight changes, plus oxidative stress indices including malondialdehyde (MDA) level and myeloperoxidase (MPO) activity were assayed. Results: A significant increase in the body weight of rats was seen in the group given C. officinalis extract 3000 mg/kg orally, oral mesalamine, and 20% intracolonic gel form of marigold extract compared with negative control and base gel groups during the experimental period. Acute inflammation and granular atrophy after UC induction were resolved completely completely by both 20% intracolonic gel and 3000 mg/kg orally. An increase in MPO activity and a decrease in MDA level in response to oral and intracolonic gel form of C. officinalis were observed 3 and and 7 days after treatment (P < 0.05). Conclusion: Our results indicate that oral and enema forms of hydroalcoholic extract of C. officinalis can be offered as are potential therapeutic agents for UC induced in rats. PMID:26831607

Healing acceleration of acetic acid-induced colitis by marigold (Calendula officinalis) in male rats.

PubMed

Tanideh, Nader; Jamshidzadeh, Akram; Sepehrimanesh, Masood; Hosseinzadeh, Masood; Koohi-Hosseinabadi, Omid; Najibi, Asma; Raam, Mozhdeh; Daneshi, Sajad; Asadi-Yousefabad, Seyedeh-Leili

2016-01-01

Ulcerative colitis (UC) is a type of chronic inflammatory bowel disease with unknown etiology. Several therapeutic strategies such as consumption of medicinal plants have been used for its treatment. The aim of this study was to evaluate healing effects of Calendula officinalis hydroalcoholic extract in experimentally induced UC in rat. Ninety-six rats, weighing 200 ± 20 g, were randomly divided into eight equal groups. UC induced by 3% acetic acid and oral doses of C. officinalis extract, 1500 and 3000 mg/kg, and enema (gel 10% and 20%) were given. Two groups as positive controls were given asacol (enema) and oral mesalamine. Negative control groups were given normal saline and base gel. On days 3 and 7, intestinal histopathology and weight changes, plus oxidative stress indices including malondialdehyde (MDA) level and myeloperoxidase (MPO) activity were assayed. A significant increase in the body weight of rats was seen in the group given C. officinalis extract 3000 mg/kg orally, oral mesalamine, and 20% intracolonic gel form of marigold extract compared with negative control and base gel groups during the experimental period. Acute inflammation and granular atrophy after UC induction were resolved completely completely by both 20% intracolonic gel and 3000 mg/kg orally. An increase in MPO activity and a decrease in MDA level in response to oral and intracolonic gel form of C. officinalis were observed 3 and and 7 days after treatment (P < 0.05). Our results indicate that oral and enema forms of hydroalcoholic extract of C. officinalis can be offered as are potential therapeutic agents for UC induced in rats.

Differential Angiogenic Regulation of Experimental Colitis

PubMed Central

Chidlow, John H.; Langston, Will; Greer, James J.M.; Ostanin, Dmitry; Abdelbaqi, Maisoun; Houghton, Jeffery; Senthilkumar, Annamalai; Shukla, Deepti; Mazar, Andrew P.; Grisham, Matthew B.; Kevil, Christopher G.

2006-01-01

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the intestinal tract with unknown multifactorial etiology that, among other things, result in alteration and dysfunction of the intestinal microvasculature. Clinical observations of increased colon microvascular density during IBD have been made. However, there have been no reports investigating the physiological or pathological importance of angiogenic stimulation during the development of intestinal inflammation. Here we report that the dextran sodium sulfate and CD4+CD45RBhigh T-cell transfer models of colitis stimulate angiogenesis that results in increased blood vessel density concomitant with increased histopathology, suggesting that the neovasculature contributes to tissue damage during colitis. We also show that leukocyte infiltration is an obligatory requirement for the stimulation of angiogenesis. The angiogenic response during experimental colitis was differentially regulated in that the production of various angiogenic mediators was diverse between the two models with only a small group of molecules being similarly controlled. Importantly, treatment with the anti-angiogenic agent thalidomide or ATN-161 significantly reduced angiogenic activity and associated tissue histopathology during experimental colitis. Our findings identify a direct pathological link between angiogenesis and the development of experimental colitis, representing a novel therapeutic target for IBD. PMID:17148665

In vivo detection of morphological and microvascular changes of the colon in association with colitis using fiberoptic confocal imaging (FOCI).

PubMed

McLaren, Wendy J; Anikijenko, Peter; Thomas, Steven G; Delaney, Peter M; King, Roger G

2002-11-01

Using a well-established rodent model of inflammatory bowel disease (IBD), the present study examined changes in the microvasculature of the colonic mucosa in association with ulcerative colitis (UC). The results were compared to microscopic alterations in tissue morphology to establish a temporal relationship between microcirculatory dysfunction and IBD pathology. Mild colitis was induced in rats by the oral consumption of 5% dextran sulfate sodium (DSS) in drinking water. Control animals were provided with water ad libitum. After 3, 5, and 7 days of oral ingestion of DSS, anesthetized rats were laparotomized. The mucosal surface of the distal colon was then examined using fiber optic confocal imaging (FOCI; excitation 488 nm argon ion laser, detection above 515 nm). Changes in the mucosal architecture were examined following the topical application of the fluorescent dye, tetracycline hydrochloride. Tetracycline hydrochloride, an antibiotic used widely in clinical medicine, enabled imaging of the crypts at the surface of the mucosa. Spatial changes in the microvascular structure were assessed following the intravenous administration of fluorescein isothiocyanate dextran (FITC-dextran). Confocal images were correlated with clinical parameters, including weight loss, occult blood, and stool consistency. Attenuation of the colonic epithelium was detected on day 3 colitis. Morphological changes including crypt loss, crypt distortion, and inflammatory cell infiltrate were detected on day 5 and day 7 colitis. Dual channel imaging showed the mucosal capillary network outlining the stromal confines of the mucus-secreting glands in control tissue. Experimental colitis resulted in diffuse hypervascularity and tortuosity of the capillary vessels. Evidence of increased vessel leakiness (leakage of FITC-dextran from the lumen) was first detected on day 5 colitis. Complete disruption of the normal honeycomb pattern of the vessels and capillary dilation was evident after 7 days

TRPV2 in the development of experimental colitis.

PubMed

Issa, C M; Hambly, B D; Wang, Y; Maleki, S; Wang, W; Fei, J; Bao, S

2014-11-01

Colitis is still a significant disease challenge in humans, but its underlying mechanism remains to be fully elucidated. The transient receptor potential vanilloid (TRPV) ion channel plays an important pathological role in host immunity, as deficiency of TRPV compromises host defence in vivo and in vitro. Using a DSS-induced colitis mouse model, the function of TRPV2 in the development of colitis was investigated, utilizing TRPV2(-/-) and Wt mice. Less severe colitis was observed in TRPV2(-/-) , compared to that of Wt mice, at the clinical, histopathological and immunohistochemical levels. Compared to Wt mice, reduced severity of colitis in TRPV2(-/-) mice may be due to less intestinal inflammation via reduced recruitment of macrophages. The TRPV2 pathway contributes to the development of colitis. These data provide useful information for potential therapeutic intervention in colitis patients. © 2014 John Wiley & Sons Ltd.

Oral delivery of prolyl hydroxylase inhibitor: AKB-4924 promotes localized mucosal healing in a mouse model of colitis.

PubMed

Marks, Ellen; Goggins, Bridie J; Cardona, Jocelle; Cole, Siobhan; Minahan, Kyra; Mateer, Sean; Walker, Marjorie M; Shalwitz, Robert; Keely, Simon

2015-02-01

Pharmacological induction of hypoxia-inducible factor (HIF), a global transcriptional regulator of the hypoxic response, by prolyl hydroxylase inhibitors (PHDi) is protective in murine models of colitis, and epithelial cells are critical for the observed therapeutic efficacy. Because systemic HIF activation may lead to potentially negative off-target effects, we hypothesized that targeting epithelial HIF through oral delivery of PHDi would be sufficient to protect against colitis in a mouse model. Using a chemically induced trinitrobenzene sulfonic acid murine model of colitis, we compared the efficacy of oral and intraperitoneal (i.p.) delivery of the PHDi; AKB-4924 in preventing colitis, as measured by endoscopy, histology, barrier integrity, and immune profiling. Furthermore, we measured potential off-target effects, examining HIF and HIF target genes in the heart and kidney, as well as erythropoietin and hematocrit levels. Oral administration of AKB-4924 exhibited mucosal protection comparable i.p. dosing. Oral delivery of PHDi led to reduced colonic epithelial HIF stabilization compared with i.p. delivery, but this was still sufficient to induce transcription of downstream HIF targets. Furthermore, oral delivery of PHDi led to reduced stabilization of HIF and activation of HIF targets in extraintestinal organs. Oral delivery of PHDi therapies to this intestinal mucosa protects against colitis in animal models and represents a potential therapeutic strategy for inflammatory bowel disease, which also precludes unwanted extraintestinal effects.

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

Microscopic colitis syndrome.

PubMed Central

Veress, B; Löfberg, R; Bergman, L

1995-01-01

The colorectal biopsy specimens from 30 patients with chronic watery diarrhoea but normal endoscopic and radiographic findings were studied by light microscopy, morphometry, immunohistochemistry, and two patients with electron microscopy. The histological changes in the colorectum were originally diagnosed in six patients as lymphocytic colitis and in 24 patients as collagenous colitis. The analysis of the specimens for this study could delineate three distinct groups of microscopic colitis: lymphocytic colitis (six patients), collagenous colitis without lymphocytic attack on the surface epithelium (seven patients), and a mixed form presenting with both thickening of the collagen plate and increased number of intraepithelial lymphocytes (17 patients). No transformation was seen from one type to another during follow up of six patients for four to seven years. Increased numbers of active pericryptal myofibroblasts were found with the electron microscope in one patient with mixed microscopic colitis showing also myofibroblasts entrapped within the collagen layer. Hitherto undescribed flat mucosa of the ileum was found in one patient with lymphocytic colitis and both flat mucosa and thickening of the collagen plate in the ileum were seen in one patient with the mixed form of the disease. In another patient with mixed microscopic colitis, normalisation of the colorectal morphology occurred after temporary loop ileostomy, followed by the reappearance of both diarrhoea, inflammation, and thickening of the collagen plate after the ileostomy was reversed. No association was found between non-steroid anti-inflammatory drug (NSAID) consumption and collagenous or mixed microscopic colitis. The primary cause of microscopic colitis is probably an immunological reaction to luminal antigen/s, perhaps of ileal origin. The engagement of the pericryptal myofibroblasts in the disease process might result in the development of the various forms of microscopic colitis. An inverse

Pseudomembranous Colitis

PubMed Central

Farooq, Priya D.; Urrunaga, Nathalie H.; Tang, Derek M.; von Rosenvinge, Erik C.

2015-01-01

Pseudomembranous colitis is an inflammatory condition of the colon characterized by elevated yellow-white plaques that coalesce to form pseudomembranes on the mucosa. Patients with the condition commonly present with abdominal pain, diarrhea, fever, and leukocytosis. Because pseudomembranous colitis is often associated with C. difficile infection, stool testing and empiric antibiotic treatment should be initiated when suspected. When results of C. difficile testing are negative and symptoms persist despite escalating empiric treatment, early gastroenterology consultation and lower endoscopy would be the next step in the appropriate clinical setting. If pseudomembranous colitis is confirmed endoscopically, colonic biopsies should be obtained, as histology can offer helpful clues to the underlying diagnosis. The less common non-C. difficile causes of pseudomembranous colitis should be entertained, as a number of etiologies can result in this condition. Examples include Behcet’s disease, collagenous colitis, inflammatory bowel disease, ischemic colitis, other infections organisms (e.g. bacteria, parasites, viruses), and a handful of drugs and toxins. Pinpointing the correct underlying etiology would better direct patient care and disease management. Surgical specialists would be most helpful in colonic perforation, gangrenous colon, or severe disease. PMID:25769243

Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis.

PubMed

Schneditz, Georg; Rentner, Jana; Roier, Sandro; Pletz, Jakob; Herzog, Kathrin A T; Bücker, Roland; Troeger, Hanno; Schild, Stefan; Weber, Hansjörg; Breinbauer, Rolf; Gorkiewicz, Gregor; Högenauer, Christoph; Zechner, Ellen L

2014-09-09

Antibiotic therapy disrupts the human intestinal microbiota. In some patients rapid overgrowth of the enteric bacterium Klebsiella oxytoca results in antibiotic-associated hemorrhagic colitis (AAHC). We isolated and identified a toxin produced by K. oxytoca as the pyrrolobenzodiazepine tilivalline and demonstrated its causative action in the pathogenesis of colitis in an animal model. Tilivalline induced apoptosis in cultured human cells in vitro and disrupted epithelial barrier function, consistent with the mucosal damage associated with colitis observed in human AAHC and the corresponding animal model. Our findings reveal the presence of pyrrolobenzodiazepines in the intestinal microbiota and provide a mechanism for colitis caused by a resident pathobiont. The data link pyrrolobenzodiazepines to human disease and identify tilivalline as a target for diagnosis and neutralizing strategies in prevention and treatment of colitis.

Beneficial effect of butyrate, Lactobacillus casei and L-carnitine combination in preference to each in experimental colitis

PubMed Central

Moeinian, Mahsa; Ghasemi-Niri, Seyedeh Farnaz; Mozaffari, Shilan; Abdolghaffari, Amir Hossein; Baeeri, Maryam; Navaea-Nigjeh, Mona; Abdollahi, Mohammad

2014-01-01

AIM: To investigate the beneficial effect of the combination of butyrate, Lactobacillus casei, and L-carnitine in a rat colitis model. METHODS: Rats were divided into seven groups. Four groups received oral butyrate, L-carnitine, Lactobacillus casei and the combination of three agents for 10 consecutive days. The remaining groups included negative and positive controls and a sham group. Macroscopic, histopathological examinations, and biomarkers such as tumor necrosis factor-alpha (TNF-α) and interlukin-1β (IL-1β), myeloperoxidase (MPO), thiobarbituric acid reactive substances (TBARS), and ferric reduced ability of plasma (FRAP) were determined in the colon. RESULTS: The combination therapy exhibited a significant beneficial effect in alleviation of colitis compared to controls. Overall changes in reduction of TNF-α (114.66 ± 18.26 vs 171.78 ± 9.48 pg/mg protein, P < 0.05), IL-1β (24.9 ± 1.07 vs 33.06 ± 2.16 pg/mg protein, P < 0.05), TBARS (0.2 ± 0.03 vs 0.49 ± 0.04 μg/mg protein, P < 0.01), MPO (15.32 ± 0.4 vs 27.24 ± 3.84 U/mg protein, P < 0.05), and elevation of FRAP (23.46 ± 1.2 vs 15.02 ± 2.37 μmol/L, P < 0.05) support the preference of the combination therapy in comparison to controls. Although the monotherapies were also effective in improvement of colitis markers, the combination therapy was much better in improvement of colon oxidative stress markers including FRAP, TBARS, and MPO. CONCLUSION: The present combination is a suitable mixture in control of experimental colitis and should be trialed in the clinical setting. PMID:25152589

Effect of a probiotic beverage consumption (Enterococcus faecium CRL 183 and Bifidobacterium longum ATCC 15707) in rats with chemically induced colitis.

PubMed

Celiberto, Larissa Sbaglia; Bedani, Raquel; Dejani, Naiara Naiana; Ivo de Medeiros, Alexandra; Sampaio Zuanon, José Antonio; Spolidorio, Luis Carlos; Tallarico Adorno, Maria Angela; Amâncio Varesche, Maria Bernadete; Carrilho Galvão, Fábio; Valentini, Sandro Roberto; Font de Valdez, Graciela; Rossi, Elizeu Antonio; Cavallini, Daniela Cardoso Umbelino

2017-01-01

Some probiotic strains have the potential to assist in relieving the symptoms of inflammatory bowel disease. The impact of daily ingestion of a soy-based product fermented by Enterococcus faecium CRL 183 and Lactobacillus helveticus 416 with the addition of Bifidobacterium longum ATCC 15707 on chemically induced colitis has been investigated thereof within a period of 30 days. Colitis was induced by dextran sulfate sodium. The animals were randomly assigned into five groups: Group C: negative control; Group CL: positive control; Group CLF: DSS with the fermented product; Group CLP: DSS with the non-fermented product (placebo); Group CLS: DSS with sulfasalazine. The following parameters were monitored: disease activity index, fecal microbial analyses, gastrointestinal survival of probiotic microorganisms and short-chain fatty acids concentration in the feces. At the end of the protocol the animals' colons were removed so as to conduct a macroscopical and histopathological analysis, cytokines and nitrite quantification. Animals belonging to the CLF group showed fewer symptoms of colitis during the induction period and a lower degree of inflammation and ulceration in their colon compared to the CL, CLS and CLP groups (p<0.05). The colon of the animals in groups CL and CLS presented severe crypt damage, which was absent in CLF and CLP groups. A significant increase in the population of Lactobacillus spp. and Bifidobacterium spp. at the end of the protocol was verified only in the CLF animals (p<0.05). This group also showed an increase in short-chain fatty acids (propionate and acetate). Furthermore, the intestinal survival of E. faecium CRL 183 and B. longum ATCC 15707 in the CLF group has been confirmed by biochemical and molecular analyzes. The obtained results suggest that a regular intake of the probiotic product, and placebo to a lesser extent, can reduce the severity of DSS-induced colitis on rats.

[Immunopathology of ulcerative colitis and granulomatous colitis (author's transl)].

PubMed

Bläker, F

1975-08-01

There is no convincing evidence as yet for a key role of immunological processes in the pathogenesis of unspecific colitis. However clinical findings as well as immunological data do support the hypothesis that immune reactions are involved primarily or secondarily in the pathogenesis and the clinical course of ulcerative colitis and granulomatous colitis. In such patients a specific adaptation of humoral and cell-bound immune reactions against antigenic material from the colon and other tissues has been found in peripheral blood, lymphatic tissue and bowel wall. In this context it seems to be especially noteworthy, that lymphocytes taken from patients with colitis lead to disintegration of colon epithelial cells in vitro. This cytotoxic effect of the lymphocytes is lost after colectomy or remission of the disease. Ulcerative and granulomatous colitis do have many clinical and immunological peculiarities in common. This makes one think, that possibly the same noxious factors induce differential local reactions because of different hereditary disposition.

Enhanced activity of a hydrogen sulphide-releasing derivative of mesalamine (ATB-429) in a mouse model of colitis

PubMed Central

Fiorucci, S; Orlandi, S; Mencarelli, A; Caliendo, G; Santagada, V; Distrutti, E; Santucci, L; Cirino, G; Wallace, J L

2007-01-01

Background and Purpose: Mesalamine is the first-line therapy for colitis, but it lacks potency and is only effective for mild-to-moderate forms of this disease. Hydrogen sulphide has been shown to be a potent, endogenous anti-inflammatory substance, modulating leukocyte-endothelial adhesion and leukocyte migration. The purpose of this study was to determine if an H2S-releasing derivative of mesalamine (ATB-429) would exhibit increased potency and effectiveness in a mouse model of colitis. Experimental Approach: Colitis was induced in mice with trinitrobenzene sulphonic acid and the effects of ATB-429 and mesalamine were compared in several treatment regimens. The severity of colitis was determined using several indices, including a disease activity score (comprised of scores for diarrhea, weight loss and fecal blood), colonic myeloperoxidase activity and macroscopic/microscopic scoring of tissue injury. Key Results: Irrespective of the treatment regiment, ATB-429 was more effective than mesalamine in reducing the severity of colitis. ATB-429 was particularly effective in reducing granulocyte infiltration into the colonic tissue (by ∼70%), as well as reducing the expression of mRNA for several key proinflammatory cytokines/chemokines (e.g., TNFα, IFNγ). Treatment with ADT-OH, the H2S-releasing moiety of ATB-429, did not affect severity of colitis. Conclusions and Implications: ATB-429 exhibits a marked increase in anti-inflammatory activity and potency in a murine model of colitis, as compared to mesalamine. These results are consistent with recently described anti-inflammatory effects of H2S. ATB-429 may represent an attractive alternative to mesalamine for the treatment of inflammatory bowel disease. PMID:17339831

Mice deficient in Muc4 are resistant to experimental colitis and colitis-associated colorectal cancer.

PubMed

Das, S; Rachagani, S; Sheinin, Y; Smith, L M; Gurumurthy, C B; Roy, H K; Batra, S K

2016-05-19

MUC4, a large transmembrane mucin normally expressed in the small and large intestine, is differentially expressed during inflammatory and malignant conditions of the colon. However, the expression pattern and the role of MUC4 in colitis and colorectal cancer (CRC) are inconclusive. Therefore, the aim of this study was to understand the role of Muc4 during inflammatory and malignant conditions of the colon. Here, we generated Muc4(-/-) mice and addressed its role in colitis and colitis-associated CRC using dextran sodium sulfate (DSS) and azoxymethane (AOM)-DSS experimental models, respectively. Muc4(-/-) mice were viable, fertile with no apparent defects. Muc4(-/-) mice displayed increased resistance to DSS-induced colitis compared with wild-type (WT) littermates that was evaluated by survival rate, body weight loss, diarrhea and fecal blood score, and histological score. Reduced infiltration of inflammatory cells, that is, CD3(+) lymphocytes and F4/80(+) macrophages was observed in the inflamed mucosa along with reduction in the mRNA levels of inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α and anti-microbial genes Lysozyme M and SLPI in the colon of Muc4(-/-) mice compared with WT littermates. Compensatory upregulation of Muc2 and Muc3 mucins under basal and DSS treatment conditions partly explains the resistance observed in Muc4(-/-) mice. Accordingly, Muc4(-/-) mice exhibited significantly reduced tumor burden compared with WT mice assessed in a colitis-induced tumor model using AOM/DSS. An increased percentage of Ki67(+) nuclei was observed in the tumors from WT compared with Muc4(-/-) mice suggesting Muc4 to be critical in intestinal cell proliferation during tumorigenesis. Taken together, we conclusively demonstrate for the first time the role of Muc4 in driving intestinal inflammation and inflammation-associated tumorigenesis using a novel Muc4(-/-) mouse model.

Protective effect of naringenin on acetic acid-induced ulcerative colitis in rats

PubMed Central

Al-Rejaie, Salim S; Abuohashish, Hatem M; Al-Enazi, Maher M; Al-Assaf, Abdullah H; Parmar, Mihir Y; Ahmed, Mohammed M

2013-01-01

AIM: To evaluate the ameliorative effect of naringenin (NG) during ulcerative colitis (UC) in rats. METHODS: Rats were treated with three different doses (25, 50 and 100 mg/kg per day) of NG and a single dose of mesalazine (MES, 300 mg/kg per day) for seven days prior to ulcerative colitis induction by 4% acetic acid (AA). Twenty four hours after AA rectal administration, animals were scarified and the colonic tissues were dissected. Colonic mucus content was estimated using Alcian blue dye binding technique. In colon tissues, levels of total glutathione sulphadryls (T-GSH), non-protein sulphadryls (NP-SH) and thiobarbituric acid reactive substances (TBARS) were evaluated. The activities of the antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD) were measured. Concentrations of nucleic acids (DNA and RNA) and total protein were also estimated in colon tissues. Colonic levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), prostaglandin E2 (PGE2) and nitric oxide (NO) were estimated. In cross section of colitis tissue the histopathological changes were observed. RESULTS: Colonic mucus content was decreased in AA compared to controls (587.09 ± 65.59 mg/kg vs 941.78 ± 68.41 mg/kg, P < 0.001). AA administration markedly reduced T-GSH (5.25 ± 0.37 nmol/L vs 3.04 ± 0.24 nmol/L, P < 0.01), NP-SH (3.16 ± 0.04 nmol/L vs 2.16 ± 0.30 nmol/L, P < 0.01), CAT (6.77 ± 0.40 U/mg vs 3.04 ± 0.2 U/mg, P < 0.01) and SOD (3.10 ± 0.11 U/mg vs 1.77 ± 0.18 U/mg, P < 0.01) while TBARS, TNF-α, IL-1β, IL-6, PGE2 and NO levels (15.09 ± 3.84 nmol/L vs 59.90 ± 16.34 nmol/L, P < 0.01; 113.56 ± 1.91 pg/mg vs 134.24 ± 4.77 pg/mg, P < 0.01; 209.20 ± 36.38 pg/mg vs 422.19 ± 31.47 pg/mg, P < 0.01; 250.83 ± 25.09 pg/mg vs 638.58 ± 115.9 pg/mg, P < 0.01; 248.19 ± 36.98 pg/mg vs 541.74 ± 58.34 pg/mg, P < 0.01 and 81.26 ± 2.98 mmol/g vs 101.90 ± 10.73 mmol/g, P < 0.001) were increased in colon of rats with UC compared controls

Pretreatment of Gymnema sylvestre revealed the protection against acetic acid-induced ulcerative colitis in rats

PubMed Central

2014-01-01

Background Overproduction of free radicals and decreased antioxidant capacity are well-known risk factors for inflammatory bowel diseases. Gymnema sylvestre (GS) leaves extract is distinguished for its anti-diabetic, antioxidant and anti-inflammatory properties. Present study is designed to evaluate the preventative activities of GS against acetic acid (AA)-induced ulcerative colitis in Wistar rats. Methods Experimentally ulcerative colitis (UC) was induced by AA in animals pretreated with three different doses of GS leaves extract (50, 100, 200 mg/kg/day) and a single dose of mesalazine (MES, 300 mg/kg/day) for seven days. Twenty four hours later, animals were sacrificed and the colonic tissues were collected. Colonic mucus content was determined using Alcian blue dye binding technique. Levels of thiobarbituric acid reactive substances (TBARS), total glutathione sulfhydryl group (T-GSH) and non-protein sulfhydryl group (NPSH) as well as the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were estimated in colon tissues. Colonic nucleic acids (DNA and RNA) and total protein (TP) concentrations were also determined. Levels of pro-inflammatory cytokines including interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) as well as prostaglandin E2 (PGE2) and nitric oxide (NO) were estimated in colonic tissues. The histopathological changes of the colonic tissues were also observed. Results In AA administered group TBARS levels were increased, while colonic mucus content, T-GSH and NP-SH, SOD and CAT were reduced in colon. Pretreatment with GS inhibited TBARS elevation as well as mucus content, T-GSH and NP-SH reduction. Enzymatic activities of SOD and CAT were brought back to their normal levels in GS pretreated group. A significant reduction in DNA, RNA and TP levels was seen following AA administration and this inhibition was significantly eliminated by GS treatment. GS pretreatment also inhibited

Pretreatment of Gymnema sylvestre revealed the protection against acetic acid-induced ulcerative colitis in rats.

PubMed

Aleisa, Abdulaziz M; Al-Rejaie, Salim S; Abuohashish, Hatem M; Ola, Mohammed S; Parmar, Mihir Y; Ahmed, Mohammed M

2014-02-10

Overproduction of free radicals and decreased antioxidant capacity are well-known risk factors for inflammatory bowel diseases. Gymnema sylvestre (GS) leaves extract is distinguished for its anti-diabetic, antioxidant and anti-inflammatory properties. Present study is designed to evaluate the preventative activities of GS against acetic acid (AA)-induced ulcerative colitis in Wistar rats. Experimentally ulcerative colitis (UC) was induced by AA in animals pretreated with three different doses of GS leaves extract (50, 100, 200 mg/kg/day) and a single dose of mesalazine (MES, 300 mg/kg/day) for seven days. Twenty four hours later, animals were sacrificed and the colonic tissues were collected. Colonic mucus content was determined using Alcian blue dye binding technique. Levels of thiobarbituric acid reactive substances (TBARS), total glutathione sulfhydryl group (T-GSH) and non-protein sulfhydryl group (NPSH) as well as the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were estimated in colon tissues. Colonic nucleic acids (DNA and RNA) and total protein (TP) concentrations were also determined. Levels of pro-inflammatory cytokines including interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) as well as prostaglandin E2 (PGE2) and nitric oxide (NO) were estimated in colonic tissues. The histopathological changes of the colonic tissues were also observed. In AA administered group TBARS levels were increased, while colonic mucus content, T-GSH and NP-SH, SOD and CAT were reduced in colon. Pretreatment with GS inhibited TBARS elevation as well as mucus content, T-GSH and NP-SH reduction. Enzymatic activities of SOD and CAT were brought back to their normal levels in GS pretreated group. A significant reduction in DNA, RNA and TP levels was seen following AA administration and this inhibition was significantly eliminated by GS treatment. GS pretreatment also inhibited AA-induced elevation of pro

Moxibustion inhibits interleukin-12 and tumor necrosis factor alpha and modulates intestinal flora in rat with ulcerative colitis

PubMed Central

Wang, Xiao-Mei; Lu, Yuan; Wu, Lu-Yi; Yu, Shu-Guang; Zhao, Bai-Xiao; Hu, Hong-Yi; Wu, Huan-Gan; Bao, Chun-Hui; Liu, Hui-Rong; Wang, Jin-Hai; Yao, Yi; Hua, Xue-Gui; Guo, Hui-Ying; Shen, Li-Rong

2012-01-01

AIM: To investigate the effect of moxibustion on intestinal flora and release of interleukin-12 (IL-12) and tumor necrosis factor-α (TNF-α) from the colon in rat with ulcerative colitis (UC). METHODS: A rat model of UC was established by local stimulation of the intestine with supernatant from colonic contents harvested from human UC patients. A total of 40 male Sprague-Dawley rats were randomly divided into the following groups: normal (sham), model (UC), herb-partition moxibustion (HPM-treated), and positive control sulfasalazine (SA-treated). Rats treated with HPM received HPM at acupuncture points ST25 and RN6, once a day for 15 min, for a total of 8 d. Rats in the SA group were perfused with SA twice a day for 8 d. The colonic histopathology was observed by hematoxylin-eosin. The levels of intestinal flora, including Bifidobacterium, Lactobacillus, Escherichia coli (E. coli), and Bacteroides fragilis (B. fragilis), were tested by real-time quantitative polymerase chain reaction to detect bacterial 16S rRNA/DNA in order to determine DNA copy numbers of each specific species. Immunohistochemical assays were used to observe the expression of TNF-α and IL-12 in the rat colons. RESULTS: HPM treatment inhibited immunopathology in colonic tissues of UC rats; the general morphological score and the immunopathological score were significantly decreased in the HPM and SA groups compared with the model group [3.5 (2.0-4.0), 3.0 (1.5-3.5) vs 6.0 (5.5-7.0), P < 0.05 for the general morphological score, and 3.00 (2.00-3.50), 3.00 (2.50-3.50) vs 5.00 (4.50-5.50), P < 0.01 for the immunopathological score]. As measured by DNA copy number, we found that Bifidobacterium and Lactobacillus, which are associated with a healthy colon, were significantly higher in the HPM and SA groups than in the model group (1.395 ± 1.339, 1.461 ± 1.152 vs 0.045 ± 0.036, P < 0.01 for Bifidobacterium, and 0.395 ± 0.325, 0.851 ± 0.651 vs 0.0015 ± 0.0014, P < 0.01 for Lactobacillus). On the

Rivastigmine Alleviates Experimentally Induced Colitis in Mice and Rats by Acting at Central and Peripheral Sites to Modulate Immune Responses

PubMed Central

Shifrin, Helena; Nadler-Milbauer, Mirela; Shoham, Shai; Weinstock, Marta

2013-01-01

The cholinergic anti-inflammatory system and α7 nicotinic receptors in macrophages have been proposed to play a role in neuroimmunomodulation and in the etiology of ulcerative colitis. We investigated the ability of a cholinesterase (ChE) inhibitor rivastigmine, to improve the pathology of ulcerative colitis by increasing the concentration of extracellular acetylcholine in the brain and periphery. In combination with carbachol (10 µM), rivastigmine (1 µM) significantly decreased the release of nitric oxide, TNF-α, IL-1β and IL-6 from lipopolysaccharide-activated RAW 264.7 macrophages and this effect was abolished by α7 nicotinic receptor blockade by bungarotoxin. Rivastigmine (1 mg/kg) but not (0.5 mg/kg), injected subcutaneously once daily in BALB/c mice with colitis induced by 4% dextran sodium sulphate (DSS), reduced the disease activity index (DAI) by 60% and damage to colon structure. Rivastigmine (1 mg/kg) also reduced myeloperoxidase activity and IL-6 by >60%, and the infiltration of CD11b expressing cells by 80%. These effects were accompanied by significantly greater ChE inhibition in cortex, brain stem, plasma and colon than that after 0.5 mg/kg. Co-administration of rivastigmine (1 mg/kg) with the muscarinic antagonist scopolamine significantly increased the number of CD11b expressing cells in the colon but did not change DAI compared to those treated with rivastigmine alone. Rivastigmine 1 and 2 mg given rectally to rats with colitis induced by rectal administration of 30 mg dintrobezene sulfonic acid (DNBS) also caused a dose related reduction in ChE activity in blood and colon, the number of ulcers and area of ulceration, levels of TNF-α and in MPO activity. The study revealed that the ChE inhibitor rivastigmine is able to reduce gastro-intestinal inflammation by actions at various sites at which it preserves ACh. These include ACh released from vagal nerve endings that activates alpha7 nicotinic receptors on circulating macrophages and in

Rivastigmine alleviates experimentally induced colitis in mice and rats by acting at central and peripheral sites to modulate immune responses.

PubMed

Shifrin, Helena; Nadler-Milbauer, Mirela; Shoham, Shai; Weinstock, Marta

2013-01-01

The cholinergic anti-inflammatory system and α7 nicotinic receptors in macrophages have been proposed to play a role in neuroimmunomodulation and in the etiology of ulcerative colitis. We investigated the ability of a cholinesterase (ChE) inhibitor rivastigmine, to improve the pathology of ulcerative colitis by increasing the concentration of extracellular acetylcholine in the brain and periphery. In combination with carbachol (10 µM), rivastigmine (1 µM) significantly decreased the release of nitric oxide, TNF-α, IL-1β and IL-6 from lipopolysaccharide-activated RAW 264.7 macrophages and this effect was abolished by α7 nicotinic receptor blockade by bungarotoxin. Rivastigmine (1 mg/kg) but not (0.5 mg/kg), injected subcutaneously once daily in BALB/c mice with colitis induced by 4% dextran sodium sulphate (DSS), reduced the disease activity index (DAI) by 60% and damage to colon structure. Rivastigmine (1 mg/kg) also reduced myeloperoxidase activity and IL-6 by >60%, and the infiltration of CD11b expressing cells by 80%. These effects were accompanied by significantly greater ChE inhibition in cortex, brain stem, plasma and colon than that after 0.5 mg/kg. Co-administration of rivastigmine (1 mg/kg) with the muscarinic antagonist scopolamine significantly increased the number of CD11b expressing cells in the colon but did not change DAI compared to those treated with rivastigmine alone. Rivastigmine 1 and 2 mg given rectally to rats with colitis induced by rectal administration of 30 mg dintrobezene sulfonic acid (DNBS) also caused a dose related reduction in ChE activity in blood and colon, the number of ulcers and area of ulceration, levels of TNF-α and in MPO activity. The study revealed that the ChE inhibitor rivastigmine is able to reduce gastro-intestinal inflammation by actions at various sites at which it preserves ACh. These include ACh released from vagal nerve endings that activates alpha7 nicotinic receptors on circulating macrophages and in

Genetics Home Reference: ulcerative colitis

MedlinePlus

... colitis is most common in North America and Western Europe; however the prevalence is increasing in other ... 3 links) Encyclopedia: Ulcerative Colitis Encyclopedia: Ulcerative Colitis (Image) Health Topic: Ulcerative Colitis Additional NIH Resources (1 ...

Effect of Arctium lappa L. in the dextran sulfate sodium colitis mouse model.

PubMed

Huang, Tzou-Chi; Tsai, Shinn-Shyong; Liu, Li-Fang; Liu, Yu Lin; Liu, Hung-Jen; Chuang, Kuo Pin

2010-09-07

To analyze the possible protective role of Arctium lappa L. (AL) in a murine model of ulcerative colitis (UC). BALB/c mice were administered 100 mg/kg AL powder orally each day. After 7 d, colitis was induced by administration of dextran sulfate sodium (DSS) (5% W/V) in drinking water for a further 8 consecutive days. Diarrhea and bloody stools as well as colonic histology were observed. The level of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in colonic sections were detected by immunohistochemistry. There were significant differences in mean body weight values and disease activity indices between controls and AL-treated animals. Moreover, the histological findings showed that AL treatment can prevent mucosal edema, submucosal erosions, ulceration, inflammatory cell infiltration and colon damage. In addition, immunohistochemistry analysis showed that the levels of the inflammatory cytokines, IL-6 and TNF-alpha were also decreased in AL-treated groups. We suggest that AL can prevent intestinal damage and decrease inflammatory cytokines in mice with DSS-induced colitis. Thus, AL could prove to be a useful food for UC.

Effect of a probiotic beverage consumption (Enterococcus faecium CRL 183 and Bifidobacterium longum ATCC 15707) in rats with chemically induced colitis

PubMed Central

Celiberto, Larissa Sbaglia; Bedani, Raquel; Dejani, Naiara Naiana; Ivo de Medeiros, Alexandra; Sampaio Zuanon, José Antonio; Spolidorio, Luis Carlos; Tallarico Adorno, Maria Angela; Amâncio Varesche, Maria Bernadete; Carrilho Galvão, Fábio; Valentini, Sandro Roberto; Font de Valdez, Graciela; Rossi, Elizeu Antonio

2017-01-01

Background Some probiotic strains have the potential to assist in relieving the symptoms of inflammatory bowel disease. The impact of daily ingestion of a soy-based product fermented by Enterococcus faecium CRL 183 and Lactobacillus helveticus 416 with the addition of Bifidobacterium longum ATCC 15707 on chemically induced colitis has been investigated thereof within a period of 30 days. Methods Colitis was induced by dextran sulfate sodium. The animals were randomly assigned into five groups: Group C: negative control; Group CL: positive control; Group CLF: DSS with the fermented product; Group CLP: DSS with the non-fermented product (placebo); Group CLS: DSS with sulfasalazine. The following parameters were monitored: disease activity index, fecal microbial analyses, gastrointestinal survival of probiotic microorganisms and short-chain fatty acids concentration in the feces. At the end of the protocol the animals’ colons were removed so as to conduct a macroscopical and histopathological analysis, cytokines and nitrite quantification. Results Animals belonging to the CLF group showed fewer symptoms of colitis during the induction period and a lower degree of inflammation and ulceration in their colon compared to the CL, CLS and CLP groups (p<0.05). The colon of the animals in groups CL and CLS presented severe crypt damage, which was absent in CLF and CLP groups. A significant increase in the population of Lactobacillus spp. and Bifidobacterium spp. at the end of the protocol was verified only in the CLF animals (p<0.05). This group also showed an increase in short-chain fatty acids (propionate and acetate). Furthermore, the intestinal survival of E. faecium CRL 183 and B. longum ATCC 15707 in the CLF group has been confirmed by biochemical and molecular analyzes. Conclusions The obtained results suggest that a regular intake of the probiotic product, and placebo to a lesser extent, can reduce the severity of DSS-induced colitis on rats. PMID:28437455

Ischemic Colitis

PubMed Central

Montessori, Gino; Liepa, Egils V.

1970-01-01

Twenty cases of ischemic colitis are reviewed; 19 were obtained from autopsy files and the diagnosis in one was made from a surgical specimen. The majority of the patients were elderly with generalized arteriosclerosis. In approximately two-thirds of the patients the ischemic colitis was precipitated by preceding trauma, operation or congestive heart failure. Clinically, ischemic colitis is characterized by abdominal pain, distension and bleeding per rectum. Perforation of large bowel may occur. The lesions tend to be localized around the splenic flexure and junction of the descending and sigmoid colon, and in cases following aortic graft surgery the rectum is involved. Microscopically, there is necrosis, hemorrhage and ulceration. In less severe cases the mucosa only is affected. Cases with perforation show necrosis of all layers. It is considered that ischemic colitis is comparatively frequent and should be distinguished from other inflammatory conditions of the colon. ImagesFIG. 1FIG. 2FIG. 3FIG. 4FIG. 5FIG. 6FIG. 7FIG. 8FIG. 9 PMID:5308923

Mice deficient in Muc4 are resistant to experimental colitis and colitis-associated colorectal cancer

PubMed Central

Das, S; Rachagani, S; Sheinin, Y; Smith, LM; Gurumurthy, CB; Roy, HK; Batra, SK

2017-01-01

MUC4, a large transmembrane mucin normally expressed in the small and large intestine, is differentially expressed during inflammatory and malignant conditions of the colon. However, the expression pattern and the role of MUC4 in colitis and colorectal cancer (CRC) are inconclusive. Therefore, the aim of this study was to understand the role of Muc4 during inflammatory and malignant conditions of the colon. Here, we generated Muc4−/− mice and addressed its role in colitis and colitis-associated CRC using dextran sodium sulfate (DSS) and azoxymethane (AOM)-DSS experimental models, respectively. Muc4−/− mice were viable, fertile with no apparent defects. Muc4−/− mice displayed increased resistance to DSS-induced colitis compared with wild-type (WT) littermates that was evaluated by survival rate, body weight loss, diarrhea and fecal blood score, and histological score. Reduced infiltration of inflammatory cells, that is, CD3+ lymphocytes and F4/80+ macrophages was observed in the inflamed mucosa along with reduction in the mRNA levels of inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α and anti-microbial genes Lysozyme M and SLPI in the colon of Muc4−/− mice compared with WT littermates. Compensatory upregulation of Muc2 and Muc3 mucins under basal and DSS treatment conditions partly explains the resistance observed in Muc4−/− mice. Accordingly, Muc4−/− mice exhibited significantly reduced tumor burden compared with WT mice assessed in a colitis-induced tumor model using AOM/DSS. An increased percentage of Ki67+ nuclei was observed in the tumors from WT compared with Muc4−/− mice suggesting Muc4 to be critical in intestinal cell proliferation during tumorigenesis. Taken together, we conclusively demonstrate for the first time the role of Muc4 in driving intestinal inflammation and inflammation-associated tumorigenesis using a novel Muc4−/− mouse model. PMID:26364605

Colitis and Colon Cancer in WASP-Deficient Mice Require Helicobacter Spp.

PubMed Central

Nguyen, Deanna D.; Muthupalani, Suresh; Goettel, Jeremy A.; Eston, Michelle A.; Mobley, Melissa; Taylor, Nancy S.; McCabe, Amanda; Marin, Romela; Snapper, Scott B.; Fox, James G.

2014-01-01

Background Wiskott-Aldrich Syndrome protein (WASP)-deficient patients and mice are immunodeficient and can develop inflammatory bowel disease. The intestinal microbiome is critical to the development of colitis in most animal models, in which, Helicobacter spp. have been implicated in disease pathogenesis. We sought to determine the role of Helicobacter spp. in colitis development in WASP-deficient (WKO) mice. Methods Feces from WKO mice raised under specific pathogen free conditions were evaluated for the presence of Helicobacter spp., after which, a subset of mice were rederived in Helicobacter spp.-free conditions. Helicobacter spp.-free WKO animals were subsequently infected with Helicobacter bilis. Results Helicobacter spp. were detected in feces from WKO mice. After re-derivation in Helicobacter spp.-free conditions, WKO mice did not develop spontaneous colitis but were susceptible to radiation-induced colitis. Moreover, a T-cell transfer model of colitis dependent on WASP-deficient innate immune cells also required Helicobacter spp. colonization. Helicobacter bilis infection of rederived WKO mice led to typhlitis and colitis. Most notably, several H. bilis-infected animals developed dysplasia with 10% demonstrating colon carcinoma, which was not observed in uninfected controls. Conclusions Spontaneous and T-cell transfer, but not radiation-induced, colitis in WKO mice is dependent on the presence of Helicobacter spp. Furthermore, H. bilis infection is sufficient to induce typhlocolitis and colon cancer in Helicobacter spp.-free WKO mice. This animal model of a human immunodeficiency with chronic colitis and increased risk of colon cancer parallels what is seen in human colitis and implicates specific microbial constituents in promoting immune dysregulation in the intestinal mucosa. PMID:23820270

Etiology of Tetracycline-Associated Pseudomembranous Colitis in Hamsters

PubMed Central

Toshniwal, Renu; Fekety, Robert; Silva, Joseph

1979-01-01

Tetracyclines were implicated in the 1950s in induction of protracted diarrhea and pseudomembranous colitis. Because the pathogenetic mechanism of these illnesses has been questioned recently, we studied tetracycline in hamster models of antibiotic-associated colitis. Orogastric administration of tetracycline caused diarrhea and death, with evidence of hemorrhagic typhlitis. Filtrates of cecal contents were toxic when inoculated into normal hamsters and cell culture monolayers, and toxicity was neutralized with Clostridium sordellii antitoxin. Tetracycline-resistant C. difficile was cultured from stools of these hamsters, but Staphylococcus aureus was not isolated. The value of tetracycline for treatment or prevention of clindamycin-induced colitis in hamsters was also studied, and it was found that daily orogastric administration of tetracycline was poorly protective against clindamycin-induced colitis. PMID:485127

Determination of the mitigating effect of colon-specific bioreversible codrugs of mycophenolic acid and aminosugars in an experimental colitis model in Wistar rats

PubMed Central

Chopade, Shakuntala Santosh; Dhaneshwar, Suneela Sunil

2018-01-01

AIM To design colon-targeted codrugs of mycophenolic acid (MPA) and aminosugars as a safer option to mycophenolate mofetil (MMF) in the management of inflammatory bowel disease. METHODS Codrugs were synthesized by coupling MPA with aminosugars (D-glucosamine and D-galactosamine) using EDCI coupling. The structures were confirmed by infrared radiation, nuclear magnetic resonance, mass spectroscopy and elemental analysis. The release profile of codrugs was extensively studied in aqueous buffers, upper gastrointestinal homogenates, faecal matter and caecal homogenates (in vitro) and rat blood (in vitro). Anti-colitic activity was assessed in 2,4,6-trinitrobezenesulfonic acid-induced colitis in Wistar rats by the estimation of various demarcating parameters. Statistical evaluation was performed by applying one-way and two-way ANOVA when compared with the disease control. RESULTS The prodrugs resisted activation in HCl buffer (pH 1.2) and stomach homogenates of rats with negligible hydrolysis in phosphate buffer (pH 7.4) and intestinal homogenates. Incubation with colon homogenates (in vitro) produced 76% to 89% release of MPA emphasizing colon-specific activation of codrugs and the release of MPA and aminosugars at the site of action. In the in vitro studies, the prodrug of MPA with D-glucosamine (MGLS) was selected which resulted in 68% release of MPA in blood. in vitro studies on MGLS revealed its colon-specific activation after a lag time of 8 h which could be ascribed to the hydrolytic action of N-acyl amidases found in the colon. The synthesized codrugs markedly diminished disease activity score and revived the disrupted architecture of the colon that was comparable to MMF but superior to MPA. CONCLUSION The significant attenuating effect of prodrugs and individual aminosugars on colonic inflammation proved that the rationale of the codrug approach is valid. PMID:29563754

Propionyl-L-Carnitine is Efficacious in Ulcerative Colitis Through its Action on the Immune Function and Microvasculature.

