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Sample records for adult intestinal homeostasis

  1. Requirement of matrix metalloproteinase-1 for intestinal homeostasis in the adult Drosophila midgut

    SciTech Connect

    Lee, Shin-Hae; Park, Joung-Sun; Kim, Young-Shin; Chung, Hae-Young; Yoo, Mi-Ae

    2012-03-10

    Stem cells are tightly regulated by both intrinsic and extrinsic signals as well as the extracellular matrix (ECM) for tissue homeostasis and regenerative capacity. Matrix metalloproteinases (MMPs), proteolytic enzymes, modulate the turnover of numerous substrates, including cytokine precursors, growth factors, and ECM molecules. However, the roles of MMPs in the regulation of adult stem cells are poorly understood. In the present study, we utilize the Drosophila midgut, which is an excellent model system for studying stem cell biology, to show that Mmp1 is involved in the regulation of intestinal stem cells (ISCs). The results showed that Mmp1 is expressed in the adult midgut and that its expression increases with age and with exposure to oxidative stress. Mmp1 knockdown or Timp-overexpressing flies and flies heterozygous for a viable, hypomorphic Mmp1 allele increased ISC proliferation in the gut, as shown by staining with an anti-phospho-histone H3 antibody and BrdU incorporation assays. Reduced Mmp1 levels induced intestinal hyperplasia, and the Mmp1depletion-induced ISC proliferation was rescued by the suppression of the EGFR signaling pathway, suggesting that Mmp1 regulates ISC proliferation through the EGFR signaling pathway. Furthermore, adult gut-specific knockdown and whole-animal heterozygotes of Mmp1 increased additively sensitivity to paraquat-induced oxidative stress and shortened lifespan. Our data suggest that Drosophila Mmp1 is involved in the regulation of ISC proliferation for maintenance of gut homeostasis. -- Highlights: Black-Right-Pointing-Pointer Mmp1 is expressed in the adult midgut. Black-Right-Pointing-Pointer Mmp1 is involved in the regulation of ISC proliferation activity. Black-Right-Pointing-Pointer Mmp1-related ISC proliferation is associated with EGFR signaling. Black-Right-Pointing-Pointer Mmp1 in the gut is required for the intestinal homeostasis and longevity.

  2. The ADP-ribose polymerase Tankyrase regulates adult intestinal stem cell proliferation during homeostasis in Drosophila.

    PubMed

    Wang, Zhenghan; Tian, Ai; Benchabane, Hassina; Tacchelly-Benites, Ofelia; Yang, Eungi; Nojima, Hisashi; Ahmed, Yashi

    2016-05-15

    Wnt/β-catenin signaling controls intestinal stem cell (ISC) proliferation, and is aberrantly activated in colorectal cancer. Inhibitors of the ADP-ribose polymerase Tankyrase (Tnks) have become lead therapeutic candidates for Wnt-driven cancers, following the recent discovery that Tnks targets Axin, a negative regulator of Wnt signaling, for proteolysis. Initial reports indicated that Tnks is important for Wnt pathway activation in cultured human cell lines. However, the requirement for Tnks in physiological settings has been less clear, as subsequent studies in mice, fish and flies suggested that Tnks was either entirely dispensable for Wnt-dependent processes in vivo, or alternatively, had tissue-specific roles. Here, using null alleles, we demonstrate that the regulation of Axin by the highly conserved Drosophila Tnks homolog is essential for the control of ISC proliferation. Furthermore, in the adult intestine, where activity of the Wingless pathway is graded and peaks at each compartmental boundary, Tnks is dispensable for signaling in regions where pathway activity is high, but essential where pathway activity is relatively low. Finally, as observed previously for Wingless pathway components, Tnks activity in absorptive enterocytes controls the proliferation of neighboring ISCs non-autonomously by regulating JAK/STAT signaling. These findings reveal the requirement for Tnks in the control of ISC proliferation and suggest an essential role in the amplification of Wnt signaling, with relevance for development, homeostasis and cancer. PMID:27190037

  3. Autophagy and Intestinal Homeostasis

    PubMed Central

    Patel, Khushbu K.; Stappenbeck, Thaddeus S.

    2013-01-01

    Nutrient absorption is the basic function that drives mammalian intestinal biology. To facilitate nutrient uptake, the host’s epithelial barrier is composed of a single layer of cells. This constraint is problematic, as a design of this type can be easily disrupted. The solution during the course of evolution was to add numerous host defense mechanisms that can help prevent local and systemic infection. These mechanisms include specialized epithelial cells that produce a physiochemical barrier overlying the cellular barrier, robust and organized adaptive and innate immune cells, and the ability to mount an inflammatory response that is commensurate with a specific threat level. The autophagy pathway is a critical cellular process that strongly influences all these functions. Therefore, a fundamental understanding of the components of this pathway and their influence on inflammation, immunity, and barrier function will facilitate our understanding of homeostasis in the gastrointestinal tract. PMID:23216414

  4. Autophagy and intestinal homeostasis.

    PubMed

    Patel, Khushbu K; Stappenbeck, Thaddeus S

    2013-01-01

    Nutrient absorption is the basic function that drives mammalian intestinal biology. To facilitate nutrient uptake, the host's epithelial barrier is composed of a single layer of cells. This constraint is problematic, as a design of this type can be easily disrupted. The solution during the course of evolution was to add numerous host defense mechanisms that can help prevent local and systemic infection. These mechanisms include specialized epithelial cells that produce a physiochemical barrier overlying the cellular barrier, robust and organized adaptive and innate immune cells, and the ability to mount an inflammatory response that is commensurate with a specific threat level. The autophagy pathway is a critical cellular process that strongly influences all these functions. Therefore, a fundamental understanding of the components of this pathway and their influence on inflammation, immunity, and barrier function will facilitate our understanding of homeostasis in the gastrointestinal tract. PMID:23216414

  5. Phasic study of intestinal homeostasis disruption in experimental intestinal obstruction

    PubMed Central

    Yu, Xiang-Yang; Zou, Chang-Lin; Zhou, Zhen-Li; Shan, Tao; Li, Dong-Hua; Cui, Nai-Qiang

    2014-01-01

    AIM: To investigate the phasic alteration of intestinal homeostasis in an experimental model of intestinal obstruction. METHODS: A rabbit model of intestinal obstruction was established by transforming parts of an infusion set into an in vivo pulled-type locking clamp and creating a uniform controllable loop obstruction in the mesenteric non-avascular zone 8 cm from the distal end of the ileum. The phasic alteration of intestinal homeostasis was studied after intestinal obstruction. The changes in goblet cells, intraepithelial lymphocytes, lamina propria lymphocytes, and intestinal epithelium were quantified from periodic acid-Schiff-stained sections. Ornithine decarboxylase (ODC) activity and serum citrulline levels were measured by high-performance liquid chromatography. Claudin 1 mRNA expression was examined by real-time polymerase chain reaction analysis. Intestinal microorganisms, wet/dry weight ratios, pH values, and endotoxin levels were determined at multiple points after intestinal obstruction. Furthermore, the number and ratio of CD3+, CD4+ and CD8+ T cells were determined by flow cytometry, and secretory IgA levels were measured with an enzyme-linked immunosorbent assay. RESULTS: A suitable controllable rabbit model of intestinal obstruction was established. Intestinal obstruction induced goblet cell damage and reduced cell number. Further indicators of epithelial cell damage were observed as reduced serum citrulline levels and claudin 1 gene expression, and a transient increase in ODC activity. In addition, the wet/dry weight ratio and pH of the intestinal lumen were also dramatically altered. The ratio of Bacillus bifidus and enterobacteria was reversed following intestinal obstruction. The number and area of Peyer’s patches first increased then sharply decreased after the intestinal obstruction, along with an alteration in the ratio of CD4/CD8+ T cells, driven by an increase in CD3+ and CD8+ T cells and a decrease in CD4+ T cells. The number of

  6. Homeostasis and Inflammation in the Intestine

    PubMed Central

    Garrett, Wendy S.; Gordon, Jeffrey I.; Glimcher, Laurie H.

    2010-01-01

    The gut is home to our largest collection of microbes. The ability of the immune system to co-evolve with the microbiota during postnatal life allows the host and microbiota to coexist in a mutually beneficial relationship. Failure to achieve or maintain an equilibrium between a host and its microbiota has negative consequences for both intestinal and systemic health. In this Review, we consider the many cellular and molecular methods by which inflammatory responses are regulated to maintain intestinal homeostasis and the disease states that can ensue when this balance is lost. PMID:20303876

  7. Breast milk, microbiota, and intestinal immune homeostasis.

    PubMed

    Walker, W Allan; Iyengar, Rajashri Shuba

    2015-01-01

    Newborns adjust to the extrauterine environment by developing intestinal immune homeostasis. Appropriate initial bacterial colonization is necessary for adequate intestinal immune development. An environmental determinant of adequate colonization is breast milk. Although the full-term infant is developmentally capable of mounting an immune response, the effector immune component requires bacterial stimulation. Breast milk stimulates the proliferation of a well-balanced and diverse microbiota, which initially influences a switch from an intrauterine TH2 predominant to a TH1/TH2 balanced response and with activation of T-regulatory cells by breast milk-stimulated specific organisms (Bifidobacteria, Lactobacillus, and Bacteroides). As an example of its effect, oligosaccharides in breast milk are fermented by colonic bacteria producing an acid milieu for bacterial proliferation. In addition, short-chain fatty acids in breast milk activate receptors on T-reg cells and bacterial genes, which preferentially mediate intestinal tight junction expression and anti-inflammation. Other components of breast milk (defensins, lactoferrin, etc.) inhibit pathogens and further contribute to microbiota composition. The breast milk influence on initial intestinal microbiota also prevents expression of immune-mediated diseases (asthma, inflammatory bowel disease, type 1 diabetes) later in life through a balanced initial immune response, underscoring the necessity of breastfeeding as the first source of nutrition. PMID:25310762

  8. Apoptosis, Necrosis, and Necroptosis in the Gut and Intestinal Homeostasis

    PubMed Central

    Negroni, Anna; Cucchiara, Salvatore; Stronati, Laura

    2015-01-01

    Intestinal epithelial cells (IECs) form a physiochemical barrier that separates the intestinal lumen from the host's internal milieu and is critical for electrolyte passage, nutrient absorption, and interaction with commensal microbiota. Moreover, IECs are strongly involved in the intestinal mucosal inflammatory response as well as in mucosal innate and adaptive immune responses. Cell death in the intestinal barrier is finely controlled, since alterations may lead to severe disorders, including inflammatory diseases. The emerging picture indicates that intestinal epithelial cell death is strictly related to the maintenance of tissue homeostasis. This review is focused on previous reports on different forms of cell death in intestinal epithelium. PMID:26483605

  9. Intestinal Iron Homeostasis and Colon Tumorigenesis

    PubMed Central

    Xue, Xiang; Shah, Yatrik M.

    2013-01-01

    Colorectal cancer (CRC) is the third most common cause of cancer-related deaths in industrialized countries. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Iron is an essential nutrient for cell growth. Iron overload caused by hereditary mutations or excess dietary iron uptake has been identified as a risk factor for CRC. Intestinal iron is tightly controlled by iron transporters that are responsible for iron uptake, distribution, and export. Dysregulation of intestinal iron transporters are observed in CRC and lead to iron accumulation in tumors. Intratumoral iron results in oxidative stress, lipid peroxidation, protein modification and DNA damage with consequent promotion of oncogene activation. In addition, excess iron in intestinal tumors may lead to increase in tumor-elicited inflammation and tumor growth. Limiting intratumoral iron through specifically chelating excess intestinal iron or modulating activities of iron transporter may be an attractive therapeutic target for CRC. PMID:23812305

  10. Innate immune activation in intestinal homeostasis.

    PubMed

    Harrison, Oliver J; Maloy, Kevin J

    2011-01-01

    Loss of intestinal immune regulation leading to aberrant immune responses to the commensal microbiota are believed to precipitate the chronic inflammation observed in the gastrointestinal tract of patients with inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. Innate immune receptors that recognize conserved components derived from the microbiota are widely expressed by both epithelial cells and leucocytes of the gastrointestinal tract and play a key role in host protection from infectious pathogens; yet precisely how pathogenic and commensal microbes are distinguished is not understood. Furthermore, aberrant innate immune activation may also drive intestinal pathology, as patients with IBD exhibit extensive infiltration of innate immune cells to the inflamed intestine, and polymorphisms in many innate immunity genes influence susceptibility to IBD. Thus, a balanced interaction between the microbiota and innate immune activation is required to maintain a healthy mutualistic relationship between the microbiota and the host, which when disturbed can result in intestinal inflammation. PMID:21912101

  11. Role of Autophagy in the Maintenance of Intestinal Homeostasis

    PubMed Central

    Baxt, Leigh A.; Xavier, Ramnik J.

    2015-01-01

    Genome-wide association studies of inflammatory bowel disease have identified several risk loci in genes that regulate autophagy, and studies have provided insight into the functional effects of these polymorphisms. We review the mechanisms by which autophagy contributes to intestinal homeostasis, focusing on its cell type-specific roles in regulating gut ecology, restricting pathogenic bacteria, and controlling inflammation. Based on this information, we are beginning to understand how alterations in autophagy can contribute to intestinal inflammation. PMID:26170139

  12. [Epithelial cell in intestinal homeostasis and inflammatory bowel diseases].

    PubMed

    Zouiten-Mekki, Lilia; Serghini, Meriem; Fekih, Monia; Kallel, Lamia; Matri, Samira; Ben Mustapha, Nadia; Boubaker, Jalel; Filali, Azza

    2013-12-01

    Crohn's disease (CD) and ulcerative colitis (UC) are the principal inflammatory bowel diseases (IBD) which physiopathology is currently poorly elucidated. During these diseases, the participation of the epithelial cell in the installation and the perpetuation of the intestinal inflammation is now clearly implicated. In fact, the intestinal epithelium located at the interface between the internal environment and the intestinal luminal, is key to the homeostatic regulation of the intestinal barrier. This barrier can schematically be regarded as being three barriers in one: a physical, chemical and immune barrier. The barrier function of epithelial cell can be altered by various mechanisms as occurs in IBD. The goal of this article is to review the literature on the role of the epithelial cell in intestinal homeostasis and its implication in the IBD. PMID:24356146

  13. Understanding epithelial homeostasis in the intestine

    PubMed Central

    De Mey, Jan R.; Freund, Jean-Noël

    2013-01-01

    The intestinal epithelium constitutes the barrier between the gut lumen and the rest of the body and a very actively renewing cell population. The crypt/villus and crypt/cuff units of the mouse small intestine and colon are its basic functional units. The field is confronted with competing concepts with regard to the nature of the cells that are responsible for all the day-to day cell replacement and those that act to regenerate the tissue upon injury and with two diametrically opposed models for lineage specification. The review revisits groundbreaking pioneering studies to provide non expert readers and crypt watchers with a factual analysis of the origins of the current models deduced from the latest spectacular advances. It also discusses recent progress made by addressing these issues in the crypts of the colon, which need to be better understood, since they are the preferred sites of major pathologies. PMID:24665395

  14. Wine consumption and intestinal redox homeostasis

    PubMed Central

    Biasi, Fiorella; Deiana, Monica; Guina, Tina; Gamba, Paola; Leonarduzzi, Gabriella; Poli, Giuseppe

    2014-01-01

    Regular consumption of moderate doses of wine is an integral part of the Mediterranean diet, which has long been considered to provide remarkable health benefits. Wine׳s beneficial effect has been attributed principally to its non-alcoholic portion, which has antioxidant properties, and contains a wide variety of phenolics, generally called polyphenols. Wine phenolics may prevent or delay the progression of intestinal diseases characterized by oxidative stress and inflammation, especially because they reach higher concentrations in the gut than in other tissues. They act as both free radical scavengers and modulators of specific inflammation-related genes involved in cellular redox signaling. In addition, the importance of wine polyphenols has recently been stressed for their ability to act as prebiotics and antimicrobial agents. Wine components have been proposed as an alternative natural approach to prevent or treat inflammatory bowel diseases. The difficulty remains to distinguish whether these positive properties are due only to polyphenols in wine or also to the alcohol intake, since many studies have reported ethanol to possess various beneficial effects. Our knowledge of the use of wine components in managing human intestinal inflammatory diseases is still quite limited, and further clinical studies may afford more solid evidence of their beneficial effects. PMID:25009781

  15. Wine consumption and intestinal redox homeostasis.

    PubMed

    Biasi, Fiorella; Deiana, Monica; Guina, Tina; Gamba, Paola; Leonarduzzi, Gabriella; Poli, Giuseppe

    2014-01-01

    Regular consumption of moderate doses of wine is an integral part of the Mediterranean diet, which has long been considered to provide remarkable health benefits. Wine's beneficial effect has been attributed principally to its non-alcoholic portion, which has antioxidant properties, and contains a wide variety of phenolics, generally called polyphenols. Wine phenolics may prevent or delay the progression of intestinal diseases characterized by oxidative stress and inflammation, especially because they reach higher concentrations in the gut than in other tissues. They act as both free radical scavengers and modulators of specific inflammation-related genes involved in cellular redox signaling. In addition, the importance of wine polyphenols has recently been stressed for their ability to act as prebiotics and antimicrobial agents. Wine components have been proposed as an alternative natural approach to prevent or treat inflammatory bowel diseases. The difficulty remains to distinguish whether these positive properties are due only to polyphenols in wine or also to the alcohol intake, since many studies have reported ethanol to possess various beneficial effects. Our knowledge of the use of wine components in managing human intestinal inflammatory diseases is still quite limited, and further clinical studies may afford more solid evidence of their beneficial effects. PMID:25009781

  16. Intestinal inflammation and stem cell homeostasis in aging Drosophila melanogaster

    PubMed Central

    Ayyaz, Arshad; Jasper, Heinrich

    2013-01-01

    As a barrier epithelium, the intestinal epithelium has to coordinate physiological functions like digestion and nutrient resorption with the control of commensal bacteria and the prevention of pathogenic infections. It can therefore mount powerful innate immune and inflammatory responses, while, at the same time, maintaining tissue homeostasis through regenerative processes. How these different functions are coordinated remains unclear, and further insight is required to understand the age-related loss of homeostasis in this system, as well as the etiology of inflammatory and proliferative diseases of the gut. Recent work in Drosophila melanogaster has provided important new insight into the regulation of regenerative activity, innate immune homeostasis, commensal control, as well as age-related dysfunction in the intestine. Interestingly, many of the identified processes and mechanisms mirror similar homeostatic processes in the vertebrate intestine. This review summarized the current understanding of how innate immune responses, changes in commensal bacteria, and other challenges influence regenerative activity in the aging intestinal epithelium of flies and draws parallels to similar processes in mammals. PMID:24380076

  17. Intestinal Epithelium and Autophagy: Partners in Gut Homeostasis

    PubMed Central

    Randall-Demllo, Sarron; Chieppa, Marcello; Eri, Rajaraman

    2013-01-01

    One of the most significant challenges of cell biology is to understand how each type of cell copes with its specific workload without suffering damage. Among the most intriguing questions concerns intestinal epithelial cells in mammals; these cells act as a barrier between the internally protected region and the external environment that is exposed constantly to food and microbes. A major process involved in the processing of microbes is autophagy. In the intestine, through multiple, complex signaling pathways, autophagy including macroautophagy and xenophagy is pivotal in mounting appropriate intestinal immune responses and anti-microbial protection. Dysfunctional autophagy mechanism leads to chronic intestinal inflammation, such as inflammatory bowel disease (IBD). Studies involving a number of in vitro and in vivo mouse models in addition to human clinical studies have revealed a detailed role for autophagy in the generation of chronic intestinal inflammation. A number of genome-wide association studies identified roles for numerous autophagy genes in IBD, especially in Crohn’s disease. In this review, we will explore in detail the latest research linking autophagy to intestinal homeostasis and how alterations in autophagy pathways lead to intestinal inflammation. PMID:24137160

  18. Role of the Enteric Microbiota in Intestinal Homeostasis and Inflammation

    PubMed Central

    Koboziev, Iurii; Webb, Cynthia Reinoso; Furr, Kathryn L.; Grisham, Matthew B.

    2014-01-01

    The mammalian intestine encounters many more microorganisms than any other tissue in the body thus making it the largest and most complex component of the immune system. Indeed, there are greater than 100 trillion (1014) microbes within the healthy human intestine where the total number of genes derived from this diverse microbiome exceeds that of the entire human genome by at least 100-fold. Our coexistence with the gut microbiota represents a dynamic and mutually beneficial relationship that is thought to be a major determinant of health and disease. Because of the potential for intestinal microorganisms to induce local and/or systemic inflammation, the intestinal immune system has developed a number of immune mechanisms to protect the host from pathogenic infections while limiting the inflammatory tissue injury that accompanies these immune responses. Failure to properly regulate intestinal mucosal immunity is thought to be responsible for the inflammatory tissue injury observed in the inflammatory bowel diseases (IBD; Crohn's disease, ulcerative colitis). An accumulating body of experimental and clinical evidence strongly suggest that IBD results from a dysregulated immune response to components of the normal gut flora in genetically-susceptible individuals. The objective of this review is to present our current understanding of the role that enteric microbiota play in intestinal homeostasis and pathogenesis of chronic intestinal inflammation. PMID:24275541

  19. Debra-mediated Ci degradation controls tissue homeostasis in Drosophila adult midgut.

    PubMed

    Li, Zhouhua; Guo, Yueqin; Han, Lili; Zhang, Yan; Shi, Lai; Huang, Xudong; Lin, Xinhua

    2014-02-11

    Adult tissue homeostasis is maintained by resident stem cells and their progeny. However, the underlying mechanisms that control tissue homeostasis are not fully understood. Here, we demonstrate that Debra-mediated Ci degradation is important for intestinal stem cell (ISC) proliferation in Drosophila adult midgut. Debra inhibition leads to increased ISC activity and tissue homeostasis loss, phenocopying defects observed in aging flies. These defects can be suppressed by depleting Ci, suggesting that increased Hedgehog (Hh) signaling contributes to ISC proliferation and tissue homeostasis loss. Consistently, Hh signaling activation causes the same defects, whereas depletion of Hh signaling suppresses these defects. Furthermore, the Hh ligand from multiple sources is involved in ISC proliferation and tissue homeostasis. Finally, we show that the JNK pathway acts downstream of Hh signaling to regulate ISC proliferation. Together, our results provide insights into the mechanisms of stem cell proliferation and tissue homeostasis control. PMID:24527387

  20. Debra-Mediated Ci Degradation Controls Tissue Homeostasis in Drosophila Adult Midgut

    PubMed Central

    Li, Zhouhua; Guo, Yueqin; Han, Lili; Zhang, Yan; Shi, Lai; Huang, Xudong; Lin, Xinhua

    2014-01-01

    Summary Adult tissue homeostasis is maintained by resident stem cells and their progeny. However, the underlying mechanisms that control tissue homeostasis are not fully understood. Here, we demonstrate that Debra-mediated Ci degradation is important for intestinal stem cell (ISC) proliferation in Drosophila adult midgut. Debra inhibition leads to increased ISC activity and tissue homeostasis loss, phenocopying defects observed in aging flies. These defects can be suppressed by depleting Ci, suggesting that increased Hedgehog (Hh) signaling contributes to ISC proliferation and tissue homeostasis loss. Consistently, Hh signaling activation causes the same defects, whereas depletion of Hh signaling suppresses these defects. Furthermore, the Hh ligand from multiple sources is involved in ISC proliferation and tissue homeostasis. Finally, we show that the JNK pathway acts downstream of Hh signaling to regulate ISC proliferation. Together, our results provide insights into the mechanisms of stem cell proliferation and tissue homeostasis control. PMID:24527387

  1. Regulation of intestinal homeostasis by innate and adaptive immunity.

    PubMed

    Kayama, Hisako; Takeda, Kiyoshi

    2012-11-01

    The intestine is a unique tissue where an elaborate balance is maintained between tolerance and immune responses against a variety of environmental factors such as food and the microflora. In a healthy individual, the microflora stimulates innate and adaptive immune systems to maintain gut homeostasis. However, the interaction of environmental factors with particular genetic backgrounds can lead to dramatic changes in the composition of the microflora (i.e. dysbiosis). Many of the specific commensal-bacterial products and the signaling pathways they trigger have been characterized. The role of T(h)1, T(h)2 and T(h)17 cells in inflammatory bowel disease has been widely investigated, as has the contribution of epithelial cells and subsets of dendritic cells and macrophages. To date, multiple regulatory cells in adaptive immunity, such as regulatory T cells and regulatory B cells, have been shown to maintain gut homeostasis by preventing inappropriate innate and adaptive immune responses to commensal bacteria. Additionally, regulatory myeloid cells have recently been identified that prevent intestinal inflammation by inhibiting T-cell proliferation. An increasing body of evidence has shown that multiple regulatory mechanisms contribute to the maintenance of gut homeostasis. PMID:22962437

  2. Windpipe Controls Drosophila Intestinal Homeostasis by Regulating JAK/STAT Pathway via Promoting Receptor Endocytosis and Lysosomal Degradation

    PubMed Central

    Li, Min; Wu, Longfei; Wang, Guolun; Baeg, Gyeong-Hun; You, Jia; Li, Zhouhua; Lin, Xinhua

    2015-01-01

    The adult intestinal homeostasis is tightly controlled by proper proliferation and differentiation of intestinal stem cells. The JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) signaling pathway is essential for the regulation of adult stem cell activities and maintenance of intestinal homeostasis. Currently, it remains largely unknown how JAK/STAT signaling activities are regulated in these processes. Here we have identified windpipe (wdp) as a novel component of the JAK/STAT pathway. We demonstrate that Wdp is positively regulated by JAK/STAT signaling in Drosophila adult intestines. Loss of wdp activity results in the disruption of midgut homeostasis under normal and regenerative conditions. Conversely, ectopic expression of Wdp inhibits JAK/STAT signaling activity. Importantly, we show that Wdp interacts with the receptor Domeless (Dome), and promotes its internalization for subsequent lysosomal degradation. Together, these data led us to propose that Wdp acts as a novel negative feedback regulator of the JAK/STAT pathway in regulating intestinal homeostasis. PMID:25923769

  3. Vasoactive Intestinal Polypeptide Promotes Intestinal Barrier Homeostasis and Protection Against Colitis in Mice

    PubMed Central

    Wu, Xiujuan; Conlin, Victoria S.; Morampudi, Vijay; Ryz, Natasha R.; Nasser, Yasmin; Bhinder, Ganive; Bergstrom, Kirk S.; Yu, Hong B.; Waterhouse, Chris C. M.; Buchan, Allison M. J.; Popescu, Oana E.; Gibson, William T.; Waschek, James A.; Vallance, Bruce A.; Jacobson, Kevan

    2015-01-01

    Inflammatory bowel disease is a chronic gastrointestinal inflammatory disorder associated with changes in neuropeptide expression and function, including vasoactive intestinal peptide (VIP). VIP regulates intestinal vasomotor and secretomotor function and motility; however, VIP’s role in development and maintenance of colonic epithelial barrier homeostasis is unclear. Using VIP deficient (VIPKO) mice, we investigated VIP’s role in epithelial barrier homeostasis, and susceptibility to colitis. Colonic crypt morphology and epithelial barrier homeostasis were assessed in wildtype (WT) and VIPKO mice, at baseline. Colitic responses were evaluated following dinitrobenzene sulfonic acid (DNBS) or dextran-sodium sulfate (DSS) exposure. Mice were also treated with exogenous VIP. At baseline, VIPKO mice exhibited distorted colonic crypts, defects in epithelial cell proliferation and migration, increased apoptosis, and altered permeability. VIPKO mice also displayed reduced goblet cell numbers, and reduced expression of secreted goblet cell factors mucin 2 and trefoil factor 3. These changes were associated with reduced expression of caudal type homeobox 2 (Cdx2), a master regulator of intestinal function and homeostasis. DNBS and DSS-induced colitis were more severe in VIPKO than WT mice. VIP treatment rescued the phenotype, protecting VIPKO mice against DSS colitis, with results comparable to WT mice. In conclusion, VIP plays a crucial role in the development and maintenance of colonic epithelial barrier integrity under physiological conditions and promotes epithelial repair and homeostasis during colitis. PMID:25932952

  4. Microbiota-Produced Succinate Improves Glucose Homeostasis via Intestinal Gluconeogenesis.

    PubMed

    De Vadder, Filipe; Kovatcheva-Datchary, Petia; Zitoun, Carine; Duchampt, Adeline; Bäckhed, Fredrik; Mithieux, Gilles

    2016-07-12

    Beneficial effects of dietary fiber on glucose and energy homeostasis have long been described, focusing mostly on the production of short-chain fatty acids by the gut commensal bacteria. However, bacterial fermentation of dietary fiber also produces large amounts of succinate and, to date, no study has focused on the role of succinate on host metabolism. Here, we fed mice a fiber-rich diet and found that succinate was the most abundant carboxylic acid in the cecum. Dietary succinate was identified as a substrate for intestinal gluconeogenesis (IGN), a process that improves glucose homeostasis. Accordingly, dietary succinate improved glucose and insulin tolerance in wild-type mice, but those effects were absent in mice deficient in IGN. Conventional mice colonized with the succinate producer Prevotella copri exhibited metabolic benefits, which could be related to succinate-activated IGN. Thus, microbiota-produced succinate is a previously unsuspected bacterial metabolite improving glycemic control through activation of IGN. PMID:27411015

  5. Opposing activities of Notch and Wnt signaling regulate intestinal stem cells and gut homeostasis.

    PubMed

    Tian, Hua; Biehs, Brian; Chiu, Cecilia; Siebel, Christian W; Wu, Yan; Costa, Mike; de Sauvage, Frederic J; Klein, Ophir D

    2015-04-01

    Proper organ homeostasis requires tight control of adult stem cells and differentiation through the integration of multiple inputs. In the mouse small intestine, Notch and Wnt signaling are required both for stem cell maintenance and for a proper balance of differentiation between secretory and absorptive cell lineages. In the absence of Notch signaling, stem cells preferentially generate secretory cells at the expense of absorptive cells. Here, we use function-blocking antibodies against Notch receptors to demonstrate that Notch blockade perturbs intestinal stem cell function by causing a derepression of the Wnt signaling pathway, leading to misexpression of prosecretory genes. Importantly, attenuation of the Wnt pathway rescued the phenotype associated with Notch blockade. These studies bring to light a negative regulatory mechanism that maintains stem cell activity and balanced differentiation, and we propose that the interaction between Wnt and Notch signaling described here represents a common theme in adult stem cell biology. PMID:25818302

  6. EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila

    PubMed Central

    Jiang, Huaqi; Grenley, Marc O.; Bravo, Maria-Jose; Blumhagen, Rachel Z.; Edgar, Bruce A.