PubMed

Scioli, Maria Giovanna; Stasi, Maria Antonietta; Passeri, Daniela; Doldo, Elena; Costanza, Gaetana; Camerini, Roberto; Fociani, Paolo; Arcuri, Gaetano; Lombardo, Katia; Pace, Silvia; Borsini, Franco; Orlandi, Augusto

2014-03-20

Microvascular endothelial dysfunction characterizes ulcerative colitis (UC), the most widespread form of inflammatory bowel disease. Intestinal mucosal microvessels in UC display aberrant expression of cell adhesion molecules (CAMs) and increased inflammatory cell recruitment. Propionyl-L-carnitine (PLC), an ester of L-carnitine required for the mitochondrial transport of fatty acids, ameliorates propionyl-CoA bioavailability and reduces oxidative stress in ischemic tissues. The present study aimed to document the efficacy of anti-oxidative stress properties of PLC in counteracting intestinal microvascular endothelial dysfunction and inflammation. To evaluate the efficacy in vivo, we analyzed the effects in intestinal biopsies of patients with mild-to-moderate UC receiving oral PLC co-treatment and in rat TNBS-induced colitis; in addition, we investigated antioxidant PLC action in TNF-α-stimulated human intestinal microvascular endothelial cells (HIMECs) in vitro. Four-week PLC co-treatment reduced intestinal mucosal polymorph infiltration and CD4(+) lymphocytes, ICAM-1(+) and iNOS(+) microvessels compared with placebo-treated patients with UC. Oral and intrarectal administration of PLC but not L-carnitine or propionate reduced intestinal damage and microvascular dysfunction in rat TNBS-induced acute and reactivated colitis. In cultured TNF-α-stimulated HIMECs, PLC restored β-oxidation and counteracted NADPH oxidase 4-generated oxidative stress-induced CAM expression and leukocyte adhesion. Inhibition of β-oxidation by L-aminocarnitine increased reactive oxygen species production and PLC beneficial effects on endothelial dysfunction and leukocyte adhesion. Finally, PLC reduced iNOS activity and nitric oxide accumulation in rat TNBS-induced colitis and in HIMEC cultures. Our results show that the beneficial antioxidant effect of PLC targeting intestinal microvasculature restores endothelial β-oxidation and function, and reduces mucosal inflammation in UC

Effect of Arctium lappa L. in the dextran sulfate sodium colitis mouse model

PubMed Central

Huang, Tzou-Chi; Tsai, Shinn-Shyong; Liu, Li-Fang; Liu, Yu Lin; Liu, Hung-Jen; Chuang, Kuo Pin

2010-01-01

AIM: To analyze the possible protective role of Arctium lappa L. (AL) in a murine model of ulcerative colitis (UC). METHODS: BALB/c mice were administered 100 mg/kg AL powder orally each day. After 7 d, colitis was induced by administration of dextran sulfate sodium (DSS) (5% W/V) in drinking water for a further 8 consecutive days. Diarrhea and bloody stools as well as colonic histology were observed. The level of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in colonic sections were detected by immunohistochemistry. RESULTS: There were significant differences in mean body weight values and disease activity indices between controls and AL-treated animals. Moreover, the histological findings showed that AL treatment can prevent mucosal edema, submucosal erosions, ulceration, inflammatory cell infiltration and colon damage. In addition, immunohistochemistry analysis showed that the levels of the inflammatory cytokines, IL-6 and TNF-α were also decreased in AL-treated groups. CONCLUSION: We suggest that AL can prevent intestinal damage and decrease inflammatory cytokines in mice with DSS-induced colitis. Thus, AL could prove to be a useful food for UC. PMID:20806438

Comparison of anti-inflammatory mechanisms of mango (Mangifera Indica L.) and pomegranate (Punica Granatum L.) in a preclinical model of colitis

PubMed Central

Kim, Hyemee; Banerjee, Nivedita; Ivanov, Ivan; Pfent, Catherine M.; Prudhomme, Kalan R.; Bisson, William H.; Dashwood, Rodrick H.; Talcott, Stephen T.; Mertens-Talcott, Susanne U.

2016-01-01

Scope Tannin-rich fruits have been evaluated as alternative prevention strategies for colorectal cancer based on their anti-inflammatory properties. This study compared tannin-rich preparations from mango (rich in gallotannins) and pomegranate (rich in ellagitannins) in the dextran sodium sulfate-induced colitis model. Methods and results In rats, mango and pomegranate beverages decreased intestinal inflammation and the levels of pro-inflammatory cytokines in mucosa and serum. The mango beverage suppressed the ratio of phosphorylated/total protein expression of the IGF-1R-AKT/mTOR axis and down-regulated mRNA expression of Igf1, Insr, and pik3cv. Pomegranate decreased p70S6K and RPS6, as well as Rps6ka2, Map2k2, and Mapk1 mRNA. In silico modeling indicated a high binding-docked of gallic acid to the catalytic domain of IGF-1R, which may suppress the activity of the enzyme. Ellagic acid docked effectively into the catalytic domains of both IGF-1R and EGFR. In vitro assays with lipopolysaccharide-treated CCD-18Co cells using polyphenolic extracts from each beverage, as well as pure compounds, corroborated the predictions made in silico. Conclusion Mango polyphenols inhibited the IGF-1R- AKT/mTOR axis, and pomegranate polyphenols downregulate the mTOR downstream pathway through reductions in ERK1/2. These results suggest that extracts rich in gallo- and ellagitannins act on different molecular targets in the protection against ulcerative colitis. PMID:27028006

Validation of bovine glycomacropeptide as an intestinal anti-inflammatory nutraceutical in the lymphocyte-transfer model of colitis.

PubMed

Ortega-González, Mercedes; Capitán-Cañadas, Fermín; Requena, Pilar; Ocón, Borja; Romero-Calvo, Isabel; Aranda, Carlos; Suárez, María Dolores; Zarzuelo, Antonio; Sánchez de Medina, Fermín; Martínez-Augustin, Olga

2014-04-14

Milk κ-casein-derived bovine glycomacropeptide (GMP) exerts immunomodulatory effects. It exhibits intestinal anti-inflammatory activity in chemically induced models of colitis. However, to validate its clinical usefulness as a nutraceutical, it is important to assess its effects in a model with a closer pathophysiological connection with human inflammatory bowel disease. Therefore, in the present study, we used the lymphocyte-transfer model of colitis in mice and compared the effects of GMP in this model with those obtained in the dextran sulphate sodium (DSS) model. GMP (15 mg/d) resulted in higher body-weight gain and a reduction of the colonic damage score and myeloperoxidase (MPO) activity in Rag1(-/-) mice with colitis induced by the transfer of naïve T cells. The colonic and ileal weight:length ratio was decreased by approximately 25%, albeit non-significantly. GMP treatment reduced the percentage of CD4⁺ interferon (IFN)-γ⁺ cells in mesenteric lymph nodes (MLN). The basal production of IL-6 by MLN obtained from the GMP-treated mice ex vivo was augmented. However, concanavalin A-evoked production was similar. The colonic expression of regenerating islet-derived protein 3γ, S100A8, chemokine (C-X-C motif) ligand 1 and IL-1β was unaffected by GMP, while that of TNF-α and especially IFN-γ was paradoxically increased. In the DSS model, GMP also reduced the activity of colonic MPO, but it failed to alter weight gain or intestinal weight:length ratio. GMP augmented the production of IL-10 by MLN cells and was neutral towards other cytokines, except exhibiting a trend towards increasing the production of IL-6. The lower effect was attributed to the lack of the effect of GMP on epithelial cells. In conclusion, GMP exerts intestinal anti-inflammatory effects in lymphocyte-driven colitis.

Of mice and men: a novel dietary supplement for the treatment of ulcerative colitis.

PubMed

Shapira, Shiran; Leshno, Ari; Katz, Daniel; Maharshak, Nitsan; Hevroni, Gil; Jean-David, Maayan; Kraus, Sarah; Galazan, Lior; Aroch, Ilan; Kazanov, Dina; Hallack, Aharon; Becker, Stewart; Umanski, Mark; Moshkowitz, Menachem; Dotan, Iris; Arber, Nadir

2018-01-01

Curcumin, green tea polyphenols and selenium possess anti-inflammatory and anti-oxidant properties. Individually they have demonstrated some efficacy in animal models and human subjects with inflammatory bowel disease (IBD). To evaluate the efficacy and safety of Coltect [Curcumin (500 mg), green tea (250 mg) and selenium (100 µg)] in vivo and in patients with ulcerative colitis (UC). Each component was compared to placebo in a DSS mice colitis model. The efficacy was validated in a 2,4,6-trinitrobenzenesulfonic acid (TNBS) rat colitis model. Twenty patients with mild-to-moderate UC received two Coltect tablets twice daily for 8 weeks. Enrollees underwent sigmoidoscopy at study entrance and closure, and physical and laboratory evaluation at baseline, 4 and 8 weeks. Coltect showed a synergistic therapeutic effect in the DSS and TNBS models. Disease activity was significantly higher in the placebo versus the treated group ( p < 0.05). Selenium was the more active component. The contribution of green tea was minor. In the TNBS model, the Wallace scores for macroscopic lesions were 4.8 ± 1.5 (treatment) and 8.2 ± 0.5 (placebo) ( p = 0.01). In humans, Coltect was well tolerated and effective. Fourteen subjects (70%) improved: nine (45%) went into complete remission, four (20%) experienced marked improvement and one (5%) experienced moderate improvement at the end of the trial. Clinical activity index decreased significantly at 4 and 8 weeks ( p < 0.001). Two patients had no change in their symptoms, and one withdrew after 4 weeks. Flare-up in four subjects caused three to withdraw from the study after less than 4 weeks. Endoscopic improvement was observed in 11 (69%) patients, and four patients (25%) achieved complete remission. Coltect may serve as a first-line or add-on therapy in patients with mild-to-moderate UC.

Polyphenol-rich sorghum brans alter colon microbiota and impact species diversity and species richness after multiple bouts of dextran sodium sulfate-induced colitis.

PubMed

Ritchie, Lauren E; Sturino, Joseph M; Carroll, Raymond J; Rooney, Lloyd W; Azcarate-Peril, M Andrea; Turner, Nancy D

2015-03-01

The microbiota affects host health, and dysbiosis is involved in colitis. Sorghum bran influences butyrate concentrations during dextran sodium sulfate (DSS) colitis, suggesting microbiota changes. We aimed to characterize the microbiota during colitis, and ascertain if polyphenol-rich sorghum bran diets mitigate these effects. Rats (n = 80) were fed diets containing 6% fiber from cellulose, or Black (3-deoxyanthocyanins), Sumac (condensed tannins), or Hi Tannin black (both) sorghum bran. Inflammation was induced three times using 3% DSS for 48 h (40 rats, 2 week separation), and the microbiota characterized by pyrosequencing. The Firmicutes/Bacteroidetes ratio was higher in Cellulose DSS rats. Colonic injury negatively correlated with Firmicutes, Actinobacteria, Lactobacillales and Lactobacillus, and positively correlated with Unknown/Unclassified. Post DSS#2, richness was significantly lower in Sumac and Hi Tannin black. Post DSS#3 Bacteroidales, Bacteroides, Clostridiales, Lactobacillales and Lactobacillus were reduced, with no Clostridium identified. Diet significantly affected Bacteroidales, Bacteroides, Clostridiales and Lactobacillus post DSS#2 and #3. Post DSS#3 diet significantly affected all genus, including Bacteroides and Lactobacillus, and diversity and richness increased. Sumac and Hi Tannin black DSS had significantly higher richness compared to controls. Thus, these sorghum brans may protect against alterations observed during colitis including reduced microbial diversity and richness, and dysbiosis of Firmicutes/Bacteroidetes. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Effects of modified Sanhuang decoction () enema on serum tumor necrosis factor-α and colonic mucosa interleukin-1β, interleukin-6 levels in ulcerative colitis rats.

PubMed

Wang, Shuai; Zhou, Tao; Zhai, Jun-Peng; Wang, Li-Hua; Chen, Jing

2014-11-01

To investigate the effects of Modified Sanhuang Decoction (, MSD) enema on the serum tumor necrosis factor alpha (TNF-α) and colonic mucosa interleukin-1β (IL-1β), interleukin-6 (IL-6) levels in experimental ulcerative colitis (UC) rats. Forty-five male Wistar rats were randomly divided into 4 groups: normal group (n=12), model group (n=11), salazosulfapyridine (SASP) group (n=11) and MSD group (n=11). The UC model was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS)/ethanol solution. Rats in the normal group and model group were clystered with 0.9% normal saline, while in the SASP group and MSD group were clystered with SASP and MSD enema, respectively. After drug administration (10 mL/kg body weight, for 7 days), colonic gross changes and colonic mucosa histology were observed, serum TNF-α and colonic mucosa IL-1β, IL-6 levels were tested by enzyme linked immunosorbent assay and radioimmunoassay, respectively. As compared with the normal group, the experimental UC rats, the colonic mucosal damage index scores (CMDIs), histopathological scores (HS) and the serum TNF-α and colonic mucosa IL-1β, IL-6 levels significantly increased (P<0.05 or P<0.01). In the MSD and SASP groups, the ulcer area significantly reduced, and edema disappeared. The CMDIs, HS, the serum TNF-α and colonic mucosa IL-1β, IL-6 levels in the MSD and SASP groups significantly decreased (P<0.05 or P<0.01) compared with the model group. The CMDIs in the MSD group were lower than that in the SASP group (P<0.05), but there were no significant differences in HS, serum TNF-α or colonic mucosa IL-1β, IL-6 levels between the MSD and SASP groups. MSD enema can improve colonic mucosa impairment and decrease serum TNF-α and colonic mucosa IL-1β, IL-6 levels in experimental UC.

Propionyl-L-Carnitine is Efficacious in Ulcerative Colitis Through its Action on the Immune Function and Microvasculature

PubMed Central

Scioli, Maria Giovanna; Stasi, Maria Antonietta; Passeri, Daniela; Doldo, Elena; Costanza, Gaetana; Camerini, Roberto; Fociani, Paolo; Arcuri, Gaetano; Lombardo, Katia; Pace, Silvia; Borsini, Franco; Orlandi, Augusto

2014-01-01

Objectives: Microvascular endothelial dysfunction characterizes ulcerative colitis (UC), the most widespread form of inflammatory bowel disease. Intestinal mucosal microvessels in UC display aberrant expression of cell adhesion molecules (CAMs) and increased inflammatory cell recruitment. Propionyl-L-carnitine (PLC), an ester of L-carnitine required for the mitochondrial transport of fatty acids, ameliorates propionyl-CoA bioavailability and reduces oxidative stress in ischemic tissues. The present study aimed to document the efficacy of anti-oxidative stress properties of PLC in counteracting intestinal microvascular endothelial dysfunction and inflammation. Methods: To evaluate the efficacy in vivo, we analyzed the effects in intestinal biopsies of patients with mild-to-moderate UC receiving oral PLC co-treatment and in rat TNBS-induced colitis; in addition, we investigated antioxidant PLC action in TNF-α-stimulated human intestinal microvascular endothelial cells (HIMECs) in vitro. Results: Four-week PLC co-treatment reduced intestinal mucosal polymorph infiltration and CD4+ lymphocytes, ICAM-1+ and iNOS+ microvessels compared with placebo-treated patients with UC. Oral and intrarectal administration of PLC but not L-carnitine or propionate reduced intestinal damage and microvascular dysfunction in rat TNBS-induced acute and reactivated colitis. In cultured TNF-α-stimulated HIMECs, PLC restored β-oxidation and counteracted NADPH oxidase 4-generated oxidative stress-induced CAM expression and leukocyte adhesion. Inhibition of β-oxidation by L-aminocarnitine increased reactive oxygen species production and PLC beneficial effects on endothelial dysfunction and leukocyte adhesion. Finally, PLC reduced iNOS activity and nitric oxide accumulation in rat TNBS-induced colitis and in HIMEC cultures. Conclusions: Our results show that the beneficial antioxidant effect of PLC targeting intestinal microvasculature restores endothelial β-oxidation and function, and

Effect of combination of thalidomide and sulfasalazine in experimentally induced inflammatory bowel disease in rats.

PubMed

Prakash, O; Medhi, B; Saikia, U N; Pandhi, P

2011-09-01

Thalidomide provided significant protection against tri nitro benzene sulfonic acid induced colitis. Combination therapy also reduced colonic inflammation and all the biochemical parameters (myeloperoxidase assay, malondialdehyde assay and tumor necrosis factor-alpha, estimation) were significant as compared to control as well as thalidomide alone treated group. Combination therapy showed additive effect of thalidomide which restored lipid peroxidation as well as reduced myeloperoxidase and TNF-a towards the normal levels. Morphological and histological scores were significantly reduced in combination groups. In experimental model of colitis, oral administration of thalidomide (150 mg/kg) alone as well as its combination with sulfasalazine (360 mg/kg) significantly reduced the colonic inflammation. The results indicate the additive effect of thalidomide with sulfasalazine in rat colitis model which requires further confirmation in human studies.

Colonic and Hepatic Modulation by Lipoic Acid and/or N-Acetylcysteine Supplementation in Mild Ulcerative Colitis Induced by Dextran Sodium Sulfate in Rats

PubMed Central

Moura, Fabiana Andréa; de Andrade, Kívia Queiroz; de Araújo, Orlando Roberto Pimentel; Santos, Juliana Célia de Farias

2016-01-01

Lipoic acid (LA) and N-acetylcysteine (NAC) are antioxidant and anti-inflammatory agents that have not yet been tested on mild ulcerative colitis (UC). This study aims to evaluate the action of LA and/or NAC, on oxidative stress and inflammation markers in colonic and hepatic rat tissues with mild UC, induced by dextran sodium sulfate (DSS) (2% w/v). LA and/or NAC (100 mg·kg·day−1, each) were given, once a day, in the diet, in a pretreatment phase (7 days) and during UC induction (5 days). Colitis induction was confirmed by histological and biochemical analyses (high performance liquid chromatography, spectrophotometry, and Multiplex®). A redox imbalance occurred before an immunological disruption in the colon. NAC led to a decrease in hydrogen peroxide (H2O2), malondialdehyde (MDA) levels, and myeloperoxidase activity. In the liver, DSS did not cause damage but treatments with both antioxidants were potentially harmful, with LA increasing MDA and LA + NAC increasing H2O2, tumor necrosis factor alpha, interferon gamma, and transaminases. In summary, NAC exhibited the highest colonic antioxidant and anti-inflammatory activity, while LA + NAC caused hepatic damage. PMID:27957238

Evaluation of eight cephalosporins in hamster colitis model.

PubMed Central

Ebright, J R; Fekety, R; Silva, J; Wilson, K H

1981-01-01

Eight commonly used cephalosporins were evaluated in the hamster colitis mode. They were all found to cause hemorrhagic cecitis and death within 10 days of being given as subcutaneous or oral challenges. Necropsy findings were indistinguishable from clindamycin-induced cecitis. Bacteria-free cecal filtrate obtained from hamsters dying of cephalosporin-induced cecitis contained toxin similar or identical to hat produced by Clostridium difficile isolated from the cecum of a hamster. Daily oral administration of poorly absorbed cephalosporins protected hamsters from clindamycin-induced cecitis and death as long as the cephalosporins were continued. The absorbable cephalosporins were ineffective in protecting hamsters from clindamycin-induced cecitis. This difference probably relates to the lower concentrations of absorbable cephalosporins maintained in the ceca of the hamsters. The possible correlation of these findings to human cases of cephalosporin-induced pseudomembranous colitis is discussed. PMID:6973951

Comparison of multiple enzyme activatable near infrared fluorescent molecular probes for detection and quantification of inflammation in murine colitis models

PubMed Central

Ding, Shengli; Blue, Randal E.; Morgan, Douglas R.; Lund, Pauline K.

2015-01-01

Background Activatable near-infrared fluorescent (NIRF) probes have been used for ex vivo and in vivo detection of intestinal tumors in animal models. We hypothesized that NIRF probes activatable by cathepsins or MMPs will detect and quantify dextran sulphate sodium (DSS) induced acute colonic inflammation in wild type (WT) mice or chronic colitis in IL-10 null mice ex vivo or in vivo. Methods WT mice given DSS, water controls and IL-10 null mice with chronic colitis were administered probes by retro-orbital injection. FMT2500 LX system imaged fresh and fixed intestine ex vivo and mice in vivo. Inflammation detected by probes was verified by histology and colitis scoring. NIRF signal intensity was quantified using 2D region of interest (ROI) ex vivo or 3D ROI-analysis in vivo. Results Ex vivo, seven probes tested yielded significant higher NIRF signals in colon of DSS treated mice versus controls. A subset of probes was tested in IL-10 null mice and yielded strong ex vivo signals. Ex vivo fluorescence signal with 680 series probes was preserved after formalin fixation. In DSS and IL-10 null models, ex vivo NIRF signal strongly and significantly correlated with colitis scores. In vivo, ProSense680, CatK680FAST and MMPsense680 yielded significantly higher NIRF signals in DSS treated mice than controls but background was high in controls. Conclusion Both cathepsin or MMP-activated NIRF-probes can detect and quantify colonic inflammation ex vivo. ProSense680 yielded the strongest signals in DSS colitis ex vivo and in vivo, but background remains a problem for in vivo quantification of colitis. PMID:24374874

TRPA1 and substance P mediate colitis in mice.

PubMed

Engel, Matthias A; Leffler, Andreas; Niedermirtl, Florian; Babes, Alexandru; Zimmermann, Katharina; Filipović, Miloš R; Izydorczyk, Iwona; Eberhardt, Mirjam; Kichko, Tatjana I; Mueller-Tribbensee, Sonja M; Khalil, Mohammad; Siklosi, Norbert; Nau, Carla; Ivanović-Burmazović, Ivana; Neuhuber, Winfried L; Becker, Christoph; Neurath, Markus F; Reeh, Peter W

2011-10-01

The neuropeptides calcitonin gene-related peptide (CGRP) and substance P, and calcium channels, which control their release from extrinsic sensory neurons, have important roles in experimental colitis. We investigated the mechanisms of colitis in 2 different models, the involvement of the irritant receptor transient receptor potential of the ankyrin type-1 (TRPA1), and the effects of CGRP and substance P. We used calcium-imaging, patch-clamp, and neuropeptide-release assays to evaluate the effects of 2,4,6-trinitrobenzene-sulfonic-acid (TNBS) and dextran-sulfate-sodium-salt on neurons. Colitis was induced in wild-type, knockout, and desensitized mice. TNBS induced TRPA1-dependent release of colonic substance P and CGRP, influx of Ca2+, and sustained ionic inward currents in colonic sensory neurons and transfected HEK293t cells. Analysis of mutant forms of TRPA1 revealed that TNBS bound covalently to cysteine (and lysine) residues in the cytoplasmic N-terminus. A stable sulfinic acid transformation of the cysteine-SH group, shown by mass spectrometry, might contribute to sustained sensitization of TRPA1. Mice with colitis had increased colonic neuropeptide release, mediated by TRPA1. Endogenous products of inflammatory lipid peroxidation also induced TRPA1-dependent release of colonic neuropeptides; levels of 4-hydroxy-trans-2-nonenal increased in each model of colitis. Colitis induction by TNBS or dextran-sulfate-sodium-salt was inhibited or reduced in TRPA1-/- mice and by 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopro-pylphenyl)-acetamide, a pharmacologic inhibitor of TRPA1. Substance P had a proinflammatory effect that was dominant over CGRP, based on studies of knockout mice. Ablation of extrinsic sensory neurons prevented or attenuated TNBS-induced release of neuropeptides and both forms of colitis. Neuroimmune interactions control intestinal inflammation. Activation and sensitization of TRPA1 and release of substance P induce and

Use of butyrate or glutamine in enema solution reduces inflammation and fibrosis in experimental diversion colitis

PubMed Central

Pacheco, Rodrigo Goulart; Esposito, Christiano Costa; Müller, Lucas CM; Castelo-Branco, Morgana TL; Quintella, Leonardo Pereira; Chagas, Vera Lucia A; de Souza, Heitor Siffert P; Schanaider, Alberto

2012-01-01

AIM: To investigate whether butyrate or glutamine enemas could diminish inflammation in experimental diversion colitis. METHODS: Wistar specific pathogen-free rats were submitted to a Hartmann’s end colostomy and treated with enemas containing glutamine, butyrate, or saline. Enemas were administered twice a week in the excluded segment of the colon from 4 to 12 wk after the surgical procedure. Follow-up colonoscopy was performed every 4 wk for 12 wk. The effect of treatment was evaluated using video-endoscopic and histologic scores and measuring interleukin-1β, tumor necrosis factor-alpha, and transforming growth factor beta production in organ cultures by enzyme linked immunosorbent assay. RESULTS: Colonoscopies of the diverted segment showed mucosa with hyperemia, increased number of vessels, bleeding and mucus discharge. Treatment with either glutamine or butyrate induced significant reductions in both colonoscopic (P < 0.02) and histological scores (P < 0.01) and restored the densities of collagen fibers in tissue (P = 0.015; P = 0.001), the number of goblet cells (P = 0.021; P = 0.029), and the rate of apoptosis within the epithelium (P = 0.043; P = 0.011) to normal values. The high levels of cytokines in colon explants from rats with diversion colitis significantly decreased to normal values after treatment with butyrate or glutamine. CONCLUSION: The improvement of experimental diversion colitis following glutamine or butyrate enemas highlights the importance of specific luminal nutrients in the homeostasis of the colonic mucosa and supports their utilization for the treatment of human diversion colitis. PMID:22969190

Comparison of anti-inflammatory mechanisms of mango (Mangifera Indica L.) and pomegranate (Punica Granatum L.) in a preclinical model of colitis.

PubMed

Kim, Hyemee; Banerjee, Nivedita; Ivanov, Ivan; Pfent, Catherine M; Prudhomme, Kalan R; Bisson, William H; Dashwood, Roderick H; Talcott, Stephen T; Mertens-Talcott, Susanne U

2016-09-01

Tannin-rich fruits have been evaluated as alternative prevention strategies for colorectal cancer based on their anti-inflammatory properties. This study compared tannin-rich preparations from mango (rich in gallotannins) and pomegranate (rich in ellagitannins) in the dextran sodium sulfate-induced colitis model. In rats, mango and pomegranate beverages decreased intestinal inflammation and the levels of pro-inflammatory cytokines in mucosa and serum. The mango beverage suppressed the ratio of phosphorylated/total protein expression of the IGF-1R-AKT/mTOR axis and downregulated mRNA expression of Igf1, Insr, and pik3cv. Pomegranate decreased p70S6K and RPS6, as well as Rps6ka2, Map2k2, and Mapk1 mRNA. In silico modeling indicated a high binding of docked of gallic acid to the catalytic domain of IGF-1R, which may suppress the activity of the enzyme. Ellagic acid docked effectively into the catalytic domains of both IGF-1R and EGFR. In vitro assays with lipopolysaccharide-treated CCD-18Co cells using polyphenolic extracts from each beverage, as well as pure compounds, corroborated the predictions made in silico. Mango polyphenols inhibited the IGF-1R- AKT/mTOR axis, and pomegranate polyphenols downregulate the mTOR downstream pathway through reductions in ERK1/2. These results suggest that extracts rich in gallo- and ellagitannins act on different molecular targets in the protection against ulcerative colitis. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Animal models of ulcerative colitis and their application in drug research

PubMed Central

Low, Daren; Nguyen, Deanna D; Mizoguchi, Emiko

2013-01-01

The specific pathogenesis underlying inflammatory bowel disease is complex, and it is even more difficult to decipher the pathophysiology to explain for the similarities and differences between two of its major subtypes, Crohn’s disease and ulcerative colitis (UC). Animal models are indispensable to pry into mechanistic details that will facilitate better preclinical drug/therapy design to target specific components involved in the disease pathogenesis. This review focuses on common animal models that are particularly useful for the study of UC and its therapeutic strategy. Recent reports of the latest compounds, therapeutic strategies, and approaches tested on UC animal models are also discussed. PMID:24250223

Dietary Salt Exacerbates Experimental Colitis.

PubMed

Tubbs, Alan L; Liu, Bo; Rogers, Troy D; Sartor, R Balfour; Miao, Edward A

2017-08-01

The Western diet is characterized by high protein, sugar, fat, and low fiber intake, and is widely believed to contribute to the incidence and pathogenesis of inflammatory bowel disease (IBD). However, high sodium chloride salt content, a defining feature of processed foods, has not been considered as a possible environmental factor that might drive IBD. We set out to bridge this gap. We examined murine models of colitis on either a high salt diet (HSD) or a low salt diet. We demonstrate that an HSD exacerbates inflammatory pathology in the IL-10-deficient murine model of colitis relative to mice fed a low salt diet. This was correlated with enhanced expression of numerous proinflammatory cytokines. Surprisingly, sodium accumulated in the colons of mice on an HSD, suggesting a direct effect of salt within the colon. Similar to the IL-10-deficient model, an HSD also enhanced cytokine expression during infection by Salmonella typhimurium This occurred in the first 3 d of infection, suggesting that an HSD potentiates an innate immune response. Indeed, in cultured dendritic cells we found that high salt media potentiates cytokine expression downstream of TLR4 activation via p38 MAPK and SGK1. A third common colitis model, administration of dextran sodium sulfate, was hopelessly confounded by the high sodium content of the dextran sodium sulfate. Our results raise the possibility that high dietary salt is an environmental factor that drives increased inflammation in IBD. Copyright © 2017 by The American Association of Immunologists, Inc.

Lactobacillus reuteri increases mucus thickness and ameliorates dextran sulphate sodium-induced colitis in mice.

PubMed

Ahl, D; Liu, H; Schreiber, O; Roos, S; Phillipson, M; Holm, L

2016-08-01

The aim of this study was to investigate whether two Lactobacillus reuteri strains (rat-derived R2LC and human-derived ATCC PTA 4659 (4659)) could protect mice against colitis, as well as delineate the mechanisms behind this protection. Mice were given L. reuteri R2LC or 4659 by gavage once daily for 14 days, and colitis was induced by addition of 3% DSS (dextran sulphate sodium) to drinking water for the last 7 days of this period. The severity of disease was assessed through clinical observations, histological evaluation and ELISA measurements of myeloperoxidase (MPO) and pro-inflammatory cytokines from colonic samples. Mucus thickness was measured in vivo with micropipettes, and tight junction protein expression was assessed using immunohistochemistry. Colitis severity was significantly reduced by L. reuteri R2LC or 4659 when evaluated both clinically and histologically. The inflammation markers MPO, IL-1β, IL-6 and mKC (mouse keratinocyte chemoattractant) were increased by DSS and significantly reduced by the L. reuteri strains. The firmly adherent mucus thickness was reduced by DSS, but significantly increased by L. reuteri in both control and DSS-treated mice. Expression of the tight junction proteins occludin and ZO-1 was significantly increased in the bottom of the colonic crypts by L. reuteri R2LC. These results demonstrate that each of the two different L. reuteri strains, one human-derived and one-rat-derived, protects against colitis in mice. Mechanisms behind this protection could at least partly be explained by the increased mucus thickness as well as a tightened epithelium in the stem cell area of the crypts. © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Nitric oxide-releasing aspirin but not conventional aspirin improves healing of experimental colitis

PubMed Central

Zwolinska-Wcislo, Malgorzata; Brzozowski, Tomasz; Ptak-Belowska, Agata; Targosz, Aneta; Urbanczyk, Katarzyna; Kwiecien, Slawomir; Sliwowski, Zbigniew

2011-01-01

AIM: To determine the effect of non-selective cyclooxygenase (COX) inhibitors, selective COX-2 inhibitors and nitric oxide (NO)-releasing aspirin in the healing of ulcerative colitis. METHODS: Rats with 2,4,6 trinitrobenzenesulfon-ic acid (TNBS)-induced colitis received intragastric (ig) treatment with vehicle, aspirin (ASA) (a non-selective COX inhibitor), celecoxib (a selective COX-2 inhibitor) or NO-releasing ASA for a period of ten days. The area of colonic lesions, colonic blood flow (CBF), myeloperoxidase (MPO) activity and expression of proinflammatory markers COX-2, inducible form of nitric oxide synthase (iNOS), IL-1β and tumor necrosis factor (TNF)-α were assessed. The effects of glyceryl trinitrate (GTN), a NO donor, and 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-​tetramethyl-1H-imidazolyl-1-oxy-3-oxide, onopotassium salt (carboxy-PTIO), a NO scavenger, administered without and with ASA or NO-ASA, and the involvement of capsaicin-sensitive afferent nerves in the mechanism of healing the experimental colitis was also determined. RESULTS: Rats with colitis developed macroscopic and microscopic colonic lesions accompanied by a significant decrease in the CBF, a significant rise in colonic weight, MPO activity and plasma IL-1β and TNF-α levels. These effects were aggravated by ASA and 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560), but not celecoxib and counteracted by concurrent treatment with a synthetic prostaglandin E2 (PGE2) analog. Treatment with NO-ASA dose-dependently accelerated colonic healing followed by a rise in plasma NOx content and CBF, suppression of MPO and downregulation of COX-2, iNOS, IL-1β and TNF-α mRNAs. Treatment with GTN, the NO donor, significantly inhibited the ASA-induced colonic lesions and increased CBF, while carboxy-PTIO or capsaicin-denervation counteracted the NO-ASA-induced improvement of colonic healing and the accompanying increase in the CBF. These effects were restored by co

Suppression of Murine Colitis and its Associated Cancer by Carcinoembryonic Antigen-Specific Regulatory T Cells

PubMed Central

Blat, Dan; Zigmond, Ehud; Alteber, Zoya; Waks, Tova; Eshhar, Zelig

2014-01-01

The adoptive transfer of regulatory T cells (Tregs) offers a promising strategy to combat pathologies that are characterized by aberrant immune activation, including graft rejection and autoinflammatory diseases. Expression of a chimeric antigen receptor (CAR) gene in Tregs redirects them to the site of autoimmune activity, thereby increasing their suppressive efficiency while avoiding systemic immunosuppression. Since carcinoembryonic antigen (CEA) has been shown to be overexpressed in both human colitis and colorectal cancer, we treated CEA-transgenic mice that were induced to develop colitis with CEA-specific CAR Tregs. Two disease models were employed: T-cell-transfer colitis as well as the azoxymethane–dextran sodium sulfate model for colitis-associated colorectal cancer. Systemically administered CEA-specific (but not control) CAR Tregs accumulated in the colons of diseased mice. In both model systems, CEA-specific CAR Tregs suppressed the severity of colitis compared to control Tregs. Moreover, in the azoxymethane–dextran sodium sulfate model, CEA-specific CAR Tregs significantly decreased the subsequent colorectal tumor burden. Our data demonstrate that CEA-specific CAR Tregs exhibit a promising potential in ameliorating ulcerative colitis and in hindering colorectal cancer development. Collectively, this study provides a proof of concept for the therapeutic potential of CAR Tregs in colitis patients as well as in other autoimmune inflammatory disorders. PMID:24686242

A study comparing the efficacy of antimicrobial agents versus enzyme (P-gp) inducers in the treatment of 2,4,6 trinitrobenzenesulfonic acid-induced colitis in rats.

PubMed

Toklu, H Z; Kabasakal, L; Imeryuz, N; Kan, B; Celikel, C; Cetinel, S; Orun, O; Yuksel, M; Dulger, G A

2013-08-01

The intestinal microflora is an important cofactor in the pathogenesis of intestinal inflammation; and the epithelial cell barrier function is critical in providing protection against the stimulation of mucosal immune system by the microflora. In the present study, therapeutic role of the antibacterial drugs rifampicin and ciprofloxacine were investigated in comparison to spironolactone, an enzyme inducer, in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis of the rats. Drugs were administered for 14 days following induction of colitis. All drug treatments ameliorated the clinical hallmarks of colitis as determined by body weight loss and assessment of diarrhea, colon length, and histology. Oxidative damage and neutrophil infiltration as well as nuclear factor κB (NF-κB) and tumor necrosis factor α (TNF-α) expressions that were increased during colitis, were decreased significantly. Rifampicin and ciprofloxacin were probably effective due to their antibacterial and immunomodulating properties. The multidrug resistence gene (MDR1) and its product p-glycoprotein (P-gp) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). In the present study, findings of the P-gp expression were inconclusive but regarding previous studies, it can be suggested that the beneficial effects of rifampicin and spironolactone may be partly due to their action as a P-gp ligand. Spironolactone has been reported to supress the transcription of proinflamatory cytokines that are considered to be of importance in immunoinflammatory diseases. It is also a powerful pregnane X receptor (PXR) inducer; thus, inhibition of the expression of NF-κB and TNF-α, and amelioration of inflammation by spironolactone suggest that this may have been through the activation of PXR. However, our findings regarding PXR expression were inconclusive. Activation of PXR by spironolactone probably also contributed to the induction of P-gp, resulting in extrusion of noxious substances

Autoimmune thyroid disease with ulcerative colitis.

PubMed

Modebe, O

1986-06-01

Two cases of co-existing thyroid disease and ulcerative colitis are reported. Thyroid disorder preceded ulcerative colitis in each case. The presence of acute colitis delayed and obscured the clinical diagnosis of thyrotoxicosis in one case and the colitis could not be controlled until her thyrotoxicosis was treated. Although the specific factors involved in this relationship are now known, an interplay of immunological factors is most probable.

Protective effects of Fc-fused PD-L1 on two different animal models of colitis.

PubMed

Song, Mi-Young; Hong, Chun-Pyo; Park, Seong Jeong; Kim, Jung-Hwan; Yang, Bo-Gie; Park, Yunji; Kim, Sae Won; Kim, Kwang Soon; Lee, Ji Yeung; Lee, Seung-Woo; Jang, Myoung Ho; Sung, Young-Chul

2015-02-01

Programmed death-ligand 1 (PD-L1) has been shown to negatively regulate immune responses via its interaction with PD-1 receptor. In this study, we investigated the effects of PD-L1-Fc treatment on intestinal inflammation using two murine models of inflammatory colitis induced by dextran sulfate sodium (DSS) and T-cell transfer. The anti-colitis effect of adenovirus expressing Fc-conjugated PD-L1 (Ad/PD-L1-Fc) and recombinant PD-L1-Fc protein was evaluated in DSS-treated wild-type and Rag-1 knockout (KO) mice. We examined differentiation of T-helper cells, frequency of innate immune cells, and cytokine production by dendritic cells (DCs) in the colon from DSS-treated mice after PD-L1-Fc administration. In Rag-1 KO mice reconstituted with CD4 CD45RB(high) T cells, we assessed the treatment effect of PD-L1-Fc protein on the development of colitis. Administration of Ad/PD-L1-Fc significantly ameliorated DSS-induced colitis, which was accompanied by diminished frequency of interleukin (IL)-17A-producing CD4 T cells and increased interferon-γ-producing CD4 T cells in the colon of DSS-fed mice. The anti-colitic effect of PD-L1-Fc treatment was also observed in DSS-treated Rag-1 KO mice, indicating lymphoid cell independency. PD-L1-Fc modulated cytokine production by colonic DCs and the effect was dependent on PD-1 expression. Furthermore, PD-L1-Fc protein could significantly reduce the severity of colitis in CD4 CD45RB(high) T-cell-transferred Rag-1 KO mice. Based on the protective effect of PD-L1-Fc against DSS-induced and T-cell-induced colitis, our results suggest that PD-1-mediated inhibitory signals have a crucial role in limiting the development of colonic inflammation. This implicates that PD-L1-Fc may provide a novel therapeutic approach to treat inflammatory bowel disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Stable gastric pentadecapeptide BPC 157 heals cysteamine-colitis and colon-colon-anastomosis and counteracts cuprizone brain injuries and motor disability.

PubMed

Klicek, R; Kolenc, D; Suran, J; Drmic, D; Brcic, L; Aralica, G; Sever, M; Holjevac, J; Radic, B; Turudic, T; Kokot, A; Patrlj, L; Rucman, R; Seiwerth, S; Sikiric, P

2013-10-01

Stable gastric pentadecapeptide BPC 157 was suggested to link inflammatory bowel disease and multiple sclerosis, and thereby, shown to equally counteract the models of both of those diseases. For colitis, cysteamine (400 mg/kg intrarectally (1 ml/rat)) and colon-colon anastomosis (sacrifice at day 3, 5, 7, and 14) were used. BPC 157 (10 μg/kg, 10 ng/kg) was applied either intraperitoneally once time daily (first application immediately after surgery, last at 24 hours before sacrifice) or per-orally in drinking water (0.16 μg/ml/12 ml/day till the sacrifice) while controls simultaneously received an equivolume of saline (5 ml/kg) intraperitoneally or drinking water only (12 ml/day). A multiple sclerosis suited toxic rat model, cuprizone (compared with standard, a several times higher regimen, 2.5% of diet regimen + 1 g/kg intragastrically/day) was combined with BPC 157 (in drinking water 0.16 μg or 0.16 ng/ml/12 ml/day/rat + 10 μg or 10 ng/kg intragastrically/day) till the sacrifice at day 4. In general, the controls could not heal cysteamine colitis and colon-colon anastomosis. BPC 157 induced an efficient healing of both at the same time. Likewise, cuprizone-controls clearly exhibited an exaggerated and accelerated damaging process; nerve damage appeared in various brain areas, with most prominent damage in corpus callosum, laterodorsal thalamus, nucleus reunions, anterior horn motor neurons. BPC 157-cuprizone rats had consistently less nerve damage in all damaged areas, especially in those areas that otherwise were most affected. Consistently, BPC 157 counteracted cerebellar ataxia and impaired forelimb function. Thereby, this experimental evidence advocates BPC 157 in both inflammatory bowel disease and multiple sclerosis therapy.

Clinical course of severe colitis: a comparison between Crohn’s Disease and ulcerative colitis.

PubMed

Sinagra, E; Orlando, A; Mocciaro, F; Criscuoli, V; Oliva, L; Maisano, S; Giunta, M; La Seta, F; Solina, G; Rizzo, A G; Leone, A; Tomasello, G; Cappello, F; Cottone, M

2018-01-01

Few data are available about the clinical course of severe colonic Crohn’s disease (CD). The aim of this study is to describe the clinical course of severe Crohn’s colitis in a patient cohort with isolated colonic or ileocolonic CD, and to compare it with the clinical course of patients with severe ulcerative colitis (UC). Thirty-four patients with severe Crohn’s colitis were prospectively identified in our cohort of 593 consecutive hospitalized patients through evaluation of the Crohn’s Disease Activity Index score and the Harvey-Bradshaw Index. One hundred sixty-nine patients with severe ulcerative colitis were prospectively identified in our cohort of 449 consecutive hospitalized patients through evaluation of the Lichtiger score and the Truelove-Witts score. We evaluated the following data/aspects: response to steroids, response to biologics, colectomy rate in acute, colectomy rate during follow-up, megacolon and cytomegalovirus infection rate. We did not find significant differences in the response to steroids and to biologics, in the percentage of cytomegalovirus infection and of megacolon, while the rate of colectomy in acute turned out to be greater in patients with severe Crohn’s colitis compared to patients with severe UC, and this difference appeared to be the limit of statistical significance (Chi-squared 3.31, p = 0.069, OR 0.39); the difference between the colectomy rates at the end of the follow-up was also not significant. In the whole population, by univariate analysis, according to the linear regression model, a young age at diagnosis is associated with a higher overall colectomy rate (p = 0.024) and a higher elective colectomy rate (p = 0.022), but not with a higher acute colectomy rate, and an elevated ESR is correlated with a higher overall colectomy rate (p = 0.014) and a higher acute colectomy rate (p = 0.032), but not with a higher elective colectomy rate. This correlation was significant on multivariate analysis. The overall rate of

Low-level light therapy induces mucosal healing in a murine model of dextran-sodium-sulfate induced colitis.

PubMed

Zigmond, Ehud; Varol, Chen; Kaplan, Michail; Shapira, Oz; Melzer, Ehud

2014-08-01

The aim of this study was to demonstrate the effect of low-level light therapy (LLLT) in an acute colitis model in mice. Low-level light therapy (LLLT) has been shown to be an effective treatment for various inflammatory processes such as oral mucositis and diabetic foot ulcers. Colitis was induced by dextran sodium sulfate (DSS) in mice in four blinded controlled studies (validation of model, efficacy study, and two studies for evaluation of optimal dose). LLLT was applied to the colon utilizing a small diameter endoscope with an LED-based light source in several wavelengths (440, 660, and 850 nm at 1 J/cm(2)) and then 850 nm at several doses (1, 0.5, 0.25, and 0.1 J/cm(2)). LLLT was initiated 1 day prior to induction of colitis and went on for the 6 day induction period as well as for the following 3-10 days. Dose was controlled by changing exposure time. Disease activity was scored endoscopically and by histopathological assessment. Statistically significant improvement in disease severity was observed in the treatment groups compared with the control groups. The three wavelengths used demonstrated efficacy, and a clear dose-response curve was observed for one of the wavelengths (850 nm). On day 11, colonoscopic scoring in the sham-treated mice increased from 7.9±1.3 to 12.2±2.2, while activity in all treated groups remained stable. Photobiostimulation with LLLT has a significant positive effect on disease progression in mice with DSS colitis.

Combined Therapy with Rheum tanguticum Polysaccharide and Low-dose 5-ASA Ameliorates TNBS-Induced Colitis in Rats by Suppression of NF-κB.

PubMed

Liu, Linna; Liu, Zhenxiong; Zhang, Tian; Shi, Lei; Zhang, Wenjuan; Zhang, Yan

2015-06-01

The most common conventional therapy for inflammatory bowel disease in clinical practice involves the use of nonsteroidal anti-inflammatory drugs, such as 5-amino salicylic acid. However, a high dose of 5-amino salicylic acid may bring about severe side effects. Chinese people have used Rheum tanguticum as a folk remedy for gastrointestinal disease for two thousand years. Our group has isolated R. tanguticum polysaccharide 1 from R. tanguticum and verified that it can attenuate 2,4,6-trinitrobenzene sulfonic acid-induced colitis in murines/rats. The present study aims to evaluate whether the addition of R. tanguticum polysaccharide 1 can improve efficacy and limit subsequent side effects of conventional treatment (5-amino salicylic acid) in rats with 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Sixty Sprague-Dawley male rats were randomized into five groups and treated with (1) saline (saline, 0.2 mL/day × 5, p. o.), (2) 2,4,6-trinitrobenzene sulfonic acid alone (saline, 0.2 mL/day × 5, p. o.), (3) 2,4,6-trinitrobenzene sulfonic acid + 5-amino salicylic acid (5-amino salicylic acid, 75 mg/kg/day × 5, p.o), (4) 2,4,6-trinitrobenzene sulfonic acid + R. tanguticum polysaccharide 1 (R. tanguticum polysaccharide 1, 200 mg/kg/day × 5, p. o.), and (5) 2,4,6-trinitrobenzene sulfonic acid + 5-amino salicylic acid + R. tanguticum polysaccharide 1 (5-amino salicylic acid, 25 mg/kg/day × 5, p.o; R. tanguticum polysaccharide 1, 200 mg/kg/day × 5, p. o.). All the rats were sacrificed on the 6th day after treatment using an overdose of anesthesia. A histological assessment was performed using semiquantitative scores; nuclear factor-kappa B and tumor necrosis factor-α were measured with Western blot, cyclooxygenase 1 and cyclooxygenase 2 protein expressions were investigated by RT-polymerase chain reaction, and prostoglandin E2 and inducible nitric oxide synthase productions were investigated by ELISA. The extent and

The application of molecular topology for ulcerative colitis drug discovery.

PubMed

Bellera, Carolina L; Di Ianni, Mauricio E; Talevi, Alan

2018-01-01

Although the therapeutic arsenal against ulcerative colitis has greatly expanded (including the revolutionary advent of biologics), there remain patients who are refractory to current medications while the safety of the available therapeutics could also be improved. Molecular topology provides a theoretic framework for the discovery of new therapeutic agents in a very efficient manner, and its applications in the field of ulcerative colitis have slowly begun to flourish. Areas covered: After discussing the basics of molecular topology, the authors review QSAR models focusing on validated targets for the treatment of ulcerative colitis, entirely or partially based on topological descriptors. Expert opinion: The application of molecular topology to ulcerative colitis drug discovery is still very limited, and many of the existing reports seem to be strictly theoretic, with no experimental validation or practical applications. Interestingly, mechanism-independent models based on phenotypic responses have recently been reported. Such models are in agreement with the recent interest raised by network pharmacology as a potential solution for complex disorders. These and other similar studies applying molecular topology suggest that some therapeutic categories may present a 'topological pattern' that goes beyond a specific mechanism of action.

Anti-inflammatory effects and mechanisms of vagal nerve stimulation combined with electroacupuncture in a rodent model of TNBS-induced colitis.

PubMed

Jin, Haifeng; Guo, Jie; Liu, Jiemin; Lyu, Bin; Foreman, Robert D; Yin, Jieyun; Shi, Zhaohong; Chen, Jiande D Z

2017-09-01

The purpose of this study was to determine the effects and mechanisms of vagal nerve stimulation (VNS) and additive effects of electroacupuncture (EA) on colonic inflammation in a rodent model of IBD. Chronic inflammation in rats was induced by intrarectal TNBS (2,4,6-trinitrobenzenesulfonic acid). The rats were then treated with sham ES (electrical stimulation), VNS, or VNS + EA for 3 wk. Inflammatory responses were assessed by disease activity index (DAI), macroscopic scores and histological scores of colonic tissues, plasma levels of TNFα, IL-1β, and IL-6, and myeloperoxidase (MPO) activity of colonic tissues. The autonomic function was assessed by the spectral analysis of heart rate variability (HRV) derived from the electrocardiogram. It was found that 1 ) the area under curve (AUC) of DAI was substantially decreased with VNS + EA and VNS, with VNS + EA being more effective than VNS ( P < 0.001); 2 ) the macroscopic score was 6.43 ± 0.61 in the sham ES group and reduced to 1.86 ± 0.26 with VNS ( P < 0.001) and 1.29 ± 0.18 with VNS + EA ( P < 0.001); 3 ) the histological score was 4.05 ± 0.58 in the sham ES group and reduced to 1.93 ± 0.37 with VNS ( P < 0.001) and 1.36 ± 0.20 with VNS + EA ( P < 0.001); 4 ) the plasma levels of TNFα, IL-1β, IL-6, and MPO were all significantly decreased with VNS and VNS + EA compared with the sham ES group; and 5 ) autonomically, both VNS + EA and VNS substantially increased vagal activity and decreased sympathetic activity compared with sham EA ( P < 0.001, P < 0.001, respectively). In conclusion, chronic VNS improves inflammation in TNBS-treated rats by inhibiting proinflammatory cytokines via the autonomic mechanism. Addition of noninvasive EA to VNS may enhance the anti-inflammatory effect of VNS. NEW & NOTEWORTHY This is the first study to address and compare the effects of vagal nerve stimulation (VNS), electrical acupuncture (EA) and VNS + EA on TNBS (2,4,6-trinitrobenzenesulfonic acid

NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease

PubMed Central

Strøbæk, D; Brown, DT; Jenkins, DP; Chen, Y-J; Coleman, N; Ando, Y; Chiu, P; Jørgensen, S; Demnitz, J; Wulff, H; Christophersen, P

2013-01-01

Background and Purpose The KCa3.1 channel is a potential target for therapy of immune disease. We identified a compound from a new chemical class of KCa3.1 inhibitors and assessed in vitro and in vivo inhibition of immune responses. Experimental Approach We characterized the benzothiazinone NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2H-1,4-benzothiazin-3(4H)-one) with respect to potency and molecular site of action on KCa3.1 channels, selectivity towards other targets, effects on T-cell activation as well as pharmacokinetics and inflammation control in colitis induced by 2,4-dinitrobenzene sulfonic acid, a rat model of inflammatory bowel disease (IBD). Key Results NS6180 inhibited cloned human KCa3.1 channels (IC50 = 9 nM) via T250 and V275, the same amino acid residues conferring sensitivity to triarylmethanes such as like TRAM-34. NS6180 inhibited endogenously expressed KCa3.1 channels in human, mouse and rat erythrocytes, with similar potencies (15–20 nM). NS6180 suppressed rat and mouse splenocyte proliferation at submicrolar concentrations and potently inhibited IL-2 and IFN-γ production, while exerting smaller effects on IL-4 and TNF-α and no effect on IL-17 production. Antibody staining showed KCa3.1 channels in healthy colon and strong up-regulation in association with infiltrating immune cells after induction of colitis. Despite poor plasma exposure, NS6180 (3 and 10 mg·kg−1 b.i.d.) dampened colon inflammation and improved body weight gain as effectively as the standard IBD drug sulfasalazine (300 mg·kg−1 q.d.). Conclusions and Implications NS6180 represents a novel class of KCa3.1 channel inhibitors which inhibited experimental colitis, suggesting KCa3.1 channels as targets for pharmacological control of intestinal inflammation. PMID:22891655

Methamphetamine colitis: a rare case of ischemic colitis in a young patient.

PubMed

Holubar, Stefan D; Hassinger, James P; Dozois, Eric J; Masuoka, Howard C

2009-08-01

Worldwide, methamphetamine (ie, "crystal meth") abuse is increasing, and is especially prevalent in rural America. However, ischemic colitis secondary to methamphetamine abuse has rarely been reported. We describe the case of a young man who presented with signs and symptoms suggestive of ischemic colitis.

Schistosoma japonicum ova maintains epithelial barrier function during experimental colitis.

PubMed

Xia, Chen-Mei; Zhao, Yuan; Jiang, Li; Jiang, Jie; Zhang, Shun-Cai

2011-11-21

To evaluate the impacts of Schistosoma japonicum (S. japonicum) ova on the tight junction barriers in a trinitrobenzenesulfonic acid (TNBS)-induced colitis model. Balb/c mice were randomly divided into three groups: control group; TNBS(+)ova(-) group and TNBS(+)ova(+) group. TNBS was used intracolonic to induce colitis and mice of the TNBS(+)ova(+) group were pre-exposed to S. japonicum ova as a prophylactic intervention. Colon inflammation was quantified using following variables: mouse mortality, weight loss, colon extent and microscopic inflammation score. Serum expression of tumor necrosis factor-α and interferon-γ were assessed to evaluate the systemic inflammatory response. NOD2 and its mRNA were also tested. Bacterial translocations were tested by culturing blood and several tissues. ZO-1 and occludin were chosen as the representations of tight junction proteins. Both the proteins and mRNA were assessed. Ova pre-treatment contributed to the relief of colitis and decreased the mortality of the models. NOD2 expression was significantly downregulated when pretreated with the ova. The TNBS injection caused a significant downregulation of ZO-1 and occludin mRNA together with their proteins in the colon; ova pre-exposure reversed these alterations. Treatment with S. japonicum ova in the colitis model caused lower intestinal bacterial translocation frequency. S. japonicum ova can maintain epithelial barrier function through increasing tight junction proteins, thus causing less exposure of NOD2 to the luminal antigens which may activate a series of inflammatory factors and induce colitis.

DNFB-DNS hapten-induced colitis in mice should not be considered a model of inflammatory bowel disease.

PubMed

Bailón, Elvira; Cueto-Sola, Margarita; Utrilla, Pilar; Nieto, Ana; Garrido-Mesa, Natividad; Celada, Antonio; Zarzuelo, Antonio; Xaus, Jordi; Gálvez, Julio; Comalada, Mònica

2011-10-01

The dinitrofluorobenzene/dinitrosulfonic acid (DNFB/DNS) model was originally described as an experimental model of intestinal inflammation resembling human ulcerative colitis (UC). Due to the absence of acceptable UC experimental models for pharmacological preclinical assays, here we examine the immune response induced in this model. Balb/c mice were sensitized by skin application of DNFB on day 1, followed by an intrarectal challenge with DNS on day 5. We further expanded this model by administering a second DNS challenge on day 15. The features of colonic inflammation and immune response were evaluated. The changes observed in colonic tissue corresponded, in comparison to the trinitrobenzene sulfonic acid (TNBS) colitis model, to a mild mucosal effect in the colon, which spontaneously resolved in less than 5 days. Furthermore, the second hapten challenge did not exacerbate the inflammatory response. In contrast to other studies, we did not observe any clear involvement of tumor necrosis factor alpha (TNF-α) or other Th1 cytokines during the initial inflammatory response; however, we found that a more Th2-humoral response appeared to mediate the first contact with the hapten. An increased humoral response was detected during the second challenge, although an increased Th1/Th17-cytokine expression profile was also simultaneously observed. On the basis of these results, although the DNFB/DNS model can display some features found in human UC, it should be considered as a model for the study of the intestinal hypersensitivity seen, for example, during food allergy or irritable bowel syndrome but not intestinal inflammation per se. Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.

Psychological factors in ulcerative colitis.

PubMed

Murray, J B

1984-04-01

Almost 50 years ago ulcerative colitis was included among the seven classical psychosomatic diseases. The psychodynamics and personality structures specific to ulcerative colitis sufferers were sought and the main-stay of treatment was psychotherapy. However, for the past decade the psychogenic approach to this disorder has been replaced by physiological and immunological explanations and treatments. The history of medical and psychogenic explanations and treatments of ulcerative colitis has been traced to the present. Ulcerative colitis remains a "riddle," as it was described almost 50 years ago, a complex disorder whose pattern is to flare up and subside, its cause and cure still unknown despite almost 100 years of study.

Induction of Indoleamine 2,3 Dioxygenase-1 by Immunostimulatory-DNA Limits Severity of Experimental Colitis

PubMed Central

Ciorba, Matthew A; Bettonville, Ellen E; McDonald, Keely G; Metz, Richard; Prendergast, George C; Newberry, Rodney D; Stenson, William F

2010-01-01

The chronic inflammatory bowel diseases are characterized by aberrant innate and adaptive immune responses to commensal luminal bacteria. In both human IBD and in experimental models of colitis there is an increased expression of the enzyme indoleamine 2,3 dioxygenase (IDO). IDO expression has the capacity to exert antimicrobial effects and dampen adaptive immune responses. In the murine TNBS model of colitis, inhibition of this enzyme leads to worsened disease severity suggesting that IDO acts as a natural break in limiting colitis. In this investigation we show that induction of IDO-1 by a TLR-9 agonist, immunostimulatory-DNA (ISS-DNA), critically contributes to its colitis limiting capacities. ISS-DNA induces intestinal expression of IDO-1, but not the recently described paralog enzyme IDO-2. This induction occurred in both epithelial cells and in subsets of CD11c+ and CD11b+ cells of the lamina propria which also increase after ISS-ODN. Signaling required for intestinal IDO-1 induction involves interferon dependent pathways, as IDO-1 was not induced in STAT-1 knockout mice. Using both the TNBS and DSS models of colitis we show the importance of IDO-1s induction in limiting colitis severity. The clinical parameters and histologic correlates of colitis in these models were improved by administration of the TLR-9 agonist; however, when the function of IDO is inhibited, the colitis limiting effects of ISS-ODN were abrogated. These findings support the possibility that targeted induction of IDO-1 is an approach deserving further investigation as a therapeutic strategy for diseases of intestinal inflammation. PMID:20181893

Lubiprostone induced ischemic colitis.

PubMed

Sherid, Muhammed; Sifuentes, Humberto; Samo, Salih; Deepak, Parakkal; Sridhar, Subbaramiah

2013-01-14

Ischemic colitis accounts for 6%-18% of the causes of acute lower gastrointestinal bleeding. It is often multifactorial and more commonly encountered in the elderly. Several medications have been implicated in the development of colonic ischemia. We report a case of a 54-year old woman who presented with a two-hour history of nausea, vomiting, abdominal pain, and bloody stool. The patient had recently used lubiprostone with close temporal relationship between the increase in the dose and her symptoms of rectal bleeding. The radiologic, colonoscopic and histopathologic findings were all consistent with ischemic colitis. Her condition improved without any serious complications after the cessation of lubiprostone. This is the first reported case of ischemic colitis with a clear relationship with lubiprostone (Naranjo score of 10). Clinical vigilance for ischemic colitis is recommended for patients receiving lubiprostone who are presenting with abdominal pain and rectal bleeding.

Lubiprostone induced ischemic colitis

PubMed Central

Sherid, Muhammed; Sifuentes, Humberto; Samo, Salih; Deepak, Parakkal; Sridhar, Subbaramiah

2013-01-01

Ischemic colitis accounts for 6%-18% of the causes of acute lower gastrointestinal bleeding. It is often multifactorial and more commonly encountered in the elderly. Several medications have been implicated in the development of colonic ischemia. We report a case of a 54-year old woman who presented with a two-hour history of nausea, vomiting, abdominal pain, and bloody stool. The patient had recently used lubiprostone with close temporal relationship between the increase in the dose and her symptoms of rectal bleeding. The radiologic, colonoscopic and histopathologic findings were all consistent with ischemic colitis. Her condition improved without any serious complications after the cessation of lubiprostone. This is the first reported case of ischemic colitis with a clear relationship with lubiprostone (Naranjo score of 10). Clinical vigilance for ischemic colitis is recommended for patients receiving lubiprostone who are presenting with abdominal pain and rectal bleeding. PMID:23345954

Crohn's colitis perforation due to superimposed invasive amebic colitis: a case report.

PubMed

Ozdoğan, Mehmet; Küpelioğlu, Ali

2006-06-01

The clinical and microscopic appearances of inflammatory bowel disease may be very similar to those of amebic colitis. The coexistence of invasive amebiasis with inflammatory bowel disease may have disastrous results. Patients with inflammatory bowel disease have a greater prevalence of amebiasis, but this association is more significant for ulcerative colitis. There have been very few reports in the literature presenting the superimposition of amebiasis on Crohn's disease. In this report, a rare case of Crohn's colitis with superimposed amebiasis resulting in colonic perforation is presented. Patients with inflammatory bowel disease traveling to endemic areas may benefit from receiving a course of prophylactic anti-amebic medication.

Effects of a high fat or a balanced omega 3/omega 6 diet on cytokines levels and DNA damage in experimental colitis.

PubMed

Vieira de Barros, Karina; Gomes de Abreu, Gilclay; Xavier, Roberta Araujo Navarro; Real Martinez, Carlos Augusto; Ribeiro, Marcelo Lima; Gambero, Alessandra; de Oliveira Carvalho, Patrícia; Silveira, Vera Lúcia Flor

2011-02-01

High-fat diets have been shown to be a risk factor for ulcerative colitis (UC). Omega-6 polyunsaturated fatty acids are considered to increase lipid peroxidation, while the omega-3 polyunsaturated fatty acid exerts a chemopreventative effect. We evaluated the effect of high-fat diets (20%) enriched with fish or soybean oil on colonic inflammation and DNA damage in dextran sulfate sodium-induced colitis. Male Wistar rats (28-30 days) were fed an American Institute of Nutrition (AIN)-93 diet for 47 days and divided into five groups: control normal fat non-colitic (C) or control colitis (CC), high soybean fat group (HS) colitis, high fish fat group colitis, or high-fat soybean plus fish oil colitis. UC was induced from day 35 until day 41 by 3% dextran sulfate sodium. On day 47, the rats were anesthetized; blood samples collected for corticosterone determination, and the distal colon was excised to quantify interleukin-4 (IL-4), IL-10, and interferon-gamma levels, myeloperoxidase activity, histological analyses, and DNA damage. The disease activity index was recorded daily. The disease activity index, histological analysis, myeloperoxidase activity, IL-4, interferon-gamma, and corticosterone levels did not differ among the colitic groups. IL-10 was significantly increased by the high fish fat group diet in relation to HS, but only the high soybean-fish fat diet increased the IL-10/IL-4 ratio (anti-inflammatory/pro-inflammatory) to levels closer to the C group and reduced DNA damage compared to the HS group (P<0.05). The data show that high-fat diets did not exacerbate UC and suggest that the soybean and fish oil mixture, more than the fish oil alone, could be a complementary therapy to achieve a cytokine balance in UC. Copyright © 2011 Elsevier Inc. All rights reserved.

Perspectives of IBD China: Is Crohn's and Colitis Foundation Model a Solution to Health Care Issues for the Country?

PubMed

Chen, Yan

2018-04-21

The success of the Crohn's and Colitis Foundation of America (CCFA), now Crohn's and Colitis Foundation (CCF) has established a role model for developing countries with an increasing incidence of inflammatory bowel disease (IBD), including China. While there are shared etiopathogenetic pathways and clinical features in IBD between Eastern and Western countries, patients with IBD as well as health care professionals in China are facing distinctive challenges, including the fragmented and inconsistent health insurance, social support system, and three-tiered health care service. Financial burden remains to be a tremendous obstacle to the management of IBD. In addition, poor rapport between patients and clinicians, and the lack of properly trained IBD specialists makes a noticeable gap in the management of IBD between China and Western countries. The China Crohn's &Colitis Foundation (CCCF), closely following the successful model of CCF, was established under the same doctrine, and served as a non-profit, volunteer-driven organization dedicated to improving quality of life of patients in by IBD through education and training.

Blueberry husks, rye bran and multi-strain probiotics affect the severity of colitis induced by dextran sulphate sodium.

PubMed

Håkansson, Asa; Bränning, Camilla; Adawi, Diya; Molin, Göran; Nyman, Margareta; Jeppsson, Bengt; Ahrné, Siv

2009-01-01

The enteric microbiota is a pivotal factor in the development of intestinal inflammation in humans but probiotics, dietary fibres and phytochemicals can have anti-inflammatory effects. The aim of this study was to evaluate the therapeutic effect of multi-strain probiotics and two conceivable prebiotics in an experimental colitis model. Sprague-Dawley rats were fed a fibre-free diet alone or in combination with Lactobacillus crispatus DSM 16743, L. gasseri DSM 16737 and Bifidobacterium infantis DSM 15158 and/or rye bran and blueberry husks. Colitis was induced by 5% dextran sulphate sodium (DSS) given by oro-gastric tube. Colitis severity, inflammatory markers, gut-load of lactobacilli and Enterobacteriaceae, bacterial translocation and formation of carboxylic acids (CAs) were analysed. The disease activity index (DAI) was lower in all treatment groups. Viable counts of Enterobacteriaceae were reduced and correlated positively with colitis severity, while DAI was negatively correlated with several CAs, e.g. butyric acid. The addition of probiotics to blueberry husks lowered the level of caecal acetic acid and increased that of propionic acid, while rye bran in combination with probiotics increased caecal CA levels and decreased distal colonic levels. Blueberry husks with probiotics reduced the incidence of bacterial translocation to the liver, colonic levels of myeloperoxidase, malondialdehyde and serum interleukin-12. Acetic and butyric acids in colonic content correlated negatively to malondialdehyde. A combination of probiotics and blueberry husks or rye bran enhanced the anti-inflammatory effects compared with probiotics or dietary fibres alone. These combinations can be used as a preventive or therapeutic approach to dietary amelioration of intestinal inflammation.

Hypersensitive prostaglandin and thromboxane response to hormones in rabbit colitis

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

Zipser, R.D.; Patterson, J.B.; Kao, H.W.

1985-10-01

Inflammation of the colon is associated with increased production of prostaglandins (PG) and thromboxanes (Tx), and these eicosanoids may contribute to the inflammatory, secretory, and motility dysfunctions in colitis. To evaluate the potential role of peptide hormones in the enhanced eicosanoid release, colitis was established in rabbits by a delayed-type hypersensitivity reaction to dinitrochlorobenzene and by an immune-complex-mediated reaction. PG and Tx were identified in the venous effluent of isolated perfused colons by radiochromatography after ( UC)arachidonic acid prelabeling, as well as by bioassay, and then quantitated by immunoassay. The two colitis models were morphologically similar. Basal release of PGE2,more » PGI2, and TxA2 was two- to threefold greater from colitis tissue than from control tissue. Bradykinin (BK) and angiotensin II (ANG II) increased release of UC-labeled eicosanoids, whereas several gastrointestinal hormones had no effect. In control colons, BK and ANG II increased PGE2 and PGI2 release (by about 2-fold) but did not alter TxA2. In contrast, BK and ANG II markedly exaggerated the release of eicosanoids in colitis. Since BK and possibly ANG II are increased at sites of inflammation, the hypersensitive eicosanoid response to these peptides may augment the eicosanoid-mediated manifestations of colitis.« less

Effects of Prunus mume Sieb. et Zucc. extract and its biopolymer encapsulation on a mouse model of colitis.

PubMed

Lee, Seung Yun; Lee, Seung-Jae; Hur, Sun Jin

2017-01-01

Prunus mume suppresses various diseases caused by inflammation response and exhibits antioxidant and free radical-scavenging activities. Therefore this study determined the effect of an aqueous P. mume (PM) extract in a mouse colitis model and investigated the value of biopolymer encapsulation, facilitating targeted delivery to the colon. Colitis was induced by administration of 30 g kg -1 dextran sulfate sodium to male BALB/c mice for 7 days prior to treatment with vehicle, 50 mg kg -1 PM extract or biopolymer-encapsulated PM extract, or 50 mg kg -1 sulfasalazine. Histological examination of the colon in BALB/c mice showed epithelial destruction and mucosal infiltration of inflammatory cells. These changes were attenuated in PM-treated mice, which had lower levels of inflammatory cytokines, cyclooxygenase 2 and immunoglobulins (IgA, IgM and IgE) compared with the vehicle-treated colitis group. The PM extract showed concentration-dependent radical scavenging and superoxide dismutase-like antioxidant activities. These results indicated that the effects of the PM extract on colitis were not influenced by biopolymer encapsulation and that this PM extract could be a potential therapeutic agent for inflammatory bowel disease. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Use of Budesonide in the Treatment of Microscopic Colitis

PubMed Central

Tangri, Vikram; Chande, Nilesh

2010-01-01

Collagenous colitis and lymphocytic colitis, the two types of microscopic colitis, cause watery diarrhea. Budesonide, a glucocorticoid medication with limited systemic availability, is commonly used to treat these illnesses. Budesonide has proven efficacy in the induction of clinical remission in both collagenous colitis and lymphocytic colitis. Budesonide is effective as a maintenance drug for patients with collagenous colitis, but has not been studied for this indication in patients with lymphocytic colitis. This drug improves quality of life in patients while causing few mild adverse events. Budesonide is an effective treatment of microscopic colitis that is safe and well tolerated. PMID:20616427

Ulcerative colitis masked by giant urticaria.

PubMed

Caroselli, C; Plocco, M; Pratticò, F; Bruno, C; Antonaglia, C; Rota, F; Curreli, I; Caroselli, A; Bruno, G

2007-01-01

The occurrence of giant urticaria and ulcerative colitis is very infrequent. A 23 year-old female reported the initial eruption of short-lived cutaneous itchy weals on her arms. Then lesions ran together and became confluent, extending to her legs, followed by undefined abdominal pain and a slight increase of body temperature. Exams showed hystologically confirmed ulcerative colitis, with perinuclear anti-neutrophil cytoplasmic antibody positivity. Ulcerative colitis therapy led not only to the remission of the colitic symptoms, but also to the prompt recovery of skin manifestations. Urticaria was the epiphenomenon of ulcerative colitis.

Serum calprotectin levels correlate with biochemical and histological markers of disease activity in TNBS colitis

PubMed Central

Cury, Didia Bismara; Mizsputen, Sender Jankiel; Versolato, Clara; Miiji, Luciana Odashiro; Pereira, Edson; Delboni, Maria Aparecida; Schor, Nestor; Moss, Alan C.

2014-01-01

Background and aim Serum calprotectin is elevated in patients with inflammatory bowel disease (IBD). Whether it correlates other markers of disease activity is unknown. The aim of this study was to correlate serum calprotectin with biochemical and histological measures of intestinal inflammation. Materials and methods TNBS colitis was induced in wistar rats, and serial blood samples were collected at 0, 3, and 12 days. Animals were subsequently sacrificed for pathological evaluation at day 12. Serum calprotectin and cytokines were measured by ELISA. Pathologic changes were classified at the macroscopic and microscopic levels. Results TNBS colitis induced elevated serum calprotectin, TNF and IL-6 within 24 h. Levels of serum calprotectin remained elevated in parallel to persistence of loose stool and weight loss to day 12. Serum calprotectin levels correlated with serum levels of TNF-α and IL6 (p < 0.001), but not CRP. Animals with liquid stool had significantly higher levels of serum calprotectin than control animals. There was a correlation between macroscopic colitis scores, and levels of serum calprotectin. Conclusion Serum calprotectin levels correlate with biochemical and histological markers of inflammation in TNBS colitis. This biomarker may have potential for diagnostic use in patients with IBD. PMID:23685388

High vitamin D3 diet administered during active colitis negatively affects bone metabolism in an adoptive T cell transfer model.

PubMed

Larmonier, C B; McFadden, R-M T; Hill, F M; Schreiner, R; Ramalingam, R; Besselsen, D G; Ghishan, F K; Kiela, P R

2013-07-01

Decreased bone mineral density (BMD) represents an extraintestinal complication of inflammatory bowel disease (IBD). Vitamin D₃ has been considered a viable adjunctive therapy in IBD. However, vitamin D₃ plays a pleiotropic role in bone modeling and regulates the bone formation-resorption balance, depending on the physiological environment, and supplementation during active IBD may have unintended consequences. We evaluated the effects of vitamin D₃ supplementation during the active phase of disease on colonic inflammation, BMD, and bone metabolism in an adoptive IL-10-/- CD4⁺ T cell transfer model of chronic colitis. High-dose vitamin D₃ supplementation for 12 days during established disease had negligible effects on mucosal inflammation. Plasma vitamin D₃ metabolites correlated with diet, but not disease, status. Colitis significantly reduced BMD. High-dose vitamin D₃ supplementation did not affect cortical bone but led to a further deterioration of trabecular bone morphology. In mice fed a high vitamin D₃ diet, colitis more severely impacted bone formation markers (osteocalcin and bone alkaline phosphatase) and increased bone resorption markers, ratio of receptor activator of NF-κB ligand to osteoprotegrin transcript, plasma osteoprotegrin level, and the osteoclast activation marker tartrate-resistant acid phosphatase (ACp5). Bone vitamin D receptor expression was increased in mice with chronic colitis, especially in the high vitamin D₃ group. Our data suggest that vitamin D₃, at a dose that does not improve inflammation, has no beneficial effects on bone metabolism and density during active colitis or may adversely affect BMD and bone turnover. These observations should be taken into consideration in the planning of further clinical studies with high-dose vitamin D₃ supplementation in patients with active IBD.

Plasma cytokine levels in ulcerative colitis.

PubMed

Goral, Vedat; Celenk, Tahir; Kaplan, Abdurahman; Sit, Dede

2007-06-01

Some immunological factors are responsible in the pathogenesis of ulcerative colitis. There is a relationship between cytokines and ulcerative colitis. In this study 20 ulcerative colitis patients (mean age 36.2 years old, 9 women, 11 men) and 20 healthy control groups (mean age 27.2 years old, 11 women, 9 men) were involved in the study. We established that IL-2Rsp, IL-6, IL-8 and IL-10 levels were different at the patients and control groups (p < 0.005). TNF-alpha and IL-1 beta were similar at the both groups. According to these results, IL-2Rsp, IL-6, 11-8 and IL-10 play an important role in the pathogenesis of ulcerative colitis. We consider that these cytokines are beneficial parameters in the diagnosis, treatment and prognosis of ulcerative colitis.

Geraniol ameliorates TNBS-induced colitis: Involvement of Wnt/β-catenin, p38MAPK, NFκB, and PPARγ signaling pathways.

PubMed

Soubh, Ayman A; Abdallah, Dalaal M; El-Abhar, Hanan S

2015-09-01

Geraniol, a natural component of plant essential oils, exhibits potent chemopreventive effects in the colon; however, its possible role/mechanisms in experimental colitis have not been elucidated, which is the aim of this study. To fulfill this goal, rats were treated for 11days with geraniol and/or sulfasalazine using a TNBS-induced colitis model. Geraniol significantly hindered the colitis-clinical signs (weight loss, colon edema,ulcerative area, colon/spleen mass indices) and opposed the altered oxidative/nitrosative stress. It restored the depleted total antioxidant capacity and lessened the elevated levels of nitric oxide and lipid peroxide. TNBS induced apoptosis and inflammatory cell infiltration, whereas geraniol curtailed these effects by diminishing the levels of caspase-3, intercellular adhesion molecule-1, and myeloperoxidase. The anti-inflammatory effect was documented by inhibiting the colon contents of prostaglandin E2 and interleukin-1β. In order to delve into the anti-colitic signaling pathways, geraniol inhibited the content/expression of glycogen synthase kinase (GSK)-3β, β-catenin, p38 mitogen activated protein kinase (p38MAPK), and nuclear factor kappa B (NFκB), but upregulated that of peroxisome proliferator activated receptor γ (PPARγ). These effects were comparable to those of sulfasalazine, the standard drug, whereas its combination with geraniol mediated effects that surpassed either treatment alone. Geraniol in the current study improved experimental colitis partly via its antioxidant, anti-inflammatory, and immunosuppressive potentials, possibly by modulating the Wnt/GSK-3β/β-catenin, p38MAPK, NFκB, and PPARγ signaling pathways. The study also revealed that geraniol represents a valuable asset against colitis alone or in combination with the conventional anti-colitic therapies. Copyright © 2015 Elsevier Inc. All rights reserved.

CT findings in ulcerative, granulomatous, and indeterminate colitis

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

Gore, R.M.; Marn, C.S.; Kirby, D.F.

1984-08-01

Eight patients with ulcerative colitis, three with colitis indeterminate, and 15 patients with Crohn disease were studied by computed tomography (CT) to establish CT criteria for each disorder in hopes of providing a new diagnostic perspective useful in the radiographic evaluation of inflammatory colitis. The CT findings in ulcerative colitis included thickening of the colon wall, which was characterized by inhomogeneous attenuation and a target appearance of the rectum, and proliferation of perirectal fat. Bowel wall thickening with homogeneous attenuation, fistula and abscess formation, and mesenteric abnormalities were observed in patients with Crohn colitis. Patients with colitis indeterminate showed colonicmore » changes on CT observed in both disorders. Initial experience suggests that CT can differentiate patients with well established ulcerative and Crohn colitis.« less

Microscopic colitis: the tip of the iceberg?

PubMed

Kitchen, Paul A; Levi, A Jonathen; Domizio, Paula; Talbot, Ian C; Forbes, Alastair; Price, Ashley B

2002-11-01

The aims were to determine whether a wide variation exists between hospitals in the diagnosis of microscopic colitis and to assimilate clinical data. Retrospective study of 90 patients with microscopic colitis aged between 16 and 92 years from 11 hospitals in south-east England. A questionnaire was designed to collect relevant data from all patients in whom a new diagnosis of microscopic colitis had been made at the source hospital between January 1990 and December 1996. The inclusion criteria were presentation with watery diarrhoea, a normal endoscopy and a histological report of microscopic colitis. Histology slides were then requested and reviewed. Clinical data were analysed with reference to the confirmed diagnosis. The number of patients diagnosed at each hospital ranged between zero and 30, with a median of six. Sixty-eight patients had histological slides reviewed. The numbers of patients with a final reviewed diagnosis of collagenous colitis, lymphocytic colitis and microscopic colitis, type undesignated, were 37, 18 and seven respectively. In thirty-one patients (34%) there was a recent history of the use of non-steroidal anti-inflammatory drugs. These data confirm that there is wide hospital variation in the diagnosis of microscopic colitis. Furthermore, the small group with the undesignated type may be associated with the use of non-steroidal anti-inflammatory drugs.

Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis

PubMed Central

Fukata, Masayuki; Shang, Limin; Santaolalla, Rebeca; Sotolongo, John; Pastorini, Cristhine; España, Cecilia; Ungaro, Ryan; Harpaz, Noam; Cooper, Harry S.; Elson, Greg; Kosco-Vilbois, Marie; Zaias, Julia; Perez, Maria T.; Mayer, Lloyd; Vamadevan, Arunan S.; Lira, Sergio A.; Abreu, Maria T.

2010-01-01

Chronic intestinal inflammation culminates in cancer and a link to TLR4 has been suggested by our observation that TLR4 deficiency prevents colitis-associated neoplasia. In the current study, we address the effect of the aberrant activation of epithelial TLR4 on induction of colitis and colitis-associated tumor development. We take a translational approach to address the consequences of increased TLR signaling in the intestinal mucosa. Mice transgenic for a constitutively-active TLR4 under the intestine-specific villin promoter (villin-TLR4 mice) were treated with DSS for acute colitis and azoxymethane-dextran sulfate sodium. TLR4 expression was analyzed by immunohistochemistry in colonic tissue from patients with ulcerative colitis and ulcerative colitis associated cancer. The effect of an antagonist TLR4 Ab was tested in prevention of colitis-associated neoplasia in the AOM-DSS model. Villin-TLR4 mice were highly susceptible to both acute colitis and colitis-associated neoplasia. Villin-TLR4 mice had increased epithelial expression of COX-2 and mucosal PGE2 production at baseline. Increased severity of colitis in villin-TLR4 mice was characterized by enhanced expression of inflammatory mediators and increased neutrophilic infiltration. In human UC samples, TLR4 expression was upregulated in almost all CAC and progressively increases with grade of dysplasia. As a proof of principle, a TLR4/MD-2 antagonist antibody inhibited colitis-associated neoplasia in the mouse model. Our results show that regulation of TLR's can affect the outcome of both acute colitis and its consequences—cancer. Targeting TLR4 and other TLR's may ultimately play a role in prevention or treatment of colitis-associated cancer. PMID:21674704

Cathelicidin Signaling via the Toll-Like Receptor Protects Against Colitis in Mice

PubMed Central

Koon, Hon Wai; Shih, David Quan; Chen, Jeremy; Bakirtzi, Kyriaki; Hing, Tressia C; Law, Ivy; Ho, Samantha; Ichikawa, Ryan; Zhao, Dezheng; Xu, Hua; Gallo, Richard; Dempsey, Paul; Cheng, Genhong; Targan, Stephan R; Pothoulakis, Charalabos

2011-01-01

Background & Aims Cathelicidin (encoded by Camp) is an anti-microbial peptide in the innate immune system. We examined whether macrophages express cathelicidin in colons of mice with experimental colitis and patients with inflammatory bowel disease; we investigated its signaling mechanisms. Methods Quantitative, real-time, reverse transcription PCR, bacterial 16S PCR, immunofluorescence, and small interfering (si)RNA analyses were performed. Colitis was induced in mice using sodium dextran sulfate (DSS); levels of cathelicidin were measured in human primary monocytes. Results Expression of cathelicidin increased in the inflamed colonic mucosa of mice with DSS-induced colitis, compared with controls. Cathelicidin expression localized to mucosal macrophages in inflamed colon tissues of patients and mice. Exposure of human primary monocytes to E coli DNA induced expression of Camp mRNA, which required signaling by ERK; expression was reduced by siRNAs against toll-like receptor (TLR)9 and MyD88. Intracolonic administration of bacterial DNA to wild-type mice induced expression of cathelicidin in colons of control mice and mice with DSS-induced colitis. Colon expression of cathelicidin was significantly reduced in TLR9 −/− mice with DSS-induced colitis. Compared with wild-type mice, Camp −/− mice developed a more severe form of DSS-induced colitis, particularly after intracolonic administration of E coli DNA. Expression of cathelicidin from bone marrow-derived immune cells regulated DSS induction of colitis in transplantation studies in mice. Conclusions Cathelicidin protects against colitis induction in mice. Increased expression of cathelicidin in monocytes and experimental models of colitis involves activation of TLR9–ERK signaling by bacterial DNA. This pathway might be involved in pathogenesis of ulcerative colitis. PMID:21762664

Dose-dependent antiinflammatory effect of ursodeoxycholic acid in experimental colitis.

PubMed

Martínez-Moya, Patricia; Romero-Calvo, Isabel; Requena, Pilar; Hernández-Chirlaque, Cristina; Aranda, Carlos J; González, Raquel; Zarzuelo, Antonio; Suárez, María Dolores; Martínez-Augustin, Olga; Marín, José Juan G; de Medina, Fermín Sánchez

2013-02-01

The denomination of inflammatory bowel disease comprises a group of chronic inflammatory diseases of the digestive tract, ulcerative colitis and Crohn's disease being the most important conditions. Bile acids may play a role both in etiology and pharmacology of this disease. Thus, although deoxycholic acid is regarded as a proinflammatory agent ursodeoxycholic acid, which is currently being used to treat certain types of cholestasis and primary biliary cirrhosis, because of their choleretic, cytoprotective and immunomodulatory effects, it has been reported to exert an anti-inflammatory activity. We aim to confirm and characterize the intestinal antiinflammatory activity of ursodeoxycholic acid. The experimental model trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats has been used. Animal status was characterized by a number of macroscopic and biochemical parameters. Oral administration of ursodeoxycholic acid was able to ameliorate experimental colonic inflammation. This occurred only at a relatively high dose (50 mg/kg day), whereas ursodeoxycholic acid was without significant effect at doses of 10 and 25 mg/kg day. The therapeutic effect was evidenced, among others, by a higher body weight recovery, a diminished affected to total mucosal area and lower alkaline phosphatase activity in treated vs. control (TNBS treated) animals. These results indicate that, at the appropriate dose, ursodeoxycholic acid is a potentially useful drug to reduce intestinal inflammation and could be envisaged to be incorporated in the treatment of inflammatory bowel diseases. Copyright © 2012 Elsevier B.V. All rights reserved.

Short-chain fatty acids administration is protective in colitis-associated colorectal cancer development.

PubMed

Tian, Yun; Xu, Qing; Sun, Liqun; Ye, Ying; Ji, Guozhong

2018-03-17

Reduced short-chain fatty acids (SCFAs) have been reported in patients with ulcerative colitis, and increased intake of dietary fiber has shown to be clinically beneficial for colitis. Whether SCFAs suppress tumorigenesis in colitis-associated colorectal cancer remains unknown. The chemopreventive effect of SCFAs in colitis-associated colorectal cancer was evaluated in this study. Model of colitis-associated colorectal cancer in male BALB/c mice was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). SCFAs mix (67.5 mM acetate, 40 mM butyrate, 25.9 mM propionate) was administered in drink water during the study period. Macroscopic and histological studies were performed to examine the colorectal inflammation and tumorigenesis in AOM/DSS-induced mice treated with or without SCFA mix. The effects of SCFAs mix on colonic epithelial cellular proliferation were also assessed using Ki67 immunohistochemistry and TUNEL staining. The administration of SCFAs mix significantly reduced the tumor incidence and size in mice with AOM/DSS-induced colitis associated colorectal cancer. SCFAs mix protected from AOM/DSS-induced colorectal cancer by improving colon inflammation and disease activity index score as well as suppressing the expression of proinflammatory cytokines including IL-6, TNF-α and IL-17. A decrease in cell proliferation markers and an increase in TUNEL-positive tumor epithelial cells were also demonstrated in AOM/DSS mice treated with SCFAs mix. SCFAs mix administration prevented development of tumor and attenuated the colonic inflammation in a mouse model of colitis-associated colorectal cancer. SCFAs mix may be a potential agent in the prevention and treatment of colitis-associated colorectal cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

Orally Administered Enoxaparin Ameliorates Acute Colitis by Reducing Macrophage-Associated Inflammatory Responses

PubMed Central

Lean, Qi Ying; Eri, Rajaraman D.; Randall-Demllo, Sarron; Sohal, Sukhwinder Singh; Stewart, Niall; Peterson, Gregory M.; Gueven, Nuri; Patel, Rahul P.

2015-01-01

Inflammatory bowel diseases, such as ulcerative colitis, cause significant morbidity and decreased quality of life. The currently available treatments are not effective in all patients, can be expensive and have potential to cause severe side effects. This prompts the need for new treatment modalities. Enoxaparin, a widely used antithrombotic agent, is reported to possess anti-inflammatory properties and therefore we evaluated its therapeutic potential in a mouse model of colitis. Acute colitis was induced in male C57BL/6 mice by administration of dextran sulfate sodium (DSS). Mice were treated once daily with enoxaparin via oral or intraperitoneal administration and monitored for colitis activities. On termination (day 8), colons were collected for macroscopic evaluation and cytokine measurement, and processed for histology and immunohistochemistry. Oral but not intraperitoneal administration of enoxaparin significantly ameliorated DSS-induced colitis. Oral enoxaparin-treated mice retained their body weight and displayed less diarrhea and fecal blood loss compared to the untreated colitis group. Colon weight in enoxaparin-treated mice was significantly lower, indicating reduced inflammation and edema. Histological examination of untreated colitis mice showed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and the presence of edema, while all aspects of this pathology were alleviated by oral enoxaparin. Reduced number of macrophages in the colon of oral enoxaparin-treated mice was accompanied by decreased levels of pro-inflammatory cytokines. Oral enoxaparin significantly reduces the inflammatory pathology associated with DSS-induced colitis in mice and could therefore represent a novel therapeutic option for the management of ulcerative colitis. PMID:26218284

High vitamin D3 diet administered during active colitis negatively affects bone metabolism in an adoptive T cell transfer model

PubMed Central

Larmonier, C. B.; McFadden, R.-M. T.; Hill, F. M.; Schreiner, R.; Ramalingam, R.; Besselsen, D. G.; Ghishan, F. K.

2013-01-01

Decreased bone mineral density (BMD) represents an extraintestinal complication of inflammatory bowel disease (IBD). Vitamin D3 has been considered a viable adjunctive therapy in IBD. However, vitamin D3 plays a pleiotropic role in bone modeling and regulates the bone formation-resorption balance, depending on the physiological environment, and supplementation during active IBD may have unintended consequences. We evaluated the effects of vitamin D3 supplementation during the active phase of disease on colonic inflammation, BMD, and bone metabolism in an adoptive IL-10−/− CD4+ T cell transfer model of chronic colitis. High-dose vitamin D3 supplementation for 12 days during established disease had negligible effects on mucosal inflammation. Plasma vitamin D3 metabolites correlated with diet, but not disease, status. Colitis significantly reduced BMD. High-dose vitamin D3 supplementation did not affect cortical bone but led to a further deterioration of trabecular bone morphology. In mice fed a high vitamin D3 diet, colitis more severely impacted bone formation markers (osteocalcin and bone alkaline phosphatase) and increased bone resorption markers, ratio of receptor activator of NF-κB ligand to osteoprotegrin transcript, plasma osteoprotegrin level, and the osteoclast activation marker tartrate-resistant acid phosphatase (ACp5). Bone vitamin D receptor expression was increased in mice with chronic colitis, especially in the high vitamin D3 group. Our data suggest that vitamin D3, at a dose that does not improve inflammation, has no beneficial effects on bone metabolism and density during active colitis or may adversely affect BMD and bone turnover. These observations should be taken into consideration in the planning of further clinical studies with high-dose vitamin D3 supplementation in patients with active IBD. PMID:23639807

Angiogenesis blockade as a new therapeutic approach to experimental colitis

PubMed Central

Danese, Silvio; Sans, Miquel; Spencer, David M; Beck, Ivy; Doñate, Fernando; Plunkett, Marian L; de la Motte, Carol; Redline, Raymond; Shaw, David E; Levine, Alan D; Mazar, Andrew P; Fiocchi, Claudio

2007-01-01

Background Neoangiogenesis is a critical component of chronic inflammatory disorders. Inhibition of angiogenesis is an effective treatment in animal models of inflammation, but has not been tested in experimental colitis. Aim To investigate the effect of ATN‐161, an anti‐angiogenic compound, on the course of experimental murine colitis. Method Interleukin 10‐deficient (IL10−/−) mice and wild‐type mice were kept in ultra‐barrier facilities (UBF) or conventional housing, and used for experimental conditions. Dextran sodium sulphate (DSS)‐treated mice were used as a model of acute colitis. Mice were treated with ATN‐161 or its scrambled peptide ATN‐163. Mucosal neoangiogenesis and mean vascular density (MVD) were assessed by CD31 staining. A Disease Activity Index (DAI) was determined, and the severity of colitis was determined by a histological score. Colonic cytokine production was measured by ELISA, and lamina propria mononuclear cell proliferation by thymidine incorporation. Result MVD increased in parallel with disease progression in IL10−/− mice kept in conventional housing, but not in IL10−/− mice kept in UBF. Angiogenesis also occurred in DSS‐treated animals. IL10−/− mice with established disease treated with ATN‐161, but not with ATN‐163, showed a significant and progressive decrease in DAI. The histological colitis score was significantly lower in ATN‐161‐treated mice than in scrambled peptide‐treated mice. Inhibition of angiogenesis was confirmed by a significant decrease of MVD in ATN‐161‐treated mice than in ATN‐163‐treated mice. No therapeutic effects were observed in the DSS model of colitis. ATN‐161 showed no direct immunomodulatory activity in vitro. Conclusion Active angiogenesis occurs in the gut of IL10−/− and DSS‐treated colitic mice and parallels disease progression. ATN‐161 effectively decreases angiogenesis as well as clinical severity and histological inflammation in IL10�

[Topical therapy of ulcerative colitis].

PubMed

Rogler, G; Beglinger, C; Mottet, C; Seibold, F; Gross, V

2011-11-16

The availability of new topical preparations for the treatment of left sided ulcerative colitis ulcerosa offers a therapy optimization for many patients. Rectal application of steroids and 5-aminosalicylic acid (5-ASA) is associated with fewer side effects and has a higher therapeutic efficacy in mild to moderate-active left-sided colitis as compared to a systemic therapy. Often it is argued that the patients' compliance is insufficient with a rectal therapy. However, with sufficient information on the proven advantages this is usually not the case. The rectal application of drugs in distal ulcerative colitis is suitable also for the maintenance of remission. Therefore the new therapy guidelines recommend topical therapy more than in former times. Subsequently, these manuscripts focussed specifically on the topical therapy of distal colitis, to elucidate that clear treatment advantages are present in daily practice.

Recommendations for improved use of the murine TNBS-induced colitis model in evaluating anti-inflammatory properties of lactic acid bacteria: technical and microbiological aspects.

PubMed

Foligné, Benoit; Nutten, Sophie; Steidler, Lothar; Dennin, Véronique; Goudercourt, Denise; Mercenier, Annick; Pot, Bruno

2006-02-01

Probiotic bacteria have been shown to exert promising beneficial effects in different types of intestinal disorders, including chronic inflammation. In this context, animal models of inflammatory bowel disease are useful in studying the possible prophylactic role of candidate probiotic strains. This study aimed at evaluating the critical technological and microbiological parameters as well as the robustness of the murine trinitrobenzene sulfonic acid (TNBS)-induced model of colitis, after intragastric administration of lactic acid bacteria (LAB) preparations. A standardized methodology was applied to assess the protective effect achieved by various bacterial concentrations and culture conditions of the reference strain Lactobacillus plantarum NCIMB 8826. Not only was protection found to vary in function in different levels of colitis, but also repeated experiments showed a clear bacterial dose-dependent attenuation of colitis. The physiological stage of bacteria was shown to impact as well, with substantial, mild, or reduced improvement of inflammatory scores for exponentially growing, stationary-phase, or killed bacteria, respectively. A recombinant strain, secreting murine interleukin-10 (IL-10) and previously reported to successfully treat colitis in two different models of murine colitis (dextran sulfate sodium [DSS] and IL-10-deficient mice), was used to validate the final experimental conditions. In conclusion, we identified and optimized some of the key parameters that need to be controlled in order to ensure reliable comparison of results generated over a long period of time or independent experiments. The recommendations for an improved model presented here will prove to be helpful for reproducible, independent comparison of the anti-inflammatory potential of wild-type or recombinant candidate probiotic strains, whether administered as pure cultures or as blends.