    2010-01-01

    Many tissues in higher animals undergo dynamic homeostatic growth, wherein damaged or aged cells are replaced by the progeny of resident stem cells. To maintain homeostasis, stem cells must respond to tissue needs. Here we show that in response to damage or stress in the intestinal (midgut) epithelium of adult Drosophila, multiple EGFR ligands and rhomboids (intramembrane proteases that activate some EGFR ligands) are induced, leading to the activation of EGFR signaling in intestinal stem cells (ISCs). Activation of EGFR signaling promotes ISC division and midgut epithelium regeneration, thus maintaining tissue homeostasis. ISCs defective in EGFR signaling cannot grow or divide, are poorly maintained, and cannot support midgut epithelium regeneration following enteric infection by the bacterium, Pseudomonas entomophila. Furthermore, ISC proliferation induced by Jak/Stat signaling is dependent upon EGFR signaling. Thus the EGFR/Ras/MAPK signaling pathway plays central, essential roles in ISC maintenance and the feedback system that mediates intestinal homeostasis. PMID:21167805

  7. Intestinal stem cells in the adult Drosophila midgut

    SciTech Connect

    Jiang, Huaqi; Edgar, Bruce A.

    2011-11-15

    Drosophila has long been an excellent model organism for studying stem cell biology. Notably, studies of Drosophila's germline stem cells have been instrumental in developing the stem cell niche concept. The recent discovery of somatic stem cells in adult Drosophila, particularly the intestinal stem cells (ISCs) of the midgut, has established Drosophila as an exciting model to study stem cell-mediated adult tissue homeostasis and regeneration. Here, we review the major signaling pathways that regulate the self-renewal, proliferation and differentiation of Drosophila ISCs, discussing how this regulation maintains midgut homeostasis and mediates regeneration of the intestinal epithelium after injury. -- Highlights: Black-Right-Pointing-Pointer The homeostasis and regeneration of adult fly midguts are mediated by ISCs. Black-Right-Pointing-Pointer Damaged enterocytes induce the proliferation of intestinal stem cells (ISC). Black-Right-Pointing-Pointer EGFR and Jak/Stat signalings mediate compensatory ISC proliferation. Black-Right-Pointing-Pointer Notch signaling regulates ISC self-renewal and differentiation.

  8. Intestinal histoplasmosis in immunocompetent adults

    PubMed Central

    Zhu, Lin-Lin; Wang, Jin; Wang, Zi-Jing; Wang, Yi-Ping; Yang, Jin-Lin

    2016-01-01

    AIM: To present a retrospective analysis of clinical and endoscopic features of 4 cases of immunocompetent hosts with intestinal histoplasmosis (IH). METHODS: Four immunocompetent adults were diagnosed with IH between October 2005 and March 2015 at West China Hospital of Sichuan University. Clinical and endoscopic characteristics were summarized and analyzed retrospectively. GMS (Gomori methenamine silver), PAS (periodic acid-Schiff) and Giemsa staining technique were used to confirm Histoplasma capsulatum(H. capsulatum). The symptoms, signs, endoscopic presentations, radiographic imaging, pathological stain results and follow-up are presented as tables and illustrations. RESULTS: The cases were male patients, ranging from 33 to 61 years old, and primarily presented with non-specific symptoms such as irregular fever, weight loss, abdominal pain and distention. Hepatosplenomegaly and lymphadenopathy were the most common signs. Endoscopic manifestations were localized or diffuse congestion, edema, ulcers, and polypoid nodules with central erosion involving the terminal ileum, ascending colon, transverse colon, descending colon, sigmoid colon and rectum, similar to intestinal tuberculosis, tumor, and inflammatory bowel disease. Numerous yeast-like pathogens testing positive for PAS and GMS stains but negative for Giemsa were detected in the cytoplasm of the histiocytes, which were highly suggestive of H. capsulatum. CONCLUSION: Immunocompetent individuals suffering from histoplasmosis are rarely reported. It is necessary that gastroenterologists and endoscopists consider histoplasmosis as a differential diagnosis, even in immunocompetent patients. PMID:27099446

  9. Loss of Survivin in Intestinal Epithelial Progenitor Cells Leads to Mitotic Catastrophe and Breakdown of Gut Immune Homeostasis.

    PubMed

    Martini, Eva; Wittkopf, Nadine; Günther, Claudia; Leppkes, Moritz; Okada, Hitoshi; Watson, Alastair J; Podstawa, Eva; Backert, Ingo; Amann, Kerstin; Neurath, Markus F; Becker, Christoph

    2016-02-01

    A tightly regulated balance of proliferation and cell death of intestinal epithelial cells (IECs) is essential for maintenance of gut homeostasis. Survivin is highly expressed during embryogenesis and in several cancer types, but little is known about its role in adult gut tissue. Here, we show that Survivin is specifically expressed in transit-amplifying cells and Lgr5(+) stem cells. Genetic loss of Survivin in IECs resulted in destruction of intestinal integrity, mucosal inflammation, and death of the animals. Survivin deletion was associated with decreased epithelial proliferation due to defective chromosomal segregation. Moreover, Survivin-deficient animals showed induced phosphorylation of p53 and H2AX and increased levels of cell-intrinsic apoptosis in IECs. Consequently, induced deletion of Survivin in Lgr5(+) stem cells led to cell death. In summary, Survivin is a key regulator of gut tissue integrity by regulating epithelial homeostasis in the stem cell niche. PMID:26832409

  10. Notch in the intestine: regulation of homeostasis and pathogenesis.

    PubMed

    Noah, Taeko K; Shroyer, Noah F

    2013-01-01

    The small and large intestines are tubular organs composed of several tissue types. The columnar epithelium that lines the inner surface of the intestines distinguishes the digestive physiology of each region of the intestine and consists of several distinct cell types that are rapidly and continually renewed by intestinal stem cells that reside near the base of the crypts of Lieberkühn. Notch signaling controls the fate of intestinal stem cells by regulating the expression of Hes genes and by repressing Atoh1. Alternate models of Notch pathway control of cell fate determination are presented. Roles for Notch signaling in development of the intestine, including mesenchymal and neural cells, are discussed. The oncogenic activities of Notch in colorectal cancer, as well as the tumor suppressive activities of Atoh1, are reviewed. Therapeutic targeting of the Notch pathway in colorectal cancers is discussed, along with potential caveats. PMID:23190077

  11. The role for protein tyrosine phosphatase non-receptor type 22 in regulating intestinal homeostasis

    PubMed Central

    Spalinger, Marianne R

    2015-01-01

    Inflammatory bowel disease represents a chronic intestinal inflammation. Recent knowledge suggests a crucial role for genetic, immunological and bacterial factors in inflammatory bowel disease pathogenesis. Variations within the gene locus encoding PTPN22 have been associated with inflammatory bowel disease. PTPN22 is critically involved in controlling immune cell activation and thereby plays an important role in maintaining intestinal homeostasis. Although in B and T cells the mechanism showing how PTPN22 affects cell signalling pathways is well studied, its role in myeloid cells remains less defined. Regulation of the innate immune system plays an essential role in the intestine, and levels of PTPN22 in myeloid cells are drastically reduced in the intestine of inflammatory bowel disease patients. Therefore, additional studies to define the role of PTPN22 in myeloid cells might clearly enhance our understanding of how PTPN22 contributes to intestinal homeostasis.

  12. Clock genes, intestinal transport and plasma lipid homeostasis.

    PubMed

    Hussain, M Mahmood; Pan, Xiaoyue

    2009-05-01

    Light and food are two major environmental factors that impact daily life. Light entrainment is centrally controlled by suprachiasmatic nuclei of the hypothalamus. Food entrainment might require cooperation between the intestine and dorsomedial hypothalamus. Clock genes that are essential for light entrainment also play a part in food entrainment. Understanding the role of clock genes in the entrainment of intestinal functions, as well as in gut-brain communication during food entrainment, will enhance our understanding of gastrointestinal and metabolic disorders. This review highlights recent studies examining light- and food-entrained regulation of plasma lipids and of various intestinal activities and offers insight into the role of the intestine in food entrainment. PMID:19349191

  13. Effect of Ozone on Intestinal Epithelial Homeostasis in a Rat Model

    PubMed Central

    Sukhotnik, Igor; Starikov, Alona; Coran, Arnold G.; Pollak, Yulia; Sohotnik, Rima; Shaoul, Ron

    2015-01-01

    Background: The positive effects of ozone therapy have been described in many gastrointestinal disorders. The mechanisms of this positive effect of ozone therapy are poorly understood. The purpose of the present study was to investigate whether the use of ozone may potentiate the gut intestinal mucosal homeostasis in a rat model. Methods: Adult rats weighing 250–280 g were randomly assigned to one of three experimental groups of 8 rats each: 1) Control rats were given 2 mL of water by gavage and intraperitoneally (IP) for 5 days; 2) O3-PO rats were treated with 2 mL of ozone/oxygen mixture by gavage and 2 mL of water IP for 5 days; 3) O3-IP rats were treated with 2 mL of water by gavage and 2 mL of ozone/oxygen mixture IP for 5 days. Rats were sacrificed on day 6. Bowel and mucosal weight, mucosal DNA and protein, villus height and crypt depth, and cell proliferation and apoptosis were evaluated following sacrifice. Results: The group of O3-IP rats demonstrated a greater jejunal and ileal villus height and crypt depth, a greater enterocyte proliferation index in jejunum, and lower enterocyte apoptosis in ileum compared to control animals. Oral administration of the ozone/oxygen mixture resulted in a less significant effect on cell turnover. Conclusions: Treatment with an ozone/oxygen mixture stimulates intestinal cell turnover in a rat model. Intraperitoneal administration of ozone resulted in a more significant intestinal trophic effect than oral administration. PMID:25717388

  14. Granulocyte macrophage colony-stimulating factor and the intestinal innate immune cell homeostasis in Crohn's disease.

    PubMed

    Däbritz, Jan

    2014-03-01

    Current literature consolidates the view of Crohn's disease (CD) as a form of immunodeficiency highlighting dysregulation of intestinal innate immunity in the pathogenesis of CD. Intestinal macrophages derived from blood monocytes play a key role in sustaining the innate immune homeostasis in the intestine, suggesting that the monocyte/macrophage compartment might be an attractive therapeutic target for the management of CD. Granulocyte macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor that also promotes myeloid cell activation, proliferation, and differentiation. GM-CSF has a protective effect in human CD and mouse models of colitis. However, the role of GM-CSF in immune and inflammatory reactions in the intestine is not well defined. Beneficial effects exerted by GM-CSF during intestinal inflammation could relate to modulation of the mucosal barrier function in the intestine, including epithelial cell proliferation, survival, restitution, and immunomodulatory actions. The aim of this review is to summarize potential mechanistic roles of GM-CSF in intestinal innate immune cell homeostasis and to highlight its central role in maintenance of the intestinal immune barrier in the context of immunodeficiency in CD. PMID:24503766

  15. Microbial activities and intestinal homeostasis: A delicate balance between health and disease

    PubMed Central

    Ohland, Christina L.; Jobin, Christian

    2015-01-01

    The concept that the intestinal microbiota modulates numerous physiological processes including immune development and function, nutrition and metabolism as well as pathogen exclusion is relatively well established in the scientific community. The molecular mechanisms driving these various effects and the events leading to the establishment of a “healthy” microbiome are slowly emerging. The objective of this review is to bring into focus important aspects of microbial/host interactions in the intestine and to discuss key molecular mechanisms controlling health and disease states. We will discuss recent evidence on how microbes interact with the host and one another and their impact on intestinal homeostasis. PMID:25729763

  16. Distinct Roles for Intestinal Epithelial Cell-Specific Hdac1 and Hdac2 in the Regulation of Murine Intestinal Homeostasis.

    PubMed

    Gonneaud, Alexis; Turgeon, Naomie; Boudreau, François; Perreault, Nathalie; Rivard, Nathalie; Asselin, Claude

    2016-02-01

    The intestinal epithelium responds to and transmits signals from the microbiota and the mucosal immune system to insure intestinal homeostasis. These interactions are in part conveyed by epigenetic modifications, which respond to environmental changes. Protein acetylation is an epigenetic signal regulated by histone deacetylases, including Hdac1 and Hdac2. We have previously shown that villin-Cre-inducible intestinal epithelial cell (IEC)-specific Hdac1 and Hdac2 deletions disturb intestinal homeostasis. To determine the role of Hdac1 and Hdac2 in the regulation of IEC function and the establishment of the dual knockout phenotype, we have generated villin-Cre murine models expressing one Hdac1 allele without Hdac2, or one Hdac2 allele without Hdac1. We have also investigated the effect of short-term deletion of both genes in naphtoflavone-inducible Ah-Cre and tamoxifen-inducible villin-Cre(ER) mice. Mice with one Hdac1 allele displayed normal tissue architecture, but increased sensitivity to DSS-induced colitis. In contrast, mice with one Hdac2 allele displayed intestinal architecture defects, increased proliferation, decreased goblet cell numbers as opposed to Paneth cells, increased immune cell infiltration associated with fibrosis, and increased sensitivity to DSS-induced colitis. In comparison to dual knockout mice, intermediary activation of Notch, mTOR, and Stat3 signaling pathways was observed. While villin-Cre(ER) Hdac1 and Hdac2 deletions led to an impaired epithelium and differentiation defects, Ah-Cre-mediated deletion resulted in blunted proliferation associated with the induction of a DNA damage response. Our results suggest that IEC determination and intestinal homeostasis are highly dependent on Hdac1 and Hdac2 activity levels, and that changes in the IEC acetylome may alter the mucosal environment. PMID:26174178

  17. Diet and host-microbial crosstalk in postnatal intestinal immune homeostasis.

    PubMed

    Jain, Nitya; Walker, W Allan

    2015-01-01

    Neonates face unique challenges in the period following birth. The postnatal immune system is in the early stages of development and has a range of functional capabilities that are distinct from the mature adult immune system. Bidirectional immune-microbial interactions regulate the development of mucosal immunity and alter the composition of the microbiota, which contributes to overall host well-being. In the past few years, nutrition has been highlighted as a third element in this interaction that governs host health by modulating microbial composition and the function of the immune system. Dietary changes and imbalances can disturb the immune-microbiota homeostasis, which might alter susceptibility to several autoimmune and metabolic diseases. Major changes in cultural traditions, socioeconomic status and agriculture are affecting the nutritional status of humans worldwide, which is altering core intestinal microbial communities. This phenomenon is especially relevant to the neonatal and paediatric populations, in which the microbiota and immune system are extremely sensitive to dietary influences. In this Review, we discuss the current state of knowledge regarding early-life nutrition, its effects on the microbiota and the consequences of diet-induced perturbation of the structure of the microbial community on mucosal immunity and disease susceptibility. PMID:25201040

  18. Essential contribution of IRF3 to intestinal homeostasis and microbiota-mediated Tslp gene induction.

    PubMed

    Negishi, Hideo; Miki, Shoji; Sarashina, Hana; Taguchi-Atarashi, Naoko; Nakajima, Akira; Matsuki, Kosuke; Endo, Nobuyasu; Yanai, Hideyuki; Nishio, Junko; Honda, Kenya; Taniguchi, Tadatsugu

    2012-12-18

    The large intestinal epithelial cells and immune cells are exposed to a variety of molecules derived from commensal microbiota that can activate innate receptors, such as Toll-like receptors (TLRs) and retinoic acid-inducible gene-I-like receptors (RLRs). Although the activation of these receptors is known to be critical for homeostasis of the large intestine, the underlying gene regulatory mechanisms are not well understood. Here, we show that IFN regulatory factor (IRF)3 is critical for the suppression of dextran sulfate sodium-induced colitis. IRF3-deficient mice exhibited lethal defects in the inflammatory and recovery phases of the colitis, accompanied by marked defects in the gene induction for thymic stromal lymphopoietin (TSLP), a cytokine known to be essential for protection of the large intestine. We further provide evidence that DNA and RNA of the large intestinal contents are critical for Tslp gene induction via IRF3 activation by cytosolic nucleic acid receptors. We also demonstrate that IRF3 indeed activates the gene promoter of Tslp via IRF-binding sequences. This newly identified intestinal gene regulatory mechanism, wherein IRF3 activated by microbiota-derived nucleic acids plays a critical role in intestinal homeostasis, may have clinical implication in colonic inflammatory disorders. PMID:23213237

  19. Lipid-Induced Peroxidation in the Intestine Is Involved in Glucose Homeostasis Imbalance in Mice

    PubMed Central

    Marsollier, Nicolas; Masseboeuf, Myriam; Payros, Gaëlle; Kabani, Catherine; Denom, Jessica; Lacombe, Amélie; Thiers, Jean-Claude; Negre-Salvayre, Anne; Luquet, Serge; Burcelin, Rémy; Cruciani-Guglielmacci, Céline; Magnan, Christophe

    2011-01-01

    Background Daily variations in lipid concentrations in both gut lumen and blood are detected by specific sensors located in the gastrointestinal tract and in specialized central areas. Deregulation of the lipid sensors could be partly involved in the dysfunction of glucose homeostasis. The study aimed at comparing the effect of Medialipid (ML) overload on insulin secretion and sensitivity when administered either through the intestine or the carotid artery in mice. Methodology/Principal Findings An indwelling intragastric or intracarotid catheter was installed in mice and ML or an isocaloric solution was infused over 24 hours. Glucose and insulin tolerance and vagus nerve activity were assessed. Some mice were treated daily for one week with the anti-lipid peroxidation agent aminoguanidine prior to the infusions and tests. The intestinal but not the intracarotid infusion of ML led to glucose and insulin intolerance when compared with controls. The intestinal ML overload induced lipid accumulation and increased lipid peroxidation as assessed by increased malondialdehyde production within both jejunum and duodenum. These effects were associated with the concomitant deregulation of vagus nerve. Administration of aminoguanidine protected against the effects of lipid overload and normalized glucose homeostasis and vagus nerve activity. Conclusions/Significance Lipid overload within the intestine led to deregulation of gastrointestinal lipid sensing that in turn impaired glucose homeostasis through changes in autonomic nervous system activity. PMID:21698161

  20. GATAe regulates intestinal stem cell maintenance and differentiation in Drosophila adult midgut.

    PubMed

    Okumura, Takashi; Takeda, Koji; Kuchiki, Megumi; Akaishi, Marie; Taniguchi, Kiichiro; Adachi-Yamada, Takashi

    2016-02-01

    Adult intestinal tissues, exposed to the external environment, play important roles including barrier and nutrient-absorption functions. These functions are ensured by adequately controlled rapid-cell metabolism. GATA transcription factors play essential roles in the development and maintenance of adult intestinal tissues both in vertebrates and invertebrates. We investigated the roles of GATAe, the Drosophila intestinal GATA factor, in adult midgut homeostasis with its first-generated knock-out mutant as well as cell type-specific RNAi and overexpression experiments. Our results indicate that GATAe is essential for proliferation and maintenance of intestinal stem cells (ISCs). Also, GATAe is involved in the differentiation of enterocyte (EC) and enteroendocrine (ee) cells in both Notch (N)-dependent and -independent manner. The results also indicate that GATAe has pivotal roles in maintaining normal epithelial homeostasis of the Drosophila adult midgut through interaction of N signaling. Since recent reports showed that mammalian GATA-6 regulates normal and cancer stem cells in the adult intestinal tract, our data also provide information on the evolutionally conserved roles of GATA factors in stem-cell regulation. PMID:26719127

  1. Small intestinal permeability in older adults

    PubMed Central

    Valentini, Luzia; Ramminger, Sara; Haas, Verena; Postrach, Elisa; Werich, Martina; Fischer, André; Koller, Michael; Swidsinski, Alexander; Bereswill, Stefan; Lochs, Herbert; Schulzke, Jörg‐Dieter

    2014-01-01

    Abstract It is not yet clear whether intestinal mucosal permeability changes with advancing age in humans. This question is of high importance for drug and nutrition approaches for older adults. Our main objective was to answer the question if small intestinal barrier integrity deteriorates with healthy aging. We conducted a cross‐sectional study including the pooled data of 215 nonsmoking healthy adults (93 female/122 male), 84 of whom were aged between 60 and 82 years. After a 12‐h fast, all participants ingested 10 g of lactulose and 5 g of mannitol. Urine was collected for 5 h afterwards and analyzed for test sugars. The permeability index (PI = lactulose/mannitol) was used to assess small intestinal permeability. Low‐grade inflammation defined by high‐sensitivity C‐reactive protein ≥1 mL/L and kidney function (estimated glomerular filtration rate) were determined in the older age group. The PI was similar in older compared to younger adults (P =0.887). However, the urinary recovery of lactulose and mannitol was lower in the older adults and this change was neither associated with urinary volume nor glomerular filtration rate. The PI was not significantly correlated with low‐grade inflammation or presence of noninsulin‐dependent type 2 diabetes. However, it significantly deteriorated in the copresence of both conditions compared to low‐grade inflammation alone (P =0.043) or type 2 diabetes alone (P =0.015). Small intestinal mucosal barrier does not deteriorate with age per se. But low‐grade inflammation coupled with minor disease challenges, such as type 2 diabetes, can compromise the small intestinal barrier. PMID:24771689

  2. IRF8 Transcription-Factor-Dependent Classical Dendritic Cells Are Essential for Intestinal T Cell Homeostasis.

    PubMed

    Luda, Katarzyna M; Joeris, Thorsten; Persson, Emma K; Rivollier, Aymeric; Demiri, Mimoza; Sitnik, Katarzyna M; Pool, Lieneke; Holm, Jacob B; Melo-Gonzalez, Felipe; Richter, Lisa; Lambrecht, Bart N; Kristiansen, Karsten; Travis, Mark A; Svensson-Frej, Marcus; Kotarsky, Knut; Agace, William W

    2016-04-19

    The role of dendritic cells (DCs) in intestinal immune homeostasis remains incompletely defined. Here we show that mice lacking IRF8 transcription-factor-dependent DCs had reduced numbers of T cells in the small intestine (SI), but not large intestine (LI), including an almost complete absence of SI CD8αβ(+) and CD4(+)CD8αα(+) T cells; the latter requiring β8 integrin expression by migratory IRF8 dependent CD103(+)CD11b(-) DCs. SI homing receptor induction was impaired during T cell priming in mesenteric lymph nodes (MLN), which correlated with a reduction in aldehyde dehydrogenase activity by SI-derived MLN DCs, and inefficient T cell localization to the SI. These mice also lacked intestinal T helper 1 (Th1) cells, and failed to support Th1 cell differentiation in MLN and mount Th1 cell responses to Trichuris muris infection. Collectively these results highlight multiple non-redundant roles for IRF8 dependent DCs in the maintenance of intestinal T cell homeostasis. PMID:27067057

  3. RAB and RHO GTPases regulate intestinal crypt cell homeostasis and enterocyte function.

    PubMed

    Zhang, Xiao; Gao, Nan

    2016-04-01

    Recent human and mouse genetic studies have highlighted important contributions of several small GTPases, in particular Rab8a, (1) Cdc42, (2-4) and Rab11a, (5-8) to the proper morphogenesis and function of the mature intestinal epithelia. Additional insights about the involvement of these factors in maintaining intestinal stem cell homeostasis have also been obtained. (9,10) These studies suggest a conserved vesicular and membrane trafficking program utilized by the gastrointestinal tissue to support the rapid epithelial cell turnover and the highly sophisticated physiology of mature epithelial cells. PMID:27142493

  4. Requirement of full TCR repertoire for regulatory T cells to maintain intestinal homeostasis.

    PubMed

    Nishio, Junko; Baba, Minato; Atarashi, Koji; Tanoue, Takeshi; Negishi, Hideo; Yanai, Hideyuki; Habu, Sonoko; Hori, Shohei; Honda, Kenya; Taniguchi, Tadatsugu

    2015-10-13

    The regulation of intestinal homeostasis by the immune system involves the dynamic interplay between gut commensal microbiota and resident immune cells. It is well known that a large and diverse lymphocyte antigen receptor repertoire enables the immune system to recognize and respond to a wide range of invading pathogens. There is also an emerging appreciation for a critical role the T-cell receptor (TCR) repertoire serves in the maintenance of peripheral tolerance by regulatory T cells (Tregs). Nevertheless, how the diversity of the TCR repertoire in Tregs affects intestinal homeostasis remains unknown. To address this question, we studied mice whose T cells express a restricted TCR repertoire. We observed the development of spontaneous colitis, accompanied by the induction of T-helper type 17 cells in the colon that is driven by gut commensal microbiota. We provide further evidence that a restricted TCR repertoire causes a loss of tolerogenicity to microbiota, accompanied by a paucity of peripherally derived, Helios(-) Tregs and hyperactivation of migratory dendritic cells. These results thus reveal a new facet of the TCR repertoire in which Tregs require a diverse TCR repitoire for intestinal homeostasis, suggesting an additional driving force in the evolutional significance of the TCR repertoire. PMID:26420876