Anti-colitis and -adhesion effects of daikenchuto via endogenous adrenomedullin enhancement in Crohn's disease mouse model.

PubMed

Kono, Toru; Kaneko, Atsushi; Hira, Yoshiki; Suzuki, Tatsuya; Chisato, Naoyuki; Ohtake, Nobuhiro; Miura, Naoko; Watanabe, Tsuyoshi

2010-06-01

Adrenomedullin (ADM) is a member of the calcitonin family of regulatory peptides, and is reported to have anti-inflammatory effects in animal models of Crohn's disease (CD). We investigated the therapeutic effects of daikenchuto (DKT), an extracted Japanese herbal medicine, on the regulation of endogenous ADM in the gastrointestinal tract in a CD mouse model. Colitis was induced in mice by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS); afterwards, DKT was given orally. Colonic damage was assessed on day 3 by macroscopic and microscopic observation, enzyme immunoassays of proinflammatory cytokines in the colonic mucosa, and serum amyloid A (SAA), a hepatic acute-phase protein. To determine the involvement of ADM, an ADM antagonist was instilled intrarectally before DKT administration. The effect of DKT on ADM production by intestinal epithelial cells was evaluated by enzyme immunoassay and real-time PCR. DKT significantly attenuated mucosal damage and colonic inflammatory adhesions, and inhibited elevations of SAA in plasma and the proinflammatory cytokines TNFα and IFNγ in the colon. Small and large intestinal epithelial cells produced higher levels of ADM after DKT stimulation. A DKT-treated IEC-6 cell line also showed enhanced ADM production at protein and mRNA levels. Abolition of this effect by pretreatment with an ADM antagonist shows that DKT appears to exert its anti-colitis effect via up-regulation of endogenous ADM in the intestinal tract. DKT exerts beneficial effects in a CD mouse model through endogenous release and production of ADM. Endogenous ADM may be a therapeutic target for CD. Copyright © 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Birth-cohort patterns of mortality from ulcerative colitis and peptic ulcer.

PubMed

Sonnenberg, Amnon

2008-10-01

The aim was to follow the time trends of mortality from ulcerative colitis and compare them with those of gastric and duodenal ulcer. Mortality data from 21 different countries between 1941 and 2004 were analyzed. The age-specific death rates of each individual country, as well as the average age-specific rates of all countries, were plotted against the periods of birth and death. The average trends of mortality from ulcerative colitis, gastric and duodenal ulcer reveal distinctive and unique birth-cohort patterns of all three diseases. Similar to both types of peptic ulcer, the risk of developing ulcerative colitis started to rise in successive generations born during the second half of the 19(th) century. It peaked shortly before the turn of the century and has continued to decline since then. The rise and fall in the occurrence of ulcerative colitis preceded those of both ulcer types. The birth-cohort pattern indicates that exposure to the relevant risk factors of ulcerative colitis occurs during early life. As the model of H. pylori and its associated birth-cohort patterns of gastric and duodenal ulcer suggest, an enteric infection provides a possible explanation for such temporal trends of ulcerative colitis as well.

Superoxide dismutase recombinant Lactobacillus fermentum ameliorates intestinal oxidative stress through inhibiting NF-κB activation in a trinitrobenzene sulphonic acid-induced colitis mouse model.

PubMed

Hou, C L; Zhang, J; Liu, X T; Liu, H; Zeng, X F; Qiao, S Y

2014-06-01

Superoxide dismutase (SOD) can prevent and cure inflammatory bowel diseases by decreasing the amount of reactive oxygen species. Unfortunately, short half-life of SOD in the gastrointestinal tract limited its application in the intestinal tract. This study aimed to investigate the treatment effects of recombinant SOD Lactobacillus fermentum in a colitis mouse model. In this study, we expressed the sodA gene in Lact. fermentum I5007 to obtain the SOD recombinant strain. Then, we determined the therapeutic effects of this SOD recombinant strain in a trinitrobenzene sulphonic acid (TNBS)-induced colitis mouse model. We found that SOD activity in the recombinant Lact. fermentum was increased by almost eightfold compared with that in the wild type. Additionally, both the wild type and the recombinant Lact. fermentum increased the numbers of lactobacilli in the colon of mice (P < 0·05). Colitis mice treated with recombinant Lact. fermentum showed a higher survival rate and lower disease activity index (P < 0·05). Recombinant Lact. fermentum significantly decreased colonic mucosa histological scoring for infiltration of inflammatory cells, lipid peroxidation, the expression of pro-inflammatory cytokines and myeloperoxidase (P < 0·05) and inhibited NF-κB activity in colitis mice (P < 0·05). SOD recombinant Lact. fermentum significantly reduced oxidative stress and inflammation through inhibiting NF-κB activation in the TNBS-induced colitis model. This study provides insights into the anti-inflammatory effects of SOD recombinant Lact. fermentum, indicating the potential therapeutic effects in preventing and curing intestinal bowel diseases. © 2014 The Society for Applied Microbiology.

Probiotics and prebiotics in ulcerative colitis.

PubMed

Derikx, Lauranne A A P; Dieleman, Levinus A; Hoentjen, Frank

2016-02-01

The intestinal microbiota is one of the key players in the etiology of ulcerative colitis. Manipulation of this microflora with probiotics and prebiotics is an attractive strategy in the management of ulcerative colitis. Several intervention studies for both the induction and maintenance of remission in ulcerative colitis patients have been performed. Most of these studies evaluated VSL#3 or E. Coli Nissle 1917 and in general there is evidence for efficacy of these agents for induction and maintenance of remission. However, studies are frequently underpowered, lack a control group, and are very heterogeneous investigating different probiotic strains in different study populations. The absence of well-powered robust randomized placebo-controlled trials impedes the widespread use of probiotics and prebiotics in ulcerative colitis. However, given the promising results that are currently available, probiotics and prebiotics may find their way to the treatment algorithm for ulcerative colitis in the near future. Copyright © 2016 Elsevier Ltd. All rights reserved.

Boswellic Acid Improves Cognitive Function in a Rat Model Through Its Antioxidant Activity

PubMed Central

Ebrahimpour, Saeedeh; Fazeli, Mehdi; Mehri, Soghra; Taherianfard, Mahnaz; Hosseinzadeh, Hossein

2017-01-01

Objectives: Boswellic acid (BA), a compound isolated from the gum-resin of Boswellia carterii, is a pentacyclic terpenoid that is active against many inflammatory diseases, including cancer, arthritis, chronic colitis, ulcerative colitis, Crohn's disease, and memory impairment, but the mechanism is poorly understood. This study investigated the effects of boswellic acid on spatial learning and memory impairment induced by trimethyltin (TMT) in Wistar rats. Methods: Forty male Wistar rats were randomly divided into 5 groups: Normal group, TMT-administrated rats (8.0 mg/kg, Intraperitoneally, i.p.) and TMT + BA (40, 80 and 160 mg/kg, i.p.)-administrated rats. BA was used daily for 21 days. To evaluate the cognitive improving of BA, we performed the Morris water maze test. Moreover, to investigate the neuroprotective effect of BA, we determined the acetylcholinesterase (AchE) activity, the malondialdehyde (MDA) level as a marker of lipid peroxidation, and the glutathione (GSH) content in the cerebral cortex. Results: Treatment with TMT impaired learning and memory, and treatment with BA at a dose of 160 mg/kg produced a significant improvement in learning and memory abilities in the water maze tasks. Consistent with behavioral data, the activity of AChE was significantly increased in the TMT-injected rats compared to the control group (P < 0.01) whereas all groups treated with BA presented a more significant inhibitory effect against AChE than the TMT-injected animals. In addition, TMT reduced the GSH content and increased the MDA level in the cerebral cortex as compared to the control group) P < 0.01). On the other hand, treatment with BA at 160 mg/kg slightly increased the GSH content and reduced the MDA level in comparison to the TMT-administered group (P < 0.01). Conclusion: The above results suggest that the effect of BA in improving the cognitive function may be mediated through its antioxidant activity. PMID:28392957

Characterization of Growth Hormone Resistance in Experimental and Ulcerative Colitis.

PubMed

Soendergaard, Christoffer; Kvist, Peter Helding; Thygesen, Peter; Reslow, Mats; Nielsen, Ole Haagen; Kopchick, John Joseph; Holm, Thomas Lindebo

2017-09-23

Growth hormone (GH) resistance may develop as a consequence of inflammation during conditions such as inflammatory bowel disease, encompassing ulcerative colitis (UC). However, the specific role of the GH-insulin growth factor (IGF)-1-axis and/or the functional consequences of GH resistance in this condition are unclear. In situ hybridization targeting the GH receptor (GHR) and relevant transcriptional analyses were performed in patients with UC and in IL-10 knock-out mice with piroxicam accelerated colitis (PAC). Using cultured primary epithelial cells, the effects of inflammation on the molecular mechanisms governing GH resistance was verified. Also, the therapeutic potential of GH on mucosal healing was tested in the PAC model. Inflammation induced intestinal GH resistance in UC and experimental colitis by down-regulating GHR expression and up-regulating suppressor of cytokine signalling (SOCS) proteins. These effects are driven by pro-inflammatory mediators (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6) as confirmed using primary epithelial cells. Treatment of experimental colitis with GH increased IGF-1 and body weight of the mice, but had no effects on colonic inflammation or mucosal healing. The high transcriptional similarity between UC and experimental colitis accentuates the formation of intestinal GH resistance during inflammation. Inflammation-induced GH resistance not only impairs general growth but induces a state of local resistance, which potentially impairs the actions of GH on mucosal healing during colitis when using long-acting GH therapy.

Characterization of Growth Hormone Resistance in Experimental and Ulcerative Colitis

PubMed Central

Kvist, Peter Helding; Thygesen, Peter; Reslow, Mats; Nielsen, Ole Haagen; Kopchick, John Joseph; Holm, Thomas Lindebo

2017-01-01

Growth hormone (GH) resistance may develop as a consequence of inflammation during conditions such as inflammatory bowel disease, encompassing ulcerative colitis (UC). However, the specific role of the GH–insulin growth factor (IGF)-1-axis and/or the functional consequences of GH resistance in this condition are unclear. In situ hybridization targeting the GH receptor (GHR) and relevant transcriptional analyses were performed in patients with UC and in IL-10 knock-out mice with piroxicam accelerated colitis (PAC). Using cultured primary epithelial cells, the effects of inflammation on the molecular mechanisms governing GH resistance was verified. Also, the therapeutic potential of GH on mucosal healing was tested in the PAC model. Inflammation induced intestinal GH resistance in UC and experimental colitis by down-regulating GHR expression and up-regulating suppressor of cytokine signalling (SOCS) proteins. These effects are driven by pro-inflammatory mediators (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6) as confirmed using primary epithelial cells. Treatment of experimental colitis with GH increased IGF-1 and body weight of the mice, but had no effects on colonic inflammation or mucosal healing. The high transcriptional similarity between UC and experimental colitis accentuates the formation of intestinal GH resistance during inflammation. Inflammation-induced GH resistance not only impairs general growth but induces a state of local resistance, which potentially impairs the actions of GH on mucosal healing during colitis when using long-acting GH therapy. PMID:28946616

Eosinophilic colitis in infants.

PubMed

Lozinsky, Adriana Chebar; Morais, Mauro Batista de

2014-01-01

To review the literature for clinical data on infants with allergic or eosinophilic colitis. MEDLINE search of all indexes was performed using the words "colitis or proctocolitis and eosinophilic" or "colitis or proctocolitis and allergic" between 1966 and February of 2013. All articles that described patients' characteristics were selected. A total of 770 articles were identified, of which 32 met the inclusion criteria. The 32 articles included a total of 314 infants. According to the available information, 61.6% of infants were male and 78.6% were younger than 6 months. Of the 314 patients, 49.0% were fed exclusively breast milk, 44.2% received cow's milk protein, and 6.8% received soy protein. Diarrheal stools were described in 28.3% of patients. Eosinophilia was found in 43.8% (115/263) of infants. Colonic or rectal biopsy showed infiltration by eosinophils (between 5 and 25 per high-power field) in 89.3% (236/264) of patients. Most patients showed improvement with the removal of the protein in cow's milk from their diet or the mother's diet. Allergy challenge tests with cow's milk protein were cited by 12 of the 32 articles (66 patients). Eosinophilic colitis occurs predominantly in the first six months of life and in males. Allergy to cow's milk was considered the main cause of eosinophilic colitis. Exclusion of cow's milk from the diet of the lactating mother or from the infant's diet is generally an effective therapeutic measure. Copyright © 2013 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Fermented herbal formula KIOM-MA-128 protects against acute colitis induced by dextran sodium sulfate in mice.

PubMed

Kim, Dong-Gun; Lee, Mi-Ra; Yoo, Jae-Myung; Park, Kwang-Il; Ma, Jin-Yeul

2017-07-05

Colitis is a well-known subtype of inflammatory bowel disease and is caused by diverse factors. Previous research has shown that KIOM-MA elicits anti-inflammatory and anti-allergic effects on various diseases. KIOM-MA-128, our novel herbal formula, was generated from KIOM-MA using probiotics to improve the therapeutic efficacy. We investigated whether KIOM-MA-128 has protective activity in a mouse model of acute colitis induced by dextran sodium sulfate (DSS). Colitis was induced by DSS administered to ICR mice in drinking water. KIOM-MA-128 (125 or 250 mg/kg) was orally administered once per day. The body weights of the mice were measured daily, and colonic endoscopies were performed at 5 and 8 days. Colon length as well as histological and cytokine changes were observed at the end of drug administration. KIOM-MA-128 has pharmacological activity in an acute colitis model. KIOM-MA-128 reduced the loss of body weight and disease activity index (DAI) and inhibited the abnormally short colon lengths and the colonic damage in this mouse model of acute colitis. Moreover, KIOM-MA-128 suppressed pro-inflammatory cytokine expression and maintained the integrity of the tight junctions during DSS-induced colitis. The results indicated that KIOM-MA-128 protects against DSS-induced colitis in mice and suggested that this formula might be a candidate treatment for inflammatory bowel disease (IBD).

Ulcerative colitis

MedlinePlus

... discharge Living with your ileostomy Low-fiber diet Total colectomy or proctocolectomy - ... Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus. Gastroenterology . ...

Effect of mesalamine and prednisolone on TNBS experimental colitis, following various doses of orally administered iron.

PubMed

Triantafillidis, John K; Douvi, Georgia; Agrogiannis, George; Patsouris, Efstratios; Gikas, Aristofanis; Papalois, Apostolos E

2014-01-01

Experimental data suggest that oral iron (I.) supplementation can worsen colitis in animals. To investigate the influence of various concentrations of orally administered I. in normal gut mucosa and mucosa of animals with TNBS colitis, as well as the influence of Mesalamine (M.) and Prednisolone (P.) on the severity of TNBS colitis following orally administered I. 156 Wistar rats were allocated into 10 groups. Colitis was induced by TNBS. On the 8th day, all animals were euthanatized. Activity of colitis and extent of tissue damage were assessed histologically. The levels of tissue tumor necrosis factor- α (t-TNF- α ) and tissue malondialdehyde (t-MDA) were estimated in all animal groups. Moderate and high I. supplementation induced inflammation in the healthy colon and increased the activity of the experimentally induced TNBS colitis. Administration of M. on TNBS colitis following moderate iron supplementation (0.3 g/Kg diet) resulted in a significant improvement in the overall histological score as well as in two individual histological parameters. M. administration, however, did not significantly reduce the t-TNF- α levels (17.67 ± 4.92 versus 14.58 ± 5.71, P = 0.102), although it significantly reduced the t-MDA levels (5.79 ± 1.55 versus 3.67 ± 1.39, P = 0.000). Administration of M. on TNBS colitis following high iron supplementation (3.0 g/Kg diet) did not improve the overall histological score and the individual histological parameters, neither reduced the levels of t-TNF- α (16.57 ± 5.61 versus 14.65 ± 3.88, P = 0.296). However, M. significantly reduced the t-MDA levels (5.99 ± 1.37 versus 4.04 ± 1.41, P = 0.000). Administration of P. on TNBS colitis after moderate iron supplementation resulted in a significant improvement in the overall histological score as well as in three individual histological parameters. P. also resulted in a significant reduction in the t-TNF- α levels (17.67 ± 4.92 versus 12.64 ± 3.97, P = 0.003) and the t-MDA levels

Effect of Mesalamine and Prednisolone on TNBS Experimental Colitis, following Various Doses of Orally Administered Iron

PubMed Central

Triantafillidis, John K.; Douvi, Georgia; Agrogiannis, George; Patsouris, Efstratios; Gikas, Aristofanis; Papalois, Apostolos E.

2014-01-01

Background. Experimental data suggest that oral iron (I.) supplementation can worsen colitis in animals. Aim. To investigate the influence of various concentrations of orally administered I. in normal gut mucosa and mucosa of animals with TNBS colitis, as well as the influence of Mesalamine (M.) and Prednisolone (P.) on the severity of TNBS colitis following orally administered I. Methods and Materials. 156 Wistar rats were allocated into 10 groups. Colitis was induced by TNBS. On the 8th day, all animals were euthanatized. Activity of colitis and extent of tissue damage were assessed histologically. The levels of tissue tumor necrosis factor-α (t-TNF-α) and tissue malondialdehyde (t-MDA) were estimated in all animal groups. Results. Moderate and high I. supplementation induced inflammation in the healthy colon and increased the activity of the experimentally induced TNBS colitis. Administration of M. on TNBS colitis following moderate iron supplementation (0.3 g/Kg diet) resulted in a significant improvement in the overall histological score as well as in two individual histological parameters. M. administration, however, did not significantly reduce the t-TNF-α levels (17.67 ± 4.92 versus 14.58 ± 5.71, P = 0.102), although it significantly reduced the t-MDA levels (5.79 ± 1.55 versus 3.67 ± 1.39, P = 0.000). Administration of M. on TNBS colitis following high iron supplementation (3.0 g/Kg diet) did not improve the overall histological score and the individual histological parameters, neither reduced the levels of t-TNF-α (16.57  ± 5.61 versus 14.65 ± 3.88, P = 0.296). However, M. significantly reduced the t-MDA levels (5.99 ± 1.37 versus 4.04 ± 1.41, P = 0.000). Administration of P. on TNBS colitis after moderate iron supplementation resulted in a significant improvement in the overall histological score as well as in three individual histological parameters. P. also resulted in a significant reduction in the t-TNF-α levels (17.67 ± 4

Temporal comorbidity of mental disorder and ulcerative colitis.

PubMed

Cawthorpe, David; Davidson, Marta

2015-01-01

Ulcerative colitis is an inflammatory bowel disease that rarely exists in isolation in affected patients. We examined the association of ulcerative colitis and International Classification of Diseases mental disorder, as well as the temporal comorbidity of three broad International Classification of Diseases groupings of mental disorders in patients with ulcerative colitis to determine if mental disorder is more likely to occur before or after ulcerative colitis. We used physician diagnoses from the regional health zone of Calgary, Alberta, for patient visits from fiscal years 1994 to 2009 for treatment of any presenting concern in that Calgary health zone (763,449 patients) to identify 5113 patients age younger than 1 year to age 92 years (2120 males, average age = 47 years; 2993 females, average age = 48 years) with a diagnosis of ulcerative colitis. The 16-year cumulative prevalence of ulcerative colitis was 0.0058%, or 58 cases per 10,000 persons (95% confidence interval = 56-60 per 10,000). Although the cumulative prevalence of mental disorder in the overall sample was 5390 per 10,000 (53.9%), we found that 4192 patients with ulcerative colitis (82%) also had a diagnosis of a mental disorder. By annual rate of ulcerative colitis, patients with mental disorder had a significantly higher annual prevalence. The mental disorder grouping neuroses/depressive disorders was most likely to arise before ulcerative colitis (odds ratio = 1.87 for males; 2.24 for females). A temporal association was observed between specific groups of International Classification of Diseases mental disorder and ulcerative colitis, indicating a possible etiologic relationship between the disorders or their treatments, or both.

Experimental colitis models: Insights into the pathogenesis of inflammatory bowel disease and translational issues.

PubMed

Valatas, Vassilis; Bamias, Giorgos; Kolios, George

2015-07-15

Inflammatory bowel diseases, ulcerative colitis and Crohn׳s disease are characterized by chronic relapsing inflammation of the gastrointestinal tract of unknown etiology that seems to be the consequence of a genetically driven dysregulated immune response against various local and environmental triggers through a defective epithelial barrier. During the last decades, a large number of animal experimental models of intestinal inflammation have been generated and provided valuable insights into the mechanisms that either maintain mucosal homeostasis or drive intestinal inflammation. Their study enabled the identification of various treatment targets and the development a large pipeline of new drugs, mostly biologics. Safety and therapeutic efficacy of these agents have been evaluated in a large number of clinical trials but only a minority has reached the clinic so far. Translational successes but mostly translational failures have prompted to re-evaluate results of efficacy and safety generated by pre-clinical testing and to re-examine the way to interpret experimental in vivo data. This review examines the contribution of the most popular experimental colitis models to our understanding of the pathogenesis of human inflammatory bowel diseases and their translational input in drug development and discusses ways to improve translational outcome. Copyright © 2015 Elsevier B.V. All rights reserved.

Oral administration of red ginseng powder fermented with probiotic alleviates the severity of dextran-sulfate sodium-induced colitis in a mouse model.

PubMed

Jang, Sun-Hee; Park, Jisang; Kim, Sae-Hae; Choi, Kyung-Min; Ko, Eun-Sil; Cha, Jeong-Dan; Lee, Young-Ran; Jang, Hyonseok; Jang, Yong-Suk

2017-03-01

Red ginseng is a well-known alternative medicine with anti-inflammatory activity. It exerts pharmacological effects through the transformation of saponin into metabolites by intestinal microbiota. Given that intestinal microflora vary among individuals, the pharmacological effects of red ginseng likely vary among individuals. In order to produce homogeneously effective red ginseng, we prepared probiotic-fermented red ginseng and evaluated its activity using a dextran sulfate sodium (DSS)-induced colitis model in mice. Initial analysis of intestinal damage indicated that the administration of probiotic-fermented red ginseng significantly decreased the severity of colitis, compared with the control and the activity was higher than that induced by oral administration of ginseng powder or probiotics only. Subsequent analysis of the levels of serum IL-6 and TNF-α, inflammatory biomarkers that are increased at the initiation stage of colitis, were significantly decreased in probiotic-fermented red ginseng-treated groups in comparison to the control group. The levels of inflammatory cytokines and mRNAs for inflammatory factors in colorectal tissues were also significantly decreased in probiotic-fermented red ginseng-treated groups. Collectively, oral administration of probiotic-fermented red ginseng reduced the severity of colitis in a mouse model, suggesting that it can be used as a uniformly effective red ginseng product. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Ulcerative colitis associated with primary biliary cirrhosis.

PubMed

Koulentaki, M; Koutroubakis, I E; Petinaki, E; Tzardi, M; Oekonomaki, H; Mouzas, I; Kouroumalis, E A

1999-10-01

Primary biliary cirrhosis and ulcerative colitis are two diseases with many features of autoimmunity. Thirteen cases of coexistence of the two diseases have been reported in the literature so far. Patients are usually younger and more often males than the ordinary primary biliary cirrhosis patient, while the colitis is mild and easily controllable. In a homogeneous population of 550,000 inhabitants of the island of Crete, 412 cases of ulcerative colitis and 82 individuals with primary biliary cirrhosis or autoimmune cholangitis have been identified. In two cases, coexistence of the two diseases was found. Immunological screening for AMA positivity in 150 ulcerative colitis sera disclosed no further cases. Prevalence of primary biliary cirrhosis in ulcerative colitis patients seems at least 30 times higher than in the general population in our area. A possible immunological link between the two diseases is discussed.

Essential roles of high-mobility group box 1 in the development of murine colitis and colitis-associated cancer

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

Maeda, Shin; Hikiba, Yohko; Shibata, Wataru

2007-08-24

High-mobility group box 1 (HMGB1) is a nuclear factor released extracellularly as a proinflammatory cytokine. We measured the HMGB1 concentration in the sera of mice with chemically induced colitis (DSS; dextran sulfate sodium salt) and found a marked increase. Inhibition of HMGB1 by neutralizing anti-HMGB1 antibody resulted in reduced inflammation in DSS-treated colons. In macrophages, HMGB1 induces several proinflammatory cytokines, such as IL-6, which are regulated by NF-{kappa}B activation. Two putative sources of HMGB1 were explored: in one, bacterial factors induce HMGB1 secretion from macrophages and in the other, necrotic epithelial cells directly release HMGB1. LPS induced a small amountmore » of HMGB1 in macrophages, but macrophages incubated with supernatant prepared from necrotic cells and containing large amounts of HMGB1 activated NF-{kappa}B and induced IL-6. Using the colitis-associated cancer model, we demonstrated that neutralizing anti-HMGB1 antibody decreases tumor incidence and size. These observations suggest that HMGB1 is a potentially useful target for IBD treatment and the prevention of colitis-associated cancer.« less

The Association Between CMV Viremia or Endoscopic Features and Histopathological Characteristics of CMV Colitis in Patients with Underlying Ulcerative Colitis.

PubMed

Yang, Hong; Zhou, Weixun; Lv, Hong; Wu, Dongsheng; Feng, Yunlu; Shu, Huijun; Jin, Meng; Hu, Lingling; Wang, Qiang; Wu, Dong; Chen, Jie; Qian, Jiaming

2017-05-01

Cytomegalovirus (CMV) infection has been shown to be related to severe or steroid-refractory ulcerative colitis (UC) flare-ups. The aim of this study was to evaluate the endoscopic and pathological characteristics of CMV colitis in patients with UC and to assess the predictive value of the endoscopic and pathological features of CMV colitis. A total of 50 consecutive UC patients with CMV infection who were admitted to Peking Union Medical College Hospital from 2010 to 2015 were enrolled in this study. Twenty-five UC patients with CMV infection (50.0%) had concurrent CMV colitis. When the cutoff value was set at 1150 copies, the sensitivity and specificity of blood CMV DNAq polymerase chain reaction for predicting CMV colitis were 44.4% and 78.9%, respectively. A higher proportion of endoscopic punched-out ulcers, irregular ulcers, and cobblestone-like appearance were observed among the patients in the CMV colitis group than those in the non-CMV colitis group (52.0% versus 20.0%, 60.0% versus 16.0%, and 20.0% versus 0%, respectively, P < 0.05). The number of CMV inclusion bodies per high-power field was significantly higher in those with punch-out ulcerations (25.7% versus 60.0%, P < 0.05). A higher grade of pathological inflammation was observed in the CMV colitis group than in the control group (68.0% versus 44.0%). Characteristic endoscopic features with punch-out ulcers and high CMV viremia load may be useful for predicting the presence of CMV colitis in histology. Punch-out ulcers were found to be associated with a higher number of inclusion bodies on histology, suggesting a role of targeted biopsy for endoscopist.

Interobserver variability and feasibility of polymerase chain reaction-based assay in distinguishing ischemic colitis from Clostridium difficile colitis in endoscopic mucosal biopsies.

PubMed

Wiland, Homer O; Procop, Gary W; Goldblum, John R; Tuohy, Marion; Rybicki, Lisa; Patil, Deepa T

2013-06-01

Polymerase chain reaction (PCR)-based assays using stool samples are currently the most effective method of detecting Clostridium difficile. This study examines the feasibility of this assay using mucosal biopsy samples and evaluates the interobserver reproducibility in diagnosing and distinguishing ischemic colitis from C difficile colitis. Thirty-eight biopsy specimens were reviewed and classified by 3 observers into C difficile and ischemic colitis. The findings were correlated with clinical data. PCR was performed on 34 cases using BD GeneOhm C difficile assay. The histologic interobserver agreement was excellent (κ= 0.86) and the agreement between histologic and clinical diagnosis was good (κ = 0.84). All 19 ischemic colitis cases tested negative (100% specificity) and 3 of 15 cases of C difficile colitis tested positive (20% sensitivity). C difficile colitis can be reliably distinguished from ischemic colitis using histologic criteria. The C difficile PCR test on endoscopic biopsy specimens has excellent specificity but limited sensitivity.

Current and emerging biologics for ulcerative colitis.

PubMed

Park, Sung Chul; Jeen, Yoon Tae

2015-01-01

Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy. Hence, different biological agents that target specific immunological pathways are be-ing investigated for treating ulcerative colitis. Anti-tumor necrosis factor (TNF) agents were the first biologics to be used for treating inflammatory bowel disease. For example, infliximab and adalimumab, which are anti-TNF agents, are be-ing used for treating ulcerative colitis. Recently, golimumab, another anti-TNF agent, and vedolizumab, an anti-adhesion therapy, have been approved for ulcerative colitis by the U.S. Food and Drug Administration. In addition, new medications such as tofacitinib, a Janus kinase inhibitor, and etrolizumab, another anti-adhesion therapy, are emerging as therapeutic agents. Therefore, there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage.

Current and Emerging Biologics for Ulcerative Colitis

PubMed Central

Park, Sung Chul; Jeen, Yoon Tae

2015-01-01

Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy. Hence, different biological agents that target specific immunological pathways are being investigated for treating ulcerative colitis. Anti-tumor necrosis factor (TNF) agents were the first biologics to be used for treating inflammatory bowel disease. For example, infliximab and adalimumab, which are anti-TNF agents, are being used for treating ulcerative colitis. Recently, golimumab, another anti-TNF agent, and vedolizumab, an anti-adhesion therapy, have been approved for ulcerative colitis by the U.S. Food and Drug Administration. In addition, new medications such as tofacitinib, a Janus kinase inhibitor, and etrolizumab, another anti-adhesion therapy, are emerging as therapeutic agents. Therefore, there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage. PMID:25547087

Allogeneic guinea pig mesenchymal stem cells ameliorate neurological changes in experimental colitis.

PubMed

Stavely, Rhian; Robinson, Ainsley M; Miller, Sarah; Boyd, Richard; Sakkal, Samy; Nurgali, Kulmira

2015-12-30

The use of mesenchymal stem cells (MSCs) to treat inflammatory bowel disease (IBD) is of great interest because of their immunomodulatory properties. Damage to the enteric nervous system (ENS) is implicated in IBD pathophysiology and disease progression. The most commonly used model to study inflammation-induced changes to the ENS is 2,4,6-trinitrobenzene-sulfonate acid (TNBS)-induced colitis in guinea pigs; however, no studies using guinea pig MSCs in colitis have been performed. This study aims to isolate and characterise guinea pig MSCs and then test their therapeutic potential for the treatment of enteric neuropathy associated with intestinal inflammation. MSCs from guinea pig bone marrow and adipose tissue were isolated and characterised in vitro. In in vivo experiments, guinea pigs received either TNBS for the induction of colitis or sham treatment by enema. MSCs were administered at a dose of 1 × 10(6) cells via enema 3 h after the induction of colitis. Colon tissues were collected 24 and 72 h after TNBS administration to assess the level of inflammation and damage to the ENS. The secretion of transforming growth factor-β1 (TGF-β1) was analysed in MSC conditioned medium by flow cytometry. Cells isolated from both sources were adherent to plastic, multipotent and expressed some human MSC surface markers. In vitro characterisation revealed distinct differences in growth kinetics, clonogenicity and cell morphology between MSC types. In an in vivo model of TNBS-induced colitis, guinea pig bone marrow MSCs were comparatively more efficacious than adipose tissue MSCs in attenuating weight loss, colonic tissue damage and leukocyte infiltration into the mucosa and myenteric plexus. MSCs from both sources were equally neuroprotective in the amelioration of enteric neuronal loss and changes to the neurochemical coding of neuronal subpopulations. MSCs from both sources secreted TGF-β1 which exerted neuroprotective effects in vitro. This study is the first

Angelica acutiloba Kitagawa Extract Attenuates DSS-Induced Murine Colitis

PubMed Central

Jang, Jong-Chan; Lee, Kang Min

2016-01-01

We examined the protective effects of Angelica acutiloba Kitagawa (AAK) extract on a murine model of acute experimental colitis. Colitis was induced by 4% dextran sulfate sodium (DSS) in the drinking water of male C57BL/6 mice, for 7 consecutive days. Oral administration of AAK extract (500 mg/kg/day) significantly alleviated DSS-induced symptoms such as anorexia, weight loss, events of diarrhea or bloody stools, and colon shortening. Histological damage was also ameliorated, as evidenced by the architectural preservation and suppression of inflammatory cell infiltration in colonic samples. Treatment improved the colonic mRNA expression of different inflammatory markers: cytokines, inducible enzymes, matrix metalloproteinases, and tight junction-related proteins. In the isolated serum, IgE levels were downregulated. Collectively, these findings indicate the therapeutic potentials of AAK as an effective complementary or alternative modality for the treatment of ulcerative colitis. PMID:27293323

Mesalamine inhibits epithelial beta-catenin activation in chronic ulcerative colitis.

PubMed

Brown, Jeffrey B; Lee, Goo; Managlia, Elizabeth; Grimm, Gery R; Dirisina, Ramanarao; Goretsky, Tatiana; Cheresh, Paul; Blatner, Nichole R; Khazaie, Khashayarsha; Yang, Guang-Yu; Li, Linheng; Barrett, Terrence A

2010-02-01

Mesalamine is a mainstay therapeutic agent in chronic ulcerative colitis (CUC) in which condition it reverses crypt architectural changes and reduces colitis-associated cancer (CAC). The present study addressed the possibility that mesalamine reduces beta-catenin-associated progenitor cell activation, Akt-phosphorylated beta-catenin(Ser552) (P-beta-catenin), and colitis-induced dysplasia (CID). Effects of mesalamine on P-beta-catenin staining and function were assessed by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in biopsy specimens of CUC in mild or "refractory" severe mucosal inflammation. Effects of mesalamine on epithelial proliferation and activation of Akt and beta-catenin were assessed in interleukin (IL)-10(-/-) colitis and CID by immunohistochemistry and Western blotting. Dysplasia was assessed by counting the number and lengths of lesions per colon. Data from IL-10(-/-) and human colitis samples show that mesalamine reduced Akt activation and P-beta-catenin levels in the middle and upper crypt. Reductions in P-beta-catenin in CUC biopsy specimens with severe inflammation suggested that mesalamine reduced P-beta-catenin levels in tissue refractory to mesalamine's anti-inflammatory effects. In IL-10(-/-) mice, mesalamine reduced CID concordant with inhibition of crypt Akt and beta-catenin signaling. The results are consistent with the model that mesalamine contributes to chemoprevention in CAC by reducing beta-catenin signaling within intestinal progenitors.

CMV colitis in early HIV infection.

PubMed

Smith, P R; Glynn, M; Sheaff, M; Aitken, C

2000-11-01

Cytomegalovirus (CMV) colitis is a well recognized complication of advanced HIV disease and is only rarely diagnosed in patients with normal immune function. A case of CMV colitis occurring in early HIV infection is described. Although CMV infection is normally confined to patients with advanced HIV disease, it is possible that a number of contributing factors may have led to clinical disease in this patient. CMV colitis is an important diagnosis to consider in all patients who present with a diarrhoeal illness associated with systemic features, regardless of underlying immunosuppression.

[Cytomegalovirus colitis in immunocompetent young male].

PubMed

Rasmussen, Eva; Grønbaek, Karin; Linnemann, Dorte

2009-04-06

A healthy young man was hospitalized due to fever, malaise and bloody stools for three weeks. The patient had a primary CMV infection based on biochemical, serological and ultrasonic results, and a colonoscopy was consistent with left-sided CMV colitis. He recovered spontaneously, though haematochezia remained present after six months. Development of IBD subsequent to CMV colitis has previously been described, and is now suspected in our patient. CMV colitis is a rare but possible differential diagnosis in immunocompetent patients with fever, elevated liver enzymes and bloody stools.

Elevated fecal peptidase D at onset of colitis in Galphai2-/- mice, a mouse model of IBD.

PubMed

Bergemalm, Daniel; Kruse, Robert; Sapnara, Maria; Halfvarson, Jonas; Hörnquist, Elisabeth Hultgren

2017-01-01

The identification of novel fecal biomarkers in inflammatory bowel disease (IBD) is hampered by the complexity of the human fecal proteome. On the other hand, in experimental mouse models there is probably less variation. We investigated the fecal protein content in mice to identify possible biomarkers and pathogenic mechanisms. Fecal samples were collected at onset of inflammation in Galphai2-/- mice, a well-described spontaneous model of chronic colitis, and from healthy littermates. The fecal proteome was analyzed by two-dimensional electrophoresis and quantitative mass spectrometry and results were then validated in a new cohort of mice. As a potential top marker of disease, peptidase D was found at a higher ratio in Galphai2-/- mouse feces relative to controls (fold change 27; p = 0.019). Other proteins found to be enriched in Gαi2-/- mice were mainly pancreatic proteases, and proteins from plasma and blood cells. A tendency of increased calprotectin, subunit S100-A8, was also observed (fold change 21; p = 0.058). Proteases are potential activators of inflammation in the gastrointestinal tract through their interaction with the proteinase-activated receptor 2 (PAR2). Accordingly, the level of PAR2 was found to be elevated in both the colon and the pancreas of Galphai2-/- mice at different stages of disease. These findings identify peptidase D, an ubiquitously expressed intracellular peptidase, as a potential novel marker of colitis. The elevated levels of fecal proteases may be involved in the pathogenesis of colitis and contribute to the clinical phenotype, possibly by activation of intestinal PAR2.

Long-term natural history and complications of collagenous colitis.

PubMed

Freeman, Hugh J

2012-09-01

Microscopic forms of colitis have been described, including collagenous colitis, a possibly heterogeneous disorder. Collagenous colitis most often appears to have an entirely benign clinical course that usually responds to limited treatment. Sometimes significant extracolonic disorders, especially arthritis, spondylitis, thyroiditis and skin disorders, such as pyoderma gangrenosum, dominate the clinical course and influence the treatment strategy. However, rare fatalities have been reported and several complications, some severe, have been attributed directly to the colitis. Toxic colitis and toxic megacolon may develop. Concomitant gastric and small intestinal inflammatory disorders have been described including celiac disease and more extensive collagenous inflammatory disease. Colonic ulceration has been associated with the use of nonsteroidal anti-inflammatory drugs, while other forms of inflammatory bowel disease, including ulcerative colitis and Crohn disease, may evolve directly from collagenous colitis. Submucosal 'dissection', colonic fractures, or mucosal tears and perforation, possibly from air insufflation during colonoscopy, have been reported. Similar changes may result from increased intraluminal pressures that may occur during radiological imaging of the colon. Neoplastic disorders of the colon may also occur during the course of collagenous colitis, including colon carcinoma and neuroendocrine tumours (ie, carcinoids). Finally, lymphoproliferative disease has been reported.

Medicinal Plants in the Treatment of Colitis: Evidence from Preclinical Studies.

PubMed

Santana, Marília T; Cercato, Luana M; Oliveira, Janaíne P; Camargo, Enilton A

2017-05-01

Ulcerative colitis is a chronic inflammatory condition whose treatment includes aminosalicylates, corticosteroids, and immunomodulators. Medicinal plants seem to be an important alternative treatment for this condition. They have been the subject of a great number of studies in recent years. This study was conducted to systematically review the medicinal plants tested in experimental models of ulcerative colitis. We conducted a systematic literature search through specialized databases (PUBMED, SCOPUS, EMBASE, MEDLINE, LILACS, SCIELO, and SCISEARCH) and selected articles published between January 2000 and June 21, 2016 by using "medicinal plants" and "ulcerative colitis" as key words. Sixty-eight studies were included, and the families Asteraceae and Lamiaceae presented the largest number of studies, but plants from several other families were cited; many of them have shown good results in experimental animals. However, only a few species (such as Andrographis paniculata and Punica granatum ) have undergone clinical tests against ulcerative colitis, and the observation that many preclinical studies reviewed are purely descriptive has certainly contributed to this fact. Chemical constituents (mainly flavonoids and terpenes) seem to play a role in the effects of the plants. Thus, the data herein reviewed reinforce the potential of medicinal plants as a source of alternative approaches to the treatment of ulcerative colitis. Georg Thieme Verlag KG Stuttgart · New York.

Potential role for ET-2 acting through ETA receptors in experimental colitis in mice.

PubMed

Claudino, R F; Leite, D F; Bento, A F; Chichorro, J G; Calixto, J B; Rae, G A

2017-02-01

This study attempted to clarify the roles of endothelins and mechanisms associated with ET A /ET B receptors in mouse models of colitis. Colitis was induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS, 1.5 mg/animal) or dextran sulfate sodium (DSS, 3%). After colitis establishment, mice received Atrasentan (ET A receptor antagonist, 10 mg/kg), A-192621 (ET B receptor antagonist, 20 mg/kg) or Dexamethasone (1 mg/kg) and several inflammatory parameters were assessed, as well as mRNA levels for ET-1, ET-2 and ET receptors. Atrasentan treatment ameliorates TNBS- and DSS-induced colitis. In the TNBS model was observed reduction in macroscopic and microscopic score, colon weight, neutrophil influx, IL-1β, MIP-2 and keratinocyte chemoattractant (KC) levels, inhibition of adhesion molecules expression and restoration of IL-10 levels. However, A192621 treatment did not modify any parameter. ET-1 and ET-2 mRNA was decreased 24 h, but ET-2 mRNA was markedly increased at 48 h after TNBS. ET-2 was able to potentiate LPS-induced KC production in vitro. ET A and ET B receptors mRNA were increased at 24, 48 and 72 h after colitis induction. Atrasentan treatment was effective in reducing the severity of colitis in DSS- and TNBS-treated mice, suggesting that ET A receptors might be a potential target for inflammatory bowel diseases.

Unusual complication of toxic megacolon in typhoid colitis.

PubMed

Arun Babu, Thirunavukkarasu; Ananthakrishnan, Shanthi; Jayakumar, P; Kullu, Poonam

2014-05-01

Colitis is a rare manifestation of enteric fever in children. Toxic megacolon complicating typhoid colitis is even rarer and requires early recognition and aggressive management due to the high mortality associated with this condition. The authors report a rare case of Toxic megacolon secondary to typhoid colitis in a seven-year-old girl.

Anti-inflammatory and anti-apoptotic effects of rosuvastatin by regulation of oxidative stress in a dextran sulfate sodium-induced colitis model

PubMed Central

Shin, Seung Kak; Cho, Jae Hee; Kim, Eui Joo; Kim, Eun-Kyung; Park, Dong Kyun; Kwon, Kwang An; Chung, Jun-Won; Kim, Kyoung Oh; Kim, Yoon Jae

2017-01-01

AIM To evaluate the anti-inflammatory and anti-apoptotic effects of rosuvastatin by regulation of oxidative stress in a dextran sulfate sodium (DSS)-induced colitis model. METHODS An acute colitis mouse model was induced by oral administration of 5% DSS in the drinking water for 7 d. In the treated group, rosuvastatin (0.3 mg/kg per day) was administered orally before and after DSS administration for 21 d. On day 21, mice were sacrificed and the colons were removed for macroscopic examination, histology, and Western blot analysis. In the in vitro study, IEC-6 cells were stimulated with 50 ng/mL tumor necrosis factor (TNF)-α and then treated with or without rosuvastatin (2 μmol/L). The levels of reactive oxygen species (ROS), inflammatory mediators, and apoptotic markers were measured. RESULTS In DSS-induced colitis mice, rosuvastatin treatment significantly reduced the disease activity index and histological damage score compared to untreated mice (P < 0.05). Rosuvastatin also attenuated the DSS-induced increase of 8-hydroxy-2’-deoxyguanosine and NADPH oxidase-1 expression in colon tissue. Multiplex ELISA analysis revealed that rosuvastatin treatment reduced the DSS-induced increase of serum IL-2, IL-4, IL-5, IL-6, IL-12 and IL-17, and G-CSF levels. The increased levels of cleaved caspase-3, caspase-7, and poly (ADP-ribose) polymerase in the DSS group were attenuated by rosuvastatin treatment. In vitro, rosuvastatin significantly reduced the production of ROS, inflammatory mediators and apoptotic markers in TNF-α-treated IEC-6 cells (P < 0.05). CONCLUSION Rosuvastatin had the antioxidant, anti-inflammatory and anti-apoptotic effects in DSS-induced colitis model. Therefore, it might be a candidate anti-inflammatory drug in patients with inflammatory bowel disease. PMID:28740344

Inflammatory Bowel Disease Therapies and Gut Function in a Colitis Mouse Model

PubMed Central

Nahidi, Lily; Leach, Steven T.; Mitchell, Hazel M.; Kaakoush, Nadeem O.; Lemberg, Daniel A.; Munday, John S.; Huinao, Karina; Day, Andrew S.

2013-01-01

Background. Exclusive enteral nutrition (EEN) is a well-established approach to the management of Crohn's disease. Aim. To determine effects of EEN upon inflammation and gut barrier function in a colitis mouse model. Methods. Interleukin-10-deficient mice (IL-10−/−) were inoculated with Helicobacter trogontum and then treated with EEN, metronidazole, hydrocortisone, or EEN and metronidazole combination. Blood and tissue were collected at 2 and 4 weeks with histology, mucosal integrity, tight junction integrity, inflammation, and H. trogontum load evaluated. Results. H. trogontum induced colitis in IL-10−/− mice with histological changes in the cecum and colon. Elevated mucosal IL-8 mRNA in infected mice was associated with intestinal barrier dysfunction indicated by decreased transepithelial electrical resistance and mRNA of tight junction proteins and increased short-circuit current, myosin light chain kinase mRNA, paracellular permeability, and tumor necrosis factor-α and myeloperoxidase plasma levels (P < 0.01 for all comparisons). EEN and metronidazole, but not hydrocortisone, treatments restored barrier function, maintained gut barrier integrity, and reversed inflammatory changes along with reduction of H. trogontum load (versus infected controls P < 0.05). Conclusion. H. trogontum infection in IL-10−/− mice induced typhlocolitis with intestinal barrier dysfunction. EEN and metronidazole, but not hydrocortisone, modulate barrier dysfunction and reversal of inflammatory changes. PMID:24027765

Pharmaceutical Activation or Genetic Absence of ClC-2 Alters Tight Junctions During Experimental Colitis.

PubMed

Jin, Younggeon; Pridgen, Tiffany A; Blikslager, Anthony T

2015-12-01

We have previously reported that the ClC-2 chloride channel has an important role in regulation of tight junction barrier function during experimental colitis, and the pharmaceutical ClC-2 activator lubiprostone initiates intestinal barrier repair in ischemic-injured intestine. Thus, we hypothesized that pharmaceutical ClC-2 activation would have a protective and therapeutic effect in murine models of colitis, which would be absent in ClC-2 mice. We administered lubiprostone to wild-type or ClC-2 mice with dextran sulfate sodium (DSS) or 2, 4, 5-trinitrobenzene sulfonic acid-induced colitis. We determined the severity of colitis and assessed intestinal permeability. Selected tight junction proteins were analyzed by Western blotting and immunofluorescence/confocal microscopy, whereas proliferative and differentiated cells were examined with special staining and immunohistochemistry. Oral preventive or therapeutic administration of lubiprostone significantly reduced the severity of colitis and reduced intestinal permeability in both DSS and trinitrobenzene sulfonic acid-induced colitis. Preventive treatment with lubiprostone induced significant recovery of the expression and distribution of selected sealing tight junction proteins in mice with DSS-induced colitis. In addition, lubiprostone reduced crypt proliferation and increased the number of differentiated epithelial cells. Alternatively, when lubiprostone was administered to ClC-2 mice, the protective effect against DSS colitis was limited. This study suggests a central role for ClC-2 in restoration of barrier function and tight junction architecture in experimental murine colitis, which can be therapeutically targeted with lubiprostone.

[Ulcerative colitis and Crohn's disease].

PubMed

Pavlović-Calić, Nada

2003-01-01

There is an enigma of inflammatory bowel diseases, despite significant advantages during last 10 years in medicamentous and surgical treatment. Ulcerative colitis and Crohns disease are chronic with remissions and recidives. Crohns disease involves any part of digestive tube. Histological changes in ulcerative colitis are: inflammation of mucosa and submucosal tissue, crypt abscesses and ulcerations, pseudopolpys, bowel shortening and toxic megacolon in severe inflammation. In Crohns disease, transmural inflammation, "jumping lesions", deeper ulcerations, coble-stone mucosa, progressive fibrosis, granuloma with gigantic epithelial cells. ulcerative colitis: mesalazine, rectal 5-ASA and hydrocortisone enemas, surgery. Crohns disease: mesalazine and prednisolone. For terminal ilcitis, corticosteroid budesonid could be applied. Severe symptomatic disease: hospitalization, parenteral nutrition, antibiotics, prednisone, surgery in partial bowel obstruction, fistulas, abscessus, perforation.

Myristica fragrans seed extract protects against dextran sulfate sodium-induced colitis in mice.

PubMed

Kim, Hyojung; Bu, Youngmin; Lee, Beom-Joon; Bae, Jinhyun; Park, Sujin; Kim, Jinsung; Lee, Kyungjin; Cha, Jae-Myung; Ryu, Bongha; Ko, Seok-Jae; Han, Gajin; Min, Byungil; Park, Jae-Woo

2013-10-01

Nutmeg (seed of Myristica fragrans [MF]) is one of the most commonly used spices in the world and also a well-known herb for the treatment of various intestinal diseases, including colitis in traditional Korean medicine. The purpose of the current study was to investigate whether water extract of MF (MFE) can protect against dextran sulfate sodium (DSS) induced colitis in a mouse model. Colitis was induced by 5% DSS in balb/c mice. MFE (100, 300 or 1000 mg/kg) was orally administered to the mice twice a day for 7 days. Body weight, colon length, clinical score, and histological score were assessed to determine the effects on colitis. Proinflammatory cytokines (interferon-γ, tumor necrosis factor-α, interleukin [IL]-1β, and IL-6) were measured to investigate the mechanisms of action. MFE dose dependently inhibited the colon shortening and histological damage to the colon. However, it did not prevent weight loss. MFE also inhibited proinflammatory cytokines. The current results suggest that MFE ameliorates DSS-induced colitis in mice by inhibiting inflammatory cytokines. Further investigation, including the exact mechanisms is needed.

Ischemic colitis related to sumatriptan overuse.

PubMed

Hodge, Joshua A; Hodge, Katherine D

2010-01-01

Serotonin-1 5-hydroxytryptamine (5-HT 1) receptor agonists are first line agents for migraine headaches. Patients with refractory headaches may use supratherapeutic doses of these medications. Described is a case of ischemic colitis related to overuse of sumatriptan. A 35-year-old woman presented with severe abdominal pain without diarrhea or hematochezia. For several days prior she had been self-treating a refractory migraine headache with frequent doses of sumatriptan. She is a nonsmoker and took no oral contraceptives or other serotonin agonists. A computed tomography scan of the abdomen revealed left-sided colitis. A colonoscopy with biopsy confirmed ischemic colitis and excluded inflammatory bowel disease (IBD). Previously published case reports have suggested an association between 5-HT 1 receptor agonists and ischemic colitis. These reports have been dismissed because the patients were taking oral contraceptives, serotonin agonists, or had other comorbidities. This healthy patient lacked risk factors for ischemia, is the youngest to be reported, and is the first without hematochezia. 5-HT 1 receptor agonists are generally considered safe. Ischemic colitis is a potentially serious complication of these agents. A retrospective review of 5-HT 1 receptor agonist users who have presented with acute onset abdominal pain or hematochezia is necessary to elucidate the incidence of this adverse event.

Therapeutic and prophylactic thalidomide in TNBS-induced colitis: Synergistic effects on TNF-α, IL-12 and VEGF production

PubMed Central

Carvalho, Ana Teresa; Souza, Heitor; Carneiro, Antonio Jose; Castelo-Branco, Morgana; Madi, Kalil; Schanaider, Alberto; Silva, Flavia; Pereira Jứnior, Fernando Antonio; Pereira, Márcia G; Tortori, Cláudio; Dines, Ilana; Carvalho, Jane; Rocha, Eduardo; Elia, Celeste

2007-01-01

AIM: To evaluated the therapeutic and prophylactic effect of thalidomide on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Thalidomide has been reported to downregulate the expression of tumor necrosis factor α (TNF-α), IL-12, and vascular endothelial growth factor (VEGF), hallmarks of intestinal inflammation in Crohn’s disease (CD). METHODS: Male Wistar rats were divided in five groups of ten animals each. Four groups received a rectal infusion of TNBS in ethanol. The first group was sacrificed 7 d after colitis induction. The second and third groups received either thalidomide or placebo by gavage and were sacrificed at 14 d. The fourth group received thalidomide 6 h before TNBS administration, and was sacrificed 7 d after induction. The fifth group acted as the control group and colitis was not induced. Histological inflammatory scores of the colon were performed and lamina propria CD4+ T cells, macrophages, and VEGF+ cells were detected by immunohistochemistry. TNF-α and IL-12 were quantified in the supernatant of organ cultures by ELISA. RESULTS: Significant reduction in the inflammatory score and in the percentage of VEGF+ cells was observed in the group treated with thalidomide compared with animals not treated with thalidomide. Both TNF-α and IL-12 levels were significantly reduced among TNBS induced colitis animals treated with thalidomide compared with animals that did not receive thalidomide. TNF-α levels were also significantly reduced among the animals receiving thalidomide prophylaxis compared with untreated animals with TNBS-induced colitis. Intestinal levels of TNF-α and IL-12 were significantly correlated with the inflammatory score and the number of VEGF+ cells. CONCLUSION: Thalidomide significantly attenuates TNBS-induced colitis by inhibiting the intestinal production of TNF-α, IL-12, and VEGF. This effect may support the use of thalidomide as an alternate approach in selected patients with CD. PMID:17465495

Therapeutic and prophylactic thalidomide in TNBS-induced colitis: synergistic effects on TNF-alpha, IL-12 and VEGF production.

PubMed

Carvalho, Ana Teresa; Souza, Heitor; Carneiro, Antonio Jose; Castelo-Branco, Morgana; Madi, Kalil; Schanaider, Alberto; Silv, Flavia; Pereira Junior, Fernando Antonio; Pereira, Marcia G; Tortori, Claudio; Dines, Ilana; Carvalho, Jane; Rocha, Eduardo; Elia, Celeste

2007-04-21

To evaluated the therapeutic and prophylactic effect of thalidomide on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Thalidomide has been reported to downregulate the expression of tumor necrosis factor alpha (TNF-alpha), IL-12, and vascular endothelial growth factor (VEGF), hallmarks of intestinal inflammation in Crohnos disease (CD). Male Wistar rats were divided in five groups of ten animals each. Four groups received a rectal infusion of TNBS in ethanol. The first group was sacrificed 7 d after colitis induction. The second and third groups received either thalidomide or placebo by gavage and were sacrificed at 14 d. The fourth group received thalidomide 6 h before TNBS administration, and was sacrificed 7 d after induction. The fifth group acted as the control group and colitis was not induced. Histological inflammatory scores of the colon were performed and lamina propria CD4+ T cells, macrophages, and VEGF+ cells were detected by immunohistochemistry. TNF-alpha and IL-12 were quantified in the supernatant of organ cultures by ELISA. Significant reduction in the inflammatory score and in the percentage of VEGF+ cells was observed in the group treated with thalidomide compared with animals not treated with thalidomide. Both TNF-alpha and IL-12 levels were significantly reduced among TNBS induced colitis animals treated with thalidomide compared with animals that did not receive thalidomide. TNF-alpha levels were also significantly reduced among the animals receiving thalidomide prophylaxis compared with untreated animals with TNBS-induced colitis. Intestinal levels of TNF-alpha and IL-12 were significantly correlated with the inflammatory score and the number of VEGF+ cells. Thalidomide significantly attenuates TNBS-induced colitis by inhibiting the intestinal production of TNF-alpha, IL-12, and VEGF. This effect may support the use of thalidomide as an alternate approach in selected patients with CD.

Combined Treatment with Hyaluronic Acid and Mesalamine Protects Rats from Inflammatory Bowel Disease Induced by Intracolonic Administration of Trinitrobenzenesulfonic Acid.

PubMed

Chiu, Chih-Tung; Kuo, Sheng-Nan; Hung, Shao-Wen; Yang, Cheng-Yao

2017-05-30

Drugs such as mesalamine (5-ASA) are currently recommended for the treatment of inflammatory bowel disease (IBD). To reduce the frequency of their administration and improve their therapeutic effect, this study investigated the adhesion efficacy, wound healing promotion, and decrease in inflammation in ulcers in the colonic tissue of rats with colitis after combined treatment with hyaluronic acid (HA) and 5-ASA (IBD98-M). HA-fluoresceinamine (FL) conjugates successfully adhered to the mucosal layer and were conjugated in the vascular tissue. In addition, macroscopic and microscopic observations indicated that colonic injuries reduced significantly after treatment with IBD98-M. Compared with PBS and 5-ASA treatment alone, treatment with IBD98-M more effectively reduced bowel inflammation and promoted colonic mucosal healing in TNBS-induced colitis. IBD98-M treatment also reduced myeloperoxidase activity and the expression levels of cyclooxygenase 2 and tumor necrosis factor-αin the colitis tissue. In conclusion, IBD98-M treatment strongly promoted wound healing in colonic injuries and significantly inhibited MPO activity in the inflamed colon tissue of rats. Combined treatment with HA and 5-ASA can accelerate wound healing and reduce inflammatory reaction in rat colitis.

Identification of inflammation-related proteins in a murine colitis model by 2D fluorescence difference gel electrophoresis and mass spectrometry.

PubMed

Naito, Yuji; Takagi, Tomohisa; Okada, Hitomi; Omatsu, Tatsushi; Mizushima, Katsura; Handa, Osamu; Kokura, Satoshi; Ichikawa, Hiroshi; Fujiwake, Hideshi; Yoshikawa, Toshikazu

2010-05-01

The aim of this study was to identify new intestinal proteins potentially associated with acute inflammation using proteomic profiling of an in vivo mice model of ulcerative colitis. 2D fluorescence difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight spectrometer (MALDI-TOF) peptide mass fingerprinting were used to determine differentially expressed proteins between normal and inflamed intestinal mucosa. Acute colitis was induced by 8.0% dextran sodium sulfate (DSS) given p.o. for 7 days. Among a total of seven protein spots showing differential expression, we identified five different proteins, of which two were upregulated and three downregulated in colitis in comparison to normal mucosa, using the MASCOT search engine. 3-Hydroxy-3-methylglutaryl-coenzyme A synthase 2 and serpin b1a were upregulated proteins, and protein disulfide-isomerase A3, peroxiredoxin-6 and vimentin were identified as downregulated proteins. These identified proteins may be responsible for the development of the intestinal inflammation. 2D-DIGE and MALDI-TOF mass spectrometry are useful in the search for the differentially expressed proteins.

Melatonin modulates adiponectin expression on murine colitis with sleep deprivation.

PubMed

Kim, Tae Kyun; Park, Young Sook; Baik, Haing-Woon; Jun, Jin Hyun; Kim, Eun Kyung; Sull, Jae Woong; Sung, Ho Joong; Choi, Jin Woo; Chung, Sook Hee; Gye, Myung Chan; Lim, Ju Yeon; Kim, Jun Bong; Kim, Seong Hwan

2016-09-07

To determine adiponectin expression in colonic tissue of murine colitis and systemic cytokine expression after melatonin treatments and sleep deprivation. The following five groups of C57BL/6 mice were used in this study: (1) group I, control; (2) group II, 2% DSS induced colitis for 7 d; (3) group III, 2% DSS induced colitis and melatonin treatment; (4) group IV, 2% DSS induced colitis with sleep deprivation (SD) using specially designed and modified multiple platform water baths; and (5) group V, 2% DSS induced colitis with SD and melatonin treatment. Melatonin (10 mg/kg) or saline was intraperitoneally injected daily to mice for 4 d. The body weight was monitored daily. The degree of colitis was evaluated histologically after sacrificing the mice. Immunohistochemical staining and Western blot analysis was performed using anti-adiponectin antibody. After sampling by intracardiac punctures, levels of serum cytokines were measured by ELISA. Sleep deprivation in water bath exacerbated DSS induced colitis and worsened weight loss. Melatonin injection not only alleviated the severity of mucosal injury, but also helped survival during stressful condition. The expression level of adiponectin in mucosa was decreased in colitis, with the lowest level observed in colitis combined with sleep deprivation. Melatonin injection significantly (P < 0.05) recovered the expression of adiponectin. The expression levels of IL-6 and IL-17 were increased in the serum of mice with DSS colitis but decreased after melatonin injection. This study suggested that melatonin modulated adiponectin expression in colonic tissue and melatonin and adiponectin synergistically potentiated anti-inflammatory effects on colitis with sleep deprivation.

Usefulness of colonoscopy in ischemic colitis.

PubMed

Lozano-Maya, M; Ponferrada-Díaz, A; González-Asanza, C; Nogales-Rincón, O; Senent-Sánchez, C; Pérez-de-Ayala, V; Jiménez-Aleixandre, P; Cos-Arregui, E; Menchén-Fernández-Pacheco, P

2010-07-01

the ischemic colitis is intestinal the most frequent cause of ischemia. With this work we determine the demographic and clinical characteristics, and the usefulness of the colonoscopy in the patients with ischemic colitis diagnosed in our centre in relation to a change of therapeutic attitude. retrospective study in which were selected 112 patients diagnosed with ischemic colitis by colonoscopy and biopsy, in a period of five years. It was analyzed: age, sex, reason for examination, factors of cardiovascular risk, endoscopic degree of ischemia, change in the therapeutic attitude, treatment and outcome. the average age was of 73.64 + or - 12.10 years with an equal incidence in women (50.9%) and the men (49.1%). The associated factors were the HTA (61.1%), tobacco (37.2%) and antecedents of cardiovascular episode (52.2%). The most frequent reason for colonoscopy was rectorrhagia (53.6%) followed of the abdominal pain (30.4%), being urgent the 65.3%. Colonoscopy allowed a change in the therapeutic attitude in the 50 increasing in the urgent one to the 65.75%. Global mortality was of 27.67%. The serious ischemic colitis (25%) was more frequent in men (64.3%) in urgent indication (85.71%) and attends with high mortality (53.57%). Surgical treatment in the 57.14% was made with a good evolution in the 50%, whereas the patients with mild or moderate ischemic colitis had a better prognosis (favourable evolution in 80.95%) with smaller requirement of the surgical treatment (4.76%), p < 0.05. the colitis ischemic are more frequent in the older age. The most frequent symptoms are the rectorrhagia and the abdominal pain. The colonoscopy is a useful technique to evaluate the gravity and it induces a change of attitude according to the result of the same one. The evidence of a serious colitis supposed an increase of the necessity of surgery and worse prognosis.

The role of laparoscopic surgery for ulcerative colitis: systematic review with meta-analysis.

PubMed

Wu, Xiao-Jian; He, Xiao-Sheng; Zhou, Xu-Yu; Ke, Jia; Lan, Ping

2010-08-01

Crohn's disease is established in laparoscopic surgery due to partial bowel dissection and low postoperative complication rate. However, laparoscopic surgery for ulcerative colitis remains further discussed even if the trend of minimally invasive technique exists. This study is to figure out how laparoscopic surgery works for ulcerative colitis. Sixteen controlled trials were identified through the search strategy mentioned below. There was only one prospective randomized study among the studies selected. A meta-analysis pooled the outcome effects of laparoscopic surgery and open surgery was performed. Fixed effect model or random effect model was respectively used depending on the heterogeneity test of trials. Postoperative fasting time and postoperative hospital stay were shorter in laparoscopic surgery for ulcerative colitis (-1.37 [-2.15, -0.58], -3.22 [-4.20, -2.24], respectively, P < 0.05). Overall complication rate was higher in open surgery, compared with laparoscopic surgery (54.8% versus 39.3%, P = 0.004). However, duration of laparoscopic surgery for ulcerative colitis was extended compared with open surgery (weighted mean difference 69.29 min, P = 0.04). As to recovery of bowel function, peritoneal abscess, anastomotic leakage, postoperative bowel obstruction, wound infection, blood loss, and mortality, laparoscopic surgery did not show any superiority over open surgery. Re-operation rate was almost even (5.2% versus 7.3%). The whole conversion to open surgery was 4.2%. Laparoscopic surgery for ulcerative colitis was at least as safe as open surgery, even better in postoperative fasting time, postoperative hospital stay, and overall complication rate. However, clinical value of laparoscopic surgery for ulcerative colitis needed further evaluation with more well-designed and long-term follow-up studies.

Comparison of anti-inflammatory activities of an anthocyanin-rich fraction from Portuguese blueberries (Vaccinium corymbosum L.) and 5-aminosalicylic acid in a TNBS-induced colitis rat model.

PubMed

Pereira, Sónia R; Pereira, Rita; Figueiredo, Isabel; Freitas, Victor; Dinis, Teresa C P; Almeida, Leonor M

2017-01-01

Despite the actual therapeutic approaches for inflammatory bowel disease (IBD), efficient and secure alternative options remain a research focus. In this context, anthocyanins seem promising natural anti-inflammatory agents, but their action mechanisms and efficacy as compared with established drugs still require more clarification. The main aim of this study was to compare the anti-inflammatory action of a chemically characterized anthocyanin-rich fraction (ARF), obtained from Portuguese blueberries (Vaccinium corymbosum L.), with that of 5-aminosalicylic acid (5-ASA), a first-line drug in IBD, in a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rat model. Such fraction showed a high content and great molecular diversity of anthocyanins, with malvidin-3-galactoside and petunidin-3-arabinoside in the highest concentrations. After daily administration by intragastric infusion for 8 days, ARF, at a molar anthocyanin concentration about 30 times lower than 5-ASA, showed a higher effectiveness in counteracting the intestinal inflammation, as assessed by i) body weight variation and colon damage score, ii) reduction in leukocyte infiltration, iii) increase in antioxidant defenses and iv) by downregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in colon tissue homogenates. The strong inhibition of COX-2 expression seems to be a crucial anti-inflammatory mechanism common to both ARF and 5-ASA, but the additional higher abilities of anthocyanins to downregulate iNOS and to decrease leukocytes infiltration and to increase antioxidant defenses in colon may account for the much higher anti-inflammatory action of anthocyanins. These data may contribute to the development of a promising natural approach in IBD management.

Comparison of anti-inflammatory activities of an anthocyanin-rich fraction from Portuguese blueberries (Vaccinium corymbosum L.) and 5-aminosalicylic acid in a TNBS-induced colitis rat model

PubMed Central

Pereira, Sónia R.; Pereira, Rita; Figueiredo, Isabel; Freitas, Victor; Dinis, Teresa C. P.; Almeida, Leonor M.

2017-01-01

Despite the actual therapeutic approaches for inflammatory bowel disease (IBD), efficient and secure alternative options remain a research focus. In this context, anthocyanins seem promising natural anti-inflammatory agents, but their action mechanisms and efficacy as compared with established drugs still require more clarification. The main aim of this study was to compare the anti-inflammatory action of a chemically characterized anthocyanin-rich fraction (ARF), obtained from Portuguese blueberries (Vaccinium corymbosum L.), with that of 5-aminosalicylic acid (5-ASA), a first-line drug in IBD, in a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rat model. Such fraction showed a high content and great molecular diversity of anthocyanins, with malvidin-3-galactoside and petunidin-3-arabinoside in the highest concentrations. After daily administration by intragastric infusion for 8 days, ARF, at a molar anthocyanin concentration about 30 times lower than 5-ASA, showed a higher effectiveness in counteracting the intestinal inflammation, as assessed by i) body weight variation and colon damage score, ii) reduction in leukocyte infiltration, iii) increase in antioxidant defenses and iv) by downregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in colon tissue homogenates. The strong inhibition of COX-2 expression seems to be a crucial anti-inflammatory mechanism common to both ARF and 5-ASA, but the additional higher abilities of anthocyanins to downregulate iNOS and to decrease leukocytes infiltration and to increase antioxidant defenses in colon may account for the much higher anti-inflammatory action of anthocyanins. These data may contribute to the development of a promising natural approach in IBD management. PMID:28329021

Current Approach to the Evaluation and Management of Microscopic Colitis.

PubMed

Cotter, Thomas G; Pardi, Darrell S

2017-02-01

Microscopic colitis is a common cause of chronic watery diarrhea, particularly in the elderly. The accompanying symptoms, which include abdominal pain and fatigue, can markedly impair patients' quality of life. Diagnosis is based upon characteristic histologic findings of the colonic mucosa. This review focuses on the current approach to evaluation and management of patients with microscopic colitis. Although the incidence of microscopic colitis has been increasing over time, recent epidemiological studies show stabilization at 21.0-24.7 cases per 100,000 person-years. Recent research has further expanded our knowledge of the underlying pathophysiology and emphasized the entity of drug-induced microscopic colitis and the association with celiac disease. Two recent randomized studies have confirmed the effectiveness of oral budesonide for both induction and maintenance treatment of microscopic colitis and is now endorsed by the American Gastroenterological Association as first-line treatment. The incidence of microscopic colitis has stabilized at just over 20 cases per 100,000 person-years. Celiac disease and drug-induced microscopic colitis should be considered in all patients diagnosed with microscopic colitis. There are a number of treatments available for patients with microscopic colitis; however, budesonide is the only option well studied in controlled trials and is effective for both induction and maintenance treatment.

[Genetic and immunological basis for ulcerative colitis].

PubMed

Tsuchiya, Kiichiro; Watanabe, Mamoru

2005-05-01

Ulcerative colitis is a chronic inflammatory disease of the rectum and colon. Results from many studies in people and animals of intestinal inflammation suggest that ulcerative colitis results from environmental factors triggering a loss of tolerance for normal intestinal flora in genetically susceptible individuals. Although progress has been made in the overall management of the disease, there are few clinical data on biological agents in contrast to Crohn' s disease. Here, we discuss the genetic and immunological basis of ulcerative colitis including the recent findings.

Naringin ameliorates acetic acid induced colitis through modulation of endogenous oxido-nitrosative balance and DNA damage in rats

PubMed Central

Kumar, Venkatashivam Shiva; Rajmane, Anuchandra Ramchandra; Adil, Mohammad; Kandhare, Amit Dattatraya; Ghosh, Pinaki; Bodhankar, Subhash Laxman

2014-01-01

The aim of this study was to evaluate the effect of naringin on experimentally induced inflammatory bowel disease in rats. Naringin (20, 40 and 80 mg/kg) was given orally for 7 days to Wistar rats before induction of colitis by intrarectal instillation of 2 mL of 4% (v/v) acetic acid solution. The degree of colonic mucosal damage was analyzed by examining mucosal damage, ulcer area, ulcer index and stool consistency. Intrarectal administration of 4% acetic acid resulted in significant modulation of serum alkaline phosphatase, lactate dehydrogenase, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and myeloperoxidase (MPO) content along with colonic nitric oxide (NO), xanthine oxidase (XO) level and protein carbonyl content in the colonic tissue as well as in blood. Naringin (40 and 80 mg/kg) exerted a dose dependent (P < 0.05) ameliorative effect, as it significantly increased hematological parameter as well as colonic SOD and GSH. There was a significant (P < 0.05) and dose dependant inhibition of macroscopical score, ulcer area along with colonic MDA, MPO activity by the 7 days of pretreatment of naringin (40 and 80 mg/kg). Biochemical studies revealed a significant (P < 0.05) dose dependant inhibition in serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels by pretreatment of naringin. Increased levels of colonic NO, XO, protein carbonyl content and DNA damage were also significantly decreased by naringin pretreatment. The findings of the present investigation propose that naringin has an anti-inflammatory, anti-oxidant and anti-apoptotic potential effect at colorectal sites as it modulates the production and expression of oxidative mediators such as MDA, MPO, NO and XO, thus reducing DNA damage. PMID:24683411

Indigo Naturalis Ameliorates Oxazolone-Induced Dermatitis but Aggravates Colitis by Changing the Composition of Gut Microflora.

PubMed

Adachi, Soichiro; Hoshi, Namiko; Inoue, Jun; Yasutomi, Eiichiro; Otsuka, Takafumi; Dhakhwa, Ramesh; Wang, Zi; Koo, Yuna; Takamatsu, Toshihiro; Matsumura, Yuriko; Yamairi, Haruka; Watanabe, Daisuke; Ooi, Makoto; Tanahashi, Toshihito; Nishiumi, Shin; Yoshida, Masaru; Azuma, Takeshi

2017-01-01

Indigo naturalis (IND) is an herbal medicine that has been used as an anti-inflammatory agent to treat diseases including dermatitis and inflammatory bowel disease in China. However, the mechanism by which IND exerts its immunomodulatory effect is not well understood. A murine model of dermatitis and inflammatory bowel disease, both induced by oxazolone (OXA), was treated with IND. The severity of dermatitis was evaluated based on ear thickness measurements and histological scoring. The severity of colitis was evaluated by measuring body weight, histological scoring, and endoscopic scoring. The expression of inflammatory cytokines in ear and colon tissue was evaluated using real-time PCR. 16S rRNA DNA sequencing of feces from OXA-induced colitis mice was performed before and after IND treatment. The effects of IND on OXA-induced colitis were also evaluated after depleting the gut flora with antibiotics to test whether alteration of the gut flora by IND influenced the course of intestinal inflammation in this model. IND treatment ameliorated OXA dermatitis with a reduction in IL-4 and eosinophil recruitment. However, OXA colitis was significantly aggravated in spite of a reduction in intestinal IL-13, a pivotal cytokine in the induction of the colitis. It was found that IND dramatically altered the gut flora and IND no longer exacerbated colitis when colitis was induced after gut flora depletion. Our data suggest that IND could modify the inflammatory immune response in multiple ways, either directly (i.e., modification of the allergic immune cell activity) or indirectly (i.e., alteration of commensal compositions). © 2017 S. Karger AG, Basel.

Ginseng Berry Extract Attenuates Dextran Sodium Sulfate-Induced Acute and Chronic Colitis

PubMed Central

Zhang, Wei; Xu, Li; Cho, Si-Young; Min, Kyung-Jin; Oda, Tatsuya; Zhang, LiJun; Yu, Qing; Jin, Jun-O

2016-01-01

This study investigates the in vivo functions of ginseng berry extract (GB) as a therapy for dextran sodium sulfate (DSS)-induced colitis. C57BL/6 mice were given drinking water containing DSS (3%) for eight days to induce acute colitis. At the same time, the mice received an oral dose of GB (50 mg/kg) once daily. The GB-treated mice were less susceptible to the development of acute colitis than were control mice treated with saline, as determined by weight loss, disease activity, and colon histology. The administration of GB to DSS-treated mice also reduced the numbers and inhibited the activation of colon-infiltrating T cells, neutrophils, intestinal CD103−CD11c+ dendritic cells (cDCs), and macrophages. In addition, GB treatment promoted the migration of CD103+CD11c+ cDCs and expansion of Foxp3+ regulatory T cells in the colons of DSS-treated mice. Similarly, in the DSS-induced chronic colitis model, GB treatment improved the macroscopic and histological appearance of the colon wall when compared to untreated control mice, as indicated by longer colon length and lower histological scores. This is the first report to show that oral administration of GB suppresses immune activation and protects against experimentally induced colitis. PMID:27058552

Overexpression of GATA-3 in T cells accelerates dextran sulfate sodium-induced colitis.

PubMed

Okamura, Midori; Yoh, Keigyou; Ojima, Masami; Morito, Naoki; Takahashi, Satoru

2014-01-01

Ulcerative colitis (UC) is an inflammatory bowel disease, and its pathogenesis includes genetic, environmental, and immunological factors, such as T helper cells and their secreted cytokines. T helper cells are classified as Th1, Th2, and Th17 cells. However, it is unclear which T helper cells are important in UC. Dextran sulfate sodium (DSS)-induced colitis is a commonly used model of UC. In this study, we induced DSS colitis in Th1 dominant (T-bet transgenic (Tg)) mice, Th2 dominant (GATA-3 Tg) mice, and Th17 dominant (RORγt Tg) mice to elucidate the roles of T helper cell in DSS colitis. The results showed that GATA-3 Tg mice developed the most severe DSS colitis compared with the other groups. GATA-3 Tg mice showed a significant decreased in weight from day 1 to day 7, and an increased high score for the disease activity index compared with the other groups. Furthermore, GATA-3 Tg mice developed many ulcers in the colon, and many neutrophils and macrophages were detected on day 4 after DSS treatment. Measurement of GATA-3-induced cytokines demonstrated that IL-13 was highly expressed in the colon from DSS-induced GATA-3 Tg mice. In conclusion, GATA-3 overexpression in T-cells and IL-13 might play important roles in the development of DSS colitis.

New Perspective on Dextran Sodium Sulfate Colitis: Antigen-Specific T Cell Development during Intestinal Inflammation

PubMed Central

Morgan, Mary E.; Zheng, Bin; Koelink, Pim J.; van de Kant, Hendrick J. G.; Haazen, Lizette C. J. M.; van Roest, Manon; Garssen, Johan; Folkerts, Gert; Kraneveld, Aletta D.

2013-01-01

CD4+ T cell responses against oral antigens can develop in inflammatory bowel disease (IBD) patients, which may modulate disease. Dextran sodium sulfate (DSS) colitis is commonly used to study IBD, however, it is not considered the best model in which to study T cell involvement in intestinal disease. Our aim was to determine if antigen-specific T cells could be induced during DSS colitis and if they could be detected after disease resolution. To induce antigen-specific T cells, the tracking antigen, ovalbumin (OVA), was administered orally during colitis initiation. Disease severity was monitored, and the antigen-reactivity of CD4+ T cells examined using CD69 expression. While OVA-directed, CD4+ Foxp3+ regulatory T cells could be detected in the spleens of both OVA-treated control and DSS mice, OVA-reactive, CD4+ Foxp3-T cells were only found in the OVA and DSS-treated mice. These results indicate that during DSS colitis T cells develop that are specific against oral antigens, and they are found systemically after colitis resolution. This gives added depth and utility to the DSS model as well as a way to track T cells that are primed against luminal antigens. PMID:23936123

Ulcerative colitis: pathogenesis, diagnosis, and current treatment.

PubMed

Griffel, L H; Das, K M

1996-01-01

Ulcerative colitis is a chronic inflammatory disease of the colon that affects the rectum and a variable length of contiguous colon. The disease is characterized by rectal bleeding and diarrhea during periods of exacerbation; these symptoms usually abate with treatment. The pathogenic mechanism of ulcerative colitis is believed to be an aberrant immune response in which antibodies are formed against colonic epithelial protein(s). The disease usually presents during the second and third decades of life, with a smaller peak after the age of 60 years. There is a genetic component to ulcerative colitis, with a higher incidence among family members and, particularly, first-degree relatives. Diagnosis depends on several factors, most notably symptoms, demonstration of uniformly inflamed mucosa beginning in the rectum, and exclusion of other causes of colitis, such as infection. There is no medical cure for ulcerative colitis, but medical therapy is effective and can improve or eliminate symptoms in more than 80% of patients. Surgery offers a cure but carries the high price of total colectomy. New surgical methods, such as ileoanal anastomosis, allow for maintenance of bowel continuity and better patient satisfaction.

Diversion colitis and pouchitis: A mini-review

PubMed Central

Tominaga, Kentaro; Kamimura, Kenya; Takahashi, Kazuya; Yokoyama, Junji; Yamagiwa, Satoshi; Terai, Shuji

2018-01-01

Diversion colitis is characterized by inflammation of the mucosa in the defunctioned segment of the colon after colostomy or ileostomy. Similar to diversion colitis, diversion pouchitis is an inflammatory disorder occurring in the ileal pouch, resulting from the exclusion of the fecal stream and a subsequent lack of nutrients from luminal bacteria. Although the vast majority of patients with surgically-diverted gastrointestinal tracts remain asymptomatic, it has been reported that diversion colitis and pouchitis might occur in almost all patients with diversion. Surgical closure of the stoma, with reestablishment of gut continuity, is the only curative intervention available for patients with diversion disease. Pharmacologic treatments using short-chain fatty acids, mesalamine, or corticosteroids are reportedly effective for those who are not candidates for surgical reestablishment; however, there are no established assessment criteria for determining the severity of diversion colitis, and no management strategies to date. Therefore, in this mini-review, we summarize and review various recently-reported treatments for diversion disease. We are hopeful that the information summarized here will assist physicians who treat patients with diversion colitis and pouchitis, leading to better case management. PMID:29713128

Proinflammatory and anti-inflammatory cytokines present in the acute phase of experimental colitis treated with Saccharomyces boulardii.

PubMed

Grijó, Nathália Nahas; Borra, Ricardo Carneiro; Sdepanian, Vera Lucia

2010-09-01

To study the proinflammatory and anti-inflammatory cytokines present in the acute phase of trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis treated with Saccharomyces boulardii. Thirty male Wistar rats were divided into three groups: (1) treated group--received Saccharomyces boulardii for 14 days; (2) non-treated group--received sodium chloride solution for 14 days; (3) control group. Colitis was induced on the seventh day of the study in the treated and the non-treated groups using TNBS (10 mg) dissolved in 50% ethanol. Quantification of cytokines, including interleukin (IL)-1beta (IL-1beta), IL-6, transforming growth factor-beta (TGF-beta), IL-10 and tumor necrosis factor-alpha (TNF-alpha), in the serum and colonic tissue collected on day 14 were carried out using an enzyme-linked immunosorbent assay (ELISA). The mean concentrations of TGF-beta in both the serum and the colonic tissue of the treated group were statistically higher than that of the control group. The mean concentration of TGF-beta in the colonic tissue of the non-treated group was also statistically higher than the control group. The group treated with Saccharomyces boulardii showed increased amounts of TGF-beta, an anti-inflammatory cytokine, during the acute phase of colitis. There were no differences in the amount of TNF-alpha, IL-1beta, IL-6, and IL-10 between the treated and the non-treated or the control groups during the acute phase of experimental colitis induced by TNBS.

Study of a Monoclonal Antibody KHK4083 in Moderate Ulcerative Colitis

ClinicalTrials.gov

2018-05-15

Ulcerative Colitis; Digestive System Diseases; Colitis, Ulcerative; Colitis; Gastrointestinal Diseases; Inflammatory Bowel Diseases; Intestinal Diseases; Colonic Diseases; Autoimmune Disease; Abdominal Pain

Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis.

PubMed

Borrelli, Francesca; Aviello, Gabriella; Romano, Barbara; Orlando, Pierangelo; Capasso, Raffaele; Maiello, Francesco; Guadagno, Federico; Petrosino, Stefania; Capasso, Francesco; Di Marzo, Vincenzo; Izzo, Angelo A

2009-11-01

Inflammatory bowel disease affects millions of individuals; nevertheless, pharmacological treatment is disappointingly unsatisfactory. Cannabidiol, a safe and non-psychotropic ingredient of marijuana, exerts pharmacological effects (e.g., antioxidant) and mechanisms (e.g., inhibition of endocannabinoids enzymatic degradation) potentially beneficial for the inflamed gut. Thus, we investigated the effect of cannabidiol in a murine model of colitis. Colitis was induced in mice by intracolonic administration of dinitrobenzene sulfonic acid. Inflammation was assessed both macroscopically and histologically. In the inflamed colon, cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) were evaluated by Western blot, interleukin-1beta and interleukin-10 by ELISA, and endocannabinoids by isotope dilution liquid chromatography-mass spectrometry. Human colon adenocarcinoma (Caco-2) cells were used to evaluate the effect of cannabidiol on oxidative stress. Cannabidiol reduced colon injury, inducible iNOS (but not cyclooxygenase-2) expression, and interleukin-1beta, interleukin-10, and endocannabinoid changes associated with 2,4,6-dinitrobenzene sulfonic acid administration. In Caco-2 cells, cannabidiol reduced reactive oxygen species production and lipid peroxidation. In conclusion, cannabidiol, a likely safe compound, prevents experimental colitis in mice.

Goniothalamin prevents the development of chemically induced and spontaneous colitis in rodents and induces apoptosis in the HT-29 human colon tumor cell line

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

Vendramini-Costa, Débora Barbosa, E-mail: vendrami

Colon cancer is the third most incident type of cancer worldwide. One of the most important risk factors for colon cancer development are inflammatory bowel diseases (IBD), thus therapies focusing on IBD treatment have great potential to be used in cancer prevention. Nature has been a source of new therapeutic and preventive agents and the racemic form of the styryl-lactone goniothalamin (GTN) has been shown to be a promising antiproliferative agent, with gastroprotective, antinociceptive and anti-inflammatory effects. As inflammation is a well-known tumor promoter, the major goal of this study was to evaluate the therapeutic and preventive potentials of GTNmore » on chemically induced and spontaneous colitis, as well as the cytotoxic effects of GTN on a human colon tumor cell line (HT-29). GTN treatments inhibited TNBS-induced acute and chronic colitis development in Wistar rats, reducing myeloperoxidase levels and inflammatory cells infiltration in the mucosa. In spontaneous-colitis using IL-10 deficient mice (C57BL/6 background), GTN prevented colitis development through downregulation of TNF-α, upregulation of SIRT-1 and inhibition of proliferation (PCNA index), without signs of toxicity after three months of treatment. In HT-29 cells, treatment with 10 μM of GTN induced apoptosis by increasing BAX/BCL2, p-JNK1/JNK1, p-P38/P38 ratios as well as through ROS generation. Caspase 8, 9 and 3 activation also occurred, suggesting caspase-dependent apoptotic pathway, culminating in PARP-1 cleavage. Together with previous data, these results show the importance of GTN as a pro-apoptotic, preventive and therapeutic agent for IBD and highlight its potential as a chemopreventive agent for colon cancer. - Highlights: • Goniothalamin (GTN) inhibits the development of TNBS-induced colitis in rats. • Moreover, GTN prevents the development of spontaneous colitis in IL-10 deficient mice. • This activity relies on downregulation of TNF-α and upregulation of SIRT-1

Ethnic Distribution of Microscopic Colitis in the United States.

PubMed

Turner, Kevin; Genta, Robert M; Sonnenberg, Amnon

2015-11-01

A large electronic database of histopathology reports was used to study the ethnic distribution of microscopic colitis in the United States. Miraca Life Sciences is a nation-wide pathology laboratory that receives biopsy specimens submitted by 1500 gastroenterologists distributed throughout the United States. In a case-control study, the prevalence of microscopic colitis in 4 ethnic groups (East Asians, Indians, Hispanics, and Jews) was compared with that of all other ethnic groups (composed of American Caucasians and African Americans), serving as reference group. A total of 11,706 patients with microscopic colitis were included in the analysis. In all ethnic groups alike, microscopic colitis was more common in women than men (78% versus 22%, odds ratio = 3.40, 95% confidence interval = 3.26-3.55). In all ethnic groups, the prevalence of microscopic colitis showed a continuous age-dependent rise. Hispanic patients with microscopic colitis were on average younger than the reference group (59.4 ± 16.2 years versus 64.2 ± 13.8 years, P < 0.001). Jewish patients with microscopic colitis were slightly older than the reference group (65.6 ± 13.4 years, P = 0.015). Compared with the reference group (prevalence = 1.20%), microscopic colitis was significantly less common among patients of Indian (prevalence = 0.28%, odds ratio = 0.32, 95% confidence interval = 0.13-0.65), East Asian (0.22%, 0.19, 0.14-0.26), or Hispanic decent (0.48%, 0.40, 0.36-0.45) and significantly more common among Jewish patients (1.30%, 1.10, 1.01-1.21). Microscopic colitis shows striking variations of its occurrence among different ethnic groups. Such variations could point at differences in the exposure to environmental risk factors.

Diterpenoid alkaloids of Aconitum laciniatum and mitigation of inflammation by 14-O-acetylneoline in a murine model of ulcerative colitis

PubMed Central

Wangchuk, Phurpa; Navarro, Severine; Shepherd, Catherine; Keller, Paul A.; Pyne, Stephen G.; Loukas, Alex

2015-01-01

Aconitum laciniatum is used in Bhutanese traditional medicine for treating various chronic infections and inflammatory conditions. We carried out in-depth isolation and characterization of the phytochemicals from the root component and determined the anti-inflammatory effects of the isolated compounds against chemically-induced colitis in mice. Five diterpenoid alkaloids - pseudaconitine, 14-veratroylpseudaconine, 14-O-acetylneoline, neoline, and senbusine A - were isolated from A. laciniatum for the first time. Two of the alkaloids were tested for anti-inflammatory properties in the TNBS-induced colitis model in mice. Various parameters were measured to assess pathology including weight loss, clinical and macroscopic scores, histological structure and IFN-γ production in the gut. Of the two alkaloids tested, 14-O-acetylneoline showed significant protection against different parameters of colitic inflammation. Compared to control mice that received TNBS alone, mice treated with 14-O-acetylneoline experienced significantly less weight loss and had significantly lower clinical scores, macroscopic pathology and grades of histological inflammation. Moreover, colonic IFN-γ mRNA levels were significantly reduced in mice that received 14-O-acetylneoline compared to control mice that received TNBS alone. This alkaloid is now considered a novel anti-colitis drug lead compound. PMID:26240038

Heligmosomoides polygyrus bakeri infection activates colonic FoxP3+ T cells enhancing their capacity to prevent colitis

USDA-ARS?s Scientific Manuscript database

Helminthic infections protect mice from colitis in murine models of inflammatory bowel disease and also may protect people. Helminths like Heligmosomoides bakeri (Hpb) can induce Tregs. Experiments explored if Hpb infection could protect mice from colitis through activation of colonic Treg and exam...

Severe and Rapid Progression in Very Early-Onset Chronic Granulomatous Disease-Associated Colitis.

PubMed

Kawai, Toshinao; Arai, Katsuhiro; Harayama, Shizuko; Nakazawa, Yumiko; Goto, Fumihiro; Maekawa, Takanobu; Tamura, Eiichiro; Uchiyama, Toru; Onodera, Masafumi

2015-08-01

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease that leads to recurrent infection and hyper-inflammation, occasionally represented by CGD-associated colitis (CGD colitis). Although clinical symptoms of CGD colitis mimic those of ulcerative colitis (UC), there is no reliable standard measurement of disease activity or standard therapeutic strategy for CGD colitis. Here, we examined the clinical manifestation of CGD colitis based on severity using a noninvasive measure of disease activity, the Pediatric Ulcerative Colitis Activity Index (PUCAI), which has been validated and widely used for pediatric UC. Sixteen of 35 CGD patients, who were diagnosed with CGD colitis based on colonoscopic and histological findings, were examined using the PUCAI. Both the PUCAI and the physician global assessment (PGA) tool were retrospectively scored by reviewing medical records. Disease activity defined by PUCAI was correlated with PGA, and increased at diagnosis of CGD colitis, especially in patients who were younger than 6 years of age (very early-onset CGD colitis: VEO-CGD colitis) when diagnosed with CGD colitis. All severe patients had a more progressive form of VEO-CGD colitis. Unlike mild and moderate patients, severe patients required multidrug therapy of corticosteroids and immunomodulator/immunosuppressants, and some were eventually treated with hematopoietic stem cell transplantation. Although the validation of PUCAI in CGD colitis should be considered for future use, our results indicate that noninvasive measures could be effective to measure disease activity and help to determine suitable treatment for CGD colitis. In patients with VEO-CGD colitis, multidrug therapy would need to be considered at an early stage on the basis of disease activity.

Is appendectomy a causative factor in ulcerative colitis?

PubMed

Russel, M G; Stockbrügger, R W

1998-06-01

There are strong indicators that the aetiology of inflammatory bowel disease should be regarded as multifactorial, involving an interaction between genetic and environmental factors which give rise to an inadequate immunological response. During the past decade at least seven case-control studies have shown an inverse association between appendectomy and ulcerative colitis. Conclusions have been that either ulcerative colitis protects against appendicitis, or appendectomy protects against ulcerative colitis. The immunological function of the appendix is not well known, but experimental studies suggest that the appendix is possibly an important site for priming of the cells involved in the development of inflammatory bowel disease. Experimental and prospective cohort studies are needed to provide more insight in a possible relation between ulcerative colitis and the appendix.

Nitric oxide increases Wnt-induced secreted protein-1 (WISP-1/CCN4) expression and function in colitis.

PubMed

Wang, Hongying; Zhang, Rui; Wen, Shoubin; McCafferty, Donna-Marie; Beck, Paul L; MacNaughton, Wallace K

2009-04-01

Nitric oxide (NO) derived from the inducible NO synthase (iNOS) is an important and complex mediator of inflammation in the intestine. Wnt-inducible secreted protein (WISP)-1 (CCN4), a member of the connective tissue growth factor family, is involved in tissue repair. We sought to determine the relationship between iNOS and WISP-1 in colitis. By analyzing human colonic biopsy samples, we showed that the expression of mRNA for both iNOS and WISP-1 was significantly higher in ulcerative colitis samples compared with control tissue. The upregulation of WISP-1 was positively correlated with iNOS expression in two models of colitis, induced by intrarectal trinitrobenzenesulfonic acid (TNBS) or occurring spontaneously in IL-10 deficient mice. Loss of iNOS, studied using iNOS(-/-) mice in both TNBS-induced and IL-10(-/-) colitis models, significantly attenuated the colitis-related WISP-1 increase. In human colonic epithelial cell lines, the NO donor, DETA-NONOate, elevated WISP-1 mRNA and protein expression through a beta-catenin and CREB-dependent, but Wnt-1-independent, pathway. In addition, NO-induced WISP-1 directly induced secretion of soluble collagen in colonic fibroblast cells. NO increases WISP-1 expression both in vitro and in vivo, suggesting a new role for iNOS and NO in colitis.

Ameliorative effect of IDS 30, a stinging nettle leaf extract, on chronic colitis.