  5. Requirement of full TCR repertoire for regulatory T cells to maintain intestinal homeostasis

    PubMed Central

    Nishio, Junko; Baba, Minato; Atarashi, Koji; Tanoue, Takeshi; Negishi, Hideo; Yanai, Hideyuki; Habu, Sonoko; Hori, Shohei; Honda, Kenya; Taniguchi, Tadatsugu

    2015-01-01

    The regulation of intestinal homeostasis by the immune system involves the dynamic interplay between gut commensal microbiota and resident immune cells. It is well known that a large and diverse lymphocyte antigen receptor repertoire enables the immune system to recognize and respond to a wide range of invading pathogens. There is also an emerging appreciation for a critical role the T-cell receptor (TCR) repertoire serves in the maintenance of peripheral tolerance by regulatory T cells (Tregs). Nevertheless, how the diversity of the TCR repertoire in Tregs affects intestinal homeostasis remains unknown. To address this question, we studied mice whose T cells express a restricted TCR repertoire. We observed the development of spontaneous colitis, accompanied by the induction of T-helper type 17 cells in the colon that is driven by gut commensal microbiota. We provide further evidence that a restricted TCR repertoire causes a loss of tolerogenicity to microbiota, accompanied by a paucity of peripherally derived, Helios− Tregs and hyperactivation of migratory dendritic cells. These results thus reveal a new facet of the TCR repertoire in which Tregs require a diverse TCR repitoire for intestinal homeostasis, suggesting an additional driving force in the evolutional significance of the TCR repertoire. PMID:26420876

  6. The role of innate signaling in the homeostasis of tolerance and immunity in the intestine.

    PubMed

    Wells, Jerry M; Loonen, Linda M P; Karczewski, Jurgen M

    2010-01-01

    In the intestine innate recognition of microbes is achieved through pattern recognition receptor (PRR) families expressed in immune cells and different cell lineages of the intestinal epithelium. Toll-like receptor (TLR) and nucleotide-binding and oligomerization domain-like receptor (NLR) families are emerging as key mediators of immunity through their role as maturation factors of immune cells and triggers for the production of cytokines and chemokines and antimicrobial factors. At the mucosal surface chronic activation of the immune system is avoided through the epithelial production of a glycocalyx, steady-state production of antimicrobial factors as well as the selective expression and localization of PRRs. Additionally, the polarization of epithelial TLR signaling and suppression of NF-kappaB activation by luminal commensals appears to contribute to the homeostasis of tolerance and immunity. Several studies have demonstrated that TLR signaling in epithelial cells contributes to a range of homeostatic mechanisms including proliferation, wound healing, epithelial integrity, and regulation of mucosal immune functions. The intestinal epithelium appears to have uniquely evolved to maintain mucosal tolerance and immunity, and future efforts to further understand the molecular mechanisms of intestinal homeostasis may have a major impact on human health. PMID:19783476

  7. TLR sorting by Rab11 endosomes maintains intestinal epithelial-microbial homeostasis

    PubMed Central

    Yu, Shiyan; Nie, Yingchao; Knowles, Byron; Sakamori, Ryotaro; Stypulkowski, Ewa; Patel, Chirag; Das, Soumyashree; Douard, Veronique; Ferraris, Ronaldo P; Bonder, Edward M; Goldenring, James R; Ip, Yicktung Tony; Gao, Nan

    2014-01-01

    Compartmentalization of Toll-like receptors (TLRs) in intestinal epithelial cells (IECs) regulates distinct immune responses to microbes; however, the specific cellular machinery that controls this mechanism has not been fully identified. Here we provide genetic evidences that the recycling endosomal compartment in enterocytes maintains a homeostatic TLR9 intracellular distribution, supporting mucosal tolerance to normal microbiota. Genetic ablation of a recycling endosome resident small GTPase, Rab11a, a gene adjacent to a Crohn's disease risk locus, in mouse IECs and in Drosophila midgut caused epithelial cell-intrinsic cytokine production, inflammatory bowel phenotype, and early mortality. Unlike wild-type controls, germ-free Rab11a-deficient mouse intestines failed to tolerate the intraluminal stimulation of microbial agonists. Thus, Rab11a endosome controls intestinal host-microbial homeostasis at least partially via sorting TLRs. PMID:25063677

  8. Perturbations of mucosal homeostasis through interactions of intestinal microbes with myeloid cells.

    PubMed

    Schey, Regina; Danzer, Claudia; Mattner, Jochen

    2015-02-01

    Mucosal surfaces represent the largest areas of interactions of the host with its environment. Subsequently, the mucosal immune system has evolved complex strategies to maintain the integrity of the host by inducing protective immune responses against pathogenic and tolerance against dietary and commensal microbial antigens within the broad range of molecules the intestinal epithelium is exposed to. Among many other specialized cell subsets, myeloid cell populations - due to their strategic location in the subepithelial lamina propria - are the first ones to scavenge and process these intestinal antigens and to send consecutive signals to other immune and non-immune cell subsets. Thus, myeloid cell populations represent attractive targets for clinical intervention in chronic inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease (CD) as they initiate and modulate inflammatory or regulatory immune response and shape the intestinal T cell pool. Here, we discuss the interactions of the intestinal microbiota with dendritic cell and macrophage populations and review in this context the literature on four promising candidate molecules that are critical for the induction and maintenance of intestinal homeostasis on the one hand, but also for the initiation and propagation of chronic intestinal inflammation on the other. PMID:25466587

  9. Perturbations of mucosal homeostasis through interactions of intestinal microbes with myeloid cells

    PubMed Central

    Schey, Regina; Danzer, Claudia; Mattner, Jochen

    2014-01-01

    Mucosal surfaces represent the largest areas of interactions of the host with its environment. Subsequently, the mucosal immune system has evolved complex strategies to maintain the integrity of the host by inducing protective immune responses against pathogenic and tolerance against dietary and commensal microbial antigens within the broad range of molecules the intestinal epithelium is exposed to. Among many other specialized cell subsets, myeloid cell populations - due to their strategic location in the subepithelial lamina propria - are the first ones to scavenge and process these intestinal antigens and to send consecutive signals to other immune and non-immune cell subsets. Thus, myeloid cell populations represent attractive targets for clinical intervention in chronic inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease (CD) as they initiate and modulate inflammatory or regulatory immune response and shape the intestinal T cell pool. Here, we discuss the interactions of the intestinal microbiota with dendritic cell and macrophage populations and review in this context the literature on four promising candidate molecules that are critical for the induction and maintenance of intestinal homeostasis on the one hand, but also for the initiation and propagation of chronic intestinal inflammation on the other. PMID:25466587

  10. Intestinal microflora and homeostasis of the mucosal immune response: implications for probiotic bacteria?

    PubMed

    Blum, Stephanie; Schiffrin, Eduardo J

    2003-09-01

    The intestinal microflora can be considered a postnatally acquired organ that is composed of a large diversity of bacteria that perform important functions for the host and can be modulated by environmental factors, such as nutrition. Specific components of the intestinal microflora, including lactobacilli and bifidobacteria, have been associated with beneficial effects on the host, such as promotion of gut maturation and integrity, antagonisms against pathogens and immune modulation. Beyond this, the microflora seems to play a significant role in the maintenance of intestinal immune homeostasis and prevention of inflammation. The contribution of the intestinal epithelial cell in the first line of defense against pathogenic bacteria and microbial antigens has been recognized. However, the interactions of intestinal epithelial cells with indigenous bacteria are less well understood. This review will summarize the increasing scientific attention to mechanisms of the innate immune response of the host towards different components of the microflora, and suggest a potential role for selected probiotic bacteria in the regulation of intestinal inflammation. PMID:14503689

  11. Regulation of intracellular Zn homeostasis in two intestinal epithelial cell models at various maturation time points.

    PubMed

    Gefeller, Eva-Maria; Bondzio, Angelika; Aschenbach, Jörg R; Martens, Holger; Einspanier, Ralf; Scharfen, Franziska; Zentek, Jürgen; Pieper, Robert; Lodemann, Ulrike

    2015-07-01

    After weaning, piglets are often fed diets supplemented with high concentrations of zinc (Zn) to decrease post-weaning diarrhea. The aim of this study was to elucidate the regulation of Zn homeostasis within intestinal epithelial cells during excessive Zn exposure. High Zn concentrations elevated the intracellular Zn level in IPEC-J2 and Caco-2 cells which was influenced by differentiation status and time of exposure. With increasing Zn concentrations, mRNA and protein levels of metallothionein (MT) and zinc transporter 1 (ZnT1) were upregulated, whereas zinc transporter 4 (ZIP4) expression was downregulated. Metal-regulatory transcription factor-1 (MTF1) mRNA expression was upregulated at high Zn concentrations in IPEC-J2 cells, which corresponded to higher intracellular Zn concentrations. Based on these results, we suggest that intestinal epithelial cells adapt the expression of these genes to the amount of extracellular Zn available in order to maintain Zn homeostasis. Cell line-dependent differences in the regulation of Zn homeostasis were detected. PMID:25757458

  12. Increased mitochondrial biogenesis preserves intestinal stem cell homeostasis and contributes to longevity in Indy mutant flies

    PubMed Central

    Rogers, Ryan P.; Rogina, Blanka

    2014-01-01

    The Drosophila Indy (I'm Not Dead Yet) gene encodes a plasma membrane transporter of Krebs cycle intermediates, with robust expression in tissues associated with metabolism. Reduced INDY alters metabolism and extends longevity in a manner similar to caloric restriction (CR); however, little is known about the tissue specific physiological effects of INDY reduction. Here we focused on the effects of INDY reduction in the Drosophila midgut due to the importance of intestinal tissue homeostasis in healthy aging and longevity. The expression of Indy mRNA in the midgut changes in response to aging and nutrition. Genetic reduction of Indy expression increases midgut expression of the mitochondrial regulator spargel/dPGC-1, which is accompanied by increased mitochondrial biogenesis and reduced reactive oxygen species (ROS). These physiological changes in the Indy mutant midgut preserve intestinal stem cell (ISC) homeostasis and are associated with healthy aging. Genetic studies confirm that dPGC-1 mediates the regulatory effects of INDY, as illustrated by lack of longevity extension and ISC homeostasis in flies with mutations in both Indy and dPGC1. Our data suggest INDY may be a physiological regulator that modulates intermediary metabolism in response to changes in nutrient availability and organismal needs by modulating dPGC-1 PMID:24827528

  13. CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice.

    PubMed

    Nguyen, Hang Thi Thu; Dalmasso, Guillaume; Torkvist, Leif; Halfvarson, Jonas; Yan, Yutao; Laroui, Hamed; Shmerling, Doron; Tallone, Tiziano; D'Amato, Mauro; Sitaraman, Shanthi V; Merlin, Didier

    2011-05-01

    Expression of the transmembrane glycoprotein CD98 (encoded by SLC3A2) is increased in intestinal inflammatory conditions, such as inflammatory bowel disease (IBD), and in various carcinomas, yet its pathogenetic role remains unknown. By generating gain- and loss-of-function mouse models with genetically manipulated CD98 expression specifically in intestinal epithelial cells (IECs), we explored the role of CD98 in intestinal homeostasis, inflammation, and colitis-associated tumorigenesis. IEC-specific CD98 overexpression induced gut homeostatic defects and increased inflammatory responses to DSS-induced colitis, promoting colitis-associated tumorigenesis in mice. Further analysis indicated that the ability of IEC-specific CD98 overexpression to induce tumorigenesis was linked to its capacity to induce barrier dysfunction and to stimulate cell proliferation and production of proinflammatory mediators. To validate these results, we constructed mice carrying conditional floxed Slc3a2 alleles and crossed them with Villin-Cre mice such that CD98 was downregulated only in IECs. These mice exhibited attenuated inflammatory responses and resistance to both DSS-induced colitis and colitis-associated tumorigenesis. Together, our data show that intestinal CD98 expression has a crucial role in controlling homeostatic and innate immune responses in the gut. Modulation of CD98 expression in IECs therefore represents a promising therapeutic strategy for the treatment and prevention of inflammatory intestinal diseases, such as IBD and colitis-associated cancer. PMID:21490400

  14. Interferon-γ regulates intestinal epithelial homeostasis through converging β-catenin signaling pathways

    PubMed Central

    Nava, Porfirio; Koch, Stefan; Laukoetter, Mike G; Lee, Winston Y; Kolegraff, Keli; Capaldo, Christopher T; Beeman, Neal; Addis, Caroline; Gerner-Smidt, Kirsten; Neumaier, Irmgard; Skerra, Arne; Li, Linheng; Parkos, Charles A; Nusrat, Asma

    2010-01-01

    SUMMARY Inflammatory cytokines have been proposed to regulate epithelial homeostasis during intestinal inflammation. We report here that interferon-γ (IFN-γ) regulates the crucial homeostatic functions of cell proliferation and apoptosis through serine-threonine protein kinase AKT-β-catenin and Wingless-Int (Wnt)-β-catenin signaling pathways. Short-term exposure of intestinal epithelial cells to IFN-γ resulted in activation of β-catenin through AKT, followed by induction of the secreted Wnt inhibitor Dkk1. Consequently, we observed an increase in Dkk1-mediated apoptosis upon extended IFN-γ treatment, and reduced proliferation through depletion of the Wnt co-receptor LRP6. These effects were enhanced by tumor necrosis factor-α (TNF)-α, suggesting synergism between the two cytokines. Consistent with these results, colitis in vivo was associated with decreased β-catenin-T-cell factor (TCF) signaling, loss of plasma membrane-associated LRP6, and reduced epithelial cell proliferation. Proliferation was partially restored in IFN-γ - deficient mice. Thus, we propose that IFN-γ regulates intestinal epithelial homeostasis by sequential regulation of converging β-catenin signaling pathways. PMID:20303298

  15. Carboxypeptidase E Modulates Intestinal Immune Homeostasis and Protects against Experimental Colitis in Mice

    PubMed Central

    Pagel, René; Schröder, Torsten; Schlichting, Heidi; Hirose, Misa; Lemcke, Susanne; Klinger, Antje; König, Peter; Karsten, Christian M.; Büning, Jürgen; Lehnert, Hendrik; Fellermann, Klaus; Ibrahim, Saleh M.; Sina, Christian

    2014-01-01

    Enteroendocrine cells (EEC) produce neuropeptides, which are crucially involved in the maintenance of the intestinal barrier. Hence, EEC dysfunction is suggested to be involved in the complex pathophysiology of inflammatory bowel disease (IBD), which is characterized by decreased intestinal barrier function. However, the underlying mechanisms for EEC dysfunction are not clear and suitable models for a better understanding are lacking. Here, we demonstrate that Carboxypeptidase E (CPE) is specifically expressed in EEC of the murine colon and ileum and that its deficiency is associated with reduced intestinal levels of Neuropeptide Y (NPY) and Peptide YY (PYY), which are both produced by EEC. Moreover, cpe−/− mice exhibit an aggravated course of DSS-induced chronic colitis compared to wildtype littermates. In addition, we observed elevated mucosal IL-6 and KC transcript levels already at baseline conditions in cpe−/− mice. Moreover, supernatants obtained from isolated intestinal crypts of cpe−/− mice lead to increased IL-6 and KC expression in MODE-K cells in the presence of LPS. This effect was reversible by co-administration of recombinant NPY, suggesting a CPE mediated immunosuppressive effect in the intestines by influencing the processing of specific neuropeptides. In this context, the chemotaxis of bone marrow derived macrophages towards respective supernatants was enhanced. In conclusion, our data point to an anti-inflammatory role of CPE in the intestine by influencing local cytokine levels and thus regulating the migration of myeloid immune cells into the mucosa. These findings highlight the importance of EEC for intestinal homeostasis and propose EEC as potential therapeutic targets in IBD. PMID:25051500

  16. Carboxypeptidase E modulates intestinal immune homeostasis and protects against experimental colitis in mice.

    PubMed

    Bär, Florian; Föh, Bandik; Pagel, René; Schröder, Torsten; Schlichting, Heidi; Hirose, Misa; Lemcke, Susanne; Klinger, Antje; König, Peter; Karsten, Christian M; Büning, Jürgen; Lehnert, Hendrik; Fellermann, Klaus; Ibrahim, Saleh M; Sina, Christian

    2014-01-01

    Enteroendocrine cells (EEC) produce neuropeptides, which are crucially involved in the maintenance of the intestinal barrier. Hence, EEC dysfunction is suggested to be involved in the complex pathophysiology of inflammatory bowel disease (IBD), which is characterized by decreased intestinal barrier function. However, the underlying mechanisms for EEC dysfunction are not clear and suitable models for a better understanding are lacking. Here, we demonstrate that Carboxypeptidase E (CPE) is specifically expressed in EEC of the murine colon and ileum and that its deficiency is associated with reduced intestinal levels of Neuropeptide Y (NPY) and Peptide YY (PYY), which are both produced by EEC. Moreover, cpe-/- mice exhibit an aggravated course of DSS-induced chronic colitis compared to wildtype littermates. In addition, we observed elevated mucosal IL-6 and KC transcript levels already at baseline conditions in cpe-/- mice. Moreover, supernatants obtained from isolated intestinal crypts of cpe-/- mice lead to increased IL-6 and KC expression in MODE-K cells in the presence of LPS. This effect was reversible by co-administration of recombinant NPY, suggesting a CPE mediated immunosuppressive effect in the intestines by influencing the processing of specific neuropeptides. In this context, the chemotaxis of bone marrow derived macrophages towards respective supernatants was enhanced. In conclusion, our data point to an anti-inflammatory role of CPE in the intestine by influencing local cytokine levels and thus regulating the migration of myeloid immune cells into the mucosa. These findings highlight the importance of EEC for intestinal homeostasis and propose EEC as potential therapeutic targets in IBD. PMID:25051500

  17. Epithelial adhesion molecules and the regulation of intestinal homeostasis during neutrophil transepithelial migration.

    PubMed

    Sumagin, Ronen; Parkos, Charles A

    2015-01-01

    Epithelial adhesion molecules play essential roles in regulating cellular function and maintaining mucosal tissue homeostasis. Some form epithelial junctional complexes to provide structural support for epithelial monolayers and act as a selectively permeable barrier separating luminal contents from the surrounding tissue. Others serve as docking structures for invading viruses and bacteria, while also regulating the immune response. They can either obstruct or serve as footholds for the immune cells recruited to mucosal surfaces. Currently, it is well appreciated that adhesion molecules collectively serve as environmental cue sensors and trigger signaling events to regulate epithelial function through their association with the cell cytoskeleton and various intracellular adapter proteins. Immune cells, particularly neutrophils (PMN) during transepithelial migration (TEM), can modulate adhesion molecule expression, conformation, and distribution, significantly impacting epithelial function and tissue homeostasis. This review discusses the roles of key intestinal epithelial adhesion molecules in regulating PMN trafficking and outlines the potential consequences on epithelial function. PMID:25838976

  18. Epithelial adhesion molecules and the regulation of intestinal homeostasis during neutrophil transepithelial migration

    PubMed Central

    Sumagin, Ronen; Parkos, Charles A

    2014-01-01

    Epithelial adhesion molecules play essential roles in regulating cellular function and maintaining mucosal tissue homeostasis. Some form epithelial junctional complexes to provide structural support for epithelial monolayers and act as a selectively permeable barrier separating luminal contents from the surrounding tissue. Others serve as docking structures for invading viruses and bacteria, while also regulating the immune response. They can either obstruct or serve as footholds for the immune cells recruited to mucosal surfaces. Currently, it is well appreciated that adhesion molecules collectively serve as environmental cue sensors and trigger signaling events to regulate epithelial function through their association with the cell cytoskeleton and various intracellular adapter proteins. Immune cells, particularly neutrophils (PMN) during transepithelial migration (TEM), can modulate adhesion molecule expression, conformation, and distribution, significantly impacting epithelial function and tissue homeostasis. This review discusses the roles of key intestinal epithelial adhesion molecules in regulating PMN trafficking and outlines the potential consequences on epithelial function. PMID:25838976

  19. A Deregulated Intestinal Cell Cycle Program Disrupts Tissue Homeostasis without Affecting Longevity in Drosophila*

    PubMed Central

    Petkau, Kristina; Parsons, Brendon D.; Duggal, Aashna; Foley, Edan

    2014-01-01

    Recent studies illuminate a complex relationship between the control of stem cell division and intestinal tissue organization in the model system Drosophila melanogaster. Host and microbial signals drive intestinal proliferation to maintain an effective epithelial barrier. Although it is widely assumed that proliferation induces dysplasia and shortens the life span of the host, the phenotypic consequences of deregulated intestinal proliferation for an otherwise healthy host remain unexplored. To address this question, we genetically isolated and manipulated the cell cycle programs of adult stem cells and enterocytes. Our studies revealed that cell cycle alterations led to extensive cell death and morphological disruptions. Despite the extensive tissue damage, we did not observe an impact on longevity, suggesting a remarkable degree of plasticity in intestinal function. PMID:25170078

  20. A deregulated intestinal cell cycle program disrupts tissue homeostasis without affecting longevity in Drosophila.

    PubMed

    Petkau, Kristina; Parsons, Brendon D; Duggal, Aashna; Foley, Edan

    2014-10-10

    Recent studies illuminate a complex relationship between the control of stem cell division and intestinal tissue organization in the model system Drosophila melanogaster. Host and microbial signals drive intestinal proliferation to maintain an effective epithelial barrier. Although it is widely assumed that proliferation induces dysplasia and shortens the life span of the host, the phenotypic consequences of deregulated intestinal proliferation for an otherwise healthy host remain unexplored. To address this question, we genetically isolated and manipulated the cell cycle programs of adult stem cells and enterocytes. Our studies revealed that cell cycle alterations led to extensive cell death and morphological disruptions. Despite the extensive tissue damage, we did not observe an impact on longevity, suggesting a remarkable degree of plasticity in intestinal function. PMID:25170078

  1. Macrobiota - helminths as active participants and partners of the microbiota in host intestinal homeostasis.

    PubMed

    Gause, William C; Maizels, Rick M

    2016-08-01

    Important insights have recently been gained in our understanding of the intricate relationship in the intestinal milieu between the vertebrate host mucosal immune response, commensal bacteria, and helminths. Helminths are metazoan worms (macrobiota) and trigger immune responses that include potent regulatory components capable of controlling harmful inflammation, protecting barrier function and mitigating tissue damage. They can secrete a variety of products that directly affect immune regulatory function but they also have the capacity to influence the composition of microbiota, which can also then impact immune function. Conversely, changes in microbiota can affect susceptibility to helminth infection, indicating that crosstalk between these two disparate groups of endobiota can play an essential role in host intestinal immune function and homeostasis. PMID:27116368

  2. Interleukin 10 Receptor Signaling: Master Regulator of Intestinal Mucosal Homeostasis in Mice and Humans

    PubMed Central

    Shouval, Dror S.; Ouahed, Jodie; Biswas, Amlan; Goettel, Jeremy A.; Horwitz, Bruce H.; Klein, Christoph; Muise, Aleixo M.; Snapper, Scott B.

    2016-01-01

    Interleukin 10 (IL10) is a key anti-inflammatory cytokine that can inhibit proinflammatory responses of both innate and adaptive immune cells. An association between IL10 and intestinal mucosal homeostasis became clear with the discovery that IL10 and IL10 receptor (IL10R)-deficient mice develop spontaneous intestinal inflammation. Similarly, patients with deleterious mutations in IL10, IL10RA, or IL10RB present with severe enterocolitis within the first months of life. Here, we review recent findings on how IL10- and IL10R-dependent signaling modulates innate and adaptive immune responses in the murine gastrointestinal tract, with implications of their role in the prevention of inflammatory bowel disease (IBD). In addition, we discuss the impact of IL10 and IL10R signaling defects in humans and their relationship to very early-onset IBD (VEO-IBD). PMID:24507158

  3. Macrobiota — helminths as active participants and partners of the microbiota in host intestinal homeostasis

    PubMed Central

    Gause, William C; Maizels, Rick M

    2016-01-01

    Important insights have recently been gained in our understanding of the intricate relationship in the intestinal milieu between the vertebrate host mucosal immune response, commensal bacteria, and helminths. Helminths are metazoan worms (macrobiota) and trigger immune responses that include potent regulatory components capable of controlling harmful inflammation, protecting barrier function and mitigating tissue damage. They can secrete a variety of products that directly affect immune regulatory function but they also have the capacity to influence the composition of microbiota, which can also then impact immune function. Conversely, changes in microbiota can affect susceptibility to helminth infection, indicating that crosstalk between these two disparate groups of endobiota can play an essential role in host intestinal immune function and homeostasis. PMID:27116368

  4. Dual oxidases participate in the regulation of intestinal microbiotic homeostasis in the kuruma shrimp Marsupenaeus japonicus.

    PubMed

    Yang, Hui-Ting; Yang, Ming-Chong; Sun, Jie-Jie; Shi, Xiu-Zhen; Zhao, Xiao-Fan; Wang, Jin-Xing

    2016-06-01

    The metazoan gut lumen harbors numerous microbial communities. Tolerance for high bacterial counts and maintenance of microbiota homeostasis remain insufficiently studied. In this study, we identified a novel dual oxidase (MjDUOX2) involved in reactive oxygen species (ROS) production in the kuruma shrimp Marsupenaeus japonicus. MjDUOX2 is a transmembrane protein with an N-signal peptide region (19 aa) and a peroxidase homology domain (PHD, 554 aa) in the extracellular region; seven transmembrane regions; and three EF (calcium-binding region) domains (110 aa), a FAD-binding domain (104 aa), and a NAD-binding domain (156 aa) in the intracellular region. The novel MjDUOX2 exhibits a relatively low similarity (26.84% identity) to a previously reported DUOX in the shrimp (designated as MjDUOX1). The mRNA of MjDUOXs was widely distributed in the hemocytes, heart, hepatopancreas, gills, stomach, and intestine. Oral infection of the shrimp with pathogenic bacteria upregulated the mRNA expression of MjDUOXs and increased the ROS level in the intestine. However, High ROS level could inhibit the expression of MjDUOXs in shrimp after Vibrio anguillarum infection. Knockdown of MjDUOXs by RNA interference (RNAi) decreased the ROS level, increased the bacterial count in the intestine, and decreased the survival rate of the MjDUOX-RNAi shrimp infected with V. anguillarum. These results suggest that MjDUOXs play an important role for microbiota homeostasis in intestine of shrimp. PMID:26845611

  5. Plasticity of the brush border - the yin and yang of intestinal homeostasis.

    PubMed

    Delacour, Delphine; Salomon, Julie; Robine, Sylvie; Louvard, Daniel

    2016-03-01

    The brush border on the apical surface of enterocytes is a highly specialized structure well-adapted for efficient digestion and nutrient transport, whilst at the same time providing a protective barrier for the intestinal mucosa. The brush border is constituted of a densely ordered array of microvilli, protrusions of the plasma membrane, which are supported by actin-based microfilaments and interacting proteins and anchored in an apical network of actomyosin and intermediate filaments, the so-called terminal web. The highly dynamic, specialized apical domain is both an essential partner for the gut microbiota and an efficient signalling platform that enables adaptation to physiological stimuli from the external and internal milieu. Nevertheless, genetic alterations or various pathological stresses, such as infection, inflammation, and mechanical or nutritional alterations, can jeopardize this equilibrium and compromise intestinal functions. Long-time neglected, the intestinal brush-border shall be enlightening again as the central actor of the complex but essential intestinal homeostasis. Here, we review the processes and components involved in brush border organization and discuss pathological mechanisms that can induce brush border defects and their physiological consequences. PMID:26837713

  6. Lin-28 promotes symmetric stem cell division and drives adaptive growth in the adult Drosophila intestine.

    PubMed

    Chen, Ching-Huan; Luhur, Arthur; Sokol, Nicholas

    2015-10-15

    Stem cells switch between asymmetric and symmetric division to expand in number as tissues grow during development and in response to environmental changes. The stem cell intrinsic proteins controlling this switch are largely unknown, but one candidate is the Lin-28 pluripotency factor. A conserved RNA-binding protein that is downregulated in most animals as they develop from embryos to adults, Lin-28 persists in populations of adult stem cells. Its function in these cells has not been previously characterized. Here, we report that Lin-28 is highly enriched in adult intestinal stem cells in the Drosophila intestine. lin-28 null mutants are homozygous viable but display defects in this population of cells, which fail to undergo a characteristic food-triggered expansion in number and have reduced rates of symmetric division as well as reduced insulin signaling. Immunoprecipitation of Lin-28-bound mRNAs identified Insulin-like Receptor (InR), forced expression of which completely rescues lin-28-associated defects in intestinal stem cell number and division pattern. Furthermore, this stem cell activity of lin-28 is independent of one well-known lin-28 target, the microRNA let-7, which has limited expression in the intestinal epithelium. These results identify Lin-28 as a stem cell intrinsic factor that boosts insulin signaling in intestinal progenitor cells and promotes their symmetric division in response to nutrients, defining a mechanism through which Lin-28 controls the adult stem cell division patterns that underlie tissue homeostasis and regeneration. PMID:26487778

  7. Claudin-1 Regulates Intestinal Epithelial Homeostasis through the Modulation of Notch Signaling

    PubMed Central

    Pope, Jillian L.; Bhat, Ajaz. A.; Sharma, Ashok; Ahmad, Rizwan; Krishnan, Moorthy; Washington, Mary K.; Beauchamp, Robert D.; Singh, Amar B.; Dhawan, Punita

    2014-01-01

    Objective Claudin-1 expression is increased and dysregulated in colorectal cancer and causally associates with the dedifferentiation of colonic epithelial cells, cancer progression and metastasis. Here, we have sought to determine the role claudin-1 plays in the regulation of intestinal epithelial homeostasis. Design We have used a novel Villin-claudin-1 transgenic (Cl-1Tg) mouse as model (with intestinal claudin-1 overexpression). Effect of claudin-1 expression upon colonic epithelial differentiation, lineage commitment, and Notch signaling were determined using immunohistochemical, immunoblot and real time PCR analysis. The frequently used mouse model of DSS-colitis was used to model inflammation, injury and repair. Results In Cl-1Tg mice, normal colonocyte differentiation program was disrupted and goblet cell number and muc-2 expressions were significantly downregulated while Notch- and ERK1/2-signaling were upregulated, compared to the wild type (WT)-littermates. Cl-1Tg mice were also susceptible to colonic inflammation and demonstrated impaired recovery and hyperproliferation following the DSS-colitis. Our data further show that claudin-1 regulates Notch-signaling through the regulation of MMP-9 and p-ERK signaling to regulate proliferation and differentiation. Conclusion Claudin-1 helps regulate intestinal epithelial homeostasis through the regulation of Notch-signaling. An upregulated claudin-1 expression induces MMP-9 and p-ERK signaling to activate Notch-signaling, which in turn inhibits the goblet cell differentiation. Decreased goblet cell number decreases muc-2 expression and thus enhances susceptibility to mucosal inflammation. Claudin-1 expression also induces colonic epithelial proliferation in a Notch-dependent manner. Our findings may help understand the role of claudin-1 in the regulation of IBD and CRC. PMID:23766441

  8. Messages from the Inside. The Dynamic Environment that Favors Intestinal Homeostasis.

    PubMed

    Eri, Rajaraman; Chieppa, Marcello

    2013-01-01

    An organism is defined as "an individual living thing capable of responding to stimuli, growing, reproducing, and maintaining homeostasis." Early during evolution multicellular organisms explored the advantages of a symbiotic life. Mammals harbor a complex aggregate of microorganisms (called microbiota) that includes bacteria, fungi, and archaea. Some of these bacteria have already defined beneficial roles for the human host that include the ability to break down nutrients that could not otherwise be digested, preventing the growth of harmful species, as well as the ability to produce vitamins or hormones. It is intuitive that along the evolutionary path several mechanisms favored bacteria that provided advantages to the host which, in return, avoided launching an aggressive immunological response against them. The intestinal immunological response does not ignore the lumenal content, on the contrary, immune surveillance is favored by continuous antigen sampling. Some intestinal epithelial cells (ECs) are crucial during the sampling process, others actively participate in the defense mechanism. In essence the epithelium acts as a traffic light, communicating to the inside world whether conditions are safe or dangerous, and thus influencing immunological response. In this review we will discuss the dynamic factors that act on the intestinal ECs and how they directly or indirectly influence immune cells during states of health and disease. PMID:24130559

  9. Messages from the Inside. The Dynamic Environment that Favors Intestinal Homeostasis

    PubMed Central

    Eri, Rajaraman; Chieppa, Marcello

    2013-01-01

    An organism is defined as “an individual living thing capable of responding to stimuli, growing, reproducing, and maintaining homeostasis.” Early during evolution multicellular organisms explored the advantages of a symbiotic life. Mammals harbor a complex aggregate of microorganisms (called microbiota) that includes bacteria, fungi, and archaea. Some of these bacteria have already defined beneficial roles for the human host that include the ability to break down nutrients that could not otherwise be digested, preventing the growth of harmful species, as well as the ability to produce vitamins or hormones. It is intuitive that along the evolutionary path several mechanisms favored bacteria that provided advantages to the host which, in return, avoided launching an aggressive immunological response against them. The intestinal immunological response does not ignore the lumenal content, on the contrary, immune surveillance is favored by continuous antigen sampling. Some intestinal epithelial cells (ECs) are crucial during the sampling process, others actively participate in the defense mechanism. In essence the epithelium acts as a traffic light, communicating to the inside world whether conditions are safe or dangerous, and thus influencing immunological response. In this review we will discuss the dynamic factors that act on the intestinal ECs and how they directly or indirectly influence immune cells during states of health and disease. PMID:24130559

  10. Alcohol exposure in utero perturbs retinoid homeostasis in adult rats

    PubMed Central

    Kim, Youn-Kyung; Zuccaro, Michael V.; Zhang, Changqing; Sarkar, Dipak

    2015-01-01

    Background Maternal alcohol exposure and adult alcohol intake have been shown to perturb the metabolism of various micro- and macro-nutrients, including vitamin A and its derivatives (retinoids). Therefore, it has been hypothesized that the well-known detrimental consequences of alcohol consumption may be due to deregulations of the metabolism of such nutrients rather than to a direct effect of alcohol. Alcohol exposure in utero also has long-term harmful consequences on the health of the offspring with mechanisms that have not been fully clarified. Disruption of tissue retinoid homeostasis has been linked not only to abnormal embryonic development, but also to various adult pathological conditions, including cancer, metabolic disorders and abnormal lung function. We hypothesized that prenatal alcohol exposure may permanently perturb tissue retinoid metabolism, predisposing the offspring to adult chronic diseases. Methods Serum and tissues (liver, lung and prostate from males; liver and lung from females) were collected from 60-75 day-old sprague dawley rats born from dams that were: (I) fed a liquid diet containing 6.7% alcohol between gestational day 7 and 21; or (II) pair-fed with isocaloric liquid diet during the same gestational window; or (III) fed ad libitum with regular rat chow diet throughout pregnancy. Serum and tissue retinoid levels were analyzed by reverse-phase high-performance liquid chromatography (HPLC). Serum retinol-binding protein (RBP) levels were measured by western blot analysis, and liver, lung and prostate mRNA levels of lecithin-retinol acyltransferase (LRAT) were measured by qPCR. Results Retinyl ester levels were significantly reduced in the lung of both males and females, as well as in the liver and ventral prostate of males born from alcohol-fed dams. Tissue LRAT mRNA levels remained unchanged upon maternal alcohol treatment. Conclusions Prenatal alcohol exposure in rats affects retinoid metabolism in adult life, in a tissue- and sex

  11. Characterization of a Novel Intestinal Glycerol-3-phosphate Acyltransferase Pathway and Its Role in Lipid Homeostasis.

    PubMed

    Khatun, Irani; Clark, Ronald W; Vera, Nicholas B; Kou, Kou; Erion, Derek M; Coskran, Timothy; Bobrowski, Walter F; Okerberg, Carlin; Goodwin, Bryan

    2016-02-01

    Dietary triglycerides (TG) are absorbed by the enterocytes of the small intestine after luminal hydrolysis into monacylglycerol and fatty acids. Before secretion on chylomicrons, these lipids are reesterified into TG, primarily through the monoacylglycerol pathway. However, targeted deletion of the primary murine monoacylglycerol acyltransferase does not quantitatively affect lipid absorption, suggesting the existence of alternative pathways. Therefore, we investigated the role of the glycerol 3-phosphate pathway in dietary lipid absorption. The expression of glycerol-3-phosphate acyltransferase (GPAT3) was examined throughout the small intestine. To evaluate the role for GPAT3 in lipid absorption, mice harboring a disrupted GPAT3 gene (Gpat3(-/-)) were subjected to an oral lipid challenge and fed a Western-type diet to characterize the role in lipid and cholesterol homeostasis. Additional mechanistic studies were performed in primary enterocytes. GPAT3 was abundantly expressed in the apical surface of enterocytes in the small intestine. After an oral lipid bolus, Gpat3(-/-) mice exhibited attenuated plasma TG excursion and accumulated lipid in the enterocytes. Electron microscopy studies revealed a lack of lipids in the lamina propria and intercellular space in Gpat3(-/-) mice. Gpat3(-/-) enterocytes displayed a compensatory increase in the synthesis of phospholipid and cholesteryl ester. When fed a Western-type diet, hepatic TG and cholesteryl ester accumulation was significantly higher in Gpat3(-/-) mice compared with the wild-type mice accompanied by elevated levels of alanine aminotransferase, a marker of liver injury. Dysregulation of bile acid metabolism was also evident in Gpat3-null mice. These studies identify GPAT3 as a novel enzyme involved in intestinal lipid metabolism. PMID:26644473

  12. Membrane Transporters and Folate Homeostasis; Intestinal Absorption, Transport into Systemic Compartments and Tissues

    PubMed Central

    Zhao, Rongbao; Matherly, Larry H.; Goldman, I. David

    2013-01-01

    Folates, the generic term for the family of B vitamins, are derived entirely from dietary sources, and are key one-carbon donors required for de novo nucleotide and methionine synthesis. These highly hydrophilic molecules utilize genetically distinct and functionally diverse transport systems to enter cells: the reduced folate carrier (RFC), the proton-coupled folate transporter (PCFT), and the folate receptors. Each plays a unique role in mediating folate transport across epithelia and into systemic tissues. With the recent discovery of the mechanism of intestinal folate absorption, and the clarification of the genetic basis for the autosomal recessive disorder, hereditary folate malabsorption, involving loss-of-function mutations in PCFT protein, it is now possible to piece together how these folate transporters contribute, both individually and collectively, to folate homeostasis in humans. This review focuses on the physiological roles of these major folate transporters with a brief consideration of their impact on the pharmacological activities of antifolates. PMID:19173758

  13. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells.

    PubMed

    Rimoldi, Monica; Chieppa, Marcello; Salucci, Valentina; Avogadri, Francesca; Sonzogni, Angelica; Sampietro, Gianluca M; Nespoli, Angelo; Viale, Giuseppe; Allavena, Paola; Rescigno, Maria

    2005-05-01

    The control of damaging inflammation by the mucosal immune system in response to commensal and harmful ingested bacteria is unknown. Here we show epithelial cells conditioned mucosal dendritic cells through the constitutive release of thymic stromal lymphopoietin and other mediators, resulting in the induction of 'noninflammatory' dendritic cells. Epithelial cell-conditioned dendritic cells released interleukins 10 and 6 but not interleukin 12, and they promoted the polarization of T cells toward a 'classical' noninflammatory T helper type 2 response, even after exposure to a T helper type 1-inducing pathogen. This control of immune responses seemed to be lost in patients with Crohn disease. Thus, the intimate interplay between intestinal epithelial cells and dendritic cells may help to maintain gut immune homeostasis. PMID:15821737

  14. Intestine.

    PubMed

    Smith, J M; Skeans, M A; Horslen, S P; Edwards, E B; Harper, A M; Snyder, J J; Israni, A K; Kasiske, B L

    2016-01-01

    Intestine and intestine-liver transplant plays an important role in the treatment of intestinal failure, despite decreased morbidity associated with parenteral nutrition. In 2014, 210 new patients were added to the intestine transplant waiting list. Among prevalent patients on the list at the end of 2014, 65% were waiting for an intestine transplant and 35% were waiting for an intestine-liver transplant. The pretransplant mortality rate decreased dramatically over time for all age groups. Pretransplant mortality was highest for adult candidates, at 22.1 per 100 waitlist years compared with less than 3 per 100 waitlist years for pediatric candidates, and notably higher for candidates for intestine-liver transplant than for candidates for intestine transplant without a liver. Numbers of intestine transplants without a liver increased from a low of 51 in 2013 to 67 in 2014. Intestine-liver transplants increased from a low of 44 in 2012 to 72 in 2014. Short-gut syndrome (congenital and other) was the main cause of disease leading to both intestine and intestine-liver transplant. Graft survival improved over the past decade. Patient survival was lowest for adult intestine-liver recipients and highest for pediatric intestine recipients. PMID:26755265

  15. Glucocorticoids and microbiota regulate ontogeny of intestinal fucosyltransferase 2 requisite for gut homeostasis

    PubMed Central

    Nanthakumar, N Nanda; Meng, Di; Newburg, David S

    2013-01-01

    At weaning, the intestinal mucosa surface glycans change from predominantly sialylated to fucosylated. Intestinal adaptation from milk to solid food is regulated by intrinsic and extrinsic factors. The contribution by glucocorticoid, an intrinsic factor, and colonization by microbiota, an extrinsic factor, was measured as the induction of α1,2/3-fucosyltransferase and sucrase-isomaltase (SI) activity and gene expression in conventionally raised, germ-free, and bacteria-depleted mice. In conventionally raised mice, cortisone acetate (CA) precociously accelerated SI gene expression up to 3 weeks and fut2 to 4 weeks of age. In germ-free mice, CA treatment induces only SI expression but not fucosyltransferase. In post-weaning bacteria-deficient (germ-free and bacteria-depleted) mice, fut2 expression remains at low suckling levels. In microbiota deficient mice, intestinal fut2 (but not fut1, fut4 or fut7) was induced only by adult microbiota, but not immature microbiota or CA. Fut2 induction could also be restored by colonization by Bacteroides fragilis, but not by a B. fragilis mutant unable to utilize fucose. Restoration of fut2 expression (by either microbiota or B. fragilis) in bacteria-depleted mice is necessary for recovery from dextran sulfate sodium-induced mucosal injury. Thus, glucocorticoids and microbes regulate distinct aspects of gut ontogeny: CA precociously accelerates SI expression and, only in colonized mice, fut2 early expression. The adult microbiota is required for the fut2 induction responsible for the highly fucosylated adult gut phenotype and is necessary for recovery from intestinal injury. Fut2-dependent recovery from inflammation may explain the high incidence of inflammatory disease (Crohn's and necrotizing enterocolitis) in populations with mutant FUT2 polymorphic alleles. PMID:23887940

  16. The dual oxidase gene BdDuox regulates the intestinal bacterial community homeostasis of Bactrocera dorsalis.

    PubMed

    Yao, Zhichao; Wang, Ailin; Li, Yushan; Cai, Zhaohui; Lemaitre, Bruno; Zhang, Hongyu

    2016-05-01

    The guts of metazoans are in permanent contact with the microbial realm that includes beneficial symbionts, nonsymbionts, food-borne microbes and life-threatening pathogens. However, little is known concerning how host immunity affects gut bacterial community. Here, we analyze the role of a dual oxidase gene (BdDuox) in regulating the intestinal bacterial community homeostasis of the oriental fruit fly Bactrocera dorsalis. The results showed that knockdown of BdDuox led to an increased bacterial load, and to a decrease in the relative abundance of Enterobacteriaceae and Leuconostocaceae bacterial symbionts in the gut. The resulting dysbiosis, in turn, stimulates an immune response by activating BdDuox and promoting reactive oxygen species (ROS) production that regulates the composition and structure of the gut bacterial community to normal status by repressing the overgrowth of minor pathobionts. Our results suggest that BdDuox plays a pivotal role in regulating the homeostasis of the gut bacterial community in B. dorsalis. PMID:26565723

  17. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells.

    PubMed

    Lee, Jongdae; Mo, Ji-Hun; Katakura, Kyoko; Alkalay, Irit; Rucker, Adam N; Liu, Yu-Tsueng; Lee, Hyun-Ku; Shen, Carol; Cojocaru, Gady; Shenouda, Steve; Kagnoff, Martin; Eckmann, Lars; Ben-Neriah, Yinon; Raz, Eyal

    2006-12-01

    The mechanisms by which commensal bacteria suppress inflammatory signalling in the gut are still unclear. Here, we present a cellular mechanism whereby the polarity of intestinal epithelial cells (IECs) has a major role in colonic homeostasis. TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-kappaB activation and cDNA microarray analysis. Whereas basolateral TLR9 signals IkappaBalpha degradation and activation of the NF-kappaB pathway, apical TLR9 stimulation invokes a unique response in which ubiquitinated IkappaB accumulates in the cytoplasm preventing NF-kappaB activation. Furthermore, apical TLR9 stimulation confers intracellular tolerance to subsequent TLR challenges. IECs in TLR9-deficient mice, when compared with wild-type and TLR2-deficient mice, display a lower NF-kappaB activation threshold and these mice are highly susceptible to experimental colitis. Our data provide a case for organ-specific innate immunity in which TLR expression in polarized IECs has uniquely evolved to maintain colonic homeostasis and regulate tolerance and inflammation. PMID:17128265

  18. Role of mannose-binding lectin in intestinal homeostasis and fungal elimination.

    PubMed

    Choteau, L; Parny, M; François, N; Bertin, B; Fumery, M; Dubuquoy, L; Takahashi, K; Colombel, J-F; Jouault, T; Poulain, D; Sendid, B; Jawhara, S

    2016-05-01

    Mannose-binding lectin (MBL) is a soluble lectin of the innate immune system that is produced by the liver and secreted into the circulation where it activates the lectin complement pathway, enhances phagocytosis of microorganisms by leukocytes, and modulates inflammation. MBL can recognize patterns on the surface of different pathogens, including Candida albicans. Our aims were to investigate whether MBL is expressed in the gut epithelium and to examine its effect on the modulation of intestinal inflammation and C. albicans elimination. Using reverse transcriptase-PCR, MBL transcripts were highly expressed in different parts of the mouse gut. MBL expression was also detected by immunoblotting and immunolocalization in response to C. albicans colonization of the gut; the highest expression of MBL was detected in the stomach. Blocking MBL by administering mannans to mice increased C. albicans colonization. MBL-deficient mice had a higher level of colonization than wild-type mice. Dextran sodium sulfate-induced colitis promoted C. albicans dissemination to the kidneys and lungs of MBL-deficient mice. MBL-deficient mice exhibited elevated expression of interleukin (IL)-17, IL-23, dectin-1, and Toll-like receptor-4. This study shows that MBL expression is induced in the gut in response to C. albicans sensing and is required for intestinal homeostasis and host defense against C. albicans. PMID:26442658

  19. Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia.

    PubMed

    Bindels, Laure B; Neyrinck, Audrey M; Claus, Sandrine P; Le Roy, Caroline I; Grangette, Corinne; Pot, Bruno; Martinez, Inés; Walter, Jens; Cani, Patrice D; Delzenne, Nathalie M

    2016-06-01

    Cancer cachexia is a multifactorial syndrome that includes muscle wasting and inflammation. As gut microbes influence host immunity and metabolism, we investigated the role of the gut microbiota in the therapeutic management of cancer and associated cachexia. A community-wide analysis of the caecal microbiome in two mouse models of cancer cachexia (acute leukaemia or subcutaneous transplantation of colon cancer cells) identified common microbial signatures, including decreased Lactobacillus spp. and increased Enterobacteriaceae and Parabacteroides goldsteinii/ASF 519. Building on this information, we administered a synbiotic containing inulin-type fructans and live Lactobacillus reuteri 100-23 to leukaemic mice. This treatment restored the Lactobacillus population and reduced the Enterobacteriaceae levels. It also reduced hepatic cancer cell proliferation, muscle wasting and morbidity, and prolonged survival. Administration of the synbiotic was associated with restoration of the expression of antimicrobial proteins controlling intestinal barrier function and gut immunity markers, but did not impact the portal metabolomics imprinting of energy demand. In summary, this study provided evidence that the development of cancer outside the gut can impact intestinal homeostasis and the gut microbial ecosystem and that a synbiotic intervention, by targeting some alterations of the gut microbiota, confers benefits to the host, prolonging survival and reducing cancer proliferation and cachexia. PMID:26613342

  20. Crucial roles of XCR1-expressing dendritic cells and the XCR1-XCL1 chemokine axis in intestinal immune homeostasis

    PubMed Central

    Ohta, Tomokazu; Sugiyama, Masanaka; Hemmi, Hiroaki; Yamazaki, Chihiro; Okura, Soichiro; Sasaki, Izumi; Fukuda, Yuri; Orimo, Takashi; Ishii, Ken J.; Hoshino, Katsuaki; Ginhoux, Florent; Kaisho, Tsuneyasu

    2016-01-01

    Intestinal immune homeostasis requires dynamic crosstalk between innate and adaptive immune cells. Dendritic cells (DCs) exist as multiple phenotypically and functionally distinct sub-populations within tissues, where they initiate immune responses and promote homeostasis. In the gut, there exists a minor DC subset defined as CD103+CD11b− that also expresses the chemokine receptor XCR1. In other tissues, XCR1+ DCs cross-present antigen and contribute to immunity against viruses and cancer, however the roles of XCR1+ DCs and XCR1 in the intestine are unknown. We showed that mice lacking XCR1+ DCs are specifically deficient in intraepithelial and lamina propria (LP) T cell populations, with remaining T cells exhibiting an atypical phenotype and being prone to death, and are also more susceptible to chemically-induced colitis. Mice deficient in either XCR1 or its ligand, XCL1, similarly possess diminished intestinal T cell populations, and an accumulation of XCR1+ DCs in the gut. Combined with transcriptome and surface marker expression analysis, these observations lead us to hypothesise that T cell-derived XCL1 facilitates intestinal XCR1+ DC activation and migration, and that XCR1+ DCs in turn provide support for T cell survival and function. Thus XCR1+ DCs and the XCR1/XCL1 chemokine axis have previously-unappreciated roles in intestinal immune homeostasis. PMID:27005831

  1. The presentation of malrotation of the intestine in adults.

    PubMed Central

    Gilbert, H. W.; Armstrong, C. P.; Thompson, M. H.

    1990-01-01

    Three cases of intestinal malrotation presenting in adults are reported. Each illustrates various aspects of symptomatology, investigation and treatment which are discussed. Images Figure 1 Figure 2 PMID:2382946

  2. Probiotic-derived polyphosphate enhances the epithelial barrier function and maintains intestinal homeostasis through integrin-p38 MAPK pathway.

    PubMed

    Segawa, Shuichi; Fujiya, Mikihiro; Konishi, Hiroaki; Ueno, Nobuhiro; Kobayashi, Naoyuki; Shigyo, Tatsuro; Kohgo, Yutaka

    2011-01-01

    Probiotics exhibit beneficial effects on human health, particularly in the maintenance of intestinal homeostasis in a complex manner notwithstanding the diversity of an intestinal flora between individuals. Thus, it is highly probable that some common molecules secreted by probiotic and/or commensal bacteria contribute to the maintenance of intestinal homeostasis and protect the intestinal epithelium from injurious stimuli. To address this question, we aimed to isolate the cytoprotective compound from a lactobacillus strain, Lactobacillus brevis SBC8803 which possess the ability to induce cytoprotective heat shock proteins in mouse small intestine. L. brevis was incubated in MRS broth and the supernatant was passed through with a 0.2-µm filter. Caco2/bbe cells were treated with the culture supernatant, and HSP27 expression was evaluated by Western blotting. HSP27-inducible components were separated by ammonium sulfate precipitation, DEAE anion exchange chromatography, gel filtration, and HPLC. Finally, we identified that the HSP27-inducible fraction was polyphosphate (poly P), a simple repeated structure of phosphates, which is a common product of lactobacilli and other bacteria associated with intestinal microflora without any definitive physiological functions. Then, poly P was synthesized by poly P-synthesizing enzyme polyphosphate kinase. The synthesized poly P significantly induced HSP27 from Caco2/BBE cells. In addition, Poly P suppressed the oxidant-induced intestinal permeability in the mouse small intestine and pharmacological inhibitors of p38 MAPK and integrins counteract its protective effect. Daily intrarectal administration of poly P (10 µg) improved the inflammation grade and survival rate in 4% sodium dextran sulfate-administered mice. This study, for the first time, demonstrated that poly P is the molecule responsible for maintaining intestinal barrier actions which are mediated through the intestinal integrin β1-p38 MAPK. PMID:21858054

  3. IL-27 Regulates Homeostasis of the Intestinal CD4+ Effector T Cell Pool and Limits Intestinal Inflammation in a Murine Model of Colitis1

    PubMed Central

    Troy, Amy E.; Zaph, Colby; Du, Yurong; Taylor, Betsy C.; Guild, Katherine J.; Hunter, Christopher A.; Saris, Christiaan J. M.; Artis, David

    2010-01-01

    IL-27 limits CD4+ TH17 cell development in vitro and during inflammatory responses in the CNS. However, whether IL-27-IL-27R interactions regulate the homeostasis or function of CD4+ T cell populations in the intestine is unknown. To test this, we examined CD4+ T cell populations in the intestine of wild-type and IL-27R−/− mice. Naive IL-27R−/− mice exhibited a selective decrease in the frequency of IFN-γ producing CD4+ TH1 cells and an increase in the frequency of TH17 cells in gut-associated lymphoid tissues. Associated with elevated expression of IL-17A, IL-27R−/− mice exhibited earlier onset and significantly increased severity of clinical disease compared with wild-type controls in a murine model of intestinal inflammation. Rag−/−/IL-27R−/− mice were also more susceptible than Rag−/− mice to development of dextran sodium sulfate-induced intestinal inflammation, indicating an additional role for IL-27-IL-27R in the regulation of innate immune cell function. Consistent with this, IL-27 inhibited proinflammatory cytokine production by activated neutrophils. Collectively, these data identify a role for IL-27-IL-27R interaction in controlling the homeostasis of the intestinal T cell pool and in limiting intestinal inflammation through regulation of innate and adaptive immune cell function. PMID:19596985

  4. Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of Nippostrongylus brasiliensis through induction of TH2 cytokines.