PubMed

Konrad, Astrid; Mähler, Michael; Arni, Stephan; Flogerzi, Beatrice; Klingelhöfer, Sonja; Seibold, Frank

2005-01-01

Anti-TNF-alpha antibodies are very effective in the treatment of acute Crohn's disease, but are limited by the decline of their effectiveness after repeated applications. The stinging nettle leaf extract, IDS 30, is an adjuvant remedy in rheumatic diseases dependent on a cytokine suppressive effect. We investigated the effect of IDS 30 on disease activity of murine colitis in different models. C3H.IL-10-/- and BALB/c mice with colitis induced by dextran sodium sulphate (DSS) were treated with either IDS 30 or water. Mice were monitored for clinical signs of colitis. Inflammation was scored histologically, and faecal IL-1beta and mucosal cytokines were measured by ELISA. Mononuclear cell proliferation of spleen and Peyer's patches were quantified by 3H-thymidine. Mice with chronic DSS colitis or IL-10-/- mice treated with IDS 30 clinically and histologically revealed significantly (p < 0.05) fewer signs of colitis than untreated animals. Furthermore, faecal IL-1beta and mucosal TNF-alpha concentrations were significantly lower (p < 0.05) in treated mice. Mononuclear cell proliferation after stimulation with lipopolysaccharide was significantly (p < 0.001) reduced in mice treated with IDS 30. The long-term use of IDS 30 is effective in the prevention of chronic murine colitis. This effect seems to be due to a decrease in the Th1 response and may be a new therapeutic option for prolonging remission in inflammatory bowel disease.

Chemopreventive effect of dietary glutamine on colitis-associated colon tumorigenesis in mice.

PubMed

Tian, Yun; Wang, Keming; Wang, Zhaoxia; Li, Nan; Ji, Guozhong

2013-07-01

Chronic colonic inflammation is a known risk factor for colorectal cancer (CRC). Glutamine (GLN) supplementation has shown its anti-inflammation benefit in experimental colitis. Whether GLN is effective in preventing colon carcinogenesis remains to be investigated. The chemopreventive activity of GLN was evaluated in the mouse model of dextran sulfate sodium (DSS)/azoxymethane (AOM)-induced colitis-associated CRC in this study. Mice were treated with DSS/AOM and randomized to receive either a control diet or GLN-enriched diet intermittently of the study. The disease activity index was evaluated weekly. On day 80 of the experiment, the entire colon and rectum were processed for histopathologic examination and further evaluation. Pro-inflammatory mediators and cytokines were measured by enzyme-linked immunosorbent assay, real-time-PCR and western blot analysis. Here, we show that after GLN-enriched diet, the colitis presented a statistical improvement and tumors burden decreased significantly. This was accompanied by lower activity of nuclear factor-κB (NF-κB), decreased expression of cyclooxygenase-2 and inducible nitric oxide synthase, lower expression of cytokines and chemokines as well as reduced proliferation and induced apoptosis in the colons of colitis-associated CRC mice. Our data demonstrate the protective/preventive effect of GLN in the progression of colitis-associated CRC, which was correlated with a dampening of inflammation and NF-κB activity and with a decrease of inflammatory protein overexpression.

Role of DOR-β-arrestin1-Bcl2 signal transduction pathway and intervention effects of oxymatrine in ulcerative colitis.

PubMed

Zhou, Pi-Qi; Fan, Heng; Hu, Hui; Tang, Qing; Liu, Xing-xing; Zhang, Li-juan; Zhong, Min; Shou, Zhe-xing

2014-12-01

This study was aimed to investigate the role of the delta-opioid receptor (DOR)-β-arrestin1-Bcl-2 signal transduction pathway in the pathogenesis of ulcerative colitis (UC) and the intervention effects of oxymatrine on UC. Forty Sprague-Dawley rats were divided into normal group, model group, oxymatrine-treated group and mesalazine-treated group (n=10 each) at random. The rat UC model was established by intra-colonic injection of trinitrobenzene sulfonic acid in the model group and two treatment groups. The rats in oxymatrine-treated group were subjected to intramuscular injection of oxymatrine [63 mg/(kg·day)] for 15 days, and those in mesalazine-treated group given mesalazine solution [0.5 g/(kg·day)] by gastric lavage for the same days. Animals in normal group and model group were administered 3 mL water by gastric lavage for 15 days. On the 16th day, after fasting for 24 h, the rats were sacrificed for the removal of colon tissues. The expression levels of DOR, β-arrestin1 and Bcl-2 were determined in colon tissues by immunohistochemistry and real-time quantitative polymerase chain reaction (RT-PCR), respectively. It was found that the expression levels of DOR, β-arrestin1 and Bcl-2 protein and mRNA were significantly increased in the model group as compared with the other groups (P<0.05). They were conspicuously decreased in both mesalazine-treated and oxymatrine-treated groups in contrast to the model group (P<0.05). No statistically significant difference was noted in these indices between mesalazine- and oxymatrinetreated groups (P>0.05). This study indicated that the DOR-β-arrestin1-Bcl-2 signal transduction pathway may participate in the pathogenesis of UC. Moreover, oxymatrine can attenuate the development of UC by regulating the DOR-β-arrestin1-Bcl-2 signal transduction pathway.

Development of chronic colitis is dependent on the cytokine MIF.

PubMed

de Jong, Y P; Abadia-Molina, A C; Satoskar, A R; Clarke, K; Rietdijk, S T; Faubion, W A; Mizoguchi, E; Metz, C N; Alsahli, M; ten Hove, T; Keates, A C; Lubetsky, J B; Farrell, R J; Michetti, P; van Deventer, S J; Lolis, E; David, J R; Bhan, A K; Terhorst, C; Sahli, M A

2001-11-01

The cytokine macrophage-migration inhibitory factor (MIF) is secreted by a number of cell types upon induction by lipopolysaccharide (LPS). Because colitis is dependent on interplay between the mucosal immune system and intestinal bacteria, we investigated the role of MIF in experimental colitis. MIF-deficient mice failed to develop disease, but reconstitution of MIF-deficient mice with wild-type innate immune cells restored colitis. In addition, established colitis could be treated with anti-MIF immunoglobulins. Thus, murine colitis is dependent on continuous MIF production by the innate immune system. Because we found increased plasma MIF concentrations in patients with Crohn's disease, these data suggested that MIF is a new target for intervention in Crohn's disease.

Family history of inflammatory bowel disease among patients with ulcerative colitis: a systematic review and meta-analysis.

PubMed

Childers, Ryan E; Eluri, Swathi; Vazquez, Christine; Weise, Rayna Matsuno; Bayless, Theodore M; Hutfless, Susan

2014-11-01

Despite numerous shared susceptibility loci between Crohn's disease and ulcerative colitis, the prevalence of family history among ulcerative colitis patients is not well-established and considered to be less prevalent. A systemic review and meta-analysis were conducted to estimate the prevalence of family history of inflammatory bowel disease in ulcerative colitis patients, and its effect on disease outcomes. PubMED was searched to identify studies reporting the prevalence of family history of inflammatory bowel disease among ulcerative colitis patients. Definitions of family history, study type, and subtypes of family history prevalence were abstracted, as were disease outcomes including age at ulcerative colitis diagnosis, disease location, surgery and extraintestinal manifestations. Pooled prevalence estimates were calculated using random effects models. Seventy-one studies (86,824 patients) were included. The prevalence of a family history of inflammatory bowel disease in ulcerative colitis patients was 12% (95% confidence interval [CI] 11 to 13%; range 0-39%). Family history of ulcerative colitis (9%; 22 studies) was more prevalent than Crohn's disease (2%; 18 studies). Patients younger than 18years of age at time of diagnosis had a greater family history of inflammatory bowel disease (prevalence 15%, 95% CI: 11-20%; 13 studies). There were no differences in disease location, need for surgery, or extraintestinal manifestations among those with a family history, although very few studies reported on these outcomes. Overall, 12% of ulcerative colitis patients have a family history of inflammatory bowel disease, and were more likely to have a family history of ulcerative colitis than Crohn's disease. Pediatric-onset ulcerative colitis patients were more likely to have a family history of inflammatory bowel disease. Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Opposing roles of nuclear receptor HNF4α isoforms in colitis and colitis-associated colon cancer

PubMed Central

Chellappa, Karthikeyani; Deol, Poonamjot; Evans, Jane R; Vuong, Linh M; Chen, Gang; Briançon, Nadege; Bolotin, Eugene; Lytle, Christian; Nair, Meera G; Sladek, Frances M

2016-01-01

HNF4α has been implicated in colitis and colon cancer in humans but the role of the different HNF4α isoforms expressed from the two different promoters (P1 and P2) active in the colon is not clear. Here, we show that P1-HNF4α is expressed primarily in the differentiated compartment of the mouse colonic crypt and P2-HNF4α in the proliferative compartment. Exon swap mice that express only P1- or only P2-HNF4α have different colonic gene expression profiles, interacting proteins, cellular migration, ion transport and epithelial barrier function. The mice also exhibit altered susceptibilities to experimental colitis (DSS) and colitis-associated colon cancer (AOM+DSS). When P2-HNF4α-only mice (which have elevated levels of the cytokine resistin-like β, RELMβ, and are extremely sensitive to DSS) are crossed with Retnlb-/- mice, they are rescued from mortality. Furthermore, P2-HNF4α binds and preferentially activates the RELMβ promoter. In summary, HNF4α isoforms perform non-redundant functions in the colon under conditions of stress, underscoring the importance of tracking them both in colitis and colon cancer. DOI: http://dx.doi.org/10.7554/eLife.10903.001 PMID:27166517

Curative effect of Terminalia chebula extract on acetic acid-induced experimental colitis: role of antioxidants, free radicals and acute inflammatory marker.

PubMed

Gautam, M K; Goel, Shalini; Ghatule, R R; Singh, A; Nath, G; Goel, R K

2013-10-01

The present study has evaluated the healing effects of extract of dried fruit pulp of Terminalia chebula (TCE) on acetic acid (AA)-induced colitis in rats. TCE (600 mg/kg) showed healing effects against AA-induced colonic damage score and weight when administered orally daily for 14 days. TCE was further studied for its effects on various physical (mucus/blood in stool and stool frequency, food and water intake and body weight changes), histology, antibacterial activity and free radicals (NO and LPO), antioxidants (SOD, CAT and GSH) and myeloperoxidase in colonic tissue. Intra-colonic AA administration increased colonic mucosal damage and inflammation, mucus/bloody diarrhoea, stool frequency, but decreased body weight which were reversed by TCE and sulfasalazine (SS, positive control) treatments. TCE showed antibacterial activity and both TCE and SS enhanced the antioxidants, but decreased free radicals and myeloperoxidase activities affected in acetic acid-induced colitis. TCE indicated the presence of active principles with proven antioxidants, anti-inflammatory, immunomodulatory, and free radical scavenging and healing properties. Thus, TCE seemed to be safe and effective in healing experimental colitis.

Collagenous colitis in a patient with systemic sclerosis: a rare entity.

PubMed Central

Ekiz, Fuat; Coban, Sahin; Savas, Berna; Gören, Deniz; Ensari, Arzu; Ormeci, Necati

2007-01-01

Collagenous colitis has been associated with autoimmune diseases. Co-occurence of systemic sclerosis and collagenous colitis is particularly rare. Herein, we described a 65-year-old woman with systemic sclerosis whose diarrhea and abdominal cramping were due to collagenous colitis. We have reviewed the clinical and histopathological features of collagenous colitis with regard to its concomitance with systemic sclerosis. Images Figure 1 Figure 2 PMID:17595940

Nicotine protects against DSS colitis through regulating microRNA-124 and STAT3.

PubMed

Qin, Zhen; Wan, Jing-Jing; Sun, Yang; Wu, Tingyu; Wang, Peng-Yuan; Du, Peng; Su, Ding-Feng; Yang, Yili; Liu, Xia

2017-02-01

Although it is generally believed that nicotine accounts for the beneficial effect of smoking on ulcerative colitis, the underlying mechanisms remain not well understood. Our previous finding that nicotine inhibits inflammatory responses through inducing miR-124 prompted us to ask whether the miRNA is involved in the protective action of nicotine against UC. Our present study found that miR-124 expression is upregulated in colon tissues from UC patients and DSS colitis mice. Nicotine treatment further augmented miR-124 expression in lymphocytes isolated from human ulcerative colonic mucosa and ulcerative colon tissues from DSS mice, both in infiltrated lymphocytes and epithelial cells. Moreover, knockdown of miR-124 significantly diminished the beneficial effect of nicotine on murine colitis and IL-6-treated Caco-2 colon epithelial cells. Further analysis indicated that nicotine inhibited STAT3 activation in vivo and in IL-6 treated Caco-2 cells and Jurkat human T lymphocytes, in which miR-124 knockdown led to increased activation of STAT3. Blocking STAT3 activity alone is beneficial for DSS colitis and also abolished nicotine's protective effect in this model. These data indicate that nicotine exerts its protective action in UC through inducing miR-124 and inhibiting STAT3, and suggest that the miR-124/STAT3 system is a potential target for the therapeutic intervention of UC. Nicotine upregulates miR-124 expression in ulcerative colon tissues and cells. MiR-124 is required for the protective role of nicotine in DSS colitis mice and epithelial cells. The protective effect of nicotine in murine DSS colitis depends on blocking STAT3 activation. MiR-124 mediates the inhibitory role of nicotine on STAT3/p-STAT3. Targeting miR-124 and STAT3 represents a novel approach for treating ulcerative colitis.

IL-33 signaling protects from murine oxazolone colitis by supporting intestinal epithelial function

PubMed Central

Waddell, Amanda; Vallance, Jefferson E; Moore, Preston D; Hummel, Amy T; Wu, David; Shanmukhappa, Shiva K; Fei, Lin; Washington, M Kay; Minar, Phillip; Coburn, Lori A; Nakae, Susumu; Wilson, Keith T; Denson, Lee A; Hogan, Simon P; Rosen, Michael J

2015-01-01

Background IL-33, a member of the IL-1 cytokine family that signals through ST2, is upregulated in ulcerative colitis (UC); however, the role of IL-33 in colitis remains unclear. IL-33 augments type 2 immune responses, which have been implicated in UC pathogenesis. We sought to determine the role of IL-33 signaling in oxazolone (OXA) colitis, a type 2 cytokine-mediated murine model of UC. Methods Colon mucosal IL-33 expression was compared between pediatric and adult UC and non-IBD patients using immunohistochemistry and real-time PCR. OXA colitis was induced in WT, IL-33−/− and ST2−/− mice, and histopathology, cytokine levels, and goblet cells were assessed. Transepithelial resistance (TER) was measured across IL-33-treated T84 cell monolayers. Results Colon mucosal IL-33 was increased in pediatric patients with active UC and in OXA colitis. IL-33−/− and ST2−/− OXA mice exhibited increased disease severity compared to WT OXA mice. OXA induced a mixed mucosal cytokine response, but few differences were observed between OXA WT and IL-33−/− or ST2−/− mice. Goblet cells were significantly decreased in IL-33−/− and ST2−/− OXA compared to WT OXA mice. IL-33 augmented TER in T84 cells, and this effect was blocked by the ERK1/2 inhibitor PD98,059. Conclusions OXA colitis is exacerbated in IL-33−/− and ST2−/− mice. Increased mucosal IL-33 in human UC and murine colitis may be a homeostatic response to limit inflammation, potentially through effects on epithelial barrier function. Further investigation of IL-33 protective mechanisms would inform the development of novel therapeutic approaches. PMID:26313694

Anti-inflammatory natural product goniothalamin reduces colitis-associated and sporadic colorectal tumorigenesis

PubMed Central

Vendramini-Costa, Débora Barbosa; Francescone, Ralph; Posocco, David; Hou, Vivianty; Dmitrieva, Oxana; Hensley, Harvey; de Carvalho, João Ernesto; Pilli, Ronaldo Aloise; Grivennikov, Sergei I.

2017-01-01

The tumor microenvironment offers multiple targets for cancer therapy, including pro-tumorigenic inflammation. Natural compounds represent an enormous source of new anti-inflammatory and anticancer agents. We previously showed that the styryl lactone goniothalamin (GTN) has promising antiproliferative and anti-inflammatory activities. Because inflammation is a major driver of colorectal cancer (CRC), we therefore evaluated the therapeutic and preventive potentials of GTN in colitis, colitis-associated cancer (CAC) and spontaneous CRC. First, in a simplistic model of inflammation in vitro, GTN was able to inhibit cytokine production in bone marrow-derived macrophages induced by lipopolysaccharide. Next, in dextran sulfate sodium (DSS) induced-colitis model, mice treated with GTN displayed restored tissue architecture, increased cell proliferation in the colonic crypts and reduced epithelial damage. Moreover, colon tissue from GTN-treated mice had significantly less expression of the inflammatory genes interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), S100A9, interleukin 23A (IL-23A), IL-22 and IL-17A. In the azoxymethane/DSS model of CAC, GTN reduced tumor multiplicity, load and size. Additionally, GTN suppressed production of IL-6, IL-17 and TNF-α in tumor tissue, as well as abrogated stromal immune cell activation and nuclear translocation of NF-κB. Finally, in a tamoxifen inducible model of sporadic CRC, GTN-treated mice had significantly fewer tumors and decreased levels of IL-17A, IL-6, S100A9 and TNF-α protein within the tumors. These results suggest that GTN possesses anti-inflammatory and antitumor activities and represents a preventive and therapeutic agent modulating the inflammatory environment in the colon during colitis as well as CAC and CRC development. PMID:27797827

Mangiferin attenuates DSS colitis in mice: Molecular docking and in vivo approach.

PubMed

Somani, Sahil; Zambad, Shitalkumar; Modi, Ketan

2016-06-25

Inflammation, oxidative stress and altered mucosal barrier permeability are potential etiopathological or triggering factors for inflammatory bowel disease (IBD). In this study, the therapeutic potential of Mangiferin was investigated in vivo in mouse model of colitis and also attempts were made to understand mechanistic insights of Mangiferin in IBD. In present study, colitis was induced by administration of 5% DSS for 11 days, followed by 3 days of DSS free period. On day 14, animals were sacrificed and colon tissues were taken for biochemical and histological analysis. Therapeutic treatment with Mangiferin after colitis induction (i.e. day 5) ameliorated symptoms of colitis (presence of blood in stools, body weight loss and diarrhea) as evidenced by reduced DAI score, attenuated the levels of catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO). It also decreased the colonic pro-inflammatory mediators tumor necrosis factor (TNF-α), interleukin 1β (IL-1β) levels, matrix metalloproteinase-9 (MMP-9) activity and histopathological score. Molecular docking of Mangiferin against TNF-α and MMP-9 was evaluated using GLIDE software. Mangiferin demonstrated the glide score of -8.04 kcal/mol for TNF-α and -9.97 kcal/mol for MMP-9, which indicated its binding potential with TNF-α and MMP-9. In conclusion, Mangiferin reduces colonic damage in a murine model of colitis, alleviates the oxidative and inflammatory events partly through directly influencing the activity of TNF-α and MMP-9 and therefore might have therapeutic usefulness in the management of inflammatory bowel disease. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Ulcerative colitis flair induced by mesalamine suppositories hypersensitivity

PubMed Central

Ding, Hao; Liu, Xiao-Chang; Mei, Qiao; Xu, Jian-Ming; Hu, Xiang-Yang; Hu, Jing

2014-01-01

Mesalamine suppositories have been used widely for the treatment of distal ulcerative colitis and considered to be safer than systemic administration for its limited systemic absorption. However, previous studies have shown that mesalamine suppository occasionally causes severe hypersensitivity reactions including fever, rashes, colitis exacerbation and acute eosinophilic pneumonia. Here we present a 25-year-old woman with ulcerative colitis with bloody diarrhea accompanied by abdominal pain and fever which were aggravated after introduction of mesalamine suppositories. In light of symptom exacerbation of ulcerative colitis, increased inflammatory injury of colon mucosa shown by colonoscopy and elevated peripheral eosinophil count after mesalamine suppositories administration, and the Naranjo algorithm score of 10, the possibility of hypersensitivity reaction to mesalamine suppositories should be considered, warning us to be aware of this potential reaction after administration of mesalamine formulations even if it is the suppositories. PMID:24707159

Ulcerative colitis flair induced by mesalamine suppositories hypersensitivity.

PubMed

Ding, Hao; Liu, Xiao-Chang; Mei, Qiao; Xu, Jian-Ming; Hu, Xiang-Yang; Hu, Jing

2014-04-07

Mesalamine suppositories have been used widely for the treatment of distal ulcerative colitis and considered to be safer than systemic administration for its limited systemic absorption. However, previous studies have shown that mesalamine suppository occasionally causes severe hypersensitivity reactions including fever, rashes, colitis exacerbation and acute eosinophilic pneumonia. Here we present a 25-year-old woman with ulcerative colitis with bloody diarrhea accompanied by abdominal pain and fever which were aggravated after introduction of mesalamine suppositories. In light of symptom exacerbation of ulcerative colitis, increased inflammatory injury of colon mucosa shown by colonoscopy and elevated peripheral eosinophil count after mesalamine suppositories administration, and the Naranjo algorithm score of 10, the possibility of hypersensitivity reaction to mesalamine suppositories should be considered, warning us to be aware of this potential reaction after administration of mesalamine formulations even if it is the suppositories.

Very Long O-antigen Chains Enhance Fitness during Salmonella-induced Colitis by Increasing Bile Resistance

PubMed Central

Crawford, Robert W.; Keestra, A. Marijke; Winter, Sebastian E.; Xavier, Mariana N.; Tsolis, Renée M.; Tolstikov, Vladimir; Bäumler, Andreas J.

2012-01-01

Intestinal inflammation changes the luminal habitat for microbes through mechanisms that have not been fully resolved. We noticed that the FepE regulator of very long O-antigen chain assembly in the enteric pathogen Salmonella enterica serotype Typhimurium (S. Typhimurium) conferred a luminal fitness advantage in the mouse colitis model. However, a fepE mutant was not defective for survival in tissue, resistance to complement or resistance to polymyxin B. We performed metabolite profiling to identify changes in the luminal habitat that accompany S. Typhimurium-induced colitis. This analysis suggested that S. Typhimurium-induced colitis increased the luminal concentrations of total bile acids. A mutation in fepE significantly reduced the minimal inhibitory concentration (MIC) of S. Typhimurium for bile acids in vitro. Oral administration of the bile acid sequestrant cholestyramine resin lowered the concentrations of total bile acids in colon contents during S. Typhimurium infection and significantly reduced the luminal fitness advantage conferred by the fepE gene in the mouse colitis model. Collectively, these data suggested that very long O-antigen chains function in bile acid resistance of S. Typhimurium, a property conferring a fitness advantage during luminal growth in the inflamed intestine. PMID:23028318

Rat Genome and Model Resources.

PubMed

Shimoyama, Mary; Smith, Jennifer R; Bryda, Elizabeth; Kuramoto, Takashi; Saba, Laura; Dwinell, Melinda

2017-07-01

Rats remain a major model for studying disease mechanisms and discovery, validation, and testing of new compounds to improve human health. The rat's value continues to grow as indicated by the more than 1.4 million publications (second to human) at PubMed documenting important discoveries using this model. Advanced sequencing technologies, genome modification techniques, and the development of embryonic stem cell protocols ensure the rat remains an important mammalian model for disease studies. The 2004 release of the reference genome has been followed by the production of complete genomes for more than two dozen individual strains utilizing NextGen sequencing technologies; their analyses have identified over 80 million variants. This explosion in genomic data has been accompanied by the ability to selectively edit the rat genome, leading to hundreds of new strains through multiple technologies. A number of resources have been developed to provide investigators with access to precision rat models, comprehensive datasets, and sophisticated software tools necessary for their research. Those profiled here include the Rat Genome Database, PhenoGen, Gene Editing Rat Resource Center, Rat Resource and Research Center, and the National BioResource Project for the Rat in Japan. © The Author 2017. Published by Oxford University Press.

Indigo Naturalis ameliorates murine dextran sodium sulfate-induced colitis via aryl hydrocarbon receptor activation.

PubMed

Kawai, Shoichiro; Iijima, Hideki; Shinzaki, Shinichiro; Hiyama, Satoshi; Yamaguchi, Toshio; Araki, Manabu; Iwatani, Shuko; Shiraishi, Eri; Mukai, Akira; Inoue, Takahiro; Hayashi, Yoshito; Tsujii, Masahiko; Motooka, Daisuke; Nakamura, Shota; Iida, Tetsuya; Takehara, Tetsuo

2017-08-01

Indigo Naturalis (IN) is used as a traditional herbal medicine for ulcerative colitis (UC). However, the mechanisms of action of IN have not been clarified. We aimed to evaluate the efficacy of IN for ameliorating colonic inflammation. We further investigated the mechanisms of action of IN. Colitis severity was assessed in dextran sodium sulfate-induced colitis and trinitrobenzene sulfonic acid-induced colitis models with or without the oral administration of IN or indigo, which is a known major component of IN. Colonic lamina propria (LP) mononuclear cells isolated from IN-treated mice were analyzed with quantitative reverse transcription polymerase chain reaction (qRT-PCR) and flow cytometry. LP and splenic mononuclear cells cultured in vitro with IN or indigo were also analyzed. The role of the candidate receptor for indigo, the aryl hydrocarbon receptor (AhR), was analyzed using Ahr-deficient mice. Colitis severity was significantly ameliorated in the IN and indigo treatment groups compared with the control group. The mRNA expression levels of interleukin (Il)-10 and Il-22 in the LP lymphocytes were increased by IN treatment. The treatment of splenocytes with IN or indigo increased the expression of anti-inflammatory cytokines and resulted in the expansion of IL-10-producing CD4 + T cells and IL-22-producing CD3 - RORγt + cells, but not CD4 + Foxp3 + regulatory T cells. The amelioration of colitis by IN or indigo was abrogated in Ahr-deficient mice, in association with diminished regulatory cytokine production. IN and indigo ameliorated murine colitis through AhR signaling activation, suggesting that AhR could be a promising therapeutic target for UC.

Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis.

PubMed

Franklin, Cindy; Rooms, Isabelle; Fiedler, Melanie; Reis, Henning; Milsch, Laura; Herz, Saskia; Livingstone, Elisabeth; Zimmer, Lisa; Schmid, Kurt Werner; Dittmer, Ulf; Schadendorf, Dirk; Schilling, Bastian

2017-11-01

Immune checkpoint inhibitors can cause severe immune-related adverse events, with immune-related diarrhea and colitis (irColitis) being among the most frequent ones. While the majority of patients with irColitis respond well to corticosteroid treatment ± other immunomodulatory drugs such as infliximab, some patients do not show resolution of their symptoms. In the present study, we analysed the frequency of therapy-refractory irColitis, the underlying cause, and useful diagnostic approaches. Between 2006 and 2016, 370 patients with metastatic malignant melanoma were treated with checkpoint inhibitors at the Department of Dermatology at the University Hospital Essen. All patients were identified for whom diarrhea and/or colitis was documented in the digital patient records. Patients who did not respond to standard immunosuppressive therapy within 2 weeks were classified as refractory. Demographic and clinical data of all patients were collected. We identified 41 patients with irColitis, the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%) were refractory to standard immunomodulatory treatment with corticosteroids and infliximab. Therapy-refractory cases tended to show more severe inflammation in colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005, in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis (p=0.021; p = 0.053). This report on CMV reactivation during management of checkpoint inhibitor-induced colitis emphasises the need for repetitive diagnostic measures in treatment-refractory irColitis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Efficacy profiles for different concentrations of Lactobacillus acidophilus in experimental colitis.

PubMed

Chen, Lin-Lin; Zou, Yi-You; Lu, Fang-Gen; Li, Fu-Jun; Lian, Guang-Hui

2013-08-28

To determine the efficacy profiles of different concentrations of Lactobacillus acidophilus (L. acidophilus) for treating colitis using an experimental murine model. Colitis was established in 64 BALB/c mice by adding 5% dextran sodium sulfate (DSS) to the drinking water and allowing ad libitum access for 7 d. The mice were then randomly divided into the following control and experimental model groups (n = 8 each; day 0): untreated model control; negative-treatment model control (administered gavage of 1 mL/10 g normal saline); experimental-treatment models C4-C8 (administered gavage of 10(4), 10(5), 10(6), 10(7), or 10(8) CFU/10 g L. acidophilus, respectively); positive-treatment model control (administration of the anti-inflammatory agent prednisone acetate at 45 μg/10 g). Eight mice given regular water (no DSS) and no subsequent treatments served as the normal control group. Body weight, fecal traits, and presence of fecal occult blood were assessed daily. All animals were sacrificed on post-treatment day 7 to measure colonic length, perform histological scoring, and quantify the major bacteria in the proximal and distal colon. Intergroup differences were determined by one-way ANOVA and post-hoc Student-Newman-Keuls comparison. All treatments (L. acidophilus and prednisone acetate) protected against colitis-induced weight loss (P < 0.05 vs model and normal control groups). The extent of colitis-induced colonic shortening was significantly reduced by all treatments (prednisone acetate > C4 > C5 > C7 > C8 > C6; P < 0.05 vs untreated model group), and the C6 group showed colonic length similar to that of the normal control group (P > 0.05). The C6 group also had the lowest disease activity index scores among the model groups. The bacterial profiles in the proximal colon were similar between all of the experimental-treatment model groups (all P > 0.05). In contrast, the bacterial profile in the distal colon of the C6 group showed the distinctive features (P < 0

Infliximab to treat severe ulcerative colitis

PubMed Central

Cury, Dídia Bisamra; de Souza Cury, Marcelo; Elias, Geraldo Vinicius Hemerly; Mizsputen, Sender Jankiel

2009-01-01

A 48-year-old female with severe ulcerative colitis refractory to conventional therapy was referred to our facility for management. The patient showed extensive ulcerative colitis since the age of 20 years and had failed therapy with 5-aminosalicylic acid agents and azathioprine. The disease remained active despite treatment with steroids and cyclosporine. The clinical and endoscopic parameters were consistent with severe disease. Infectious precipitants were ruled out. Given the severity of the disease and in order to avoid a colectomy, we started the patient on infliximab therapy. A dramatic clinical and endoscopic response was observed and she remained in remission at the end of a 1-year follow-up period. We discuss findings in the literature regarding the use of infliximab therapy in patients with ulcerative colitis who have failed steroids and cyclosporine. PMID:19360923

An apple oligogalactan prevents against inflammation and carcinogenesis by targeting LPS/TLR4/NF-κB pathway in a mouse model of colitis-associated colon cancer.

PubMed

Liu, Li; Li, Yu H; Niu, Yin B; Sun, Yang; Guo, Zhen J; Li, Qian; Li, Chen; Feng, Juan; Cao, Shou S; Mei, Qi B

2010-10-01

Evidence strongly supported a link between inflammation and cancer. Patients with colitis have high risk for development of colon cancer. Nuclear factor-kappa B (NF-κB), partially induced by lipopolysaccharide (LPS) binding to Toll-like receptor (TLR) 4, is a vital molecule in supervising the transformation of colitis to colon cancer. It could be a good strategy to prevent colitis carcinogenesis for targeting LPS/TLR4/NF-κB pathway. In the present study, we obtained an oligogalactan composed of five galacturonic acids from apple pectin and evaluated its protective efficacy on intestinal toxicities and carcinogenesis in a mouse model of colitis-associated colon cancer induced by 1,2-dimethylhydrazine and dextran sodium sulfate (DSS). The apple oligogalactan (AOG) was highly effective against intestinal toxicities and carcinogenesis and decreased the elevated levels of TLR4 and tumor necrosis factor-α (TNF-α) induced by inflammation in vivo in this model system. In vitro studies, AOG alone only slightly increased the levels of protein expression and messenger RNA of TLR4, phosphorylation of IκBα and production of TNF-α in HT-29 cells. However, AOG significantly decreased the elevation of all the biomarkers induced by LPS when it was combined with LPS. The effect of AOG may be related to membrane internalization and redistribution of TLR4 from cell membrane to cytoplasm. AOG is active against inflammation and carcinogenesis through targeting LPS/TLR4/NF-κB pathway. Both AOG and LPS are agonists of TLR4 for sharing the same ligand but AOG has a much lower intrinsic activity than that of LPS. AOG may be useful for treatment of colitis and prevention of carcinogenesis in the clinics.

Toll-like receptor-mediated responses of primary intestinal epithelial cells during the development of colitis.

PubMed

Singh, Joy Carmelina Indira; Cruickshank, Sheena Margaret; Newton, Darren James; Wakenshaw, Louise; Graham, Anne; Lan, Jinggang; Lodge, Jeremy Peter Alan; Felsburg, Peter John; Carding, Simon Richard

2005-03-01

The interleukin-2-deficient (IL-2(-/-)) mouse model of ulcerative colitis was used to test the hypothesis that colonic epithelial cells (CEC) directly respond to bacterial antigens and that alterations in Toll-like receptor (TLR)-mediated signaling may occur during the development of colitis. TLR expression and activation of TLR-mediated signaling pathways in primary CEC of healthy animals was compared with CEC in IL-2(-/-) mice during the development of colitis. In healthy animals, CEC expressed functional TLR, and in response to the TLR4 ligand LPS, proliferated and secreted the cytokines IL-6 and monocyte chemoattractant protein-1 (MCP-1). However, the TLR-responsiveness of CEC in IL-2(-/-) mice was different with decreased TLR4 responsiveness and augmented TLR2 responses that result in IL-6 and MCP-1 secretion. TLR signaling in CEC did not involve NF-kappaB (p65) activation with the inhibitory p50 form of NF-kappaB predominating in CEC in both the healthy and inflamed colon. Development of colitis was, however, associated with the activation of MAPK family members and upregulation of MyD88-independent signaling pathways characterized by increased caspase-1 activity and IL-18 production. These findings identify changes in TLR expression and signaling during the development of colitis that may contribute to changes in the host response to bacterial antigens seen in colitis.

Minimally invasive screening for colitis using attenuated total internal reflectance Fourier transform infrared spectroscopy

PubMed Central

Titus, Jitto; Viennois, Emilie; Merlin, Didier; Perera, A. G. Unil

2016-01-01

This article describes a rapid, simple and cost-effective technique that could lead to a screening method for colitis without the need for biopsies or in vivo measurements. This screening technique includes the testing of serum using Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy for the colitis-induced increased presence of mannose. Chronic (Interleukin 10 knockout) and acute (Dextran Sodium Sulphate-induced) models for colitis are tested using the ATR-FTIR technique. Arthritis (Collagen Antibody Induced Arthritis) and metabolic syndrome (Toll like receptor 5 knockout) models are also tested as controls. The marker identified as mannose uniquely screens and distinguishes the colitic from the non-colitic samples and the controls. The reference or the baseline spectrum could be the pooled and averaged spectra of non-colitic samples or the subject's previous sample spectrum. This shows the potential of having individualized route maps of disease status, leading to personalized diagnosis and drug management. PMID:27094092

Concomitant herpes simplex virus colitis and hepatitis in a man with ulcerative colitis

PubMed Central

Phadke, Varun K.; Friedman-Moraco, Rachel J.; Quigley, Brian C.; Farris, Alton B.; Norvell, J. P.

2016-01-01

Abstract Background: Herpesvirus infections often complicate the clinical course of patients with inflammatory bowel disease; however, invasive disease due to herpes simplex virus is distinctly uncommon. Methods: We present a case of herpes simplex virus colitis and hepatitis, review all the previously published cases of herpes simplex virus colitis, and discuss common clinical features and outcomes. We also discuss the epidemiology, clinical manifestations, diagnosis, and management of herpes simplex virus infections, focusing specifically on patients with inflammatory bowel disease. Results: A 43-year-old man with ulcerative colitis, previously controlled with an oral 5-aminosalicylic agent, developed symptoms of a colitis flare that did not respond to treatment with systemic corticosteroid therapy. One week later he developed orolabial ulcers and progressive hepatic dysfunction, with markedly elevated transaminases and coagulopathy. He underwent emergent total colectomy when imaging suggested bowel micro-perforation. Pathology from both the colon and liver was consistent with herpes simplex virus infection, and a viral culture of his orolabial lesions and a serum polymerase chain reaction assay also identified herpes simplex virus. He was treated with systemic antiviral therapy and made a complete recovery. Conclusions: Disseminated herpes simplex virus infection with concomitant involvement of the colon and liver has been reported only 3 times in the published literature, and to our knowledge this is the first such case in a patient with inflammatory bowel disease. The risk of invasive herpes simplex virus infections increases with some, but not all immunomodulatory therapies. Optimal management of herpes simplex virus in patients with inflammatory bowel disease includes targeted prophylactic therapy for patients with evidence of latent infection, and timely initiation of antiviral therapy for those patients suspected to have invasive disease. PMID:27759636

Ulcerative colitis precipitated by a verocytotoxin-producing Escherichia coli infection.

PubMed

Farina, C; Caprioli, A; Luzzi, I; Sonzogni, A; Goglio, A

1995-12-01

The aetiology of ulcerative colitis remains unknown, despite extensive research into likely causes, such as infections, diet, environmental factors, immunological or genetic defects, psychomotor disorders, and abnormalities of mucin. We report here a case of ulcerative colitis in which the first episode of the disease was associated with serologic evidence of infection by verocytotoxin (VT)-producing O157 Escherichia coli (VTEC), possibly the trigger factor of a previously silent ulcerative colitis. Although histological reports of ulcerative colitis associated with VTEC infection are sporadically reported, the trigger role of VTEC in precipitating, aggravating or prolonging this pathology should be more fully elucidated.

Salvia miltiorrhiza (dan shen) significantly ameliorates colon inflammation in dextran sulfate sodium induced colitis.

PubMed

Wen, Xiao-Dong; Wang, Chong-Zhi; Yu, Chunhao; Zhang, Zhiyu; Calway, Tyler; Wang, Yunwei; Li, Ping; Yuan, Chun-Su

2013-01-01

Inflammatory bowel disease increases the risks of human colorectal cancer. In this study, the effects of Salvia miltiorrhiza extract (SME) on chemically-induced colitis in a mouse model were evaluated. Chemical composition of SME was determined by HPLC analysis. A/J mice received a single injection of AOM 7.5 mg/kg. After one week, these mice received 2.5% DSS for eight days, or DSS plus SME (25 or 50 mg/kg). DSS-induced colitis was scored with the disease activity index (DAI). Body weight and colon length were also measured. The severity of inflammatory lesions was further evaluated by colon tissue histological assessment. HPLC assay showed that the major constituents in the tested SME were danshensu, protocatechuic aldehyde, salvianolic acid D, and salvianolic acid B. In the model group, the DAI score reached its highest level on Day 8, while the SME group on both doses showed a significantly reduced DAI score (both p < 0.01). As an objective index of the severity of inflammation, colon length was significantly shorter in the model group than the vehicle group. Treatment with 25 and 50 mg/kg of SME inhibited the shortening of colon in a dose-related manner (p < 0.05 and p < 0.01, respectively). SME groups also significantly reduced weight reduction (p < 0.05). Colitis histological data supported the pharmacological observations. Thus, Salvia miltiorrhiza could be a promising candidate in preventing and treating colitis and in reducing the risks of inflammation-associated colorectal cancer.

[Study the effect and mechanism of thalidomide in model of inflammatory bowed disease].

PubMed

Wang, Xuan; Ouyang, Qin

2005-07-01

To assess the effect of thalidomide on Trinitrobenzensulphonic acid (TNBS)-induced or oxazolone-induced colitis and discuss the possible mechanism of its action. Transmural colitis was induced by TNBS in three groups of rats (n=6 each), and distal colitis was induced by oxazolone in three groups of rats (n=6 each). Then the rats of the groups were treated with thalidomide [200 mg/(kg x d)], prednisone [5 mg/(kg x d)] or vehicle (olive oil) respectively by oral gavage. The colitis was allowed to run its course for 7 d after gavage and at that time the following endpoints were assessed. Colitis was evaluated by macroscopic and microscopic score; the expression of NF-kappaB P65 was examined by immunohistchemical (IHC); the expression of TNF-alpha mRNA was assayed by hybridization in situ (ISH); the cytokine TNF-alpha, IL-4, IFN-gamma were estimated by enzyme-linked immunoadsordent assay (ELISA). With respect to TNBS model, in the control, prednisone-treatment and thalidomide-treatment groups, the macroscopic and microscopic scores were 6.33 +/- 1.03, 1.67 +/- 0.82, 2.00 +/- 0.89 and 7.33 +/- 1.03, 2.67s +/- 0.82, 3.17 +/- 0.75 respectively; the expression levels of NF-kappaB P65 and TNF-alpha mRNA in the three groups were 62.45 +/- 12.38, 23.62 +/- 8.54, 34.18 +/- 9.65 and 12.42 +/- 4.63, 9.86 +/- 3.29, 4.35 +/- 1.74 respectively; the levels of TNF-alpha, IL-4, IFN-gamma were 540.32 +/- 80.76, 94.58 +/- 14.45, 486.18 +/- 68.47; 396.53 +/- 92.42, 78.45 +/- 12.69, 347.56 +/- 82.94; and 385.68 +/- 88.57, 123.68 +/- 38.15, 378.27 +/- 90.65 respectively. The results indicated that thalidomide treatment significantly reduced colonic inflammation, suppressed NF-kappaB activation,enhanced TNF-alpha mRNA degradation, inhibited the synthesis of the TNF-alpha, IEN-gamma and increased the production of IL-4. However, with respect to oxazolone model, the macroscopic score and microscopic score were 2.00 +/- 0.89, 0.33 +/- 0.52, 1.83 +/- 0.75 and 7.83 +/- 1.47, 3.33 +/- 0.82, 6

Lymphocytic colitis complicated by a mass in the terminal ileum.

PubMed

Hui, Chee-Kin

2015-05-01

Lymphocytic colitis is a chronic inflammatory disease affecting the bowel. The clinical course of lymphocytic colitis is believed to be benign with watery diarrhoea. We report herein what is, to the best of our knowledge, the first case of lymphocytic colitis complicated by a terminal ileal mass. A 23-year-old man presented with diarrhoea. Blind biopsies of samples taken from the terminal ileum, caecum and ascending colon showed features of lymphocytic colitis. He declined treatment with budesonide or 5-aminosalicylates. He presented 14 months later with pain over the right lumbar region and nausea. Computed tomographic enteroclysis showed a focal soft tissue enhancing mass at the terminal ileum. Excision of the soft tissue mass revealed that it was reactive nodular lymphoid hyperplasia with fibrous granulation tissue. In conclusion, an untreated lymphocytic colitis may result in the formation of an inflammatory mass lesion.

Review article: Ulcerative colitis, smoking and nicotine therapy.

PubMed

Lunney, P C; Leong, R W L

2012-12-01

Smoking is the best-characterised environmental association of ulcerative colitis (UC). Smoking has been observed to exert protective effects on both the development and progression of UC. To examine the association between UC and smoking, possible pathogenic mechanisms and the potential of nicotine as a therapeutic agent in the treatment of UC. A literature search was conducted through MEDLINE, using the MeSH search terms 'ulcerative colitis' and 'smoking' or 'nicotine'. Relevant articles were identified through manual review. The reference lists of these articles were reviewed to include further appropriate articles. Ulcerative colitis is less prevalent in smokers. Current smokers with a prior diagnosis of UC are more likely to exhibit milder disease than ex-smokers and nonsmokers. There is conflicting evidence for smokers having reduced rates of hospitalisation, colectomy and need for oral corticosteroids and immunosuppressants to manage their disease. Multiple potential active mediators in smoke may be responsible for these clinical effects, including nicotine and carbon monoxide, but the precise mechanism remains unknown. Nicotine has demonstrated variable efficacy in the induction of remission in UC when compared to placebo and conventional medicines. Despite this, the high frequency of adverse events limits its clinical significance. Nicotine's application as a therapeutic treatment in ulcerative colitis is limited. Presently, it may be an option considered only in selected cases of acute ulcerative colitis refractory to conventional treatment options. This review also questions whether nicotine is the active component of smoking that modifies risk and inflammation in ulcerative colitis. © 2012 Blackwell Publishing Ltd.

Ulcerative colitis from patients' viewpoint: a review of two Internet surveys.

PubMed

Dudley-Brown, Sharon; Baker, Kathy

2012-01-01

Ulcerative colitis negatively impacts patients' quality of life, but little is known about which aspects of patients' lives are affected, how patients' perceptions compare with patients with other chronic conditions, and how these perceptions compare with those of gastroenterologists. This review discusses two recent Internet surveys: (1) the Ulcerative Colitis: New Observations on Remission Management And Lifestyle (UC:NORMAL) and (2) the Crohn's and Colitis Foundation of America studies. The surveys revealed that the major impact ulcerative colitis has on patients includes frequent disease manifestations, a substantial psychological burden, and disruption to daily activities. This was more evident in patients with ulcerative colitis than those with migraine, asthma, or rheumatoid arthritis. Physicians' perceptions were considerably different from those of patients, as physicians believed that the disease had a lesser impact on patient quality of life. Furthermore, patients and physicians also identified nonadherence to prescribed medication as a major concern in the treatment of ulcerative colitis. Improved communication and education is needed to address nonadherence and poor health related quality of life in patients living with ulcerative colitis. The influence of Advanced Practice Registered Nurses on physicians, nurses, and patients may help improve adherence and long-term disease outcomes, including patients' health related quality of life. The nurse practitioner, working with both patients who have ulcerative colitis and the physicians who care for these patients, is uniquely placed to address these needs.

Molecular Characterization of the Onset and Progression of Colitis in Inoculated Interleukin-10 Gene-Deficient Mice: A Role for PPARα

PubMed Central

Knoch, Bianca; Barnett, Matthew P. G.; Cooney, Janine; McNabb, Warren C.; Barraclough, Diane; Laing, William; Zhu, Shuotun; Park, Zaneta A.; MacLean, Paul; Knowles, Scott O.; Roy, Nicole C.

2010-01-01

The interleukin-10 gene-deficient (Il10 −/−) mouse is a model of human inflammatory bowel disease and Ppara has been identified as one of the key genes involved in regulation of colitis in the bacterially inoculated Il10 −/− model. The aims were to (1) characterize colitis onset and progression using a histopathological, transcriptomic, and proteomic approach and (2) investigate links between PPARα and IL10 using gene network analysis. Bacterial inoculation resulted in severe colitis in Il10 −/− mice from 10 to 12 weeks of age. Innate and adaptive immune responses showed differences in gene expression relating to colitis severity. Actin cytoskeleton dynamics, innate immunity, and apoptosis-linked gene and protein expression data suggested a delayed remodeling process in 12-week-old Il10 −/− mice. Gene expression changes in 12-week-old Il10 −/− mice were related to PPARα signaling likely to control colitis, but how PPARα activation might regulate intestinal IL10 production remains to be determined. PMID:20671959

A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis

PubMed Central

Ungaro, Ryan; Fukata, Masayuki; Hsu, David; Hernandez, Yasmin; Breglio, Keith; Chen, Anli; Xu, Ruliang; Sotolongo, John; Espana, Cecillia; Zaias, Julia; Elson, Greg; Mayer, Lloyd; Kosco-Vilbois, Marie; Abreu, Maria T.