    PubMed

    McLean, Leon P; Smith, Allen; Cheung, Lumei; Urban, Joseph F; Sun, Rex; Grinchuk, Viktoriya; Desai, Neemesh; Zhao, Aiping; Raufman, Jean-Pierre; Shea-Donohue, Terez

    2016-07-01

    Despite increased appreciation for the role of nicotinic receptors in the modulation of and response to inflammation, the contribution of muscarinic receptors to mucosal homeostasis, clearance of enteric pathogens, and modulation of immune cell function remains relatively undefined. Uninfected and Nippostrongylus brasiliensis-infected wild-type and type 3 muscarinic receptor (M3R)-deficient (Chrm3(-/-)) mice were studied to determine the contribution of M3R to mucosal homeostasis as well as host defense against the TH2-eliciting enteric nematode N. brasiliensis Intestinal permeability and expression of TH1/TH17 cytokines were increased in uninfected Chrm3(-/-) small intestine. Notably, in Chrm3(-/-) mice infected with N. brasiliensis, small intestinal upregulation of TH2 cytokines was attenuated and nematode clearance was delayed. In Chrm3(-/-) mice, TH2-dependent changes in small intestinal function including smooth muscle hypercontractility, increased epithelial permeability, decreased epithelial secretion and absorption, and goblet cell expansion were absent despite N. brasiliensis infection. These findings identify an important role for M3R in host defense and clearance of N. brasiliensis, and support the expanding role of cholinergic muscarinic receptors in maintaining mucosal homeostasis. PMID:27173511

  5. The Myb-p300-CREB axis modulates intestine homeostasis, radiosensitivity and tumorigenesis

    PubMed Central

    Sampurno, S; Bijenhof, A; Cheasley, D; Xu, H; Robine, S; Hilton, D; Alexander, W S; Pereira, L; Mantamadiotis, T; Malaterre, J; Ramsay, R G

    2013-01-01

    The gastrointestinal (GI) epithelium is constantly renewing, depending upon the intestinal stem cells (ISC) regulated by a spectrum of transcription factors (TFs), including Myb. We noted previously in mice with a p300 mutation (plt6) within the Myb-interaction-domain phenocopied Myb hypomorphic mutant mice with regard to thrombopoiesis, and here, changes in GI homeostasis. p300 is a transcriptional coactivator for many TFs, most prominently cyclic-AMP response element-binding protein (CREB), and also Myb. Studies have highlighted the importance of CREB in proliferation and radiosensitivity, but not in the GI. This prompted us to directly investigate the p300–Myb–CREB axis in the GI. Here, the role of CREB has been defined by generating GI-specific inducible creb knockout (KO) mice. KO mice show efficient and specific deletion of CREB, with no evident compensation by CREM and ATF1. Despite complete KO, only modest effects on proliferation, radiosensitivity and differentiation in the GI under homeostatic or stress conditions were evident, even though CREB target gene pcna (proliferating cell nuclear antigen) was downregulated. creb and p300 mutant lines show increased goblet cells, whereas a reduction in enteroendocrine cells was apparent only in the p300 line, further resembling the Myb hypomorphs. When propagated in vitro, crebKO ISC were defective in organoid formation, suggesting that the GI stroma compensates for CREB loss in vivo, unlike in MybKO studies. Thus, it appears that p300 regulates GI differentiation primarily through Myb, rather than CREB. Finally, active pCREB is elevated in colorectal cancer (CRC) cells and adenomas, and is required for the expression of drug transporter, MRP2, associated with resistance to Oxaliplatin as well as several chromatin cohesion protein that are relevant to CRC therapy. These data raise the prospect that CREB may have a role in GI malignancy as it does in other cancer types, but unlike Myb, is not critical for GI

  6. Investigating the Relation between Stochastic Differentiation, Homeostasis and Clonal Expansion in Intestinal Crypts via Multiscale Modeling

    PubMed Central

    De Matteis, Giovanni; Antoniotti, Marco

    2014-01-01

    Colorectal tumors originate and develop within intestinal crypts. Even though some of the essential phenomena that characterize crypt structure and dynamics have been effectively described in the past, the relation between the differentiation process and the overall crypt homeostasis is still only partially understood. We here investigate this relation and other important biological phenomena by introducing a novel multiscale model that combines a morphological description of the crypt with a gene regulation model: the emergent dynamical behavior of the underlying gene regulatory network drives cell growth and differentiation processes, linking the two distinct spatio-temporal levels. The model relies on a few a priori assumptions, yet accounting for several key processes related to crypt functioning, such as: dynamic gene activation patterns, stochastic differentiation, signaling pathways ruling cell adhesion properties, cell displacement, cell growth, mitosis, apoptosis and the presence of biological noise. We show that this modeling approach captures the major dynamical phenomena that characterize the regular physiology of crypts, such as cell sorting, coordinate migration, dynamic turnover, stem cell niche correct positioning and clonal expansion. All in all, the model suggests that the process of stochastic differentiation might be sufficient to drive the crypt to homeostasis, under certain crypt configurations. Besides, our approach allows to make precise quantitative inferences that, when possible, were matched to the current biological knowledge and it permits to investigate the role of gene-level perturbations, with reference to cancer development. We also remark the theoretical framework is general and may be applied to different tissues, organs or organisms. PMID:24869488

  7. Secreted Phospholipases A2 Are Intestinal Stem Cell Niche Factors with Distinct Roles in Homeostasis, Inflammation, and Cancer.

    PubMed

    Schewe, Matthias; Franken, Patrick F; Sacchetti, Andrea; Schmitt, Mark; Joosten, Rosalie; Böttcher, René; van Royen, Martin E; Jeammet, Louise; Payré, Christine; Scott, Patricia M; Webb, Nancy R; Gelb, Michael; Cormier, Robert T; Lambeau, Gérard; Fodde, Riccardo

    2016-07-01

    The intestinal stem cell niche provides cues that actively maintain gut homeostasis. Dysregulation of these cues may compromise intestinal regeneration upon tissue insult and/or promote tumor growth. Here, we identify secreted phospholipases A2 (sPLA2s) as stem cell niche factors with context-dependent functions in the digestive tract. We show that group IIA sPLA2, a known genetic modifier of mouse intestinal tumorigenesis, is expressed by Paneth cells in the small intestine, while group X sPLA2 is expressed by Paneth/goblet-like cells in the colon. During homeostasis, group IIA/X sPLA2s inhibit Wnt signaling through intracellular activation of Yap1. However, upon inflammation they are secreted into the intestinal lumen, where they promote prostaglandin synthesis and Wnt signaling. Genetic ablation of both sPLA2s improves recovery from inflammation but increases colon cancer susceptibility due to release of their homeostatic Wnt-inhibitory role. This "trade-off" effect suggests sPLA2s have important functions as genetic modifiers of inflammation and colon cancer. PMID:27292189

  8. Intestinal microbiota in health and disease: Role of bifidobacteria in gut homeostasis

    PubMed Central

    Tojo, Rafael; Suárez, Adolfo; Clemente, Marta G; de los Reyes-Gavilán, Clara G; Margolles, Abelardo; Gueimonde, Miguel; Ruas-Madiedo, Patricia

    2014-01-01

    The pool of microbes inhabiting our body is known as “microbiota” and their collective genomes as “microbiome”. The colon is the most densely populated organ in the human body, although other parts, such as the skin, vaginal mucosa, or respiratory tract, also harbour specific microbiota. This microbial community regulates some important metabolic and physiological functions of the host, and drives the maturation of the immune system in early life, contributing to its homeostasis during life. Alterations of the intestinal microbiota can occur by changes in composition (dysbiosis), function, or microbiota-host interactions and they can be directly correlated with several diseases. The only disease in which a clear causal role of a dysbiotic microbiota has been demonstrated is the case of Clostridium difficile infections. Nonetheless, alterations in composition and function of the microbiota have been associated with several gastrointestinal diseases (inflammatory bowel disease, colorectal cancer, or irritable bowel syndrome), as well as extra-intestinal pathologies, such as those affecting the liver, or the respiratory tract (e.g., allergy, bronchial asthma, and cystic fibrosis), among others. Species of Bifidobacterium genus are the normal inhabitants of a healthy human gut and alterations in number and composition of their populations is one of the most frequent features present in these diseases. The use of probiotics, including bifidobacteria strains, in preventive medicine to maintain a healthy intestinal function is well documented. Probiotics are also proposed as therapeutic agents for gastrointestinal disorders and other pathologies. The World Gastroenterology Organization recently published potential clinical applications for several probiotic formulations, in which species of lactobacilli are predominant. This review is focused on probiotic preparations containing Bifidobacterium strains, alone or in combination with other bacteria, which have been

  9. Intestinal microbiota in health and disease: role of bifidobacteria in gut homeostasis.

    PubMed

    Tojo, Rafael; Suárez, Adolfo; Clemente, Marta G; de los Reyes-Gavilán, Clara G; Margolles, Abelardo; Gueimonde, Miguel; Ruas-Madiedo, Patricia

    2014-11-01

    The pool of microbes inhabiting our body is known as "microbiota" and their collective genomes as "microbiome". The colon is the most densely populated organ in the human body, although other parts, such as the skin, vaginal mucosa, or respiratory tract, also harbour specific microbiota. This microbial community regulates some important metabolic and physiological functions of the host, and drives the maturation of the immune system in early life, contributing to its homeostasis during life. Alterations of the intestinal microbiota can occur by changes in composition (dysbiosis), function, or microbiota-host interactions and they can be directly correlated with several diseases. The only disease in which a clear causal role of a dysbiotic microbiota has been demonstrated is the case of Clostridium difficile infections. Nonetheless, alterations in composition and function of the microbiota have been associated with several gastrointestinal diseases (inflammatory bowel disease, colorectal cancer, or irritable bowel syndrome), as well as extra-intestinal pathologies, such as those affecting the liver, or the respiratory tract (e.g., allergy, bronchial asthma, and cystic fibrosis), among others. Species of Bifidobacterium genus are the normal inhabitants of a healthy human gut and alterations in number and composition of their populations is one of the most frequent features present in these diseases. The use of probiotics, including bifidobacteria strains, in preventive medicine to maintain a healthy intestinal function is well documented. Probiotics are also proposed as therapeutic agents for gastrointestinal disorders and other pathologies. The World Gastroenterology Organization recently published potential clinical applications for several probiotic formulations, in which species of lactobacilli are predominant. This review is focused on probiotic preparations containing Bifidobacterium strains, alone or in combination with other bacteria, which have been tested

  10. Stem cell and progenitor fate in the mammalian intestine: Notch and lateral inhibition in homeostasis and disease

    PubMed Central

    Sancho, Rocio; Cremona, Catherine A; Behrens, Axel

    2015-01-01

    The control of cell fate decisions is vital to build functional organs and maintain normal tissue homeostasis, and many pathways and processes cooperate to direct cells to an appropriate final identity. Because of its continuously renewing state and its carefully organised hierarchy, the mammalian intestine has become a powerful model to dissect these pathways in health and disease. One of the signalling pathways that is key to maintaining the balance between proliferation and differentiation in the intestinal epithelium is the Notch pathway, most famous for specifying distinct cell fates in adjacent cells via the evolutionarily conserved process of lateral inhibition. Here, we will review recent discoveries that advance our understanding of how cell fate in the mammalian intestine is decided by Notch and lateral inhibition, focusing on the molecular determinants that regulate protein turnover, transcriptional control and epigenetic regulation. PMID:25855643

  11. New Insights In Intestinal Sar1B GTPase Regulation and Role in Cholesterol Homeostasis.

    PubMed

    Sané, Alain; Seidman, Ernest; Spahis, Schohraya; Lamantia, Valérie; Garofalo, Carole; Montoudis, Alain; Marcil, Valérie; Levy, Emile

    2015-10-01

    Sar1B GTPase is a key component of Coat protein complex II (COPII)-coated vesicles that bud from the endoplasmic reticulum to export newly synthesized proteins. The aims of this study were to determine whether Sar1B responds to lipid regulation and to evaluate its role in cholesterol (CHOL) homeostasis. The influence of lipids on Sar1B protein expression was analyzed in Caco-2/15 cells by Western blot. Our results showed that the presence of CHOL (200 μM) and oleic acid (0.5 mM), bound to albumin, increases Sar1B protein expression. Similarly, supplementation of the medium with micelles composed of taurocholate with monooleylglycerol or oleic acid also stimulated Sar1B expression, but the addition of CHOL (200 μM) to micelle content did not modify its regulation. On the other hand, overexpression of Sar1B impacted on CHOL transport and metabolism in view of the reduced cellular CHOL content along with elevated secretion when incubated with oleic acid-containing micelles for 24 h, thereby disclosing induced CHOL transport. This was accompanied with higher secretion of free- and esterified-CHOL within chylomicrons, which was not the case when oleic acid was replaced with monooleylglycerol or when albumin-bound CHOL was given alone. The aforementioned cellular CHOL depletion was accompanied with a low phosphorylated/non phosphorylated HMG-CoA reductase ratio, indicating elevated enzymatic activity. Combination of Sar1B overexpression with micelle incubation led to reduction in intestinal CHOL transporters (NPC1L1, SR-BI) and metabolic regulators (PCSK9 and LDLR). The present work showed that Sar1B is regulated in a time- and concentration-dependent manner by dietary lipids, suggesting an adaptation to alimentary lipid flux. Our data also suggest that Sar1B overexpression contributes to regulation of CHOL transport and metabolism by facilitating rapid uptake and transport of CHOL. PMID:25826777

  12. Regulation of Stem Cell Proliferation and Cell Fate Specification by Wingless/Wnt Signaling Gradients Enriched at Adult Intestinal Compartment Boundaries.

    PubMed

    Tian, Ai; Benchabane, Hassina; Wang, Zhenghan; Ahmed, Yashi

    2016-02-01

    Intestinal stem cell (ISC) self-renewal and proliferation are directed by Wnt/β-catenin signaling in mammals, whereas aberrant Wnt pathway activation in ISCs triggers the development of human colorectal carcinoma. Herein, we have utilized the Drosophila midgut, a powerful model for ISC regulation, to elucidate the mechanisms by which Wingless (Wg)/Wnt regulates intestinal homeostasis and development. We provide evidence that the Wg signaling pathway, activation of which peaks at each of the major compartment boundaries of the adult intestine, has essential functions. Wg pathway activation in the intestinal epithelium is required not only to specify cell fate near compartment boundaries during development, but also to control ISC proliferation within compartments during homeostasis. Further, in contrast with the previous focus on Wg pathway activation within ISCs, we demonstrate that the primary mechanism by which Wg signaling regulates ISC proliferation during homeostasis is non-autonomous. Activation of the Wg pathway in absorptive enterocytes is required to suppress JAK-STAT signaling in neighboring ISCs, and thereby their proliferation. We conclude that Wg signaling gradients have essential roles during homeostasis and development of the adult intestine, non-autonomously controlling stem cell proliferation inside compartments, and autonomously specifying cell fate near compartment boundaries. PMID:26845150

  13. Regulation of Stem Cell Proliferation and Cell Fate Specification by Wingless/Wnt Signaling Gradients Enriched at Adult Intestinal Compartment Boundaries

    PubMed Central

    Tian, Ai; Benchabane, Hassina; Wang, Zhenghan; Ahmed, Yashi

    2016-01-01

    Intestinal stem cell (ISC) self-renewal and proliferation are directed by Wnt/β-catenin signaling in mammals, whereas aberrant Wnt pathway activation in ISCs triggers the development of human colorectal carcinoma. Herein, we have utilized the Drosophila midgut, a powerful model for ISC regulation, to elucidate the mechanisms by which Wingless (Wg)/Wnt regulates intestinal homeostasis and development. We provide evidence that the Wg signaling pathway, activation of which peaks at each of the major compartment boundaries of the adult intestine, has essential functions. Wg pathway activation in the intestinal epithelium is required not only to specify cell fate near compartment boundaries during development, but also to control ISC proliferation within compartments during homeostasis. Further, in contrast with the previous focus on Wg pathway activation within ISCs, we demonstrate that the primary mechanism by which Wg signaling regulates ISC proliferation during homeostasis is non-autonomous. Activation of the Wg pathway in absorptive enterocytes is required to suppress JAK-STAT signaling in neighboring ISCs, and thereby their proliferation. We conclude that Wg signaling gradients have essential roles during homeostasis and development of the adult intestine, non-autonomously controlling stem cell proliferation inside compartments, and autonomously specifying cell fate near compartment boundaries. PMID:26845150

  14. Coordination of insulin and Notch pathway activities by microRNA miR-305 mediates adaptive homeostasis in the intestinal stem cells of the Drosophila gut

    PubMed Central

    Foronda, David; Weng, Ruifen; Verma, Pushpa; Chen, Ya-Wen

    2014-01-01

    Homeostasis of the intestine is maintained by dynamic regulation of a pool of intestinal stem cells. The balance between stem cell self-renewal and differentiation is regulated by the Notch and insulin signaling pathways. Dependence on the insulin pathway places the stem cell pool under nutritional control, allowing gut homeostasis to adapt to environmental conditions. Here we present evidence that miR-305 is required for adaptive homeostasis of the gut. miR-305 regulates the Notch and insulin pathways in the intestinal stem cells. Notably, miR-305 expression in the stem cells is itself under nutritional control via the insulin pathway. This link places regulation of Notch pathway activity under nutritional control. These findings provide a mechanism through which the insulin pathway controls the balance between stem cell self-renewal and differentiation that is required for adaptive homeostasis in the gut in response to changing environmental conditions. PMID:25367037

  15. Regulation of plasma lipid homeostasis by hepatic lipoprotein lipase in adult mice.

    PubMed

    Liu, Gan; Xu, Jun-Nan; Liu, Dong; Ding, Qingli; Liu, Meng-Na; Chen, Rong; Fan, Mengdi; Zhang, Ye; Zheng, Chao; Zou, Da-Jin; Lyu, Jianxin; Zhang, Weiping J

    2016-07-01

    LPL is a pivotal rate-limiting enzyme to catalyze the hydrolysis of TG in circulation, and plays a critical role in regulating lipid metabolism. However, little attention has been paid to LPL in the adult liver due to its relatively low expression. Here we show that endogenous hepatic LPL plays an important physiological role in plasma lipid homeostasis in adult mice. We generated a mouse model with the Lpl gene specifically ablated in hepatocytes with the Cre/LoxP approach, and found that specific deletion of hepatic Lpl resulted in a significant decrease in plasma LPL contents and activity. As a result, the postprandial TG clearance was markedly impaired, and plasma TG and cholesterol levels were significantly elevated. However, deficiency of hepatic Lpl did not change the liver TG and cholesterol contents or glucose homeostasis. Taken together, our study reveals that hepatic LPL is involved in the regulation of plasma LPL activity and lipid homeostasis. PMID:27234787

  16. Robust intestinal homeostasis relies on cellular plasticity in enteroblasts mediated by miR-8–Escargot switch

    PubMed Central

    Antonello, Zeus A; Reiff, Tobias; Ballesta-Illan, Esther; Dominguez, Maria

    2015-01-01

    The intestinal epithelium is remarkably robust despite perturbations and demand uncertainty. Here, we investigate the basis of such robustness using novel tracing methods that allow simultaneously capturing the dynamics of stem and committed progenitor cells (called enteroblasts) and intestinal cell turnover with spatiotemporal resolution. We found that intestinal stem cells (ISCs) divide “ahead” of demand during Drosophila midgut homeostasis. Their newborn enteroblasts, on the other hand, take on a highly polarized shape, acquire invasive properties and motility. They extend long membrane protrusions that make cell–cell contact with mature cells, while exercising a capacity to delay their final differentiation until a local demand materializes. This cellular plasticity is mechanistically linked to the epithelial–mesenchymal transition (EMT) programme mediated by escargot, a snail family gene. Activation of the conserved microRNA miR-8/miR-200 in “pausing” enteroblasts in response to a local cell loss promotes timely terminal differentiation via a reverse MET by antagonizing escargot. Our findings unveil that robust intestinal renewal relies on hitherto unrecognized plasticity in enteroblasts and reveal their active role in sensing and/or responding to local demand. PMID:26077448

  17. Intestinal microbiota as modulators of the immune system and neuroimmune system: impact on the host health and homeostasis.

    PubMed

    Maranduba, Carlos Magno da Costa; De Castro, Sandra Bertelli Ribeiro; de Souza, Gustavo Torres; Rossato, Cristiano; da Guia, Francisco Carlos; Valente, Maria Anete Santana; Rettore, João Vitor Paes; Maranduba, Claudinéia Pereira; de Souza, Camila Maurmann; do Carmo, Antônio Márcio Resende; Macedo, Gilson Costa; Silva, Fernando de Sá

    2015-01-01

    Many immune-based intestinal disorders, such as ulcerative colitis and Crohn's disease, as well as other illnesses, may have the intestines as an initial cause or aggravator in the development of diseases, even apparently not correlating directly to the intestine. Diabetes, obesity, multiple sclerosis, depression, and anxiety are examples of other illnesses discussed in the literature. In parallel, importance of the gut microbiota in intestinal homeostasis and immunologic conflict between tolerance towards commensal microorganisms and combat of pathogens is well known. Recent researches show that the immune system, when altered by the gut microbiota, influences the state in which these diseases are presented in the patient directly and indirectly. At the present moment, a considerable number of investigations about this subject have been performed and published. However, due to difficulties on correlating information, several speculations and hypotheses are generated. Thus, the present review aims at bringing together how these interactions work-gut microbiota, immune system, and their influence in the neuroimmune system. PMID:25759850

  18. Intestinal Microbiota as Modulators of the Immune System and Neuroimmune System: Impact on the Host Health and Homeostasis

    PubMed Central

    Maranduba, Carlos Magno da Costa; De Castro, Sandra Bertelli Ribeiro; de Souza, Gustavo Torres; da Guia, Francisco Carlos; Valente, Maria Anete Santana; Rettore, João Vitor Paes; Maranduba, Claudinéia Pereira; de Souza, Camila Maurmann; do Carmo, Antônio Márcio Resende; Macedo, Gilson Costa; Silva, Fernando de Sá

    2015-01-01

    Many immune-based intestinal disorders, such as ulcerative colitis and Crohn's disease, as well as other illnesses, may have the intestines as an initial cause or aggravator in the development of diseases, even apparently not correlating directly to the intestine. Diabetes, obesity, multiple sclerosis, depression, and anxiety are examples of other illnesses discussed in the literature. In parallel, importance of the gut microbiota in intestinal homeostasis and immunologic conflict between tolerance towards commensal microorganisms and combat of pathogens is well known. Recent researches show that the immune system, when altered by the gut microbiota, influences the state in which these diseases are presented in the patient directly and indirectly. At the present moment, a considerable number of investigations about this subject have been performed and published. However, due to difficulties on correlating information, several speculations and hypotheses are generated. Thus, the present review aims at bringing together how these interactions work—gut microbiota, immune system, and their influence in the neuroimmune system. PMID:25759850

  19. Robust intestinal homeostasis relies on cellular plasticity in enteroblasts mediated by miR-8-Escargot switch.

    PubMed

    Antonello, Zeus A; Reiff, Tobias; Ballesta-Illan, Esther; Dominguez, Maria

    2015-08-01

    The intestinal epithelium is remarkably robust despite perturbations and demand uncertainty. Here, we investigate the basis of such robustness using novel tracing methods that allow simultaneously capturing the dynamics of stem and committed progenitor cells (called enteroblasts) and intestinal cell turnover with spatiotemporal resolution. We found that intestinal stem cells (ISCs) divide "ahead" of demand during Drosophila midgut homeostasis. Their newborn enteroblasts, on the other hand, take on a highly polarized shape, acquire invasive properties and motility. They extend long membrane protrusions that make cell-cell contact with mature cells, while exercising a capacity to delay their final differentiation until a local demand materializes. This cellular plasticity is mechanistically linked to the epithelial-mesenchymal transition (EMT) programme mediated by escargot, a snail family gene. Activation of the conserved microRNA miR-8/miR-200 in "pausing" enteroblasts in response to a local cell loss promotes timely terminal differentiation via a reverse MET by antagonizing escargot. Our findings unveil that robust intestinal renewal relies on hitherto unrecognized plasticity in enteroblasts and reveal their active role in sensing and/or responding to local demand. PMID:26077448

  20. The role of immunomodulators on intestinal barrier homeostasis in experimental models.

    PubMed

    Andrade, Maria Emília Rabelo; Araújo, Raquel Silva; de Barros, Patrícia Aparecida Vieira; Soares, Anne Danieli Nascimento; Abrantes, Fernanda Alves; Generoso, Simone de Vasconcelos; Fernandes, Simone Odília Antunes; Cardoso, Valbert Nascimento

    2015-12-01

    The intestinal epithelium is composed of specialized epithelial cells that form a physical and biochemical barrier to commensal and pathogenic microorganisms. However, dysregulation of the epithelial barrier function can lead to increased intestinal permeability and bacterial translocation across the intestinal mucosa, which contributes to local and systemic immune activation. The increase in these parameters is associated with inflammatory bowel disease, physical exercise under heat stress, intestinal obstruction, ischemia, and mucositis, among other conditions. Lately, there has been growing interest in immunomodulatory nutrients and probiotics that can regulate host immune and inflammatory responses and possibly restore the intestinal barrier. Immunomodulators such as amino acids (glutamine, arginine, tryptophan, and citrulline), fatty acids (short-chain and omega-3 fatty acids and conjugated linoleic acids), and probiotics (Bifidobacterium, Saccharomyces, and Lactobacillus) have been reported in the literature. Here, we review the critical roles of immunomodulatory nutrients in supporting gut barrier integrity and function. PMID:25660317

  1. The Interplay between Wnt Mediated Expansion and Negative Regulation of Growth Promotes Robust Intestinal Crypt Structure and Homeostasis

    PubMed Central

    Du, Huijing; Nie, Qing; Holmes, William R.

    2015-01-01

    The epithelium of the small intestinal crypt, which has a vital role in protecting the underlying tissue from the harsh intestinal environment, is completely renewed every 4–5 days by a small pool of stem cells at the base of each crypt. How is this renewal controlled and homeostasis maintained, particularly given the rapid nature of this process? Here, based on the recent observations from in vitro “mini gut” studies, we use a hybrid stochastic model of the crypt to investigate how exogenous niche signaling (from Wnt and BMP) combines with auto-regulation to promote homeostasis. This model builds on the sub-cellular element method to account for the three-dimensional structure of the crypt, external regulation by Wnt and BMP, internal regulation by Notch signaling, as well as regulation by internally generated diffusible signals. Results show that Paneth cell derived Wnt signals, which have been observed experimentally to sustain crypts in cultured organs, have a dramatically different influence on niche dynamics than does mesenchyme derived Wnt. While this signaling can indeed act as a redundant backup to the exogenous gradient, it introduces a positive feedback that destabilizes the niche and causes its uncontrolled expansion. We find that in this setting, BMP has a critical role in constraining this expansion, consistent with observations that its removal leads to crypt fission. Further results also point to a new hypothesis for the role of Ephrin mediated motility of Paneth cells, specifically that it is required to constrain niche expansion and maintain the crypt’s spatial structure. Combined, these provide an alternative view of crypt homeostasis where the niche is in a constant state of expansion and the spatial structure of the crypt arises as a balance between this expansion and the action of various sources of negative regulation that hold it in check. PMID:26288152

  2. Role of GATA factors in development, differentiation, and homeostasis of the small intestinal epithelium

    PubMed Central

    Aronson, Boaz E.; Stapleton, Kelly A.

    2014-01-01

    The small intestinal epithelium develops from embryonic endoderm into a highly specialized layer of cells perfectly suited for the digestion and absorption of nutrients. The development, differentiation, and regeneration of the small intestinal epithelium require complex gene regulatory networks involving multiple context-specific transcription factors. The evolutionarily conserved GATA family of transcription factors, well known for its role in hematopoiesis, is essential for the development of endoderm during embryogenesis and the renewal of the differentiated epithelium in the mature gut. We review the role of GATA factors in the evolution and development of endoderm and summarize our current understanding of the function of GATA factors in the mature small intestine. We offer perspective on the application of epigenetics approaches to define the mechanisms underlying context-specific GATA gene regulation during intestinal development. PMID:24436352

  3. Noncanonical role of transferrin receptor 1 is essential for intestinal homeostasis

    PubMed Central

    Chen, Alan C.; Donovan, Adriana; Ned-Sykes, Renee; Andrews, Nancy C.

    2015-01-01

    Transferrin receptor 1 (Tfr1) facilitates cellular iron uptake through receptor-mediated endocytosis of iron-loaded transferrin. It is expressed in the intestinal epithelium but not involved in dietary iron absorption. To investigate its role, we inactivated the Tfr1 gene selectively in murine intestinal epithelial cells. The mutant mice had severe disruption of the epithelial barrier and early death. There was impaired proliferation of intestinal epithelial cell progenitors, aberrant lipid handling, increased mRNA expression of stem cell markers, and striking induction of many genes associated with epithelial-to-mesenchymal transition. Administration of parenteral iron did not improve the phenotype. Surprisingly, however, enforced expression of a mutant allele of Tfr1 that is unable to serve as a receptor for iron-loaded transferrin appeared to fully rescue most animals. Our results implicate Tfr1 in homeostatic maintenance of the intestinal epithelium, acting through a role that is independent of its iron-uptake function. PMID:26324903

  4. Intestinal myofibroblast-specific Tpl2-Cox-2-PGE2 pathway links innate sensing to epithelial homeostasis.

    PubMed

    Roulis, Manolis; Nikolaou, Christoforos; Kotsaki, Elena; Kaffe, Eleanna; Karagianni, Niki; Koliaraki, Vasiliki; Salpea, Klelia; Ragoussis, Jiannis; Aidinis, Vassilis; Martini, Eva; Becker, Christoph; Herschman, Harvey R; Vetrano, Stefania; Danese, Silvio; Kollias, George

    2014-10-28

    Tumor progression locus-2 (Tpl2) kinase is a major inflammatory mediator in immune cell types recently found to be genetically associated with inflammatory bowel diseases (IBDs). Here we show that Tpl2 may exert a dominant homeostatic rather than inflammatory function in the intestine mediated specifically by subepithelial intestinal myofibroblasts (IMFs). Mice with complete or IMF-specific Tpl2 ablation are highly susceptible to epithelial injury-induced colitis showing impaired compensatory proliferation in crypts and extensive ulcerations without significant changes in inflammatory responses. Following epithelial injury, IMFs sense innate or inflammatory signals and activate, via Tpl2, the cyclooxygenase-2 (Cox-2)-prostaglandin E2 (PGE2) pathway, which we show here to be essential for the epithelial homeostatic response. Exogenous PGE2 administration rescues mice with complete or IMF-specific Tpl2 ablation from defects in crypt function and susceptibility to colitis. We also show that Tpl2 expression is decreased in IMFs isolated from the inflamed ileum of IBD patients indicating that Tpl2 function in IMFs may be highly relevant to human disease. The IMF-mediated mechanism we propose also involves the IBD-associated genes IL1R1, MAPK1, and the PGE2 receptor-encoding PTGER4. Our results establish a previously unidentified myofibroblast-specific innate pathway that regulates intestinal homeostasis and may underlie IBD susceptibility in humans. PMID:25316791

  5. IL-1β in eosinophil-mediated small intestinal homeostasis and IgA production

    PubMed Central

    Jung, Y; Wen, T; Mingler, MK; Caldwell, JM; Wang, YH; Chaplin, DD; Lee, EH; Jang, MH; Woo, SY; Seoh, JY; Miyasaka, M; Rothenberg, ME

    2014-01-01

    Eosinophils are multifunctional leukocytes that reside in the gastrointestinal (GI) lamina propria, where their basal function remains largely unexplored. In this study, by examining mice with a selective deficiency of systemic eosinophils (by lineage ablation) or GI eosinophils (eotaxin-1/2 double–deficient or CC chemokine receptor 3–deficient), we show that eosinophils support immunoglobulin A (IgA) class switching, maintain intestinal mucus secretions, affect intestinal microbial composition, and promote the development of Peyer’s patches. Eosinophil-deficient mice showed reduced expression of mediators of secretory IgA production, including intestinal interleukin 1β (IL-1β), inducible nitric oxide synthase, lymphotoxin (LT) α, and LT-β, and reduced levels of retinoic acid-related orphan receptor gamma t–positive (ROR-γt+) innate lymphoid cells (ILCs) while maintaining normal levels of APRIL (a proliferation-inducing ligand), BAFF (B cell–activating factor of the tumor necrosis factor family), and TGF-β (transforming growth factor β). GI eosinophils expressed a relatively high level of IL-1β, and IL-1β–deficient mice manifested the altered gene expression profiles observed in eosinophil-deficient mice and decreased levels of IgA+ cells and ROR-γt+ ILCs. On the basis of these collective data, we propose that eosinophils are required for homeostatic intestinal immune responses including IgA production and that their affect is mediated via IL-1β in the small intestine. PMID:25563499

  6. IL-1β in eosinophil-mediated small intestinal homeostasis and IgA production.

    PubMed

    Jung, Y; Wen, T; Mingler, M K; Caldwell, J M; Wang, Y H; Chaplin, D D; Lee, E H; Jang, M H; Woo, S Y; Seoh, J Y; Miyasaka, M; Rothenberg, M E

    2015-07-01

    Eosinophils are multifunctional leukocytes that reside in the gastrointestinal (GI) lamina propria, where their basal function remains largely unexplored. In this study, by examining mice with a selective deficiency of systemic eosinophils (by lineage ablation) or GI eosinophils (eotaxin-1/2 double deficient or CC chemokine receptor 3 deficient), we show that eosinophils support immunoglobulin A (IgA) class switching, maintain intestinal mucus secretions, affect intestinal microbial composition, and promote the development of Peyer's patches. Eosinophil-deficient mice showed reduced expression of mediators of secretory IgA production, including intestinal interleukin 1β (IL-1β), inducible nitric oxide synthase, lymphotoxin (LT) α, and LT-β, and reduced levels of retinoic acid-related orphan receptor gamma t-positive (ROR-γt(+)) innate lymphoid cells (ILCs), while maintaining normal levels of APRIL (a proliferation-inducing ligand), BAFF (B cell-activating factor of the tumor necrosis factor family), and TGF-β (transforming growth factor β). GI eosinophils expressed a relatively high level of IL-1β, and IL-1β-deficient mice manifested the altered gene expression profiles observed in eosinophil-deficient mice and decreased levels of IgA(+) cells and ROR-γt(+) ILCs. On the basis of these collective data, we propose that eosinophils are required for homeostatic intestinal immune responses including IgA production and that their affect is mediated via IL-1β in the small intestine. PMID:25563499

  7. Wnt signaling in adult intestinal stem cells and cancer.

    PubMed

    Krausova, Michaela; Korinek, Vladimir

    2014-03-01

    Signaling initiated by secreted glycoproteins of the Wnt family regulates many aspects of embryonic development and it is involved in homeostasis of adult tissues. In the gastrointestinal (GI) tract the Wnt pathway maintains the self-renewal capacity of epithelial stem cells. The stem cell attributes are conferred by mutual interactions of the stem cell with its local microenvironment, the stem cell niche. The niche ensures that the threshold of Wnt signaling in the stem cell is kept in physiological range. In addition, the Wnt pathway involves various feedback loops that balance the opposing processes of cell proliferation and differentiation. Today, we have compelling evidence that mutations causing aberrant activation of the Wnt pathway promote expansion of undifferentiated progenitors and lead to cancer. The review summarizes recent advances in characterization of adult epithelial stem cells in the gut. We mainly focus on discoveries related to molecular mechanisms regulating the output of the Wnt pathway. Moreover, we present novel experimental approaches utilized to investigate the epithelial cell signaling circuitry in vivo and in vitro. Pivotal aspects of tissue homeostasis are often deduced from studies of tumor cells; therefore, we also discuss some latest results gleaned from the deep genome sequencing studies of human carcinomas of the colon and rectum. PMID:24308963

  8. Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation

    PubMed Central

    López-Posadas, Rocío; Becker, Christoph; Günther, Claudia; Tenzer, Stefan; Amann, Kerstin; Billmeier, Ulrike; Atreya, Raja; Fiorino, Gionata; Vetrano, Stefania; Danese, Silvio; Ekici, Arif B.; Wirtz, Stefan; Thonn, Veronika; Watson, Alastair J.M.; Brakebusch, Cord; Bergö, Martin; Neurath, Markus F.; Atreya, Imke

    2016-01-01

    Although defects in intestinal barrier function are a key pathogenic factor in patients with inflammatory bowel diseases (IBDs), the molecular pathways driving disease-specific alterations of intestinal epithelial cells (IECs) are largely unknown. Here, we addressed this issue by characterizing the transcriptome of IECs from IBD patients using a genome-wide approach. We observed disease-specific alterations in IECs with markedly impaired Rho-A signaling in active IBD patients. Localization of epithelial Rho-A was shifted to the cytosol in IBDs, and inflammation was associated with suppressed Rho-A activation due to reduced expression of the Rho-A prenylation enzyme geranylgeranyltransferase-I (GGTase-I). Functionally, we found that mice with conditional loss of Rhoa or the gene encoding GGTase-I, Pggt1b, in IECs exhibit spontaneous chronic intestinal inflammation with accumulation of granulocytes and CD4+ T cells. This phenotype was associated with cytoskeleton rearrangement and aberrant cell shedding, ultimately leading to loss of epithelial integrity and subsequent inflammation. These findings uncover deficient prenylation of Rho-A as a key player in the pathogenesis of IBDs. As therapeutic triggering of Rho-A signaling suppressed intestinal inflammation in mice with GGTase-I–deficient IECs, our findings suggest new avenues for treatment of epithelial injury and mucosal inflammation in IBD patients. PMID:26752649

  9. Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation.

    PubMed

    López-Posadas, Rocío; Becker, Christoph; Günther, Claudia; Tenzer, Stefan; Amann, Kerstin; Billmeier, Ulrike; Atreya, Raja; Fiorino, Gionata; Vetrano, Stefania; Danese, Silvio; Ekici, Arif B; Wirtz, Stefan; Thonn, Veronika; Watson, Alastair J M; Brakebusch, Cord; Bergö, Martin; Neurath, Markus F; Atreya, Imke

    2016-02-01

    Although defects in intestinal barrier function are a key pathogenic factor in patients with inflammatory bowel diseases (IBDs), the molecular pathways driving disease-specific alterations of intestinal epithelial cells (IECs) are largely unknown. Here, we addressed this issue by characterizing the transcriptome of IECs from IBD patients using a genome-wide approach. We observed disease-specific alterations in IECs with markedly impaired Rho-A signaling in active IBD patients. Localization of epithelial Rho-A was shifted to the cytosol in IBDs, and inflammation was associated with suppressed Rho-A activation due to reduced expression of the Rho-A prenylation enzyme geranylgeranyltransferase-I (GGTase-I). Functionally, we found that mice with conditional loss of Rhoa or the gene encoding GGTase-I, Pggt1b, in IECs exhibit spontaneous chronic intestinal inflammation with accumulation of granulocytes and CD4+ T cells. This phenotype was associated with cytoskeleton rearrangement and aberrant cell shedding, ultimately leading to loss of epithelial integrity and subsequent inflammation. These findings uncover deficient prenylation of Rho-A as a key player in the pathogenesis of IBDs. As therapeutic triggering of Rho-A signaling suppressed intestinal inflammation in mice with GGTase-I-deficient IECs, our findings suggest new avenues for treatment of epithelial injury and mucosal inflammation in IBD patients. PMID:26752649

  10. Modulation of small intestinal homeostasis along with its microflora during acclimatization at simulated hypobaric hypoxia.

    PubMed

    Adak, Atanu; Ghosh; Mondal, Keshab Chandra

    2014-11-01

    At high altitude (HA) hypobaric hypoxic environment manifested several pathophysiological consequences of which gastrointestinal (GI) disorder are very common phenomena. To explore the most possible clue behind this disorder intestinal flora, the major player of the GI functions, were subjected following simulated hypobaric hypoxic treatment in model animal. For this, male albino rats were exposed to 55 kPa (approximately 4872.9 m) air pressure consecutively for 30 days for 8 h/day and its small intestinal microflora, their secreted digestive enzymes and stress induced marker protein were investigated of the luminal epithelia. It was observed that population density of total aerobes significantly decreased, but the quantity of total anaerobes and Escherichia coli increased significantly after 30 days of hypoxic stress. The population density of strict anaerobes like Bifidobacterium sp., Bacteroides sp. and Lactobacillus sp. and obligate anaerobes like Clostridium perfringens and Peptostreptococcus sp. were expanded along with their positive growth direction index (GDI). In relation to the huge multiplication of anaerobes the amount of gas formation as well as content of IgA and IgG increased in duration dependent manner. The activity of some luminal enzymes from microbial origin like a-amylase, gluco-amylase, proteinase, alkaline phosphatase and beta-glucuronidase were also elevated in hypoxic condition. Besides, hypoxia induced in formation of malondialdehyde along with significant attenuation of catalase, glutathione peroxidase, superoxide dismutase activity and lowered GSH/GSSG pool in the intestinal epithelia. Histological study revealed disruption of intestinal epithelial barrier with higher infiltration of lymphocytes in lamina propia and atrophic structure. It can be concluded that hypoxia at HA modified GI microbial imprint and subsequently causes epithelial barrier dysfunction which may relate to the small intestinal dysfunction at HA. PMID:25434105

  11. The role of type I interferons in intestinal infection, homeostasis, and inflammation

    PubMed Central

    Cho, Hyeseon; Kelsall, Brian L.

    2014-01-01

    Summary Type I interferons are a widely expressed family of effector cytokines that promote innate antiviral and antibacterial immunity. Paradoxically, they can also suppress immune responses by driving production of anti-inflammatory cytokines, and dysregulation of these cytokines can contribute to host-mediated immunopathology and disease progression. Recent studies describe their anti-inflammatory role in intestinal inflammation and the locus containing IFNAR, a heterodimeric receptor for the type I interferons has been identified as a susceptibility region for human inflammatory bowel disease in a genome-wide association study. This review focuses on the role of type I IFNs in the gut in health and disease and their emerging role as immune modulator. Clear understanding of type I IFN-mediated immune responses may provide revenue for fine-tuning existing IFN treatment for infection and intestinal inflammation. PMID:24942688

  12. Epithelial Sel1L is required for the maintenance of intestinal homeostasis

    PubMed Central

    Sun, Shengyi; Lourie, Rohan; Cohen, Sara B.; Ji, Yewei; Goodrich, Julia K.; Poole, Angela C.; Ley, Ruth E.; Denkers, Eric Y.; McGuckin, Michael A.; Long, Qiaoming; Duhamel, Gerald E.; Simpson, Kenneth W.; Qi, Ling

    2016-01-01

    Inflammatory bowel disease (IBD) is an incurable chronic idiopathic disease that drastically decreases quality of life. Endoplasmic reticulum (ER)–associated degradation (ERAD) is responsible for the clearance of misfolded proteins; however, its role in disease pathogenesis remains largely unexplored. Here we show that the expression of SEL1L and HRD1, the most conserved branch of mammalian ERAD, is significantly reduced in ileal Crohn’s disease (CD). Consistent with this observation, laboratory mice with enterocyte-specific Sel1L deficiency (Sel1LΔIEC) develop spontaneous enteritis and have increased susceptibility to Toxoplasma gondii–induced ileitis. This is associated with profound defects in Paneth cells and a disproportionate increase of Ruminococcus gnavus, a mucolytic bacterium with known association with CD. Surprisingly, whereas both ER stress sensor IRE1α and effector CHOP are activated in the small intestine of Sel1LΔIEC mice, they are not solely responsible for ERAD deficiency–associated lesions seen in the small intestine. Thus our study points to a constitutive role of Sel1L-Hrd1 ERAD in epithelial cell biology and the pathogenesis of intestinal inflammation in CD. PMID:26631554

  13. Intestinal lactase status of adults in Papua New Guinea.

    PubMed

    Cook, G C

    1979-01-01

    Fifty hospital patients in Port Moresby (mean age 30 yr) without evidence of malnutrition or gastro-intestinal disease, who came from many parts of Papua New Guinea (P.N.G.), were given 50 g lactose orally after an overnight fast. In 49 blood glucose rise was less than 1.1 mmol 1(-1), indicating hypolactasia. Thirty-three gave a clear history of symptoms, usually diarrhoea, after lactose. Adult hypolactasia approaches 100% in P.N.G. There is no indication that the genetic structure of any part of the population of P,N.G. with regard to lactase has been influenced by genetic drift from peoples with persistence of lactase into adult life (PL). PMID:434766

  14. High intestinal lactase concentrations in adult Arbs in Saudi Arabia.

    PubMed

    Cook, G C; al-Torki, M T

    1975-07-19

    The maximum rise in blood glucose after 50 g lactose by mouth was determined in 40 adult Arabs. Out of 30 Bedouin, urban Saudi, and Yemeni and 9 of mixed ancestry (usually partly African), 25 (83%) and 2 (22%) respectively showed an increase of over 1-1 mmol/1 (20 mg/100 ml). In common with most northern Europeans and Hamitic people of northern Africa, Arabs in Saudi Arabia usually have high intestinal lactase concentrations in adult life. This persistence of high levels probably originated in the Arabian peninsula. Its selective advantage may have been associated with the fluid and calorie content of camels' milk, which is important for survival in desert nomads. PMID:1170003

  15. Lipoprotein Receptor LRP1 Regulates Leptin Signaling and Energy Homeostasis in the Adult Central Nervous System

    PubMed Central

    Liu, Qiang; Zhang, Juan; Zerbinatti, Celina; Zhan, Yan; Kolber, Benedict J.; Herz, Joachim; Muglia, Louis J.; Bu, Guojun

    2011-01-01

    Obesity is a growing epidemic characterized by excess fat storage in adipocytes. Although lipoprotein receptors play important roles in lipid uptake, their role in controlling food intake and obesity is not known. Here we show that the lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis. Conditional deletion of the Lrp1 gene in the brain resulted in an obese phenotype characterized by increased food intake, decreased energy consumption, and decreased leptin signaling. LRP1 directly binds to leptin and the leptin receptor complex and is required for leptin receptor phosphorylation and Stat3 activation. We further showed that deletion of the Lrp1 gene specifically in the hypothalamus by Cre lentivirus injection is sufficient to trigger accelerated weight gain. Together, our results demonstrate that the lipoprotein receptor LRP1, which is critical in lipid metabolism, also regulates food intake and energy homeostasis in the adult central nervous system. PMID:21264353

  16. [Surgical significance of intestinal non-rotation in adults].

    PubMed

    von Flüe, M; Herzog, U; Vogt, B; Tondelli, P; Harder, F

    1991-06-15

    Intestinal non-rotation has been recognized as a cause of obstruction in neonates and children. It is very rarely seen in the adult and assumes surgical significance owing to the potential risk of midgut or ileocecal volvulus. However, it can also cause significant intermittent abdominal pain in the adult. We describe six personally observed patients with this malformation and analyze 38 case reports published in the English and German literature since 1923. We establish that in the acute symptomatic form only emergency laparotomy can provide the correct diagnosis and decrease the risk of bowel disturbance. In the chronic forms, barium studies of the whole intestinal tract reveal varying degrees of midgut malrotation and the non-rotation is confirmed in each case. Also in these forms, exploratory laparotomy with a consequent staging of the abdominal situs is to be recommended. In the operation described by Ladd the ascending colon is sutured at the colon descendens and sigmoideum. After this procedure the mesenterial pedicle is fixed and the risk of midgut torsion remains minimal. All reported cases after surgery are symptom-free. PMID:1857952

  17. Endocrine remodelling of the adult intestine sustains reproduction in Drosophila

    PubMed Central

    Reiff, Tobias; Jacobson, Jake; Cognigni, Paola; Antonello, Zeus; Ballesta, Esther; Tan, Kah Junn; Yew, Joanne Y; Dominguez, Maria; Miguel-Aliaga, Irene

    2015-01-01

    The production of offspring is energetically costly and relies on incompletely understood mechanisms that generate a positive energy balance. In mothers of many species, changes in key energy-associated internal organs are common yet poorly characterised functionally and mechanistically. In this study, we show that, in adult Drosophila females, the midgut is dramatically remodelled to enhance reproductive output. In contrast to extant models, organ remodelling does not occur in response to increased nutrient intake and/or offspring demands, but rather precedes them. With spatially and temporally directed manipulations, we identify juvenile hormone (JH) as an anticipatory endocrine signal released after mating. Acting through intestinal bHLH-PAS domain proteins Methoprene-tolerant (Met) and Germ cell-expressed (Gce), JH signals directly to intestinal progenitors to yield a larger organ, and adjusts gene expression and sterol regulatory element-binding protein (SREBP) activity in enterocytes to support increased lipid metabolism. Our findings identify a metabolically significant paradigm of adult somatic organ remodelling linking hormonal signals, epithelial plasticity, and reproductive output. DOI: http://dx.doi.org/10.7554/eLife.06930.001 PMID:26216039

  18. A novel culture system for adult porcine intestinal crypts.

    PubMed

    Khalil, Hassan A; Lei, Nan Ye; Brinkley, Garrett; Scott, Andrew; Wang, Jiafang; Kar, Upendra K; Jabaji, Ziyad B; Lewis, Michael; Martín, Martín G; Dunn, James C Y; Stelzner, Matthias G

    2016-07-01

    Porcine models are useful for investigating therapeutic approaches to short bowel syndrome and potentially to intestinal stem cell (ISC) transplantation. Whereas techniques for the culture and genetic manipulation of ISCs from mice and humans are well established, similar methods for porcine stem cells have not been reported. Jejunal crypts were isolated from murine, human, and juvenile and adult porcine small intestine, suspended in Matrigel, and co-cultured with syngeneic intestinal subepithelial myofibroblasts (ISEMFs) or cultured without feeder cells in various culture media. Media containing epidermal growth factor, noggin, and R-spondin 1 (ENR medium) were supplemented with various combinations of Wnt3a- or ISEMF-conditioned medium (CM) and with glycogen synthase kinase 3 inhibitor (GSK3i), and their effects were studied on cultured crypts. Cell lineage differentiation was assessed by immunohistochemistry and quantitative polymerase chain reaction. Cultured porcine cells were serially passaged and transduced with a lentiviral vector. Whereas ENR medium supported murine enteroid growth, it did not sustain porcine crypts beyond 5 days. Supplementation of Wnt3a-CM and GSK3i resulted in the formation of complex porcine enteroids with budding extensions. These enteroids contained a mixture of stem and differentiated cells and were successfully passaged in the presence of GSK3i. Crypts grown in media supplemented with porcine ISEMF-CM formed spheroids that were less well differentiated than enteroids. Enteroids and spheroids were transfected with a lentivirus with high efficiency. Thus, our method maintains juvenile and adult porcine crypt cells long-term in culture. Porcine enteroids and spheroids can be successfully passaged and transduced by using lentiviral vectors. PMID:26928041

  19. Dual epithelial and immune cell function of Dvl1 regulates gut microbiota composition and intestinal homeostasis

    PubMed Central

    Belinson, Haim; Savage, Adam K.; Fadrosh, Douglas; Kuo, Yien-Ming; Lin, Din; Valladares, Ricardo; Nusse, Ysbrand; Wynshaw-Boris, Anthony; Lynch, Susan V.; Locksley, Richard M.; Klein, Ophir D.

    2016-01-01

    Homeostasis of the gastrointestinal (GI) tract is controlled by complex interactions between epithelial and immune cells and the resident microbiota. Here, we studied the role of Wnt signaling in GI homeostasis using Disheveled 1 knockout (Dvl1−/−) mice, which display an increase in whole gut transit time. This phenotype is associated with a reduction and mislocalization of Paneth cells and an increase in CD8+ T cells in the lamina propria. Bone marrow chimera experiments demonstrated that GI dysfunction requires abnormalities in both epithelial and immune cells. Dvl1−/− mice exhibit a significantly distinct GI microbiota, and manipulation of the gut microbiota in mutant mice rescued the GI transit abnormality without correcting the Paneth and CD8+ T cell abnormalities. Moreover, manipulation of the gut microbiota in wild-type mice induced a GI transit abnormality akin to that seen in Dvl1−/− mice. Together, these data indicate that microbiota manipulation can overcome host dysfunction to correct GI transit abnormalities. Our findings illustrate a mechanism by which the epithelium and immune system coregulate gut microbiota composition to promote normal GI function. PMID:27525310

  20. Chemokines and chemokine receptors in mucosal homeostasis at the intestinal epithelial barrier in inflammatory bowel disease.