2009-01-01

Dysregulated innate immune responses to commensal bacteria contribute to the development of inflammatory bowel disease (IBD). TLR4 is overexpressed in the intestinal mucosa of IBD patients and may contribute to uncontrolled inflammation. However, TLR4 is also an important mediator of intestinal repair. The aim of this study is to examine the effect of a TLR4 antagonist on inflammation and intestinal repair in two murine models of IBD. Colitis was induced in C57BL/6J mice with dextran sodium sulfate (DSS) or by transferring CD45Rbhi T cells into RAG1−/− mice. An antibody (Ab) against the TLR4/MD-2 complex or isotype control Ab was administered intraperitoneally during DSS treatment, recovery from DSS colitis, or induction of colitis in RAG1−/− mice. Colitis severity was assessed by disease activity index (DAI) and histology. The effect of the Ab on the inflammatory infiltrate was determined by cell isolation and immunohistochemistry. Mucosal expression of inflammatory mediators was analyzed by real-time PCR and ELISA. Blocking TLR4 at the beginning of DSS administration delayed the development of colitis with significantly lower DAI scores. Anti-TLR4 Ab treatment decreased macrophage and dendritic cell infiltrate and reduced mucosal expression of CCL2, CCL20, TNF-α, and IL-6. Anti-TLR4 Ab treatment during recovery from DSS colitis resulted in defective mucosal healing with lower expression of COX-2, PGE2, and amphiregulin. In contrast, TLR4 blockade had minimal efficacy in ameliorating inflammation in the adoptive transfer model of chronic colitis. Our findings suggest that anti-TLR4 therapy may decrease inflammation in IBD but may also interfere with colonic mucosal healing. PMID:19359427

Changes in the composition of intestinal fungi and their role in mice with dextran sulfate sodium-induced colitis.

PubMed

Qiu, Xinyun; Zhang, Feng; Yang, Xi; Wu, Na; Jiang, Weiwei; Li, Xia; Li, Xiaoxue; Liu, Yulan

2015-05-27

Intestinal fungi are increasingly believed to greatly influence gut health. However, the effects of fungi on intestinal inflammation and on gut bacterial constitution are not clear. Here, based on pyrosequencing method, we reveal that fungal compositions vary in different intestinal segments (ileum, cecum, and colon), prefer different colonization locations (mucosa and feces), and are remarkably changed during intestinal inflammation in dextran sulfate sodium (DSS)-colitis mouse models compare to normal controls: Penicillium, Wickerhamomyces, Alternaria, and Candida are increased while Cryptococcus, Phialemonium, Wallemia and an unidentified Saccharomycetales genus are decreased in the guts of DSS-colitis mice. Fungi-depleted mice exhibited aggravated acute DSS-colitis associated with gain of Hallella, Barnesiella, Bacteroides, Alistipes, and Lactobacillus and loss of butyrate-producing Clostridium XIVa, and Anaerostipes compare with normal control. In contrast, bacteria-depleted mice show attenuated acute DSS-colitis. Mice with severely chronic recurrent DSS-colitis show increased plasma (1,3)-β-D-glucan level and fungal translocation into the colonic mucosa, mesenteric lymph nodes and spleen. This work demonstrate the different roles of fungi in acute and chronic recurrent colitis: They are important counterbalance to bacteria in maintaining intestinal micro-ecological homeostasis and health in acutely inflamed intestines, but can harmfully translocate into abnormal sites and could aggravate disease severity in chronic recurrent colitis.

Changes in the composition of intestinal fungi and their role in mice with dextran sulfate sodium-induced colitis

PubMed Central

Qiu, Xinyun; Zhang, Feng; Yang, Xi; Wu, Na; Jiang, Weiwei; Li, Xia; Li, Xiaoxue; Liu, Yulan

2015-01-01

Intestinal fungi are increasingly believed to greatly influence gut health. However, the effects of fungi on intestinal inflammation and on gut bacterial constitution are not clear. Here, based on pyrosequencing method, we reveal that fungal compositions vary in different intestinal segments (ileum, cecum, and colon), prefer different colonization locations (mucosa and feces), and are remarkably changed during intestinal inflammation in dextran sulfate sodium (DSS)-colitis mouse models compare to normal controls: Penicillium, Wickerhamomyces, Alternaria, and Candida are increased while Cryptococcus, Phialemonium, Wallemia and an unidentified Saccharomycetales genus are decreased in the guts of DSS-colitis mice. Fungi-depleted mice exhibited aggravated acute DSS-colitis associated with gain of Hallella, Barnesiella, Bacteroides, Alistipes, and Lactobacillus and loss of butyrate-producing Clostridium XIVa, and Anaerostipes compare with normal control. In contrast, bacteria-depleted mice show attenuated acute DSS-colitis. Mice with severely chronic recurrent DSS-colitis show increased plasma (1,3)-β-D-glucan level and fungal translocation into the colonic mucosa, mesenteric lymph nodes and spleen. This work demonstrate the different roles of fungi in acute and chronic recurrent colitis: They are important counterbalance to bacteria in maintaining intestinal micro-ecological homeostasis and health in acutely inflamed intestines, but can harmfully translocate into abnormal sites and could aggravate disease severity in chronic recurrent colitis. PMID:26013555

Rapid development of colitis in NSAID-treated IL-10-deficient mice.

PubMed

Berg, Daniel J; Zhang, Juan; Weinstock, Joel V; Ismail, Hanan F; Earle, Keith A; Alila, Hector; Pamukcu, Rifat; Moore, Steven; Lynch, Richard G

2002-11-01

Interleukin (IL)-10 is an anti-inflammatory and immune regulatory cytokine. IL-10-deficient mice (IL-10(-/-)) develop chronic inflammatory bowel disease (IBD), indicating that endogenous IL-10 is a central regulator of the mucosal immune response. Prostaglandins are lipid mediators that may be important mediators of intestinal inflammation. In this study we assessed the role of prostaglandins in the regulation of mucosal inflammation in the IL-10(-/-) mouse model of IBD. Prostaglandin (PG) synthesis was inhibited with nonselective or cyclooxygenase (COX)-isoform selective inhibitors. Severity of inflammation was assessed histologically. Cytokine production was assessed by ribonuclease protection analysis and enzyme-linked immunosorbent assay. PGE(2) levels were assessed by enzyme immunoassay. COX-1 and COX-2 expression was assessed by Western blot analysis. Nonsteroidal anti-inflammatory drug (NSAID) treatment of wild-type mice had minimal effect on the colon. In contrast, NSAID treatment of 4-week-old IL-10(-/-) mice resulted in rapid development of colitis characterized by infiltration of the lamina propria with macrophages and interferon gamma-producing CD4(+) T cells. Colitis persisted after withdrawal of the NSAID. NSAID treatment decreased colonic PGE(2) levels by 75%. Treatment of IL-10(-/-) mice with sulindac sulfone (which does not inhibit PG production) did not induce colitis whereas the NSAID sulindac induced severe colitis. COX-1- or COX-2-selective inhibitors used alone did not induce IBD in IL-10(-/-) mice. However, the combination of COX-1- and COX-2-selective inhibitors did induce colitis. NSAID treatment of IL-10(-/-) mice results in the rapid development of severe, chronic IBD. Endogenous PGs are important inhibitors of the development of intestinal inflammation in IL-10(-/-) mice.

Differential expression of miR-31 between inflammatory bowel disease and microscopic colitis.

PubMed

Zhang, Chen; Zhao, Zijin; Osman, Hany; Watson, Rao; Nalbantoglu, Ilke; Lin, Jingmei

2014-01-01

Idiopathic inflammatory bowel disease (IBD) and microscopic colitis (MC) are distinct entities. However, patients with intermittent episodes of IBD and MC that are encountered in a clinical setting puzzle clinicians and pathologists. This study examined whether microRNA assisted in the classification of IBD and MC. Small RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) colon tissue and qRT-PCR was performed from cohorts of normal control (n=38), ulcerative colitis (n=36), Crohns disease (n=26), collagenous colitis (n=36), lymphocytic colitis (n=30), and patients with intermittent features of IBD and MC (n=6). Differential expression of miR-31 distinguished IBD (ulcerative colitis and Crohns disease) from MC (collagenous colitis and lymphocytic colitis), confirming the specificity of miR-31 expression in IBD (P=0.00001). In addition, expression of miR-31 was increased in collagenous colitis compared to that of lymphocytic colitis (P=0.010). Among 6 patients with alternating episodes of IBD and MC, one patient had matching miR-31 expression in different phases (lymphocytic colitis to ulcerative colitis, and then back to collagenous colitis). The other 5 patients had MC-like expression patterns in both MC and IBD episodes. In summary, IBD and MC have distinct miR-31 expression pattern. Therefore, miR-31 might be used as a biomarker to distinguish between IBD and MC in FFPE colonic tissue. In addition, miR-31 is differentially expressed in colonic tissue between lymphocytic colitis and collagenous colitis, suggesting them of separate disease processes. Finally, patients with alternating IBD and MC episodes represent a diverse group. Among them, the majority demonstrates MC-like miR-31 expression pattern in MC phases, which seems unlikely to support the speculation of MC as an inactive form of IBD. Although the mechanisms deserve further investigation, microRNA is a potentially useful biomarker to differentiate IBD and MC.

Colitis detection on abdominal CT scans by rich feature hierarchies

NASA Astrophysics Data System (ADS)

Liu, Jiamin; Lay, Nathan; Wei, Zhuoshi; Lu, Le; Kim, Lauren; Turkbey, Evrim; Summers, Ronald M.

2016-03-01

Colitis is inflammation of the colon due to neutropenia, inflammatory bowel disease (such as Crohn disease), infection and immune compromise. Colitis is often associated with thickening of the colon wall. The wall of a colon afflicted with colitis is much thicker than normal. For example, the mean wall thickness in Crohn disease is 11-13 mm compared to the wall of the normal colon that should measure less than 3 mm. Colitis can be debilitating or life threatening, and early detection is essential to initiate proper treatment. In this work, we apply high-capacity convolutional neural networks (CNNs) to bottom-up region proposals to detect potential colitis on CT scans. Our method first generates around 3000 category-independent region proposals for each slice of the input CT scan using selective search. Then, a fixed-length feature vector is extracted from each region proposal using a CNN. Finally, each region proposal is classified and assigned a confidence score with linear SVMs. We applied the detection method to 260 images from 26 CT scans of patients with colitis for evaluation. The detection system can achieve 0.85 sensitivity at 1 false positive per image.

Optimization of Aqueous Extraction and Biological Activity of Harpagophytum procumbens Root on Ex Vivo Rat Colon Inflammatory Model.

PubMed

Locatelli, Marcello; Ferrante, Claudio; Carradori, Simone; Secci, Daniela; Leporini, Lidia; Chiavaroli, Annalisa; Leone, Sheila; Recinella, Lucia; Orlando, Giustino; Martinotti, Sara; Brunetti, Luigi; Vacca, Michele; Menghini, Luigi

2017-06-01

Harpagophytum procumbens has a long story of use for the treatment of inflammatory diseases. Considering both the antiinflammatory effects of H. procumbens in multiple tissues and the stability of harpagoside in artificial intestinal fluid, the aim of the present study was to explore the possible protective role of a microwave-assisted aqueous Harpagophytum extract (1-1000 μg/mL) on mouse myoblast C2C12 and human colorectal adenocarcinoma HCT116 cell lines, and isolated rat colon specimens challenged with lipopolysaccharide (LPS), a validated ex vivo model of acute ulcerative colitis. In this context, we evaluated the effects on C2C12 and HCT116 viability, and on LPS-induced production of serotonin (5-HT), tumor necrosis factor (TNF)-α, prostaglandin (PG)E 2 and 8-iso-prostaglandin (8-iso-PG)F 2α . Harpagophytum extract was well tolerated by C2C12 cells, while reduced HCT116 colon cancer cell viability. On the other hand, Harpagophytum extract reduced H 2 O 2 -induced (1 mM) reactive oxygen species (ROS) production, in both cell lines, and inhibited LPS-induced colon production of PGE 2 , 8-iso-PGF 2α , 5-HT and TNFα. Concluding, we demonstrated the efficacy of a microwave-assisted Harpagophytum aqueous extract in modulating the inflammatory, oxidative stress and immune response in an experimental model of inflammatory bowel diseases (IBD), thus suggesting a rational use of Harpagophytum in the management and prevention of ulcerative colitis in humans. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Co-administration of α-lipoic acid and cyclosporine aggravates colon ulceration of acetic acid-induced ulcerative colitis via facilitation of NO/COX-2/miR-210 cascade

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

El-Gowelli, Hanan M., E-mail: dr_Hanan_el_gowali@hotmail.com; Saad, Evan I.; Abdel-Galil, Abdel-Galil A.

In this work, α-lipoic acid and cyclosporine demonstrated significant protection against acetic acid-induced ulcerative colitis in rats. We proposed that α-lipoic acid and cyclosporine co-administration might modulate their individual effects. Induction of ulcerative colitis in rats was performed by intra-rectal acetic acid (5% v/v) administration for 3 consecutive days. Effects of individual or combined used of α-lipoic acid (35 mg/kg ip) or cyclosporine (5 mg/kg sc) for 6 days starting 2 days prior to acetic acid were assessed. Acetic acid caused colon ulceration, bloody diarrhea and weight loss. Histologically, there was mucosal atrophy and inflammatory cells infiltration in submucosa, associatedmore » with depletion of colon reduced glutathione, superoxide dismutase and catalase activities and elevated colon malondialdehyde, serum C-reactive protein (C-RP) and tumor necrosis factor-α (TNF-α). Colon gene expression of cyclooxygenase-2 and miR-210 was also elevated. These devastating effects of acetic acid were abolished upon concurrent administration of α-lipoic acid. Alternatively, cyclosporine caused partial protection against acetic acid-induced ulcerative colitis. Cyclosporine did not restore colon reduced glutathione, catalase activity, serum C-RP or TNF-α. Unexpectedly, co-administration of α-lipoic acid and cyclosporine aggravated colon ulceration. Concomitant use of α-lipoic acid and cyclosporine significantly increased nitric oxide production, cyclooxygenase-2 and miR-210 gene expression compared to all other studied groups. The current findings suggest that facilitation of nitric oxide/cyclooxygenase-2/miR-210 cascade constitutes, at least partially, the cellular mechanism by which concurrent use of α-lipoic acid and cyclosporine aggravates colon damage. Collectively, the present work highlights the probable risk of using α-lipoic acid/cyclosporine combination in ulcerative colitis patients. - Highlights: • Lipoic acid is more effective

Tailoring the mucoadhesive and sustained release characteristics of mesalamine loaded formulations for local treatment of distal forms of ulcerative colitis.

PubMed

Ali, Hany S M; Hanafy, Ahmed F; El Achy, Samar N

2016-10-10

Direct delivery of sustained therapeutic levels of mesalamine (MS) via rectal systems to manage distal forms of ulcerative colitis was studied. The High molecular weight hydroxypropyl methylcellulose (HPMC K4M) polymer was combined with hydrophilic surfactants to control polymer hydration process allowing optimization of the mucoadhesive and controlled drug release properties for the rectal systems. Physical mixtures and granules of MS and HPMC K4M were prepared and in vitro characterized using scanning electron microscope, differential scanning calorimetry and X-ray diffraction techniques. Rectal formulations were prepared utilizing MS-HPMC K4M mixtures in different polyethylene glycol (PEG) combination bases. The developed rectal formulations were investigated for physical, mucoadhesion, in-vitro drug release and swelling characteristics. Results revealed acceptable physical characteristics of the prepared formulations with good content uniformity and minimum weight variation. Sustained release patterns of MS form HPMC K4M based formulations were observed. Formulations prepared using high proportions of the polymer or PEG 400 showed higher extent of mucoadhesion, swelling and greatly extended drug release time. Efficacy of an optimized formulation was assessed using the acetic acid induced colitis model in rats and compared to a reference polymer-free formulation of the drug. Clinical evaluation included bleeding from rectum, consistency of animal stool and colon/body weight ratio. Furthermore, histopathological analysis was carried out to evaluate the degree of inflammation and mucosal damage. Overall results showed a significant enhancement in the clinical pictures and colon histopathology of animals treated by the sustained release mucoadhesive formulation compared to the reference polymer free formulation and the non-treated colitis group. Copyright © 2016 Elsevier B.V. All rights reserved.

The effect of memantine on trinitrobenzene sulfonic acid-induced ulcerative colitis in mice.

PubMed

Motaghi, Ehsan; Hajhashemi, Valiollah; Mahzouni, Parvin; Minaiyan, Mohsen

2016-12-15

Previous reports suggest a significant role for N-Methyl-D-aspartate (NMDA) activation in inflammatory processes. So, this study was conducted to investigate the effect of memantine, a commonly used NMDA receptor antagonist, on inflammatory changes in mice model of colitis. Colitis was induced by intracolonic instillation of trinitrobenzene sulfonic acid (TNBS) (40mg/kg). Animals received memantine (12.5, 25 and 50mg/kg, i.p.), glutamate (2g/kg, p.o.) or dexamethasone (1mg/kg, i.p.) 24h before TNBS instillation and daily thereafter for 4 days. The colonic injury was measured by clinical, macroscopic, microscopic and biochemical analysis. Memantine significantly attenuated the body weight loss, colon weight, the plasma levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and colon level of tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO); as well as macroscopic and microscopic signs of colitis. Oral administration of glutamate had no significant effect on investigated parameters. Memantine as a NMDA antagonist may provide a novel venue for the development of strategies for the treatment of ulcerative colitis. Copyright © 2016 Elsevier B.V. All rights reserved.

[Changes of expression of miR-155 in colitis-associated colonic carcinogenesis].

PubMed

Li, Weiwei; Han, Wenxiao; Zhao, Xinhua; Wang, Hongying

2014-04-01

To investigate the changes of miR-155 and its target genes in colitis-associated carcinogenesis. Colitis-associated colon cancer was induced by azoxymethane (AOM) and dextran sulfate sodium (DSS) in C57BL/6 mice. Mice of three different stages during the development of colon cancer were obtained, named AD1, AD2 and AD3, respectively. A control group of mice without any treatment and a DSS only group representing chronic inflammation without cancer were set up as well. Colon tissue was collected and expression of miR-155 in the colon tissues was measured by real-time fluorescent quantitative PCR. TargetScan and PicTar were used to predict potential target genes of miR-155, which were then preliminarily screened with our gene expression microarray database of AOM-DSS mouse model. Regular PCR was used to confirm the changes of the expression of these potential target genes in AOM-DSS mouse model. Colitis-associated colon cancer was effectively induced by azoxymethane and dextran sulfate sodium in C57BL/6 mice. Histological examination revealed that the evolution process was sequentially from normal, mild dysplasia, moderate dysplasia, and severe dysplasia to adenocarcinoma in the AOM-DSS mouse model. The level of miR-155 was gradually elevated with the formation of colitis-associated colon cancer. There was no significant difference between the levels of miR-155 expression in the DSS group (0.005 6 ± 0.003 7) and control group (0.012 0 ± 0.005 1) (P > 0.05), but the level of miR-155 in the AD3 group (0.054 4 ± 0.027 0) was significantly higher than that of the DSS group (0.005 6 ± 0.003 7)(P < 0.01). No significant change of miR-155 expression was found in the DSS only group. The relative expression levels of miR-155 in the control group, DSS only group and AD3 group were 0.012 0 ± 0.005 1, 0.005 6 ± 0.003 7, 0.054 4 ± 0.027 0, respectively. Data analysis with the gene expression microarray showed that Tle4, Kcna1, Itk, Bcorl1, Cacna1c, Rspo2 and Foxo3 were

Glutamine supplementation attenuates expressions of adhesion molecules and chemokine receptors on T cells in a murine model of acute colitis.

PubMed

Hou, Yu-Chen; Wu, Jin-Ming; Wang, Ming-Yang; Wu, Ming-Hsun; Chen, Kuen-Yuan; Yeh, Sung-Ling; Lin, Ming-Tsan

2014-01-01

Migration of T cells into the colon plays a major role in the pathogenesis in inflammatory bowel disease. This study investigated the effects of glutamine (Gln) supplementation on chemokine receptors and adhesion molecules expressed by T cells in mice with dextran sulfate sodium- (DSS-) induced colitis. C57BL/6 mice were fed either a standard diet or a Gln diet replacing 25% of the total nitrogen. After being fed the diets for 5 days, half of the mice from both groups were given 1.5% DSS in drinking water to induce colitis. Mice were killed after 5 days of DSS exposure. DSS colitis resulted in higher expression levels of P-selectin glycoprotein ligand- (PSGL-) 1, leukocyte function-associated antigen- (LFA-) 1, and C-C chemokine receptor type 9 (CCR9) by T helper (Th) and cytotoxic T (Tc) cells, and mRNA levels of endothelial adhesion molecules in colons were upregulated. Gln supplementation decreased expressions of PSGL-1, LFA-1, and CCR9 by Th cells. Colonic gene expressions of endothelial adhesion molecules were also lower in Gln-colitis mice. Histological finding showed that colon infiltrating Th cells were less in the DSS group with Gln administration. Gln supplementation may ameliorate the inflammation of colitis possibly via suppression of T cell migration.

Goat whey ameliorates intestinal inflammation on acetic acid-induced colitis in rats.

PubMed

Araújo, Daline Fernandes de Souza; Guerra, Gerlane Coelho Bernardo; Júnior, Raimundo Fernandes de Araújo; Antunes de Araújo, Aurigena; Antonino de Assis, Paloma Oliveira; Nunes de Medeiros, Ariosvaldo; Formiga de Sousa, Yasmim Regis; Pintado, Maria Manuela Estevez; Gálvez, Julio; Queiroga, Rita de Cássia Ramos do Egypto

2016-12-01

Complementary or alternative medicine is of great interest for the treatment of inflammatory bowel disease, with the aim of ameliorating the side effects of the drugs commonly used or improving their efficacy. In this study, we evaluated the ability of goat whey to prevent intestinal inflammation in the experimental model of acetic acid-induced rats and compared it to sulfasalazine. Pretreatment with goat whey (1, 2, and 4g/kg) and sulfasalazine (250mg/kg) on colitic rats improved colonic inflammatory markers, including myeloperoxidase activity, leukotriene B 4 levels, as well as the production of proinflammatory cytokines IL-1β and tumor necrosis factor-α. Furthermore, the administration of goat whey significantly reduced the colonic oxidative stress by reducing malondialdehyde levels and increased total glutathione content, a potent antioxidant peptide. The histological evaluation of the colonic specimens from colitic rats confirmed these beneficial effects, as goat whey preserved the colonic tissue, especially in those rats treated with the highest dose of goat whey or with sulfasalazine. The immunohistochemistry analysis of the colonic tissue evaluation also revealed a reduction in the expression of cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloproteinase-9, together with an increased expression of suppressor of cytokine signaling-1. These results suggest that goat whey exerted a preventive effect against the intestinal damage induced by acetic acid, showing a similar efficacy to that shown by sulfasalazine, therefore making it a potential treatment for human inflammatory bowel disease. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

The Dynamics of Interleukin-10-Afforded Protection during Dextran Sulfate Sodium-Induced Colitis

PubMed Central

Cardoso, Ana; Gil Castro, Antonio; Martins, Ana Catarina; Carriche, Guilhermina M.; Murigneux, Valentine; Castro, Isabel; Cumano, Ana; Vieira, Paulo; Saraiva, Margarida

2018-01-01

Inflammatory bowel disease encompasses a group of chronic-inflammatory conditions of the colon and small intestine. These conditions are characterized by exacerbated inflammation of the organ that greatly affects the quality of life of patients. Molecular mechanisms counteracting this hyperinflammatory status of the gut offer strategies for therapeutic intervention. Among these regulatory molecules is the anti-inflammatory cytokine interleukin (IL)-10, as shown in mice and humans. Indeed, IL-10 signaling, particularly in macrophages, is essential for intestinal homeostasis. We sought to investigate the temporal profile of IL-10-mediated protection during chemical colitis and which were the underlying mechanisms. Using a novel mouse model of inducible IL-10 overexpression (pMT-10), described here, we show that mice preconditioned with IL-10 for 8 days before dextran sulfate sodium (DSS) administration developed a milder colitic phenotype. In IL-10-induced colitic mice, Ly6C cells isolated from the lamina propria showed a decreased inflammatory profile. Because our mouse model leads to transcription of the IL-10 transgene in the bone marrow and elevated seric IL-10 concentration, we investigated whether IL-10 could imprint immune cells in a long-lasting way, thus conferring sustained protection to colitis. We show that this was not the case, as IL-10-afforded protection was only observed if IL-10 induction immediately preceded DSS-mediated colitis. Thus, despite the protection afforded by IL-10 in colitis, novel strategies are required, specifically to achieve long-lasting protection. PMID:29545807

Probiotic yeasts: Anti-inflammatory potential of various non-pathogenic strains in experimental colitis in mice

PubMed Central

Foligné, Benoît; Dewulf, Joëlle; Vandekerckove, Pascal; Pignède, Georges; Pot, Bruno

2010-01-01

AIM: To evaluate the in vitro immunomodulation capacity of various non-pathogenic yeast strains and to investigate the ability of some of these food grade yeasts to prevent experimental colitis in mice. METHODS: In vitro immunomodulation was assessed by measuring cytokines [interleukin (IL)-12p70, IL-10, tumor necrosis factor and interferon γ] released by human peripheral blood mononuclear cells after 24 h stimulation with 6 live yeast strains (Saccharomyces ssp.) and with bacterial reference strains. A murine model of acute 2-4-6-trinitrobenzene sulfonic acid (TNBS)-colitis was next used to evaluate the distinct prophylactic protective capacities of three yeast strains compared with the performance of prednisolone treatment. RESULTS: The six yeast strains all showed similar non-discriminating anti-inflammatory potential when tested on immunocompetent cells in vitro. However, although they exhibited similar colonization patterns in vivo, some yeast strains showed significant anti-inflammatory activities in the TNBS-induced colitis model, whereas others had weaker or no preventive effect at all, as evidenced by colitis markers (body-weight loss, macroscopic and histological scores, myeloperoxidase activities and blood inflammatory markers). CONCLUSION: A careful selection of strains is required among the biodiversity of yeasts for specific clinical studies, including applications in inflammatory bowel disease and other therapeutic uses. PMID:20440854

Recent advances in the management of radiation colitis

PubMed Central

Kountouras, Jannis; Zavos, Christos

2008-01-01

Radiation colitis, an insidious, progressive disease of increasing frequency, develops 6 mo to 5 years after regional radiotherapy for malignancy, owing to the deleterious effects of the latter on the colon and the small intestine. When dealing with radiation colitis and its complications, the most conservative modality should be employed because the areas of intestinal injury do not tend to heal. Acute radiation colitis is mostly self-limited, and usually, only supportive management is required. Chronic radiation colitis, a poorly predictable progressive disease, is considered as a precancerous lesion; radiation-associated malignancy has a tendency to be diagnosed at an advanced stage and to bear a dismal prognosis. Therefore, management of chronic radiation colitis remains a major challenge owing to the progressive evolution of the disease, including development of fibrosis, endarteritis, edema, fragility, perforation, partial obstruction, and cancer. Patients are commonly managed conservatively. Surgical intervention is difficult to perform because of the extension of fibrosis and alterations in the gut and mesentery, and should be reserved for intestinal obstruction, perforation, fistulas, and severe bleeding. Owing to the difficulty in managing the complications of acute and chronic radiation colitis, particular attention should be focused onto the prevention strategies. Uncovering the fibrosis mechanisms and the molecular events underlying radiation bowel disease could lead to the introduction of new therapeutic and/or preventive approaches. A variety of novel, mostly experimental, agents have been used mainly as a prophylaxis, and improvements have been made in radiotherapy delivery, including techniques to reduce the amount of exposed intestine in the radiation field, as a critical strategy for prevention. PMID:19109862

Ipilimumab-induced colitis in patients with metastatic melanoma.

PubMed

De Felice, Kara M; Gupta, Arjun; Rakshit, Sagar; Khanna, Sahil; Kottschade, Lisa A; Finnes, Heidi D; Papadakis, Konstantinos A; Loftus, Edward V; Raffals, Laura E; Markovic, Svetomir N

2015-08-01

Ipilimumab is used for the treatment of metastatic melanoma and is associated with serious immune-related colitis. We aimed to report the clinical features, treatment, and outcomes of patients with ipilimumab-induced colitis. In this retrospective observational study, we identified patients with unresectable melanoma treated with ipilimumab between March 2011 and September 2013. Diarrhea was assessed using the Common Terminology Criteria for Adverse Events, v3.0. Colitis was defined by diarrhea (grade≥2) requiring steroids with or without endoscopic/histologic/radiologic evidence of colitis. A total of 103 patients with metastatic melanoma treated with ipilimumab were identified. Of these, 30 patients (29%) developed diarrhea (all grades), and 23 patients (22%) developed colitis requiring systemic corticosteroid therapy. The median number of ipilimumab doses before onset of diarrhea was 2 (range, 1-4). Six of 23 patients responded to less than 1 mg/kg daily prednisone alone. Fifteen patients required high-dose oral and/or intravenous prednisone (1-2 mg/kg body weight). Six patients had diarrhea refractory to prednisone; five required rescue therapy with budesonide (9-12 mg daily) and one was treated with infliximab (5 mg/kg, three doses). There was one case of severe diarrhea (grade 3) treated successfully with high-dose budesonide (12 mg) monotherapy. Ipilimumab-induced colitis requires early and aggressive medical therapy. Most patients can be successfully managed with systemic corticosteroids. High-dose budesonide is an attractive steroid-sparing agent, however further studies of its efficacy in this setting are needed. Infliximab should be used in refractory cases to avoid colectomy. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Clinical Presentation of Ulcerative Colitis in Pakistani Adults.

PubMed

Qureshi, Mustafa; Abbas, Zaigham

2015-01-01

The aim of this study was to determine the clinical presentation and severity of ulcerative colitis (UC) in Pakistani adult patients. An observational study. Data were obtained by reviewing the medical records of patients who visited a gastroenterology clinic between 2008 and 2012. There were 54 patients diagnosed as UC. The male to female ratio was 1:1. Mean age at diagnosis of UC was 38.7 ± 11.8 years (median 36.5, range 18-64). The predominant presenting symptoms were mucus diarrhea in 49 (90.7%), gross blood in stools in 42 (77.8%), abdominal pain or cramps in 40 (74.1%) and weight loss in 15 (27.7%). Left-sided colitis was present in 23 (42.6%), pancolitis in 15 (27.8%), extensive colitis in 11 (20.4%), and proctitis in five (9.2%). The severity of UC as judged by the Mayo scoring system showed that 68.5% were suffering from moderate to severe disease while 31.5% had mild disease. The extra-intestinal manifestation were found only in seven patients; arthritis in five patients and anterior uveitis in two patients. The arthritis was unilateral and the sites were knee joint in three patients and sacroiliac joint in two patients. Ulcerative colitis presents in our adult patients may present at any age with no gender preponderance. The disease severity is moderate to severe in the majority of patients and more than half of them have left-sided colitis or pancolitis at the time of presentation. Extraintestinal manifestations were not common. Qureshi M, Abbas Z. Clinical Presentation of Ulcerative Colitis in Pakistani Adults. Euroasian J Hepato-Gastroenterol 2015;5(2):127-130.

Histological and immunohistochemical effects of L-arginine and silymarin on TNBS-induced inflammatory bowel disease in rats.

PubMed

Al-Drees, Abdul; Khalil, Mahmoud Salah

2016-11-01

Inflammatory bowel disease (IBD) is a chronic disease that affects quality of life. Various mediators are involved in IBD pathogenesis including inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NF-κB), cytochrome c, heat shock protein 70 (HSP70) and tumor necrosis factor (TNF)-α. L-Arginine (L-Arg) can be depleted in IBD, and silymarin inhibits neutrophil infiltration, NF-κB, and TNF-α, which have crucial roles in inducing IBD. This study aimed to investigate whether silymarin and L-Arg supplementation decreases IBD progression in trinitrobenzine-sulfonic acid (TNBS)-induced colitis. Fifty adult male albino rats were randomized into five groups (10 animals per group): Group I rats orally received 100 mg silymarin/kg body weight once daily; Group II rats orally received 2 mg L-Arg/100 g body weight in 5 mL distilled water once daily; Group III rats rectally received 0.85 mL TNBS in 50% ethanol to induce colitis; Group IV rats were treated similar to group III and, on recovery from anesthesia, received silymarin as described for group I; and Group V rats were treated similar to group III and, on recovery from anesthesia, received L-Arg as described for group II. On day 7, the rats were anesthetized, and blood samples were collected to determine the serum concentrations of TNF-α. Laparotomy and total colectomy were performed for macroscopic, histological, and immunohistochemical investigations. The results showed that silymarin and L-Arg macroscopically and microscopically ameliorated TNBS-induced colitis; significantly decreased the serum levels of TNF-α; inhibited the colonic expression of iNOS, NF-κB, and cytochrome c; and increased expression of HSP70. Our results suggest that these complementary medicines could be used to supplement current treatments for IBD.

Alterations in melatonin and 5-HT signalling in the colonic mucosa of mice with dextran-sodium sulfate-induced colitis.

PubMed

MacEachern, Sarah J; Keenan, Catherine M; Papakonstantinou, Evangelia; Sharkey, Keith A; Patel, Bhavik Anil

2018-05-01

Inflammatory bowel disease (IBD) is characterized by pain, bleeding, cramping and altered gastrointestinal (GI) function. Changes in mucosal 5-HT (serotonin) signalling occur in animal models of colitis and in humans suffering from IBD. Melatonin is co-released with 5-HT from the mucosa and has a wide variety of actions in the GI tract. Here, we examined how melatonin signalling is affected by colitis and determined how this relates to 5-HT signalling. Using electroanalytical approaches, we investigated how 5-HT release, reuptake and availability as well as melatonin availability are altered in dextran sodium sulfate (DSS)-induced colitis in mice. Studies were conducted to explore if melatonin treatment during active colitis could reduce the severity of colitis. We observed an increase in 5-HT and a decrease in melatonin availability in DSS-induced colitis. A significant reduction in 5-HT reuptake was observed in DSS-induced colitis animals. A reduction in the content of 5-HT was observed, but no difference in tryptophan levels were observed. A reduction in deoxycholic acid-stimulated 5-HT availability and a significant reduction in mechanically-stimulated 5-HT and melatonin availability were observed in DSS-induced colitis. Orally or rectally administered melatonin once colitis was established did not significantly suppress inflammation. Our data suggest that DSS-induced colitis results in a reduction in melatonin availability and an increase in 5-HT availability, due to a reduction/loss of tryptophan hydroxylase 1 enzyme, 5-HT content and 5-HT transporters. Mechanosensory release was more susceptible to inflammation when compared with chemosensory release. © 2018 The British Pharmacological Society.

Intraperitoneal but not intravenous cryopreserved mesenchymal stromal cells home to the inflamed colon and ameliorate experimental colitis.

PubMed

Castelo-Branco, Morgana T L; Soares, Igor D P; Lopes, Daiana V; Buongusto, Fernanda; Martinusso, Cesonia A; do Rosario, Alyson; Souza, Sergio A L; Gutfilen, Bianca; Fonseca, Lea Mirian B; Elia, Celeste; Madi, Kalil; Schanaider, Alberto; Rossi, Maria Isabel D; Souza, Heitor S P

2012-01-01

Mesenchymal stromal cells (MSCs) were shown to have immunomodulatory activity and have been applied for treating immune-mediated disorders. We compared the homing and therapeutic action of cryopreserved subcutaneous adipose tissue (AT-MSCs) and bone marrow-derived mesenchymal stromal cells (BM-MSCs) in rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis. After colonoscopic detection of inflammation AT-MSCs or BM-MSCs were injected intraperitoneally. Colonoscopic and histologic scores were obtained. Density of collagen fibres and apoptotic rates were evaluated. Cytokine levels were measured in supernatants of colon explants. For cell migration studies MSCs and skin fibroblasts were labelled with Tc-99m or CM-DiI and injected intraperitonealy or intravenously. Intraperitoneal injection of AT-MSCs or BM-MSCs reduced the endoscopic and histopathologic severity of colitis, the collagen deposition, and the epithelial apoptosis. Levels of TNF-α and interleukin-1β decreased, while VEGF and TGF-β did not change following cell-therapy. Scintigraphy showed that MSCs migrated towards the inflamed colon and the uptake increased from 0.5 to 24 h. Tc-99m-MSCs injected intravenously distributed into various organs, but not the colon. Cm-DiI-positive MSCs were detected throughout the colon wall 72 h after inoculation, predominantly in the submucosa and muscular layer of inflamed areas. Intraperitoneally injected cryopreserved MSCs home to and engraft into the inflamed colon and ameliorate TNBS-colitis.

Association between ulcerative colitis and systemic lupus erythematosus: report of two cases.

PubMed

Koutroubakis, I E; Kritikos, H; Mouzas, I A; Spanoudakis, S M; Kapsoritakis, A N; Petinaki, E; Kouroumalis, E A; Manousos, O N

1998-05-01

Common aetiopathogenic factors may explain the association of ulcerative colitis with autoimmune disorders such as systemic lupus erythematosus. We report two cases of ulcerative colitis associated with idiopathic systemic lupus erythematosus: one patient who developed ulcerative colitis 11 years after having been diagnosed as a case of systemic lupus erythematosus and one case of simultaneous appearance of the two diseases. The lupus clinical manifestations were in neither case correlated with the treatment of ulcerative colitis. The association between ulcerative colitis and systemic lupus erythematosus is rare. Although a chance occurrence cannot be excluded it is possible that both conditions share some genetic or immunological defects.

The Stimulation of Macrophages with TLR Ligands Supports Increased IL-19 Expression in Inflammatory Bowel Disease Patients and in Colitis Models.

PubMed

Steinert, Anna; Linas, Ioannis; Kaya, Berna; Ibrahim, Mohamed; Schlitzer, Andreas; Hruz, Petr; Radulovic, Katarina; Terracciano, Luigi; Macpherson, Andrew J; Niess, Jan Hendrik

2017-10-01

IL-19, a member of the IL-10 cytokine family that signals through the IL-20 receptor type I (IL-20Rα:IL-20Rβ), is a cytokine whose function is not completely known. In this article, we show that the expression of IL19 in biopsies of patients with active ulcerative colitis was increased compared with patients with quiescent ulcerative colitis and that colitis was attenuated in IL-19-deficient mice. The disruption of the epithelial barrier with dextran sodium sulfate leads to increased IL-19 expression. Attenuated colitis in IL-19-deficient animals was associated with reduced numbers of IL-6-producing macrophages in the inflamed colonic lamina propria. Microbial-driven expression of IL-19 by intestinal macrophages may contribute to the pathogenesis of inflammatory bowel disease. Copyright © 2017 by The American Association of Immunologists, Inc.

Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases

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

Huang, T.-Y.; Division of Gastroenterology and Hepatology, Tri-Service General Hospital, Taipei, Taiwan; Chu, H.-C.

2009-05-15

In addition to its antimicrobial activity, minocycline exerts anti-inflammatory effects in several disease models. However, whether minocycline affects the pathogenesis of inflammatory bowel disease has not been determined. We investigated the effects of minocycline on experimental colitis and its underlying mechanisms. Acute and chronic colitis were induced in mice by treatment with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS), and the effect of minocycline on colonic injury was assessed clinically and histologically. Prophylactic and therapeutic treatment of mice with minocycline significantly diminished mortality rate and attenuated the severity of DSS-induced acute colitis. Mechanistically, minocycline administration suppressed inducible nitricmore » oxide synthase (iNOS) expression and nitrotyrosine production, inhibited proinflammatory cytokine expression, repressed the elevated mRNA expression of matrix metalloproteinases (MMPs) 2, 3, 9, and 13, diminished the apoptotic index in colonic tissues, and inhibited nitric oxide production in the serum of mice with DSS-induced acute colitis. In DSS-induced chronic colitis, minocycline treatment also reduced body weight loss, improved colonic histology, and blocked expression of iNOS, proinflammatory cytokines, and MMPs from colonic tissues. Similarly, minocycline could ameliorate the severity of TNBS-induced acute colitis in mice by decreasing mortality rate and inhibiting proinflammatory cytokine expression in colonic tissues. These results demonstrate that minocycline protects mice against DSS- and TNBS-induced colitis, probably via inhibition of iNOS and MMP expression in intestinal tissues. Therefore, minocycline is a potential remedy for human inflammatory bowel diseases.« less

Salvia miltiorrhiza (Dan Shen) Significantly Ameliorates Colon Inflammation in Dextran Sulfate Sodium Induced Colitis

PubMed Central

Wen, Xiao-Dong; Wang, Chong-Zhi; Yu, Chunhao; Zhang, Zhiyu; Calway, Tyler; Wang, Yunwei; Li, Ping; Yuan, Chun-Su

2014-01-01

Inflammatory bowel disease increases the risks of human colorectal cancer. In this study, the effects of Salvia miltiorrhiza extract (SME) on chemically-induced colitis in a mouse model were evaluated. Chemical composition of SME was determined by HPLC analysis. A/J mice received a single injection of AOM 7.5 mg/kg. After one week, these mice received 2.5% DSS for 8 days, or DSS plus SME (25 or 50 mg/kg). DSS-induced colitis was scored with the disease activity index (DAI). Body weight and colon length were also measured. The severity of inflammatory lesions was further evaluated by colon tissue histological assessment. HPLC assay showed that the major constituents in the tested SME were danshensu, protocatechuic aldehyde, salvianolic acid D and salvianolic acid B. In the model group, the DAI score reached its highest level on Day 8, while the SME group on both doses showed a significantly reduced DAI score (both P < 0.01). As an objective index of the severity of inflammation, colon length was reduced significantly from the vehicle group to model group. Treatment with 25 and 50 mg/kg of SME inhibited the reduction of colon in a dose-related manner (P < 0.05 and P < 0.01, respectively). SME groups also significantly reduced weight reduction (P < 0.05). Colitis histological data supported the pharmacological observations. Thus, Salvia miltiorrhiza could be a promising candidate in preventing and treating colitis and in reducing the risks of inflammation-associated colorectal cancer. PMID:24117071

Absence of stearoyl-CoA desaturase-1 does not promote DSS-induced acute colitis.

PubMed

Macdonald, Marcia L E; Bissada, Nagat; Vallance, Bruce A; Hayden, Michael R

2009-12-01

Absence of stearoyl-CoA desaturase-1 (SCD1) in mice leads to chronic inflammation of the skin and increased susceptibility to atherosclerosis, while also increasing plasma inflammatory markers. A recent report suggested that SCD1 deficiency also increases disease severity in a mouse model of inflammatory bowel disease, induced by dextran sulfate sodium (DSS). However, SCD1-deficient mice are known to consume increased amounts of water, which would also be expected to increase the intake of DSS-treated water. The aim of this study was to determine the effect of SCD1 deficiency on DSS-induced acute colitis with DSS dosing adjusted to account for genotype differences in fluid consumption. Wild-type controls were treated with 3.5% DSS for 5 days to induce moderately severe colitis, while the concentration of DSS given to SCD1-deficient mice was lowered to 2.5% to control for increased fluid consumption. Colonic inflammation was assessed by clinical and histological scoring. Although SCD1-deficient mice consumed a total intake of DSS that was greater than that of wild-type controls, colonic inflammation, colon length and fecal blood were not altered by SCD1-deficiency in DSS-induced colitis, while diarrhea and total weight loss were modestly improved. Despite SCD1 deficiency leading to chronic inflammation of the skin and increased susceptibility to atherosclerosis, it does not accelerate inflammation in the DSS-induced model of acute colitis when DSS intake is controlled. These observations suggest that SCD1 deficiency does not play a significant role in colonic inflammation in this model.

Assessing the Optimal Position for Vedolizumab in the Treatment of Ulcerative Colitis: A Simulation Model.

PubMed

Scott, Frank I; Shah, Yash; Lasch, Karen; Luo, Michelle; Lewis, James D

2018-01-18

Vedolizumab, an α4β7 integrin monoclonal antibody inhibiting gut lymphocyte trafficking, is an effective treatment for ulcerative colitis (UC). We evaluated the optimal position of vedolizumab in the UC treatment paradigm. Using Markov modeling, we assessed multiple algorithms for the treatment of UC. The base case was a 35-year-old male with steroid-dependent moderately to severely active UC without previous immunomodulator or biologic use. The model included 4 different algorithms over 1 year, with vedolizumab use prior to: initiating azathioprine (Algorithm 1), combination therapy with infliximab and azathioprine (Algorithm 2), combination therapy with an alternative anti-tumor necrosis factor (anti-TNF) and azathioprine (Algorithm 3), and colectomy (Algorithm 4). Transition probabilities and quality-adjusted life-year (QALY) estimates were derived from the published literature. Primary analyses included simulating 100 trials of 100,000 individuals, assessing clinical outcomes, and QALYs. Sensitivity analyses employed longer time horizons and ranges for all variables. Algorithm 1 (vedolizumab use prior to all other therapies) was the preferred strategy, resulting in 8981 additional individuals in remission, 18 fewer cases of lymphoma, and 1087 fewer serious infections per 100,000 patients compared with last-line use (A4). Algorithm 1 also resulted in 0.0197 to 0.0205 more QALYs compared with other algorithms. This benefit increased with longer time horizons. Algorithm 1 was preferred in all sensitivity analyses. The model suggests that treatment algorithms positioning vedolizumab prior to other therapies should be considered for individuals with moderately to severely active steroid-dependent UC. Further prospective research is needed to confirm these simulated results. © 2018 Crohn’s & Colitis Foundation of America. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Severe colitis associated with docetaxel use: A report of four cases

PubMed Central

Carrion, Andres F; Hosein, Peter J; Cooper, Eugene M; Lopes, Gilberto; Pelaez, Liset; Rocha-Lima, Caio M

2010-01-01

Diarrhea is a common side effect of chemotherapy. Pseudomembranous colitis is a well known complication of antibiotic treatment that can also be observed, albeit rarely, with certain chemotherapeutic agents. We present four cases of severe colitis in patients undergoing treatment with taxane-based chemotherapy for pancreatic, lung and breast cancer. None of them had recently received antibiotics. One patient presented with a bowel perforation and three had endoscopic findings of pseudomembranous colitis. Two of these three patients had negative stool toxin assays for Clostridium difficile. In the patient presenting with perforation, an emergency left hemicolectomy was performed and the pathological findings in the colon were acute inflammation and ischemic necrosis; the other three patients were treated with oral vancomycin and/or oral or intravenous metronidazole leading to complete resolution of the symptoms. Apart from pseudomembranous colitis, we describe patients presenting with neutropenic enterocolitis as well as ischemic colitis after docetaxel use. These cases provide some insight into the spectrum and varied clinical presentations of severe colitis associated with taxane-based chemotherapy. PMID:21160890

Surgical management of Crohn's colitis.

PubMed

Moir, Christopher R

2007-08-01

Crohn's disease in childhood is changing. The incidence is increasing, colonic disease is becoming more prevalent in younger children, and colon reconstruction is more acceptable. Genetic phenotypes are influencing decisions for surgery, and targeted immunotherapy has renewed hope for more durable remissions following less extensive resections. The tasks facing the surgeon evaluating a child with Crohn's colitis include confirming the specific diagnostic subtype and selecting the correct procedure. This chapter will review the unique aspects of pediatric Crohn's colitis and the increased complexity of surgical choice for this most challenging presentation. Recent success with less extensive surgery offers renewed hope for children with intractable colonic disease.

Hydrogen peroxide scavenger, catalase, alleviates ion transport dysfunction in murine colitis.