    PubMed

    Zimmerman, Noah P; Vongsa, Rebecca A; Wendt, Michael K; Dwinell, Michael B

    2008-07-01

    Chemokines, a large family of small chemoattractive cytokines, and their receptors play an integral role in the regulation of the immune response and homeostasis. The ability of chemokines to attract specific populations of immune cells sets them apart from other chemoattractants. Chemokines produced within the gastrointestinal mucosa are critical players in directing the balance between physiological and pathophysiological inflammation in health, inflammatory bowel disease (IBD), and the progression to colon cancer. In addition to the well-characterized role of chemokines in directed trafficking of immune cells to the gut mucosa, the expression of chemokine receptors on the cells of the epithelium makes them active participants in the chemokine signaling network. Recent findings demonstrate an important role for chemokines and chemokine receptors in epithelial barrier repair and maintenance as well as an intricate involvement in limiting metastasis of colonic carcinoma. Increased recognition of the association between barrier defects and inflammation and the subsequent progression to cancer in IBD thus implicates chemokines as key regulators of mucosal homeostasis and disease pathogenesis. PMID:18452220

  1. Amino acid absorption and homeostasis in mice lacking the intestinal peptide transporter PEPT1.

    PubMed

    Nässl, Anna-Maria; Rubio-Aliaga, Isabel; Fenselau, Henning; Marth, Mena Katharina; Kottra, Gabor; Daniel, Hannelore

    2011-07-01

    The intestinal peptide transporter PEPT1 mediates the uptake of di- and tripeptides derived from dietary protein breakdown into epithelial cells. Whereas the transporter appears to be essential to compensate for the reduced amino acid delivery in patients with mutations in amino acid transporter genes, such as in cystinuria or Hartnup disease, its physiological role in overall amino acid absorption is still not known. To assess the quantitative importance of PEPT1 in overall amino acid absorption and metabolism, PEPT1-deficient mice were studied by using brush border membrane vesicles, everted gut sacs, and Ussing chambers, as well as by transcriptome and proteome analysis of intestinal tissue samples. Neither gene expression nor proteome profiling nor functional analysis revealed evidence for any compensatory changes in the levels and/or function of transporters for free amino acids in the intestine. However, most plasma amino acid levels were increased in Pept1(-/-) compared with Pept1(+/+) animals, suggesting that amino acid handling is altered. Plasma appearance rates of (15)N-labeled amino acids determined after intragastric administration of a low dose of protein remained unchanged, whereas administration of a large protein load via gavage revealed marked differences in plasma appearance of selected amino acids. PEPT1 seems, therefore, important for overall amino acid absorption only after high dietary protein intake when amino acid transport processes are saturated and PEPT1 can provide additional absorption capacity. Since renal amino acid excretion remained unchanged, elevated basal concentrations of plasma amino acids in PEPT1-deficient animals seem to arise mainly from alterations in hepatic amino acid metabolism. PMID:21350187

  2. Isolating Intestinal Stem Cells from Adult Drosophila Midguts by FACS to Study Stem Cell Behavior During Aging

    PubMed Central

    Pandur, Petra

    2014-01-01

    Aging tissue is characterized by a continuous decline in functional ability. Adult stem cells are crucial in maintaining tissue homeostasis particularly in tissues that have a high turnover rate such as the intestinal epithelium. However, adult stem cells are also subject to aging processes and the concomitant decline in function. The Drosophila midgut has emerged as an ideal model system to study molecular mechanisms that interfere with the intestinal stem cells’ (ISCs) ability to function in tissue homeostasis. Although adult ISCs can be easily identified and isolated from midguts of young flies, it has been a major challenge to study endogenous molecular changes of ISCs during aging. This is due to the lack of a combination of molecular markers suitable to isolate ISCs from aged intestines. Here we propose a method that allows for successful dissociation of midgut tissue into living cells that can subsequently be separated into distinct populations by FACS. By using dissociated cells from the esg-Gal4, UAS-GFP fly line, in which both ISCs and the enteroblast (EB) progenitor cells express GFP, two populations of cells are distinguished based on different GFP intensities. These differences in GFP expression correlate with differences in cell size and granularity and represent enriched populations of ISCs and EBs. Intriguingly, the two GFP-positive cell populations remain distinctly separated during aging, presenting a novel technique for identifying and isolating cell populations enriched for either ISCs or EBs at any time point during aging. The further analysis, for example transcriptome analysis, of these particular cell populations at various time points during aging is now possible and this will facilitate the examination of endogenous molecular changes that occur in these cells during aging. PMID:25548862

  3. Fumonisins affect the intestinal microbial homeostasis in broiler chickens, predisposing to necrotic enteritis.

    PubMed

    Antonissen, Gunther; Croubels, Siska; Pasmans, Frank; Ducatelle, Richard; Eeckhaut, Venessa; Devreese, Mathias; Verlinden, Marc; Haesebrouck, Freddy; Eeckhout, Mia; De Saeger, Sarah; Antlinger, Birgit; Novak, Barbara; Martel, An; Van Immerseel, Filip

    2015-01-01

    Fumonisins (FBs) are mycotoxins produced by Fusarium fungi. This study aimed to investigate the effect of these feed contaminants on the intestinal morphology and microbiota composition, and to evaluate whether FBs predispose broilers to necrotic enteritis. One-day-old broiler chicks were divided into a group fed a control diet, and a group fed a FBs contaminated diet (18.6 mg FB1+FB2/kg feed). A significant increase in the plasma sphinganine/sphingosine ratio in the FBs-treated group (0.21 ± 0.016) compared to the control (0.14 ± 0.014) indicated disturbance of the sphingolipid biosynthesis. Furthermore, villus height and crypt depth of the ileum was significantly reduced by FBs. Denaturing gradient gel electrophoresis showed a shift in the microbiota composition in the ileum in the FBs group compared to the control. A reduced presence of low-GC containing operational taxonomic units in ileal digesta of birds exposed to FBs was demonstrated, and identified as a reduced abundance of Candidatus Savagella and Lactobaccilus spp. Quantification of total Clostridium perfringens in these ileal samples, previous to experimental infection, using cpa gene (alpha toxin) quantification by qPCR showed an increase in C. perfringens in chickens fed a FBs contaminated diet compared to control (7.5 ± 0.30 versus 6.3 ± 0.24 log10 copies/g intestinal content). After C. perfringens challenge, a higher percentage of birds developed subclinical necrotic enteritis in the group fed a FBs contaminated diet as compared to the control (44.9 ± 2.22% versus 29.8 ± 5.46%). PMID:26394675

  4. Malrotation of the Intestine in Adult and Colorectal Cancer.

    PubMed

    Ray, Dipankar; Morimoto, Mitsuaki

    2015-12-01

    Malrotation of the gut is a congenital anomaly and usually presents in childhood. Rarely, it may present in adults. Patients may be asymptomatic, and malrotation is detected during investigations, operation or autopsy. It can cause longstanding abdominal symptoms like pain, dyspepsia or acute abdomen due to volvulus. In adults, malrotation is found with different gastrointestinal malignancies like gastric, hepatobiliary, pancreatic and, in particular, colorectal neoplasms. We are reporting a case of 60-year-old female presented with carcinoma caecum along with malrotation of the gut. It is the first case report from India. We also reviewed documented cases of malrotation associated with colorectal malignancies. A large number of cases have been reported in Japan as compared to rest of the world. Malrotation in adults is probably associated with gastrointestinal malignancies. Possible causes of this association can be genetic factors or gut changes like chronic inflammation. These associations need further study to consider intestinal malrotation as premalignant lesion which may be very important in follow-up of children with malrotation. PMID:26884662

  5. Fibroblast-Derived MMP-14 Regulates Collagen Homeostasis in Adult Skin.

    PubMed

    Zigrino, Paola; Brinckmann, Jürgen; Niehoff, Anja; Lu, Yinhui; Giebeler, Nives; Eckes, Beate; Kadler, Karl E; Mauch, Cornelia

    2016-08-01

    Proteolytic activities in the extracellular matrix by the matrix metalloproteinase (MMP)-14 have been implicated in the remodeling of collagenous proteins during development. To analyze the function of fibroblast-derived MMP-14 in adult skin homeostasis, we generated mice with inducible deletion of MMP-14 in the dermal fibroblast (MMP-14(Sf-/-)). These mice are smaller and display a fibrosis-like phenotype in the skin. The skin of these mice showed increased stiffness and tensile strength but no altered collagen cross-links. In vivo, we measured a significantly increased amount of collagen type I accumulated in the skin of MMP-14(Sf-/-) mice without an increase in collagen fibril diameters. However, bleomycin-induced fibrosis in skin proceeded in a comparable manner in MMP-14(Sf+/+) and MMP-14(Sf-/-) mice, but resolution over time was impaired in MMP-14(Sf-/-) mice. Increased accumulation of collagen type I was detected in MMP-14(Sf-/-) fibroblasts in culture without significant enhancement of collagen de novo synthesis. This points to a degradative but not synthetic phenotype. In support of this, MMP-14(Sf-/-) fibroblasts lost their ability to process fibrillar collagen type I and to activate proMMP-2. Taken together, these data indicate that MMP-14 expression in fibroblasts plays a crucial role in collagen remodeling in adult skin and largely contributes to dermal homeostasis underlying its pathogenic role in fibrotic skin disease. PMID:27066886

  6. Laparoscopic versus Open Ladd's Procedure for Intestinal Malrotation in Adults

    PubMed Central

    Frasier, Lane L.; Leverson, Glen; Gosain, Ankush; Greenberg, Jacob

    2014-01-01

    Background Intestinal malrotation results from errors in fetal intestinal rotation and fixation. While most patients are diagnosed in childhood, some present as adults. Laparoscopic Ladd's procedure is an accepted alternative to laparotomy in children but has not been well-studied in adults. This study was designed to investigate outcomes for adults undergoing laparoscopic Ladd's repair for malrotation. Methods We performed a single-institution retrospective chart review over eleven years. Data collected included: patient age, details of pre-operative work-up and diagnosis, surgical management, complications, rates of re-operation, and symptom resolution. Patients were evaluated on an intent-to-treat basis based on their planned operative approach. Categorical data were analyzed using Fisher's exact test. Continuous data were analyzed using Student's T-test. Results Twenty-two patients were identified (age range 18-63). Fifteen were diagnosed pre-operatively; of the remaining seven patients, four received an intra-operative malrotation diagnosis during elective surgery for another problem. Most had some type of pre-operative imaging, with Computed Tomography being the most common (77.3%). Comparing patients on an intent-to-treat basis, the two groups were similar with respect to age, operative time, and estimated blood loss. Six patients underwent successful laparoscopic repair; three began laparoscopically but were converted to laparotomy. There was a statistically significant difference in length of stay (LOS) (5.0±2.5d vs 11.6±8.1d, p=0.0148) favoring the laparoscopic approach. Three patients required re-operation: 2 underwent side-to-side duodeno-duodenostomy and 1 underwent a re-do Ladd's procedure. Ultimately, 3 (2 laparoscopic, 1 open) had persistent symptoms of bloating (n=2), constipation (n=2), and/or pain (n=1). Conclusion Laparoscopic repair appears to be safe and effective in adults. While a small sample size limits the power of this study, we found

  7. Early Changes in Microbial Colonization Selectively Modulate Intestinal Enzymes, but Not Inducible Heat Shock Proteins in Young Adult Swine

    PubMed Central

    Arnal, Marie-Edith; Zhang, Jing; Messori, Stefano; Bosi, Paolo; Smidt, Hauke; Lallès, Jean-Paul

    2014-01-01

    Metabolic diseases and obesity are developing worldwide in a context of plethoric intake of high energy diets. The intestine may play a pivotal role due to diet-induced alterations in microbiota composition and increased permeability to bacterial lipopolysaccharide inducing metabolic inflammation. Early programming of metabolic disorders appearing in later life is also suspected, but data on the intestine are lacking. Therefore, we hypothesized that early disturbances in microbial colonization have short- and long-lasting consequences on selected intestinal components including key digestive enzymes and protective inducible heat shock proteins (HSP). The hypothesis was tested in swine offspring born to control mothers (n = 12) or mothers treated with the antibiotic amoxicillin around parturition (n = 11), and slaughtered serially at 14, 28 and 42 days of age to assess short-term effects. To evaluate long-term consequences, young adult offspring from the same litters were offered a normal or a fat-enriched diet for 4 weeks between 140 and 169 days of age and were then slaughtered. Amoxicillin treatment transiently modified both mother and offspring microbiota. This was associated with early but transient reduction in ileal alkaline phosphatase, HSP70 (but not HSP27) and crypt depth, suggesting a milder or delayed intestinal response to bacteria in offspring born to antibiotic-treated mothers. More importantly, we disclosed long-term consequences of this treatment on jejunal alkaline phosphatase (reduced) and jejunal and ileal dipeptidylpeptidase IV (increased and decreased, respectively) of offspring born to antibiotic-treated dams. Significant interactions between early antibiotic treatment and later diet were observed for jejunal alkaline phosphatase and sucrase. By contrast, inducible HSPs were not affected. In conclusion, our data suggest that early changes in bacterial colonization not only modulate intestinal architecture and function transiently, but

  8. The Starting Lineup: Key Microbial Players in Intestinal Immunity and Homeostasis

    PubMed Central

    Reading, Nicola C.; Kasper, Dennis L.

    2011-01-01

    The complexity of microbiota inhabiting the intestine is increasingly apparent. Delicate balance of numerous bacterial species can affect development of the immune system, how susceptible a host is to pathogenic organisms, and the auto-inflammatory state of the host. In the last decade, with the increased use of germ-free mice, gnotobiotic mice, and animal models in which a germ-free animal has been colonized with a foreign microbiota such as humanized mice, it has been possible to delineate relationships that specific bacteria have with the host immune system and to show what role they may play in overall host health. These models have not only allowed us to tease out the roles of individual species, but have also allowed the discovery and characterization of functionally unknown organisms. For example, segmented filamentous bacteria (SFB) have been shown to play a vital role in expansion of IL-17 producing cells. Prior to linking their key role in immune system development, little was known about these organisms. Bacteroides fragilis can rescue some of the immune defects of gnotobiotic mice after mono-colonization and have anti-inflammatory properties that can alleviate colitis and experimental allergic encephalitis in murine models. Additionally, Clostridium species have most recently been shown to expand regulatory T-cell populations leading to anti-inflammatory conditions. This review will highlight and summarize some of the major findings within the last decade concerning the role of select groups of bacteria including SFB, Clostridium, Bacteroides, Bifidobacterium, and Lactobacillus, and their impact on host mucosal immune systems. PMID:21779278

  9. Impact of metal ion homeostasis of genetically modified Escherichia coli Nissle 1917 and K12 (W3110) strains on colonization properties in the murine intestinal tract.

    PubMed

    Kupz, Andreas; Fischer, André; Nies, Dietrich H; Grass, Gregor; Göbel, Ulf B; Bereswill, Stefan; Heimesaat, Markus M

    2013-09-01

    Metal ions are integral parts of pro- as well as eukaryotic cell homeostasis. Escherichia coli proved a valuable in vitro model organism to elucidate essential mechanisms involved in uptake, storage, and export of metal ions. Given that E. coli Nissle 1917 is able to overcome murine colonization resistance, we generated several E. coli Nissle 1917 mutants with defects in zinc, iron, copper, nickel, manganese homeostasis and performed a comprehensive survey of the impact of metal ion transport and homeostasis for E. coli colonization capacities within the murine intestinal tract. Seven days following peroral infection of conventional mice with E. coli Nissle 1917 strains exhibiting defined defects in zinc or iron uptake, the respective mutant and parental strains could be cultured at comparable, but low levels from the colonic lumen. We next reassociated gnotobiotic mice in which the microbiota responsible for colonization resistance was abrogated by broad-spectrum antibiotics with six different E. coli K12 (W3110) mutants. Seven days following peroral challenge, each mutant and parental strain stably colonized duodenum, ileum, and colon at comparable levels. Taken together, defects in zinc, iron, copper, nickel, and manganese homeostasis do not compromise colonization capacities of E. coli in the murine intestinal tract. PMID:24265943

  10. Adult zebrafish intestine resection: a novel model of short bowel syndrome, adaptation, and intestinal stem cell regeneration

    PubMed Central

    Schall, K. A.; Holoyda, K. A.; Grant, C. N.; Levin, D. E.; Torres, E. R.; Maxwell, A.; Pollack, H. A.; Moats, R. A.; Frey, M. R.; Darehzereshki, A.; Al Alam, D.; Lien, C.

    2015-01-01

    Loss of significant intestinal length from congenital anomaly or disease may lead to short bowel syndrome (SBS); intestinal failure may be partially offset by a gain in epithelial surface area, termed adaptation. Current in vivo models of SBS are costly and technically challenging. Operative times and survival rates have slowed extension to transgenic models. We created a new reproducible in vivo model of SBS in zebrafish, a tractable vertebrate model, to facilitate investigation of the mechanisms of intestinal adaptation. Proximal intestinal diversion at segment 1 (S1, equivalent to jejunum) was performed in adult male zebrafish. SBS fish emptied distal intestinal contents via stoma as in the human disease. After 2 wk, S1 was dilated compared with controls and villus ridges had increased complexity, contributing to greater villus epithelial perimeter. The number of intervillus pockets, the intestinal stem cell zone of the zebrafish increased and contained a higher number of bromodeoxyuridine (BrdU)-labeled cells after 2 wk of SBS. Egf receptor and a subset of its ligands, also drivers of adaptation, were upregulated in SBS fish. Igf has been reported as a driver of intestinal adaptation in other animal models, and SBS fish exposed to a pharmacological inhibitor of the Igf receptor failed to demonstrate signs of intestinal adaptation, such as increased inner epithelial perimeter and BrdU incorporation. We describe a technically feasible model of human SBS in the zebrafish, a faster and less expensive tool to investigate intestinal stem cell plasticity as well as the mechanisms that drive intestinal adaptation. PMID:26089336

  11. PTEN is required to maintain luminal epithelial homeostasis and integrity in the adult mammary gland.

    PubMed

    Shore, Amy N; Chang, Chi-Hsuan; Kwon, Oh-Joon; Weston, Matthew C; Zhang, Mei; Xin, Li; Rosen, Jeffrey M

    2016-01-01

    In the mammary gland, PTEN loss in luminal and basal epithelial cells results in differentiation defects and enhanced proliferation, leading to the formation of tumors with basal epithelial characteristics. In breast cancer, PTEN loss is associated with a hormone receptor-negative, basal-like subtype that is thought to originate in a luminal epithelial cell. Here, we show that luminal-specific PTEN loss results in distinct effects on epithelial homeostasis and mammary tumor formation. Luminal PTEN loss increased proliferation of hormone receptor-negative cells, thereby decreasing the percentage of hormone receptor-positive cells. Moreover, luminal PTEN loss led to misoriented cell divisions and mislocalization of cells to the intraluminal space of mammary ducts. Despite their elevated levels of activated AKT, Pten-null intraluminal cells showed increased levels of apoptosis. One year after Pten deletion, the ducts had cleared and no palpable mammary tumors were detected. These data establish PTEN as a critical regulator of luminal epithelial homeostasis and integrity in the adult mammary gland, and further show that luminal PTEN loss alone is not sufficient to promote the progression of mammary tumorigenesis. PMID:26526198

  12. Interplay of nutrients and microbial metabolites in intestinal immune homeostasis: distinct and common mechanisms of immune regulation in the small bowel and colon.

    PubMed

    Perrigoue, Jacqueline; Das, Anuk; Mora, J Rodrigo

    2014-01-01

    The intestinal mucosa is the largest body surface exposed to the environment. While there are common features when comparing immune responses along the intestinal mucosa, the small bowel and colon exhibit striking differences in their mechanisms driving immune regulation. The vitamin A (VA) metabolite all-trans retinoic acid (RA) signaling via RA nuclear receptors plays a key role in immune homeostasis in the small bowel, and recent work indicates that RA is required for establishing immune tolerance to dietary antigens in the upper intestinal tract by inducing α4β7(+)CCR9(+) gut-tropic TREG. In contrast, microbiota-specific TREG in the colon do not appear to require RA, but can be regulated by short-chain fatty acids (SCFA), microbial metabolites that signal through the G protein-coupled receptor GPR43. Moreover, TREG do not need CCR9 to home to the colon, but utilize another G protein-coupled receptor, GPR15, which is upregulated by SCFA. Thus, the mechanisms governing intestinal tolerance to dietary antigens in the upper digestive tract differ from those controlling tolerance to the microbiota in the colon, with RA and SCFA playing key complementary roles in their respective compartments. In addition to VA and SCFA, recent studies have highlighted the roles of other dietary and microbial metabolites that influence immune cell homeostasis across the small and large bowel including dietary ligands for aryl hydrocarbon receptor and microbiota-modified bile acids. Understanding the complex and dynamic interplay between dietary metabolites and commensal microbiota within the intestinal microenvironment could therefore inform novel strategies for the treatment of food allergies and inflammatory bowel diseases. PMID:25227295

  13. Lactobacillus GG-fermented milk prevents DSS-induced colitis and regulates intestinal epithelial homeostasis through activation of epidermal growth factor receptor

    PubMed Central

    Yoda, Kazutoyo; Miyazawa, Kenji; Hosoda, Masataka; Hiramatsu, Masaru; Yan, Fang; He, Fang

    2014-01-01

    Background Fermented milk is considered one of the best sources for efficient consumption of probiotic strains by hosts to promote good health. The purpose of this study was to investigate the effects of orally administering LGG-fermented milk (LGG milk) on intestinal inflammation and injury and to study the mechanisms of LGG milk's action. Methods LGG milk and non-LGG-fermented milk (non-LGG milk) were administered through gavage to mice before and during dextran sodium sulfate (DSS)-induced intestinal injury and colitis. Inflammatory/injury score and colon length were assessed. Intestinal epithelial cells were treated with the soluble fraction of LGG milk to detect its effects on the epidermal growth factor receptor (EGFR) and its down stream target, Akt activation, cytokine-induced apoptosis, and hydrogen peroxide (H2O2)-induced disruption of tight junctions. Results LGG milk treatment significantly reduced DSS-induced colonic inflammation and injury, and colon shortening in mice, compared to that in non-LGG milk-treated and untreated mice. The soluble fraction of LGG milk, but not non-LGG milk, stimulated activation of EGFR and Akt in a concentration-dependent manner, suppressed cytokine-induced apoptosis, and attenuated H2O2-induced disruption of tight junction complex in the intestinal epithelial cells. These effects of LGG milk were blocked by the EGFR kinase inhibitor. LGG milk, but not non-LGG milk, contained two soluble proteins, p40 and p75, which have been reported to promote survival and growth of intestinal epithelial cells through activation of EGFR. Depletion of p40 and p75 from LGG milk abolished the effects of LGG milk on prevention of cytokine-induced apoptosis and H2O2-induced disruption of tight junctions. Conclusions These results suggest that LGG milk may regulate intestinal epithelial homeostasis and potentially prevent intestinal inflammatory diseases through activation of EGFR by LGG-derived proteins. PMID:23468308

  14. Non-O1 Vibrio cholerae intestinal pathology and invasion in the removable intestinal tie adult rabbit diarrhea model.

    PubMed Central

    Russell, R G; Tall, B D; Morris, J G

    1992-01-01

    A modified removable intestinal tie adult rabbit diarrhea (RITARD) model was used to investigate the intestinal pathology, intestinal bacterial colonization, intestinal fluid volume, and onset of diarrhea caused by non-O1 Vibrio cholerae. Three strains of non-O1 V. cholerae were studied. RITARD rabbits challenged with 10(3) CFU of strain NRT36S (a strain previously shown to cause diarrhea in volunteers) developed grade 3 diarrhea at 48 to 72 h. The mean counts of non-O1 V. cholerae isolated were 9.3 +/- 0.07 and 8.7 +/- 0.7 CFU/g from the small and large intestines, respectively. Histologic examination showed necrosis of the luminal epithelium in the colon and mild inflammatory cell infiltration in the adjacent lamina propria. The severity and extent of intestinal damage by strain NRT36S was dose dependent. Higher doses of strain NRT36S caused severe necrotizing colitis and enteritis, with bacteremia and mortality at less than 24 h in RITARD rabbits challenged with 10(9) CFU and at less than 48 h in RITARD rabbits challenged with 10(4) CFU. Electron and light microscopy demonstrated invasion of NRT36S into the luminal epithelial cells of the intestine. Challenge of RITARD rabbits with non-O1 V. cholerae A-5 and 2076-79 (strains which did not cause diarrhea in volunteers) did not cause diarrhea or intestinal pathology. Intestinal colonization was transient: at 72 h postchallenge, animals inoculated with strain A-5 were culture negative, while only low numbers of strain 2076-79 were detectable (approximately 0.4 to 0.8 CFU/g). Our data highlight the utility of the RITARD model, when combined with appropriate pathologic and bacteriologic studies, for obtaining insights into pathophysiologic mechanisms of enteric disease by non-O1 V. cholerae. In agreement with volunteer studies, non-O1 V. cholerae NRT36S is clearly pathogenic in this model; direct cell invasion may play a role in its ability to cause illness. Images PMID:1730473

  15. A left-sided periappendiceal abscess in an adult with intestinal malrotation

    PubMed Central

    Lee, Min Ro; Kim, Jong Hun; Hwang, Yong; Kim, Young Kon

    2006-01-01

    Left-sided periappendiceal abscesses occur in association with two types of congenital anomaly: intestinal malrotation and situs inversus. It is difficult to obtain an accurate preoperative diagnosis of these abscesses due to the abnormal position of the appendix. We present an unusual case of a left-sided periappendiceal abscess in an adult with intestinal malrotation, the diagnosis of which was a challenge. PMID:16981277

  16. Micronutrient deficiencies in pediatric and young adult intestinal transplant patients

    PubMed Central

    Ubesie, Agozie C; Cole, Conrad R; Nathan, Jaimie D; Tiao, Greg M; Alonso, Maria H; Mezoff, Adam G; Henderson, Carol J; Kocoshis, Samuel A

    2013-01-01

    Background Intestinal transplant recipients are at risk for micronutrient deficiency due to the slow process of post-transplant adaptation. Another contributing factor is calcineurin inhibitor-induced renal tubular dysfunction. Patients are typically supplemented with micronutrients during parenteral nutrition; however the risk of deficiency may persist even after a successful transition to full enteral nutrition. Objective To determine the prevalence of, and associated risk factors for, iron, zinc, magnesium, phosphorus, selenium, copper, folate, vitamins A, D, E and B12 deficiency in pediatric intestinal transplant recipients after successful transition to full enteral nutrition. Method A retrospective review of prospectively collected data from children who underwent intestinal transplantation at Cincinnati Children's Hospital Medical Center. Deficiencies of various micronutrients were defined using the hospital reference values. Results Twenty-one intestinal transplant recipients, aged one to 23 years that were successfully transitioned to full enteral nutrition were included in the study. The prevalence of micronutrient deficiency was 95.2%. The common deficient micronutrients were iron (94.7%) and magnesium (90.5%). Age ≤10 years (P=0.002) and tube feeding (P= 0.02) were significant risk factors for micronutrient deficiencies. Conclusion Pediatric intestinal transplant recipients have a high risk of micronutrient and mineral deficiencies. These deficiencies were more common among younger patients and those who received jejunal feeding. PMID:23919810

  17. Isolated intestinal transplants vs. liver-intestinal transplants in adult patients in the United States: 22 yr of OPTN data.

    PubMed

    Desai, Chirag S; Gruessner, Angelika C; Khan, Khalid M; Fishbein, Thomas M; Jie, Tun; Rodriguez Rilo, Horacio L; Gruessner, Rainer W G

    2012-01-01

    We examined the outcomes of adult intestinal transplants (ITx); isolated ITx vs. liver-intestinal transplants (L-ITx) were compared using the UNOS database (1987-2009). Of 759 ITx transplants in 687 patients, 463 (61%) were isolated and 296 (39%) were L-ITx. Patient survival for primary isolated ITx at one, three, and five yr was 84%, 66.7%, and 54.2%; and primary L-ITx was, 67%, 53.3%, and 46% (p = 0.0005). Primary isolated ITx graft survival at one, three, and five yr was 80.7%, 57.6%, 42.8%; primary L-ITx was 64.1%, 51%, 44.1% (p = 0.0003 at one, three yr, Wilcoxon test). For retransplants (n = 72), patient and graft survival for isolated ITx (n = 41) at five yr was 40% in era 1 (1987-2000) and 16% in era 2 (p = 0.47); for retransplanted L-ITx (n = 31), it improved from 14% to 64% in era 2 (p = 0.01). Cox regression: creatinine >1.3 mg/dL and pre-transplant hospitalization were negative predictors for outcome of both; bilirubin >1.3 mg/dL was a negative predictor for isolated ITx and donor age >40 yr for L-ITx. Isolated ITx should be considered prior to liver disease for adults with intestinal failure; L-ITx is preferable for retransplantation. PMID:22192061

  18. Zinc sulfide in intestinal cell granules of Ancylostoma caninum adults

    SciTech Connect

    Gianotti, A.J.; Clark, D.T.; Dash, J. )

    1991-04-01

    A source of confusion has existed since the turn of the century about the reddish brown, weakly birefringent 'sphaerocrystals' located in the intestines of strongyle nematodes, Strongylus and Ancylostoma. X-ray diffraction and energy dispersive spectrometric analyses were used for accurate determination of the crystalline order and elemental composition of the granules in the canine hookworm Ancylostoma caninum. The composition of the intestinal pigmented granules was identified unequivocally as zinc sulfide. It seems most probable that the granules serve to detoxify high levels of metallic ions (specifically zinc) present due to the large intake of host blood.

  19. The aryl hydrocarbon receptor/microRNA-212/132 axis in T cells regulates IL-10 production to maintain intestinal homeostasis.