PubMed

Barrett, Kim E; McCole, Declan F

2016-11-01

Reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ) contribute to epithelial damage and ion transport dysfunction (key events in inflammatory diarrhoea) in inflammatory bowel disease (IBD). The aim of this study was to identify if H 2 O 2 mediates suppression of colonic ion transport function in the murine dextran sulfate sodium (DSS) colitis model by using the H 2 O 2 degrading enzyme, catalase. Colitis was induced by administering DSS (4%) in drinking water for 5 days followed by 3 days on normal H 2 O. Mice were administered either pegylated catalase or saline at day -1, 0 and +1 of DSS treatment. Ion transport responses to the Ca 2+ -dependent agonist, carbachol (CCh), or the cAMP-dependent agonist, forskolin, were measured across distal colonic mucosa mounted in Ussing chambers. Parameters of DSS-induced inflammation (loss in body weight, decreased colon length, altered stool consistency), were only partially alleviated by catalase while histology was only minimally improved. However, catalase significantly reversed the DSS-induced reduction in baseline ion transport as well as colonic I sc responses to CCh. However, ion transport responses to forskolin were not significantly restored. Catalase also reduced activation of ERK MAP kinase in the setting of colitis, and increased expression of the Na + -K + -2Cl - cotransporter, NKCC1, consistent with restoration of ion transport function. Ex vivo treatment of inflamed colonic mucosae with catalase also partially restored ion transport function. Therefore, catalase partially prevents, and rescues, the loss of ion transport properties in DSS colitis even in the setting of unresolved tissue inflammation. These findings indicate a prominent role for ROS in ion transport dysfunction in colitis and may suggest novel strategies for the treatment of inflammatory diarrhoea. © 2016 John Wiley & Sons Australia, Ltd.

Efficacy of an inhibitor of adhesion molecule expression (GI270384X) in the treatment of experimental colitis.

PubMed

Panés, Julián; Aceituno, Montserrat; Gil, Fèlix; Miquel, Rosa; Piqué, Josep M; Salas, Azucena; McLean, Peter

2007-10-01

Modulation of adhesion molecule expression or function is regarded as a promising therapy for inflammatory conditions. This study evaluates the effects of an inhibitor of adhesion molecule expression (GI270384X) in two experimental models of colitis. Colitis of different severity was induced in C57BL/6J mice by administering 1, 2, or 3% dextran sulfate sodium (DSS). GI270384X (3, 10, or 25 mg.kg(-1).day(-1)) was administered as pretreatment or started 3 days after colitis induction. In IL-10-deficient mice, the highest dose was given for 2 wk. The clinical course of colitis, pathological changes, serum inflammatory biomarkers, expression of adhesion molecules, and leukocyte-endothelial cell interactions in colonic venules were measured in mice treated with vehicle or with active drug. In the most severe forms of colitis (2% and 3% DSS and IL-10-deficient mice), the magnitude of colonic inflammation was not modified by treatment with GI270384X. In a less severe form of colitis (1% DSS), GI270384X treatment dose dependently ameliorated the clinical signs of colitis, colonic pathological changes, and serum levels of biomarkers (IL-6 and serum amyloid A). Administration of 25 mg.kg(-1).day(-1) GI270384X abrogated upregulation of ICAM-1 in the inflamed colon but had no effect on VCAM-1 or E-selectin expression. This was associated with a significant reduction in number of rolling and firmly adherent leukocytes in colonic venules. These results indicate that GI270384X is effective in the treatment of experimental colitis of moderate severity. Reduced adhesion molecule expression and leukocyte recruitment to the inflamed intestine contribute to this beneficial effect.

Onset of ulcerative colitis after thyrotoxicosis: a case report and review of the literature.

PubMed

Laterza, L; Piscaglia, A C; Lecce, S; Gasbarrini, A; Stefanelli, M L

2016-01-01

Ulcerative colitis is a chronic disease that could be triggered by acute stressful events, such as gastrointestinal infections or emotional stress. We reported the case of the onset of an ulcerative colitis after a thyrotoxicosis crisis and reviewed the literature about the relationships between thyroid dysfunctions and ulcerative colitis. A 38-year-old woman was diagnosed with ulcerative colitis after her third thyrotoxicosis crisis, two years after the diagnosis of Graves' disease. In this case, thyrotoxicosis acted as a trigger for ulcerative colitis onset. Hyperthyroidism could be a trigger able to elicit ulcerative colitis in susceptible patients.

[Allergic colitis in exclusively breast-fed infants].

PubMed

Sierra Salinas, C; Blasco Alonso, J; Olivares Sánchez, L; Barco Gálvez, A; del Río Mapelli, L

2006-02-01

Eosinophilic colitis is induced by antigens present in cow's milk proteins in formula or human milk. In the last few years, an increasing number of cases have been diagnosed in exclusively breast-fed infants. We performed a retrospective study of 13 infants diagnosed with allergic colitis in our unit between January 1997 and January 2004. All the infants had been exclusively breast-fed. In all patients, initial symptoms were digestive (12 with mucus and bloody stools). Onset of symptoms occurred at 0-3 months in 77 %. Laboratory data of the allergic compound were negative. The main locations were the descending and sigmoid colon (75 %). Biopsy demonstrated acute inflammation, with neutrophil infiltration and an increase in eosinophils. In all patients, initial treatment consisted of exclusion of cow's milk proteins from the mother's diet. Ten of the 13 patients showed no improvement, requiring exclusive administration of protein-free hydrolyzate. In 3 infants, breastfeeding was maintained (breastfeeding without cow's milk proteins plus hydrolyzate). Diagnosis of eosinophilic colitis is based on exclusion of other causes of specific colitis and typical endoscopic and ultrastructural findings. Moreover, a satisfactory response to dietary treatment must be demonstrated. This diagnosis should be considered in breast-fed infants with rectal bleeding without involvement of general health status.

Co-administration of α-lipoic acid and cyclosporine aggravates colon ulceration of acetic acid-induced ulcerative colitis via facilitation of NO/COX-2/miR-210 cascade.

PubMed

El-Gowelli, Hanan M; Saad, Evan I; Abdel-Galil, Abdel-Galil A; Ibrahim, Einas R

2015-11-01

In this work, α-lipoic acid and cyclosporine demonstrated significant protection against acetic acid-induced ulcerative colitis in rats. We proposed that α-lipoic acid and cyclosporine co-administration might modulate their individual effects. Induction of ulcerative colitis in rats was performed by intra-rectal acetic acid (5% v/v) administration for 3 consecutive days. Effects of individual or combined used of α-lipoic acid (35 mg/kg ip) or cyclosporine (5mg/kg sc) for 6 days starting 2 days prior to acetic acid were assessed. Acetic acid caused colon ulceration, bloody diarrhea and weight loss. Histologically, there was mucosal atrophy and inflammatory cells infiltration in submucosa, associated with depletion of colon reduced glutathione, superoxide dismutase and catalase activities and elevated colon malondialdehyde, serum C-reactive protein (C-RP) and tumor necrosis factor-α (TNF-α). Colon gene expression of cyclooxygenase-2 and miR-210 was also elevated. These devastating effects of acetic acid were abolished upon concurrent administration of α-lipoic acid. Alternatively, cyclosporine caused partial protection against acetic acid-induced ulcerative colitis. Cyclosporine did not restore colon reduced glutathione, catalase activity, serum C-RP or TNF-α. Unexpectedly, co-administration of α-lipoic acid and cyclosporine aggravated colon ulceration. Concomitant use of α-lipoic acid and cyclosporine significantly increased nitric oxide production, cyclooxygenase-2 and miR-210 gene expression compared to all other studied groups. The current findings suggest that facilitation of nitric oxide/cyclooxygenase-2/miR-210 cascade constitutes, at least partially, the cellular mechanism by which concurrent use of α-lipoic acid and cyclosporine aggravates colon damage. Collectively, the present work highlights the probable risk of using α-lipoic acid/cyclosporine combination in ulcerative colitis patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Colitis induced bone loss is gender dependent and associated with increased inflammation

PubMed Central

Irwin, Regina; Lee, Taehyung; Young, Vincent B.; Parameswaran, Narayanan; McCabe, Laura R.

2014-01-01

Background Patients with inflammatory bowel disease (IBD) are at increase risk for bone loss and fractures. Therefore, in the present study, we examined the effect of experimental IBD on bone health. Methods We used a murine model of colitis, H. hepaticus-infected IL-10 deficient animals. Molecular and histological properties of bone and intestine were examined to identify the immunopathological consequences of colitis in male and female mice. Results At 6 weeks post-infection we observed significant trabecular bone loss in male but surprisingly not in female mice. This was true for both distal femur and vertebral locations. In addition, H. hepaticus infection suppressed osteoblast markers only in males. Consistent with effects on bone health, male mice with H. hepaticus infection had more severe colitis as determined by histology and elevated levels of inflammatory cytokines in the colon. While H. hepaticus levels in the stool appeared similar in male and female mice 1-week after infection, by 6-weeks H. hepaticus levels were greater in male mice, indicating that H. hepaticus survival and virulence within the GI tract could be gender-dependent. Conclusion In summary, H. hepaticus induced colitis severity and associated bone loss is gender regulated, possibly as a result of gender-specific effects on H. hepaticus colonization in the mouse GI tract and the consequent immunopathologic responses. PMID:23702805

Diagnosis and management of microscopic colitis: current perspectives

PubMed Central

Bohr, Johan; Wickbom, Anna; Hegedus, Agnes; Nyhlin, Nils; Hultgren Hörnquist, Elisabeth; Tysk, Curt

2014-01-01

Collagenous colitis and lymphocytic colitis, together constituting microscopic colitis, are common causes of chronic diarrhea. They are characterized clinically by chronic nonbloody diarrhea and a macroscopically normal colonic mucosa where characteristic histopathological findings are seen. Previously considered rare, they now have emerged as common disorders that need to be considered in the investigation of the patient with chronic diarrhea. The annual incidence of each disorder is five to ten per 100,000 inhabitants, with a peak incidence in 60- to 70-year-old individuals and a predominance of female patients in collagenous colitis. The etiology and pathophysiology are not well understood, and the current view suggests an uncontrolled mucosal immune reaction to various luminal agents in predisposed individuals. Clinical symptoms comprise chronic diarrhea, abdominal pain, fatigue, weight loss, and fecal incontinence that may impair the patient’s health-related quality of life. An association is reported with other autoimmune disorders, such as celiac disease, thyroid disorders, diabetes mellitus, and arthritis. The best-documented treatment, both short-term and long-term, is budesonide, which induces clinical remission in up to 80% of patients after 8 weeks’ treatment. However, after successful budesonide therapy is ended, recurrence of clinical symptoms is common, and the best possible long-term management deserves further study. The long-term prognosis is good, and the risk of complications, including colonic cancer, is low. We present an update of the epidemiology, pathogenesis, diagnosis, and management of microscopic colitis. PMID:25170275

TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice

PubMed Central

González-Navajas, José M.; Fine, Sean; Law, Jason; Datta, Sandip K.; Nguyen, Kim P.; Yu, Mandy; Corr, Maripat; Katakura, Kyoko; Eckman, Lars; Lee, Jongdae; Raz, Eyal

2010-01-01

TLRs sense various microbial products. Their function has been best characterized in DCs and macrophages, where they act as important mediators of innate immunity. TLR4 is also expressed on CD4+ T cells, but its physiological function on these cells remains unknown. Here, we have shown that TLR4 triggering on CD4+ T cells affects their phenotype and their ability to provoke intestinal inflammation. In a model of spontaneous colitis, Il10–/–Tlr4–/– mice displayed accelerated development of disease, with signs of overt colitis as early as 8 weeks of age, when compared with Il10–/– and Il10–/–Tlr9–/– mice, which did not develop colitis by 8 months. Similar results were obtained in a second model of colitis in which transfer of naive Il10–/–Tlr4–/– CD4+ T cells into Rag1–/– recipients sufficient for both IL-10 and TLR4 induced more aggressive colitis than the transfer of naive Il10–/– CD4+ T cells. Mechanistically, LPS stimulation of TLR4-bearing CD4+ T cells inhibited ERK1/2 activation upon subsequent TCR stimulation via the induction of MAPK phosphatase 3 (MKP-3). Our data therefore reveal a tonic inhibitory role for TLR4 signaling on subsequent TCR-dependent CD4+ T cell responses. PMID:20051628

Reversal of experimental colitis disease activity in mice following administration of an adenoviral IL-10 vector.

PubMed

Sasaki, Makoto; Mathis, J Michael; Jennings, Merilyn H; Jordan, Paul; Wang, Yuping; Ando, Tomoaki; Joh, Takashi; Alexander, J Steven

2005-10-31

Genetic deficiency in the expression of interleukin-10 (IL-10) is associated with the onset and progression of experimental inflammatory bowel disease (IBD). The clinical significance of IL-10 expression is supported by studies showing that immune-augmentation of IL-10 prevents inflammation and mucosal damage in animal models of colitis and in human colitis. Interleukin-10 (IL-10), an endogenous anti-inflammatory and immunomodulating cytokine, has been shown to prevent some inflammation and injury in animal and clinical studies, but the efficacy of IL-10 treatment remains unsatisfactory. We found that intra-peritoneal administration of adenoviral IL-10 to mice significantly reversed colitis induced by administration of 3% DSS (dextran sulfate), a common model of colitis. Adenoviral IL-10 (Ad-IL10) transfected mice developed high levels of IL-10 (394 +/- 136 pg/ml) within the peritoneal cavity where the adenovirus was expressed. Importantly, when given on day 4 (after the induction of colitis w/DSS), Ad-IL10 significantly reduced disease activity and weight loss and completely prevented histopathologic injury to the colon at day 10. Mechanistically, compared to Ad-null and DSS treated mice, Ad-IL10 and DSS-treated mice were able to suppress the expression of MAdCAM-1, an endothelial adhesion molecule associated with IBD. Our results suggest that Ad-IL10 (adenoviral IL-10) gene therapy of the intestine or peritoneum may be useful in the clinical treatment of IBD, since we demonstrated that this vector can reverse the course of an existing gut inflammation and markers of inflammation.

Reversal of experimental colitis disease activity in mice following administration of an adenoviral IL-10 vector

PubMed Central

Sasaki, Makoto; Mathis, J Michael; Jennings, Merilyn H; Jordan, Paul; Wang, Yuping; Ando, Tomoaki; Joh, Takashi; Alexander, J Steven

2005-01-01

Genetic deficiency in the expression of interleukin-10 (IL-10) is associated with the onset and progression of experimental inflammatory bowel disease (IBD). The clinical significance of IL-10 expression is supported by studies showing that immune-augmentation of IL-10 prevents inflammation and mucosal damage in animal models of colitis and in human colitis. Interleukin-10 (IL-10), an endogenous anti-inflammatory and immunomodulating cytokine, has been shown to prevent some inflammation and injury in animal and clinical studies, but the efficacy of IL-10 treatment remains unsatisfactory. We found that intra-peritoneal administration of adenoviral IL-10 to mice significantly reversed colitis induced by administration of 3% DSS (dextran sulfate), a common model of colitis. Adenoviral IL-10 (Ad-IL10) transfected mice developed high levels of IL-10 (394 +/- 136 pg/ml) within the peritoneal cavity where the adenovirus was expressed. Importantly, when given on day 4 (after the induction of colitis w/DSS), Ad-IL10 significantly reduced disease activity and weight loss and completely prevented histopathologic injury to the colon at day 10. Mechanistically, compared to Ad-null and DSS treated mice, Ad-IL10 and DSS-treated mice were able to suppress the expression of MAdCAM-1, an endothelial adhesion molecule associated with IBD. Our results suggest that Ad-IL10 (adenoviral IL-10) gene therapy of the intestine or peritoneum may be useful in the clinical treatment of IBD, since we demonstrated that this vector can reverse the course of an existing gut inflammation and markers of inflammation. PMID:16259632

[Generalized intestinal CMV infection with protein-losing syndrome in ulcerative colitis].

PubMed

Kraus, M; Meyenberger, C; Suter, W

2000-10-28

Infection by cytomegalovirus (CMV) in immunocompetent patients is rare, and if it occurs it is most often associated with ulcerative colitis. This case illustrates a CMV infection in a patient with an ulcerative colitis combined with CMV-induced protein losing enteropathy, a condition reported in immunocompetent individuals in only a very few cases worldwide. It demonstrates the importance of differentiating between a flare-up of ulcerative colitis and CMV colitis. The indication for antiviral therapy is discussed. A 76-years-old patient with a 23-year history of leftsided ulcerative colitis presented with acute pancolitis sparing the rectum. He showed no evidence of impaired host defence, nor has he ever had taken immunosuppressive drugs. Disseminated primary CMV infection involving of the colon, the oesophagus and the small intestine with protein losing enteropathy was diagnosed on the basis of histology, culture and serology. In view of the long duration of the illness and the highly active infection, antiviral therapy with ganciclovir was given and led to a dramatical improvement of all disease manifestations. The patient subsequently remained in remission from ulcerative colitis for three years.

Can temperature explain the latitudinal gradient of ulcerative colitis? Cohort of Norway

PubMed Central

2013-01-01

Background Incidence and prevalence of ulcerative colitis follow a north–south (latitudinal) gradient and increases northwards at the northern hemisphere or southwards at the southern hemisphere. The disease has increased during the last decades. The temporal trend has been explained by the hygiene hypothesis, but few parallel explanations exist for the spatial variability. Many factors are linked to latitude such as climate. Our purpose was to investigate the association between variables governing the climate and prospectively identified patients. Methods In this study, we used a subset of the population-based Cohort of Norway (n = 80412) where 370 prevalent cases of ulcerative colitis were identified through self-reported medication. The meteorological and climatic variables temperature, precipitation, and altitude were recorded from weather stations of the Norwegian Meteorological Institute. Summer temperature was used to capture environmental temperature. Results Summer temperature was significantly related to the prevalence of ulcerative colitis. For each one-degree increase in temperature the odds for ulcerative colitis decreased with about 9% (95% CI: 3%-15%). None of the other climatic factors were significantly associated to the risk of ulcerative colitis. Contextual variables did not change the association to the prevalence of ulcerative colitis. Conclusions The present results show that the prevalence of ulcerative colitis is associated to summer temperature. Our speculation is that summer temperature works as an instrumental variable for the effect of microbial species richness on the development of ulcerative colitis. Environmental temperature is one of the main forces governing microbial species richness and the microbial composition of the commensal gut flora is known to be an important part in the process leading to ulcerative colitis. PMID:23724802

Laparoscopic treatment of fulminant ulcerative colitis.

PubMed

Bell, R L; Seymour, N E

2002-12-01

The complexity and risks of the surgical treatment of ulcerative colitis are greater in patients with fulminant disease. Subtotal colectomy is frequently offered to such patients to control acute disease and restore immunological and nutritional status prior to a restorative procedure. The role of laparoscopy in this setting is poorly defined. The records of 18 patients with poorly controlled fulminant colitis on aggressive immunosuppressive therapy who underwent laparoscopic subtotal colectomy were reviewed. Postoperative complications occurred in six patients (33%). Postoperative length of stay was 5.0 +/- 0.3 days vs 8.8 +/- 1.8 days (p<0.05) for a group of six patients who had undergone open subtotal colectomy for the same indications. Systemic steroids were withdrawn in all patients, and 17 patients subsequently underwent proctectomy and pelvic pouch construction. The relatively high morbidity rate in these patients is likely related to their compromised status at the time of surgery. Laparoscopic subtotal colectomy in patients with fulminant ulcerative colitis allows for earlier hospital discharge, facilitates subsequent pelvic pouch, construction, and provides an excellent alternative to conventional two- and three-stage surgical treatment.

Edible Ginger-Derived Nanoparticles: A Novel Therapeutic Approach for the Prevention and Treatment of Inflammatory Bowel Disease and Colitis-Associated Cancer

PubMed Central

Zhang, Mingzhen; Viennois, Emilie; Prasad, Meena; Zhang, Yunchen; Wang, Lixin; Zhang, Zhan; Han, Moon Kwon; Xiao, Bo; Xu, Changlong; Srinivasan, Shanthi; Merlin, Didier

2016-01-01

There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. In this study, we characterized a specific population of nanoparticles derived from edible ginger (GDNPs 2) and demonstrated their efficient colon targeting following oral administration. GDNPs 2 had an average size of ~230 nm and exhibited a negative zeta potential. These nanoparticles contained high levels of lipids, a few proteins, ~125 microRNAs (miRNAs), and large amounts of ginger bioactive constituents (6-gingerol and 6-shogaol). We also demonstrated that GDNPs 2 were mainly taken up by intestinal epithelial cells (IECs) and macrophages, and were nontoxic. Using different mouse colitis models, we showed that GDNPs 2 reduced acute colitis, enhanced intestinal repair, and prevented chronic colitis and colitis-associated cancer (CAC). 2D-DIGE/MS analyses further identified molecular target candidates of GDNPs 2 involved in these mouse models. Oral administration of GDNPs 2 increased the survival and proliferation of IECs and reduced the pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), and increased the anti-inflammatory cytokines (IL-10 and IL-22) in colitis models, suggesting that GDNPs 2 has the potential to attenuate damaging factors while promoting the healing effect. In conclusion, GDNPs 2, nanoparticles derived from edible ginger, represent a novel, natural delivery mechanism for improving IBD prevention and treatment with an added benefit of overcoming limitations such as potential toxicity and limited production scale that are common with synthetic nanoparticles. PMID:27318094

In vivo treatment with the herbal phenylethanoid acteoside ameliorates intestinal inflammation in dextran sulphate sodium-induced colitis

PubMed Central

Hausmann, M; Obermeier, F; Paper, D H; Balan, K; Dunger, N; Menzel, K; Falk, W; Schoelmerich, J; Herfarth, H; Rogler, G

2007-01-01

Recently we demonstrated that in inflammatory bowel disease (IBD) macrophage-oxidative burst activity is increased and NADPH oxidase mRNA is induced. The herbal phenylethanoid acteoside isolated from Plantago lanceolata L. was shown to exhibit anti-oxidative potential. Using the dextran sulphate sodium (DSS)-induced colitis model, in this study we have assessed whether systemic application of acteoside affects colitis. Colitis was induced by DSS in Balb/c mice. Treatment with acteoside (120, 600 µg/mouse/day) was performed intraperitoneally. The colon lengths were determined. Colonic tissue was scored histologically (max. score 8) by a blinded investigator. T cells isolated from mesenteric lymph nodes (MLN) were stimulated with anti-CD3 antibody in the presence of interleukin (IL)-2 (final concentration 10 U/ml). After incubation for 24 h, IL-1β, IL-6, IL-12 tumour necrosis factor (TNF)-α and interferon (IFN)-γ levels in supernatants were analysed by the beadlyte® cytokine detection system. Histological scoring of colonic tissue revealed that application of acteoside was followed by a significantly improved histological score. In acute colitis the histological score was 3·2 with acteoside versus 5·2 with phosphate-buffered saline (PBS) (P < 0·02). In chronic colitis both 120 µg (3·3 versus 5·2) or 600 µg acteoside (3·0 versus 5·2) significantly ameliorated colitis (both P < 0·02). Stimulated MLN from mice with chronic DSS-induced colitis treated with acteoside showed a significant down-regulation of IFN-γ secretion (195 pg/ml with 600 µg acteoside versus 612 pg/ml with PBS, P < 0·02). Inhibition of oxidative burst activity with acteoside reduced mucosal tissue damage in DSS colitis and could be a therapeutic alternative for IBD treatment. Further studies of this agent are warranted. PMID:17437425

Initial surgical management of ulcerative colitis in the biologic era.

PubMed

Geltzeiler, Cristina B; Lu, Kim C; Diggs, Brian S; Deveney, Karen E; Keyashian, Kian; Herzig, Daniel O; Tsikitis, Vassiliki L

2014-12-01

The initial minimum operation for ulcerative colitis is a total abdominal colectomy. Healthy patients may undergo proctectomy at the same time; however, for ill patients, proctectomy is delayed. Since the introduction of biologic medications in 2005, ulcerative colitis medical management has changed dramatically. We examined how operative management for ulcerative colitis has changed from the prebiologic to biologic eras. We conducted a retrospective review of data on patients with ulcerative colitis who were included in the Nationwide Inpatient Sample database. This study was conducted at a single university. A total of 1,547,852 patients with ulcerative colitis who were admitted to a US hospital from 1991 to 2011 were included in the study. We examined patients whose initial operation consisted of total abdominal colectomy without proctectomy versus a total proctocolectomy with or without a pouch. We also examined which operation was done at the time of the construction of an ileoanal pouch. Patients who underwent colectomy and pouch construction in the same hospitalization were compared with those who received pouch formation at a subsequent hospitalization. Ulcerative colitis-related admissions rose by 170% during the years examined, and the number of patients who required total abdominal colectomy increased by 44%. Total abdominal colectomy increased by 15%, as opposed to total proctocolectomy (p < 0.001). Pouch construction at a subsequent operation increased by 16% (p = 0.002). Since 2008, total abdominal colectomy has surpassed total proctocolectomy as the most common initial surgical intervention for ulcerative colitis. The Nationwide Inpatient Sample is a retrospective database, and we were limited to examining the variables within it. Total abdominal colectomy is currently the most common initial operation for patients with ulcerative colitis, and an ileoanal pouch is more frequently constructed at a subsequent hospitalization. These trends coincide with

The Matricellular Protein CCN1 Promotes Mucosal Healing in Murine Colitis through IL-6

PubMed Central

Choi, Jacob S.; Kim, Ki-Hyun; Lau, Lester F.

2015-01-01

The matricellular protein CCN1 (CYR61) is known to function in wound healing and is upregulated in colons of patients with Crohn’s disease and ulcerative colitis, yet its specific role in colitis is unknown. Here we have used Ccn1dm/dm knockin mice expressing a CCN1 mutant unable to bind integrins α6β1 and αMβ2 as a model to probe CCN1 function in dextran sodium sulfate (DSS)-induced colitis. Ccn1dm/dm mice exhibited high mortality, impaired mucosal healing, and diminished IL-6 expression during the repair phase of DSS-induced colitis compared to wild type mice, despite having comparable severity of initial inflammation and tissue injury. CCN1 induced IL-6 expression in macrophages through integrin αMβ2 and in fibroblasts through α6β1, and IL-6 promoted intestinal epithelial cell (IEC) proliferation. Administration of purified CCN1 protein fully rescued Ccn1dm/dm mice from DSS-induced mortality, restored IEC proliferation and enhanced mucosal healing, whereas delivery of IL-6 partially rectified these defects. CCN1 therapy accelerated mucosal healing and recovery from DSS-induced colitis even in wild type mice. These findings reveal a critical role for CCN1 in restoring mucosal homeostasis after intestinal injury in part through integrin-mediated induction of IL-6 expression, and suggest a therapeutic potential for activating the CCN1/IL-6 axis for treating inflammatory bowel disease. PMID:25807183

The Bile Acid Receptor GPBAR-1 (TGR5) Modulates Integrity of Intestinal Barrier and Immune Response to Experimental Colitis

PubMed Central

Cipriani, Sabrina; Mencarelli, Andrea; Chini, Maria Giovanna; Distrutti, Eleonora; Renga, Barbara; Bifulco, Giuseppe; Baldelli, Franco; Donini, Annibale; Fiorucci, Stefano

2011-01-01

Background GP-BAR1, a member G protein coupled receptor superfamily, is a cell surface bile acid-activated receptor highly expressed in the ileum and colon. In monocytes, ligation of GP-BAR1 by secondary bile acids results in a cAMP-dependent attenuation of cytokine generation. Aims To investigate the role GP-BAR1 in regulating intestinal homeostasis and inflammation-driven immune dysfunction in rodent models of colitis. Methods Colitis was induced in wild type and GP-BAR1−/− mice by DSS and TNBS administration. Potential GP-BAR1 agonists were identified by in silico screening and computational docking studies. Results GP-BAR1−/− mice develop an abnormal morphology of colonic mucous cells and an altered molecular architecture of epithelial tight junctions with increased expression and abnormal subcellular distribution of zonulin 1 resulting in increased intestinal permeability and susceptibility to develop severe colitis in response to DSS at early stage of life. By in silico screening and docking studies we identified ciprofloxacin as a GP-BAR1 ligand. In monocytes, ciprofloxacin increases cAMP concentrations and attenuates TNFα release induced by TLR4 ligation in a GP-BAR1 dependent manner. Treating mice rendered colitic by TNBS with ciprofloxacin and oleanolic acid, a well characterized GP-BAR1 ligand, abrogates signs and symptoms of colitis. Colonic expression of GP-BAR1 mRNA increases in rodent models of colitis and tissues from Crohn's disease patients. Flow cytometry analysis demonstrates that ≈90% of CD14+ cells isolated from the lamina propria of TNBS-treated mice stained positively for GP-BAR1. Conclusions GP-BAR1 regulates intestinal barrier structure. Its expression increases in rodent models of colitis and Crohn's disease. Ciprofloxacin is a GP-BAR1 ligand. PMID:22046243

Colitis with wall thickening and edematous changes during oral administration of the powdered form of Qing-dai in patients with ulcerative colitis: a report of two cases.

PubMed

Kondo, Satoru; Araki, Toshimitsu; Okita, Yoshiki; Yamamoto, Akira; Hamada, Yasuhiko; Katsurahara, Masaki; Horiki, Noriyuki; Nakamura, Misaki; Shimoyama, Takahiro; Yamamoto, Takayuki; Takei, Yoshiyuki; Kusunoki, Masato

2018-03-16

Orally administered Qing-dai, called indigo naturalis in Latin, is reportedly useful for the treatment of ulcerative colitis. We herein describe two patients with ulcerative colitis who developed colitis with wall thickening and edematous changes during oral administration of the powdered form of Qing-dai. In Case 1, a 35-year-old man developed colitis similar to ischemic colitis with bloody stool that recurred each time he ingested Qing-dai. He had no signs of recurrence upon withdrawal of Qing-dai. In Case 2, a 43-year-old woman underwent ileocecal resection for treatment of an intussusception 2 months after beginning oral administration of Qing-dai. Edema and congestion but no ulceration were present in the mucosa of the resected specimen. Both patients exhibited abdominal pain with bloody diarrhea, and abdominal computed tomography showed marked wall edema affecting an extensive portion of the large bowel.

The economics of adalimumab for ulcerative colitis.

PubMed

Xie, Feng

2015-06-01

Ulcerative colitis is a chronic inflammatory disease, characterized by diffuse mucosal inflammation in the colon. Adalimumab, as a TNF-α blocker, offers a safe and efficacious treatment option for patients with moderate to severe ulcerative colitis and refractory or intolerant to conventional medications; however, its cost-effectiveness profile has not yet been well established. Future economic evaluations should choose appropriate comparators in the context of target-reimbursement decision making and focus on cost-effectiveness over a long time horizon.

Nicotinamide treatment ameliorates the course of experimental colitis mediated by enhanced neutrophil-specific antibacterial clearance.

PubMed

Bettenworth, Dominik; Nowacki, Tobias M; Ross, Matthias; Kyme, Pierre; Schwammbach, Daniela; Kerstiens, Linda; Thoennissen, Gabriela B; Bokemeyer, Carsten; Hengst, Karin; Berdel, Wolfgang E; Heidemann, Jan; Thoennissen, Nils H

2014-07-01

In previous studies, we could show that the B vitamin nicotinamide (NAM) enhanced antimicrobial activity of neutrophils. Here, we assessed the effects of NAM in two models of experimental colitis. Colitis was induced in C57BL/6 mice either by oral infection with Citrobacter rodentium or by DSS (dextran sodium sulphate) administration, and animals were systemically treated with NAM. Ex vivo bacterial clearance was assessed in murine and human whole blood, as well as isolated human neutrophils. In C. rodentium-induced colitis, NAM treatment resulted in markedly decreased systemic bacterial invasion, histological damage and increased fecal clearance of C. rodentium by up to 600-fold. In contrast, NAM had no effect when administered to neutrophil-depleted mice. Ex vivo stimulation of isolated human neutrophils, as well as murine and human whole blood with NAM led to increased clearance of C. rodentium and enhanced expression of antimicrobial peptides in neutrophils. Moreover, NAM treatment significantly ameliorated the course of DSS colitis, as assessed by body weight, histological damage and myeloperoxidase activity. Pharmacological application of NAM mediates beneficial effects in bacterial and chemically induced colitis. Future studies are needed to explore the clinical potential of NAM in the context of intestinal bacterial infections and human inflammatory bowel disease (IBD). © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Melatonin attenuates dextran sodium sulfate induced colitis with sleep deprivation: possible mechanism by microarray analysis.

PubMed

Chung, Sook Hee; Park, Young Sook; Kim, Ok Soon; Kim, Ja Hyun; Baik, Haing Woon; Hong, Young Ok; Kim, Sang Su; Shin, Jae-Ho; Jun, Jin-Hyun; Jo, Yunju; Ahn, Sang Bong; Jo, Young Kwan; Son, Byoung Kwan; Kim, Seong Hwan

2014-06-01

Inflammatory bowel disease is a chronic inflammatory condition of the gastrointestinal tract. It can be aggravated by stress, like sleep deprivation, and improved by anti-inflammatory agents, like melatonin. We aimed to investigate the effects of sleep deprivation and melatonin on inflammation. We also investigated genes regulated by sleep deprivation and melatonin. In the 2% DSS induced colitis mice model, sleep deprivation was induced using modified multiple platform water bath. Melatonin was injected after induction of colitis and colitis with sleep deprivation. Also mRNA was isolated from the colon of mice and analyzed via microarray and real-time PCR. Sleep deprivation induced reduction of body weight, and it was difficult for half of the mice to survive. Sleep deprivation aggravated, and melatonin attenuated the severity of colitis. In microarrays and real-time PCR of mice colon tissues, mRNA of adiponectin and aquaporin 8 were downregulated by sleep deprivation and upregulated by melatonin. However, mRNA of E2F transcription factor (E2F2) and histocompatibility class II antigen A, beta 1 (H2-Ab1) were upregulated by sleep deprivation and downregulated by melatonin. Melatonin improves and sleep deprivation aggravates inflammation of colitis in mice. Adiponectin, aquaporin 8, E2F2 and H2-Ab1 may be involved in the inflammatory change aggravated by sleep deprivation and attenuated by melatonin.

Developing an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS).

PubMed

Travis, Simon P L; Schnell, Dan; Krzeski, Piotr; Abreu, Maria T; Altman, Douglas G; Colombel, Jean-Frédéric; Feagan, Brian G; Hanauer, Stephen B; Lémann, Marc; Lichtenstein, Gary R; Marteau, Phillippe R; Reinisch, Walter; Sands, Bruce E; Yacyshyn, Bruce R; Bernhardt, Christian A; Mary, Jean-Yves; Sandborn, William J

2012-04-01

Variability in endoscopic assessment necessitates rigorous investigation of descriptors for scoring severity of ulcerative colitis (UC). To evaluate variation in the overall endoscopic assessment of severity, the intra- and interindividual variation of descriptive terms and to create an Ulcerative Colitis Endoscopic Index of Severity which could be validated. A two-phase study used a library of 670 video sigmoidoscopies from patients with Mayo Clinic scores 0-11, supplemented by 10 videos from five people without UC and five hospitalised patients with acute severe UC. In phase 1, each of 10 investigators viewed 16/24 videos to assess agreement on the Baron score with a central reader and agreed definitions of 10 endoscopic descriptors. In phase 2, each of 30 different investigators rated 25/60 different videos for the descriptors and assessed overall severity on a 0-100 visual analogue scale. κ Statistics tested inter- and intraobserver variability for each descriptor. A general linear mixed regression model based on logit link and β distribution of variance was used to predict overall endoscopic severity from descriptors. There was 76% agreement for 'severe', but 27% agreement for 'normal' appearances between phase I investigators and the central reader. In phase 2, weighted κ values ranged from 0.34 to 0.65 and 0.30 to 0.45 within and between observers for the 10 descriptors. The final model incorporated vascular pattern, (normal/patchy/complete obliteration) bleeding (none/mucosal/luminal mild/luminal moderate or severe), erosions and ulcers (none/erosions/superficial/deep), each with precise definitions, which explained 90% of the variance (pR(2), Akaike Information Criterion) in the overall assessment of endoscopic severity, predictions varying from 4 to 93 on a 100-point scale (from normal to worst endoscopic severity). The Ulcerative Colitis Endoscopic Index of Severity accurately predicts overall assessment of endoscopic severity of UC. Validity and

Aluminum enhances inflammation and decreases mucosal healing in experimental colitis in mice

PubMed Central

Pineton de Chambrun, G; Body-Malapel, M; Frey-Wagner, I; Djouina, M; Deknuydt, F; Atrott, K; Esquerre, N; Altare, F; Neut, C; Arrieta, M C; Kanneganti, T-D; Rogler, G; Colombel, J-F; Cortot, A; Desreumaux, P; Vignal, C

2014-01-01

The increasing incidence of inflammatory bowel diseases (IBDs) in developing countries has highlighted the critical role of environmental pollutants as causative factors in their pathophysiology. Despite its ubiquity and immune toxicity, the impact of aluminum in the gut is not known. This study aimed to evaluate the effects of environmentally relevant intoxication with aluminum in murine models of colitis and to explore the underlying mechanisms. Oral administration of aluminum worsened intestinal inflammation in mice with 2,4,6-trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis and chronic colitis in interleukin 10-negative (IL10−/−) mice. Aluminum increased the intensity and duration of macroscopic and histologic inflammation, colonic myeloperoxidase activity, inflammatory cytokines expression, and decreased the epithelial cell renewal compared with control animals. Under basal conditions, aluminum impaired intestinal barrier function. In vitro, aluminum induced granuloma formation and synergized with lipopolysaccharide to stimulate inflammatory cytokines expression by epithelial cells. Deleterious effects of aluminum on intestinal inflammation and mucosal repair strongly suggest that aluminum might be an environmental IBD risk factor. PMID:24129165

Myo-inositol reduces β-catenin activation in colitis.

PubMed

Bradford, Emily M; Thompson, Corey A; Goretsky, Tatiana; Yang, Guang-Yu; Rodriguez, Luz M; Li, Linheng; Barrett, Terrence A

2017-07-28

To assess dietary myo-inositol in reducing stem cell activation in colitis, and validate pβ-catenin S552 as a biomarker of recurrent dysplasia. We examined the effects of dietary myo-inositol treatment on inflammation, pβ-catenin S552 and pAkt levels by histology and western blot in IL-10 -/- and dextran sodium sulfate-treated colitic mice. Additionally, we assessed nuclear pβ-catenin S552 in patients treated with myo-inositol in a clinical trial, and in patients with and without a history of colitis-induced dysplasia. In mice, pβ-catenin S552 staining faithfully reported the effects of myo-inositol in reducing inflammation and intestinal stem cell activation. In a pilot clinical trial of myo-inositol administration in patients with a history of low grade dysplasia (LGD), two patients had reduced numbers of intestinal stem cell activation compared to the placebo control patient. In humans, pβ-catenin S552 staining discriminated ulcerative colitis patients with a history of LGD from those with benign disease. Enumerating crypts with increased numbers of pβ-catenin S552 - positive cells can be utilized as a biomarker in colitis-associated cancer chemoprevention trials.

Saccharomyces cerevisiae CNCM I-3856 prevents colitis induced by AIEC bacteria in the transgenic mouse model mimicking Crohn's disease.

PubMed

Sivignon, Adeline; de Vallée, Amélie; Barnich, Nicolas; Denizot, Jérémy; Darcha, Claude; Pignède, Georges; Vandekerckove, Pascal; Darfeuille-Michaud, Arlette

2015-02-01

Adherent-invasive Escherichia coli (AIEC), which colonize the ileal mucosa of patients with Crohn's disease (CD), are able to adhere to and invade intestinal epithelial cells. Overexpression of the glycoprotein CEACAM6 on host cells favors AIEC attachment and inflammation. We investigated the ability of Saccharomyces cerevisiae CNCM I-3856 to inhibit AIEC adhesion and to reduce colitis. Adhesion experiments were performed on T84 cells and on enterocytes from patients with CD with AIEC LF82 in the presence of S. cerevisiae. Colonization and symptoms of colitis were assessed in LF82-infected transgenic CEABAC10 mice treated with live S. cerevisiae or S. cerevisiae derivatives. Proinflammatory cytokines were quantified by enzyme linked immunosorbent assay. Intestinal permeability was assessed by measuring the 4 kDa dextran-FITC flux in the serum. S. cerevisiae strongly inhibited LF82 adhesion to T84 cells and to the brush border of CD enterocytes. Yeasts decreased LF82 colonization and colitis in CEABAC10 mice and restored barrier function through prevention of the LF82-induced expression of pore-forming tight junction claudin-2 at the plasma membrane of intestinal epithelial cells. These effects were accompanied by a decrease in proinflammatory cytokines IL-6, IL-1β, and KC release by the gut mucosa. Yeast derivatives exerted similar effects on LF82 colonization and colitis demonstrating that yeast viability was not essential to exert beneficial effects. S. cerevisiae yeasts reduce colitis induced by AIEC bacteria in CEACAM6-expressing mice. Such a probiotic strategy could be envisaged in a subgroup of patients with CD abnormally expressing CEACAM6 at the ileal mucosa and therefore susceptible to being colonized by AIEC bacteria.

Passiflora edulis peel intake and ulcerative colitis: approaches for prevention and treatment.

PubMed

Cazarin, Cinthia Bb; da Silva, Juliana K; Colomeu, Talita C; Batista, Angela G; Vilella, Conceição A; Ferreira, Anderson L; Junior, Stanislau Bogusz; Fukuda, Karina; Augusto, Fabio; de Meirelles, Luciana R; Zollner, Ricardo de L; Junior, Mário R Maróstica

2014-05-01

Inflammatory bowel disease is a chronic relapsing disease that affects millions of people worldwide; its pathogenesis is influenced by genetic, environmental, microbiological, and immunological factors. The aim of this study was to evaluate the effects of short- and long-term Passiflora edulis peel intake on the antioxidant status, microbiota, and short-chain fatty acids formation in rats with 2,4,6-trinitrobenzenesulphonic acid-induced colitis using two "in vivo" experiments: chronic (prevention) and acute (treatment). The colitis damage score was determined using macroscopic and microscopic analyses. In addition, the antioxidant activity in serum and other tissues (liver and colon) was evaluated. Bifidobacteria, lactobacilli, aerobic bacteria and enterobacteria, and the amount of short-chain fatty acids (acetic, butyric, and propionic acids) in cecum content were counted. Differences in the colon damage scores were observed; P. edulis peel intake improved serum antioxidant status. In the treatment protocol, decreased colon lipid peroxidation, a decreased number of aerobic bacteria and enterobacteria, and an improvement in acetic and butyric acid levels in the feces were observed. An improvement in the bifidobacteria and lactobacilli was observed in the prevention protocol. These results suggested that P. edulis peel can modulate microbiota and could be used as source of fiber and polyphenols in the prevention of oxidative stress through the improvement of serum and tissue antioxidant status.

Advances in ulcerative colitis.

PubMed

Ament, M E; Berquist, W; Vargas, J

1988-01-01

Ulcerative colitis is one of the two common chronic inflammatory bowel diseases which affect the colon of children. The disease can occur at any time during infancy and childhood and is far commoner than Crohn's disease of the colon in children less than 6 years old. The Jewish population outside of Israel is at far greater risk of developing the condition than any other ethnic group. The reason for this is unknown. The chances of a family member developing the condition is 2-3 times as great as in the general population. The etiology of the condition remains unknown; however, recent advances in the understanding of the immune mechanisms in the bowel and circulation indicate there are major immunological differences between ulcerative colitis and Crohn's disease. Intestinal B cells secrete enormously increased amounts of IgG1 and a lesser increase in IgG3 in ulcerative colitis whereas in Crohn's disease, all IgG subclasses are increased, but especially IgG2. Failure of the gut immune system to control antigen crossing the colonic mucosa may be the basis for the condition. The disease is classified as moderate to severe two thirds of children as opposed to less than one third of adults. Diagnostic testing must include 3 stool cultures negative for bacterial and viral pathogens, 3 stools negative for amebiasis, trichuriasis and other intestinal parasites and absence of clostridium difficile and its toxin in the stool. Flexible proctosigmoidoscopy and/or colonoscopy should be done in every case with biopsies. Barium enema is contraindicated in the severely ill patient. Major improvements in medical treatment being tested involve the development of nonabsorbable corticosteroid enemas and sulfapyridene-free forms of salicylazosulfapyridene for use in enema and oral form. Surgery for ulcerative colitis has made major advances with the development of the Koch pouch (internal ileostomy) and ileoproctostomy. Both procedures although associated with relatively high

Lymphocytic Colitis: Pathologic predictors of response to therapy.

PubMed

Setia, Namrata; Alpert, Lindsay; van der Sloot, Kimberley Wj; Colussi, Dora; Stewart, Kathleen O; Misdraji, Joseph; Khalili, Hamed; Lauwers, Gregory Y

2018-02-13

While the presence of intraepithelial lymphocytosis with surface epithelial damage is a unifying feature of lymphocytic colitis, there are non-classical features that create morphologic heterogeneity between cases. Limited data are available on the significance of these secondary histologic features. Cases of lymphocytic colitis diagnosed between 2002 and 2013 were identified using the Research Patient Data Registry of a tertiary referral center. Diagnostic biopsy slides were reviewed and evaluated for histologic features of lymphocytic colitis. Clinical data including type of therapy and response to treatment were collected. Chi-square (or Fischer's exact test) and logistic regression analysis were used where appropriate. Thirty-two cases of lymphocytic colitis with complete clinical data and slides available for review were identified. The mean age was 56.4 years, and the female-to-male ratio was 3:2. Eleven (11) patients improved with minimal intervention (Group 1), 14 patients responded to steroid therapy (Group 2), and 7 patients responded to mesalamine, bismuth subsalicylate and/or cholestyramine therapy (Group 3). Histologic differences in the characteristics of the subepithelial collagen table (p=0.018), the severity of lamina propria inflammation (p=0.042) and the presence of eosinophil clusters (p=0.016) were seen between groups 2 and 3. Patients in group 1 were more likely to have mild crypt architectural distortion in their biopsies than patients in groups 2 and 3. Lymphocytic colitis is a heterogeneous disease and the evaluation of histologic factors may help identify various subtypes and predict therapy response. Copyright © 2018. Published by Elsevier Inc.

The Hydrogen Peroxide Scavenger, Catalase, Alleviates Ion Transport Dysfunction in Murine Colitis

PubMed Central

Barrett, Kim E.; McCole, Declan F.

2016-01-01

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) contribute to epithelial damage and ion transport dysfunction (key events in inflammatory diarrhea) in inflammatory bowel disease (IBD). The aim of this study was to identify if H2O2 mediates suppression of colonic ion transport function in the murine dextran sulfate sodium (DSS) colitis model by using the H2O2 degrading enzyme, catalase. Colitis was induced by administering DSS (4%) in drinking water for 5 days followed by 3 days on normal H2O. Mice were administered either pegylated-catalase or saline at day −1, 0 and +1 of DSS treatment. Ion transport responses to the Ca2+-dependent agonist, carbachol (CCh), or the cAMP-dependent agonist, forskolin, were measured across distal colonic mucosa mounted in Ussing chambers. Parameters of DSS-induced inflammation (loss in body weight, decreased colon length, altered stool consistency), were only partially alleviated by catalase while histology was only minimally improved. However, catalase significantly reversed the DSS-induced reduction in baseline ion transport as well as colonic Isc responses to CCh. However, ion transport responses to forskolin were not significantly restored. Catalase also reduced activation of ERK MAP kinase in the setting of colitis, and increased expression of the Na+-K+-2Cl− cotransporter, NKCC1, consistent with restoration of ion transport function. Ex vivo treatment of inflamed colonic mucosae with catalase also partially restored ion transport function. Therefore, catalase partially prevents, and rescues, the loss of ion transport properties in DSS colitis even in the setting of unresolved tissue inflammation. These findings indicate a prominent role for ROS in ion transport dysfunction in colitis and may suggest novel strategies for the treatment of inflammatory diarrhea. PMID:27543846