    PubMed

    Chinen, Ichino; Nakahama, Taisuke; Kimura, Akihiro; Nguyen, Nam T; Takemori, Hiroshi; Kumagai, Ayako; Kayama, Hisako; Takeda, Kiyoshi; Lee, Soyoung; Hanieh, Hamza; Ripley, Barry; Millrine, David; Dubey, Praveen K; Nyati, Kishan K; Fujii-Kuriyama, Yoshiaki; Chowdhury, Kamal; Kishimoto, Tadamitsu

    2015-08-01

    Aryl hydrocarbon receptor (Ahr), a transcription factor, plays a critical role in autoimmune inflammation of the intestine. In addition, microRNAs (miRNAs), small non-coding oligonucleotides, mediate pathogenesis of inflammatory bowel diseases (IBD). However, the precise mechanism and interactions of these molecules in IBD pathogenesis have not yet been investigated. We analyzed the role of Ahr and Ahr-regulated miRNAs in colonic inflammation. Our results show that deficiency of Ahr in intestinal epithelial cells in mice exacerbated inflammation in dextran sodium sulfate-induced colitis. Deletion of Ahr in T cells attenuated colitis, which was manifested by suppressed Th17 cell infiltration into the lamina propria. Candidate miRNA analysis showed that induction of colitis elevated expression of the miR-212/132 cluster in the colon of wild-type mice, whereas in Ahr (-/-) mice, expression was clearly lower. Furthermore, miR-212/132(-/-) mice were highly resistant to colitis and had reduced levels of Th17 cells and elevated levels of IL-10-producing CD4(+) cells. In vitro analyses revealed that induction of type 1 regulatory T (Tr1) cells was significantly elevated in miR-212/132(-/-) T cells with increased c-Maf expression. Our findings emphasize the vital role of Ahr in intestinal homeostasis and suggest that inhibition of miR-212/132 represents a viable therapeutic strategy for treating colitis. PMID:25862525

  20. Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of nippostrongylus brasiliensis through induction of Th2 cytokines

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Despite increased appreciation for the role of nicotinic receptors in the modulation of and response to inflammation, the contribution of muscarinic receptors to mucosal homeostasis, clearance of enteric pathogens, and modulation of immune cell function remains relatively undefined. Uninfected and N...

  1. Enterobacteria modulate intestinal bile acid transport and homeostasis through apical sodium-dependent bile acid transporter (SLC10A2) expression.

    PubMed

    Miyata, Masaaki; Yamakawa, Hiroki; Hamatsu, Mayumi; Kuribayashi, Hideaki; Takamatsu, Yuki; Yamazoe, Yasushi

    2011-01-01

    In our study, ampicillin (AMP)-mediated decrease of enterobacteria caused increases in hepatic bile acid concentration through (at least in part) elevation of bile acid synthesis in C57BL/6N mice. We investigated the involvement of enterobacteria on intestinal bile acid absorption in AMP-treated mice in the present study. Fecal enterobacterial levels and fecal bile acid excretion rates were markedly decreased in mice treated with AMP (100 mg/kg) for 3 days, whereas bile acid concentrations in portal blood were significantly increased compared with those in mice treated with a vehicle. Ileal apical sodium-dependent bile acid transporter (SLC10A2) mRNA levels and ileal SLC10A2 protein levels in brush-border membranes were significantly increased compared with those in mice treated with the vehicle. In AMP-treated mice, total bile acid levels were increased, whereas levels of enterobacteria-biotransformed bile acid, taurodeoxycholic acid, and cholic acid were decreased in intestinal lumen. These phenomena were also observed in farnesoid X receptor-null mice treated with AMP for 3 days. Discontinuation of AMP administration after 3 days (vehicle administration for 4 days) increased levels of fecal enterobacteria, fecal bile acid excretion, and taurodeoxycholic acid and cholic acid in the intestinal lumen, whereas the discontinuation decreased ileal SLC10A2 expression and bile acid concentrations in the portal blood. Coadministration of taurodeoxycholic acid or cholic acid decreased ileal SLC10A2 expression in mice treated with AMP. These results suggest that enterobacteria-mediated bile acid biotransformation modulates intestinal bile acid transport and homeostasis through down-regulation of ileal SLC10A2 expression. PMID:20884752

  2. Wandering spleen with gastric volvulus and intestinal non-rotation in an adult male patient.

    PubMed

    Ooka, Minako; Kohda, Eiichi; Iizuka, Yuo; Nagamoto, Masashi; Ishii, Tomotaka; Saida, Yoshihisa; Shimizu, Norikazu; Gomi, Tatsuya

    2013-01-01

    We report an extremely rare case of wandering spleen (WS) complicated with gastric volvulus and intestinal non-rotation in a male adult. A 22-year-old man who had been previously treated for Wilson disease was admitted with severe abdominal pain. Radiological findings showed WS in the midline of the pelvic area. The stomach was mesenteroaxially twisted and intestinal non-rotation was observed. Radiology results did not show any evidence of splenic or gastrointestinal (GI) infarction. Elective emergency laparoscopy confirmed WS and intestinal non-rotation; however, gastric volvulus was not observed. It was suspected that the stomach had untwisted when gastric and laparoscopic tubes were inserted. Surgery is strongly recommended for WS because of the high risk of serious complications; however, some asymptomatic adult patients are still treated conservatively, such as the patient in this study. The present case is reported with reference to the literature. PMID:24349711

  3. Wandering spleen with gastric volvulus and intestinal non-rotation in an adult male patient

    PubMed Central

    Kohda, Eiichi; Iizuka, Yuo; Nagamoto, Masashi; Ishii, Tomotaka; Saida, Yoshihisa; Shimizu, Norikazu; Gomi, Tatsuya

    2013-01-01

    We report an extremely rare case of wandering spleen (WS) complicated with gastric volvulus and intestinal non-rotation in a male adult. A 22-year-old man who had been previously treated for Wilson disease was admitted with severe abdominal pain. Radiological findings showed WS in the midline of the pelvic area. The stomach was mesenteroaxially twisted and intestinal non-rotation was observed. Radiology results did not show any evidence of splenic or gastrointestinal (GI) infarction. Elective emergency laparoscopy confirmed WS and intestinal non-rotation; however, gastric volvulus was not observed. It was suspected that the stomach had untwisted when gastric and laparoscopic tubes were inserted. Surgery is strongly recommended for WS because of the high risk of serious complications; however, some asymptomatic adult patients are still treated conservatively, such as the patient in this study. The present case is reported with reference to the literature. PMID:24349711

  4. Intestinal toxemia botulism in 3 adults, Ontario, Canada, 2006-2008.

    PubMed

    Sheppard, Yolanda D; Middleton, Dean; Whitfield, Yvonne; Tyndel, Felix; Haider, Shariq; Spiegelman, Jamie; Swartz, Richard H; Nelder, Mark P; Baker, Stacey L; Landry, Lisa; Maceachern, Ross; Deamond, Sherri; Ross, Lorrie; Peters, Garth; Baird, Michelle; Rose, David; Sanders, Greg; Austin, John W

    2012-01-01

    Five cases of intestinal toxemia botulism in adults were identified within an 18-month period in or near Toronto, Ontario, Canada. We describe findings for 3 of the 5 case-patients. Clinical samples contained Clostridium botulinum spores and botulinum neurotoxins (types A and B) for extended periods (range 41-61 days), indicative of intestinal toxemia botulism. Patients' clinical signs improved with supportive care and administration of botulinum antitoxin. Peanut butter from the residence of 1 case-patient yielded C. botulinum type A, which corresponded with type A spores found in the patient's feces. The food and clinical isolates from this case-patient could not be distinguished by pulsed-field gel electrophoresis. Two of the case-patients had Crohn disease and had undergone previous bowel surgery, which may have contributed to infection with C. botulinum. These cases reinforce the view that an underlying gastrointestinal condition is a risk factor for adult intestinal toxemia botulism. PMID:22257757

  5. The sexual identity of adult intestinal stem cells controls organ size and plasticity.

    PubMed

    Hudry, Bruno; Khadayate, Sanjay; Miguel-Aliaga, Irene

    2016-02-18

    Sex differences in physiology and disease susceptibility are commonly attributed to developmental and/or hormonal factors, but there is increasing realization that cell-intrinsic mechanisms play important and persistent roles. Here we use the Drosophila melanogaster intestine to investigate the nature and importance of cellular sex in an adult somatic organ in vivo. We find that the adult intestinal epithelium is a cellular mosaic of different sex differentiation pathways, and displays extensive sex differences in expression of genes with roles in growth and metabolism. Cell-specific reversals of the sexual identity of adult intestinal stem cells uncovers the key role this identity has in controlling organ size, reproductive plasticity and response to genetically induced tumours. Unlike previous examples of sexually dimorphic somatic stem cell activity, the sex differences in intestinal stem cell behaviour arise from intrinsic mechanisms that control cell cycle duration and involve a new doublesex- and fruitless-independent branch of the sex differentiation pathway downstream of transformer. Together, our findings indicate that the plasticity of an adult somatic organ is reversibly controlled by its sexual identity, imparted by a new mechanism that may be active in more tissues than previously recognized. PMID:26887495

  6. The sexual identity of adult intestinal stem cells controls organ size and plasticity

    PubMed Central

    Hudry, Bruno; Khadayate, Sanjay; Miguel-Aliaga, Irene

    2016-01-01

    SUMMARY Sex differences in physiology and disease susceptibility are commonly attributed to developmental and/or hormonal factors, but there is increasing realisation that cell-intrinsic mechanisms play important and persistent roles1,2. Here we use the Drosophila melanogaster intestine to investigate the nature and significance of cellular sex in an adult somatic organ in vivo. We find that the adult intestinal epithelium is a cellular mosaic of different sex differentiation pathways, and displays extensive sex differences in expression of genes with roles in growth and metabolism. Cell-specific reversals of the sexual identity of adult intestinal stem cells uncover its key roles in controlling organ size, its reproductive plasticity and its response to genetically induced tumours. Unlike previous examples of sexually dimorphic somatic stem cell activity, the sex differences in intestinal stem cell behaviour arise from intrinsic mechanisms, which control cell cycle duration and involve a new doublesex- and fruitless-independent branch of the sex differentiation pathway downstream of transformer. Together, our findings indicate that the plasticity of an adult somatic organ is reversibly controlled by its sexual identity, imparted by a new mechanism that may be active in more tissues than previously recognised. PMID:26887495

  7. Microbiota-Specific CD4CD8αα Tregs: Role in Intestinal Immune Homeostasis and Implications for IBD

    PubMed Central

    Sarrabayrouse, Guillaume; Alameddine, Joudy; Altare, Frédéric; Jotereau, Francine

    2015-01-01

    In studies in murine models, active suppression by IL-10-secreting Foxp3 regulatory T cells (Tregs) has emerged as an essential mechanism in colon homeostasis. However, the role of the equivalent subset in humans remains unclear, leading to suggestions that other subsets and/or mechanisms may substitute for Foxp3 Tregs in the maintenance of colon homeostasis. We recently described a new subset of CD4CD8αα T cells reactive to the gut bacterium Faecalibacterium prausnitzii and endowed with regulatory/suppressive functions. This subset is abundant in the healthy colonic mucosa, but less common in that of patients with inflammatory bowel disease (IBD). We discuss here the physiological significance and potential role of these Tregs in preventing inflammation of the gut mucosa and the potential applications of these discoveries for IBD management. PMID:26500657

  8. Different functions of intestinal and liver-type fatty acid-binding proteins in intestine and in whole body energy homeostasis.

    PubMed

    Lagakos, William Stacy; Gajda, Angela Marie; Agellon, Luis; Binas, Bert; Choi, Victor; Mandap, Bernadette; Russnak, Timothy; Zhou, Yin Xiu; Storch, Judith

    2011-05-01

    It has long been known that mammalian enterocytes coexpress two members of the fatty acid-binding protein (FABP) family, the intestinal FABP (IFABP) and the liver FABP (LFABP). Both bind long-chain fatty acids and have similar though not identical distributions in the intestinal tract. While a number of in vitro properties suggest the potential for different functions, the underlying reasons for expression of both proteins in the same cells are not known. Utilizing mice genetically lacking either IFABP or LFABP, we directly demonstrate that each of the enterocyte FABPs participates in specific pathways of intestinal lipid metabolism. In particular, LFABP appears to target fatty acids toward oxidative pathways and dietary monoacylglycerols toward anabolic pathways, while IFABP targets dietary fatty acids toward triacylglycerol synthesis. The two FABP-null models also displayed differences in whole body response to fasting, with LFABP-null animals losing less fat-free mass and IFABP-null animals losing more fat mass relative to wild-type mice. The metabolic changes observed in both null models appear to occur by nontranscriptional mechanisms, supporting the hypothesis that the enterocyte FABPs are specifically trafficking their ligands to their respective metabolic fates. PMID:21350192

  9. TLR2-Dependent Signaling for IL-15 Production Is Essential for the Homeostasis of Intestinal Intraepithelial Lymphocytes.

    PubMed

    Qiu, Yuan; Pu, Aimin; Zheng, Hong; Liu, Minqiang; Chen, Weigang; Wang, Wensheng; Xiao, Weidong; Yang, Hua

    2016-01-01

    TLR2 signaling is related to colitis and involved in regulation of innate immunity in the intestinal tract, but the mechanisms remain unclear. The aim of this study is to investigate how TLR2 affects differentiation of intraepithelial lymphocytes (IELs) and regulates the susceptibility of colitis. IELs were isolated from the small intestine and colon of mice, respectively. The IEL phenotype, activation, and apoptosis were examined using flow cytometry and RT-PCR. IL-15 expression and IEL location were detected through immunohistochemistry. The experimental colitis was induced by administration of dextran sulfate sodium (DSS). We found that the numbers of CD8αα (+), CD8αβ (+), and TCRγδ (+) IELs were significantly decreased in TLR2-deficient mice and the residual IELs displayed reduced activation and proliferation and increased apoptosis, accompanied with impaired IL-15 expression by intestinal epithelial cells (IECs). Further study showed that TLR2 signaling maintained the expression of IL-15 in IEC via NF-κB activation. Moreover, TLR2-deficient mice were found to be more susceptible to DSS-induced colitis as shown by the increased severity of colitis. Our results demonstrate that IECs contribute to the maintenance of IELs at least partly via TLR2-dependent IL-15 production, which provides a clue that may link IECs to innate immune protection of the host via IELs. PMID:27563173

  10. TLR2-Dependent Signaling for IL-15 Production Is Essential for the Homeostasis of Intestinal Intraepithelial Lymphocytes

    PubMed Central

    Qiu, Yuan; Pu, Aimin; Liu, Minqiang; Chen, Weigang; Wang, Wensheng

    2016-01-01

    TLR2 signaling is related to colitis and involved in regulation of innate immunity in the intestinal tract, but the mechanisms remain unclear. The aim of this study is to investigate how TLR2 affects differentiation of intraepithelial lymphocytes (IELs) and regulates the susceptibility of colitis. IELs were isolated from the small intestine and colon of mice, respectively. The IEL phenotype, activation, and apoptosis were examined using flow cytometry and RT-PCR. IL-15 expression and IEL location were detected through immunohistochemistry. The experimental colitis was induced by administration of dextran sulfate sodium (DSS). We found that the numbers of CD8αα+, CD8αβ+, and TCRγδ+ IELs were significantly decreased in TLR2-deficient mice and the residual IELs displayed reduced activation and proliferation and increased apoptosis, accompanied with impaired IL-15 expression by intestinal epithelial cells (IECs). Further study showed that TLR2 signaling maintained the expression of IL-15 in IEC via NF-κB activation. Moreover, TLR2-deficient mice were found to be more susceptible to DSS-induced colitis as shown by the increased severity of colitis. Our results demonstrate that IECs contribute to the maintenance of IELs at least partly via TLR2-dependent IL-15 production, which provides a clue that may link IECs to innate immune protection of the host via IELs. PMID:27563173

  11. [Hirschsprung's disease associated with intestinal malrotation in an adult and a review of literature].

    PubMed

    Ko, S; Fujii, H; Yamamoto, K; Sado, S; Yamamoto, M; Nakano, H

    1991-04-01

    A 19-year-old woman was admitted to our clinic because of abdominal distention and severe constipation from infancy. Barium enema revealed a grossly dilated descending colon in the right of the abdomen. At laparotomy, with diagnosis of Hirschsprung's disease associated with non-obstructing intestinal malrotation (non-rotation type), division of the adhesion between caecum and duodenum, and modified Duhamel's procedure were performed. The association of Hirschsprung's disease and intestinal malrotation is rare, and to date only 20 infantile case have been reported. The present case would be the first adult case. PMID:1870577

  12. The Developmental Intestinal Regulator ELT-2 Controls p38-Dependent Immune Responses in Adult C. elegans

    PubMed Central

    Block, Dena H. S.; Twumasi-Boateng, Kwame; Kang, Hae Sung; Carlisle, Jolie A.; Hanganu, Alexandru; Lai, Ty Yu-Jen; Shapira, Michael

    2015-01-01

    GATA transcription factors play critical roles in cellular differentiation and development. However, their roles in mature tissues are less understood. In C. elegans larvae, the transcription factor ELT-2 regulates terminal differentiation of the intestine. It is also expressed in the adult intestine, where it was suggested to maintain intestinal structure and function, and where it was additionally shown to contribute to infection resistance. To study the function of elt-2 in adults we characterized elt-2-dependent gene expression following its knock-down specifically in adults. Microarray analysis identified two ELT-2-regulated gene subsets: one, enriched for hydrolytic enzymes, pointed at regulation of constitutive digestive functions as a dominant role of adult elt-2; the second was enriched for immune genes that are induced in response to Pseudomonas aeruginosa infection. Focusing on the latter, we used genetic analyses coupled to survival assays and quantitative RT-PCR to interrogate the mechanism(s) through which elt-2 contributes to immunity. We show that elt-2 controls p38-dependent gene induction, cooperating with two p38-activated transcription factors, ATF-7 and SKN-1. This demonstrates a mechanism through which the constitutively nuclear elt-2 can impact induced responses, and play a dominant role in C. elegans immunity. PMID:26016853

  13. A Case of Advanced Descending Colon Cancer in an Adult Patient with Intestinal Malrotation

    PubMed Central

    Akiyama, Masaki; Sawatsubashi, Yusuke; Minagawa, Noritaka; Torigoe, Takayuki; Hirata, Keiji

    2016-01-01

    This report presents an operative case of advanced descending colon cancer in an adult patient with intestinal malrotation. A 63-year-old Japanese male was suffering from left side abdominal pain, abdominal distension, and constipation. An endoscopic examination revealed an advanced tumor in the descending colon. Computed tomography (CT) of the abdomen revealed the thickening of the descending colon wall and superior mesenteric vein rotation. An opaque enema detected severe stenosis of the descending colon. An abdominal X-ray examination revealed the dilation of the colon and small intestine with niveau. At the insertion of an ileus tube, the C-loop of the duodenum was observed to be absent and the small intestine was located on the right side of the abdomen. After the decompression of the bowel contents, laparotomy was performed. Descending colon cancer was observed to have directly invaded the left side of the transverse colon. Left hemicolectomy, lymph node dissection, and appendectomy were performed. The patient had an uneventful recovery and was discharged from the hospital on the 16th day after surgery. This report presents a rare operative case of descending colon cancer in an adult patient with intestinal malrotation. PMID:27042367

  14. Guidelines for management of home parenteral support in adult chronic intestinal failure patients.

    PubMed

    Messing, Bernard; Joly, Francisca

    2006-02-01

    Management of home parenteral support in adult benign but chronic intestinal failure patients requires a nutrition support team using disease-specific pathways. Education of patients to ensure they self manage home parenteral nutrition (HPN) is cornerstone to obtain minimal rate of technical complications and improvement in quality of life. Nutritive mixtures, compounded by pharmacists in single "all-in-one" bags, must be tailored according to the nutritional and intestinal status of individual patients with definition of macronutrients and water-electrolyte needs, respectively. Each PN cycle should be complete in essential nutrients to be nutritionally efficient and should have sufficient amounts of amino acids, dextrose, water, minerals, and micronutrients to avoid deficiency. When the nutritional goal is achieved, a minimum number of PN cycles per week should be implemented, guided ideally by digestive balance(s) (In-Out) of macronutrients and minerals of individual patients. Indeed, HPN is, in most cases, a complementary nonexclusive mode of nutritional support. In short gut patients--who represent 75% of chronic intestinal failure patients--encouraging enteral feeding decrease PN delivery and the risk of metabolic liver disease associated with HPN. In short gut patients with no severe renal impairment, blood citrulline dosage, in association with the remnant anatomy, is a tool to delineate transient from permanent intestinal failure. The latter group includes candidates for trophic gut factors and rehabilitative or reconstructive surgery, including intestinal transplantation. Thus, outcome improvement for intestinal failure patients needs intestinal failure teams having expertise in all medical and surgical aspects of this field. PMID:16473071

  15. Nuclear factor-E2-related factor 2 is a major determinant of bile acid homeostasis in the liver and intestine

    PubMed Central

    Weerachayaphorn, Jittima; Mennone, Albert; Soroka, Carol J.; Harry, Kathy; Hagey, Lee R.; Kensler, Thomas W.

    2012-01-01

    The transcription factor nuclear factor-E2-related factor 2 (Nrf2) is a key regulator for induction of hepatic detoxification and antioxidant mechanisms, as well as for certain hepatobiliary transporters. To examine the role of Nrf2 in bile acid homeostasis and cholestasis, we assessed the determinants of bile secretion and bile acid synthesis and transport before and after bile duct ligation (BDL) in Nrf2−/− mice. Our findings indicate reduced rates of biliary bile acid and GSH excretion, higher levels of intrahepatic bile acids, and decreased expression of regulators of bile acid synthesis, Cyp7a1 and Cyp8b1, in Nrf2−/− compared with wild-type control mice. The mRNA expression of the bile acid transporters bile salt export pump (Bsep) and organic solute transporter (Ostα) were increased in the face of impaired expression of the multidrug resistance-associated proteins Mrp3 and Mrp4. Deletion of Nrf2 also decreased ileal apical sodium-dependent bile acid transporter (Asbt) expression, leading to reduced bile acid reabsorption and increased loss of bile acid in feces. Finally, when cholestasis is induced by BDL, liver injury was not different from that in wild-type BDL mice. These Nrf2−/− mice also had increased pregnane X receptor (Pxr) and Cyp3a11 mRNA expression in association with enhanced hepatic bile acid hydroxylation. In conclusion, this study finds that Nrf2 plays a major role in the regulation of bile acid homeostasis in the liver and intestine. Deletion of Nrf2 results in a cholestatic phenotype but does not augment liver injury following BDL. PMID:22345550

  16. PepT1 Expression Helps Maintain Intestinal Homeostasis by Mediating the Differential Expression of miRNAs along the Crypt-Villus Axis.

    PubMed

    Zhang, Yuchen; Viennois, Emilie; Zhang, Mingzhen; Xiao, Bo; Han, Moon Kwon; Walter, Lewins; Garg, Pallavi; Merlin, Didier

    2016-01-01

    In the jejunum, PepT1 is particularly enriched in the well-differentiated absorptive epithelial cells in the villi. Studies of expression and function of PepT1 along the crypt-villus axis demonstrated that this protein is crucial to the process of di/tripeptide absorption. We recently exhibited that PepT1 plays an important role in multiple biological functions, including the ability to regulate the expression/secretion of specific microRNAs (miRNAs) and the expression levels of multiple proteins. In this study, we observed that PepT1 knockout (KO) mice exhibited reduced body weight and shorten intestinal microvilli. We then examined the expression levels of various miRNAs and their target proteins along the crypt-villi axis in the jejunum of PepT1 KO mice. We found that PepT1 KO altered the distribution of miRNAs along the crypt-villus axis and changed the miRNA profiles of both villi and crypts. Using miRNA-target prediction and 2D-DIGE/mass spectrometry on villi and crypts samples, we found that ablation of PepT1 further directly or indirectly altered expression levels of certain protein targets. Collectively, our results suggest that PepT1 contributes to maintain balance of homeostasis and proper functions in the small intestine, and dysregulated miRNAs and proteins along the crypt-villus axis are highly related to this process. PMID:27250880

  17. PepT1 Expression Helps Maintain Intestinal Homeostasis by Mediating the Differential Expression of miRNAs along the Crypt-Villus Axis

    PubMed Central

    Zhang, Yuchen; Viennois, Emilie; Zhang, Mingzhen; Xiao, Bo; Han, Moon Kwon; Walter, Lewins; Garg, Pallavi; Merlin, Didier

    2016-01-01

    In the jejunum, PepT1 is particularly enriched in the well-differentiated absorptive epithelial cells in the villi. Studies of expression and function of PepT1 along the crypt-villus axis demonstrated that this protein is crucial to the process of di/tripeptide absorption. We recently exhibited that PepT1 plays an important role in multiple biological functions, including the ability to regulate the expression/secretion of specific microRNAs (miRNAs) and the expression levels of multiple proteins. In this study, we observed that PepT1 knockout (KO) mice exhibited reduced body weight and shorten intestinal microvilli. We then examined the expression levels of various miRNAs and their target proteins along the crypt-villi axis in the jejunum of PepT1 KO mice. We found that PepT1 KO altered the distribution of miRNAs along the crypt-villus axis and changed the miRNA profiles of both villi and crypts. Using miRNA-target prediction and 2D-DIGE/mass spectrometry on villi and crypts samples, we found that ablation of PepT1 further directly or indirectly altered expression levels of certain protein targets. Collectively, our results suggest that PepT1 contributes to maintain balance of homeostasis and proper functions in the small intestine, and dysregulated miRNAs and proteins along the crypt-villus axis are highly related to this process. PMID:27250880

  18. Contribution of Fetal, but Not Adult, Pulmonary Mesothelium to Mesenchymal Lineages in Lung Homeostasis and Fibrosis.

    PubMed

    von Gise, Alexander; Stevens, Sean M; Honor, Leah B; Oh, Jin Hee; Gao, Chi; Zhou, Bin; Pu, William T

    2016-02-01

    The lung is enveloped by a layer of specialized epithelium, the pulmonary mesothelium. In other organs, mesothelial cells undergo epithelial-mesenchymal transition and contribute to organ stromal cells. The contribution of pulmonary mesothelial cells (PMCs) to the developing lung has been evaluated with differing conclusions. PMCs have also been indirectly implicated in lung fibrosis in the progressive, fatal lung disease idiopathic pulmonary fibrosis. We used fetal or postnatal genetic pulse labeling of PMCs to assess their fate in murine development, normal lung homeostasis, and models of pulmonary fibrosis. We found that most fetal PMC-derived mesenchymal cells (PMCDCs) expressed markers of pericytes and fibroblasts, only a small minority expressed smooth muscle markers, and none expressed endothelial cell markers. Postnatal PMCs did not contribute to lung mesenchyme during normal lung homeostasis or in models of lung fibrosis. However, fetal PMCDCs were abundant and actively proliferating within fibrotic regions in lung fibrosis models, suggesting that they actively participate in the fibrotic process. These data clarify the role of fetal and postnatal PMCDCs in lung development and disease. PMID:26121126

  19. Intestinal helminth infections amongst HIV-infected adults in Mthatha General Hospital, South Africa

    PubMed Central

    Yogeswaran, Parimalaranie; Wright, Graham

    2015-01-01

    Background In South Africa, studies on the prevalence of intestinal helminth co-infection amongst HIV-infected patients as well as possible interactions between these two infections are limited. Aim To investigate the prevalence of intestinal helminth infestation amongst adults living with HIV or AIDS at Mthatha General Hospital. Setting Study participants were recruited at the outpatient department of Mthatha General Hospital, Mthatha, South Africa. Methods This cross-sectional study was conducted between October and December 2013 amongst consecutive consenting HIV-positive adult patients. Socio-demographic and clinical information were obtained using data collection forms and structured interviews. Stool samples were collected to investigate the presence of helminths whilst blood samples were obtained for the measurement of CD4+ T-cell count and viral load. Results Data were obtained on 231 participants, with a mean age of 34.9 years, a mean CD4 count of 348 cells/µL and a mean viral load of 4.8 log10 copies/mL. Intestinal helminth prevalence was 24.7%, with Ascaris Lumbricoides (42.1%) the most prevalent identified species. Statistically significant association was found between CD4 count of less than 200 cells/µL and helminth infection (p = 0.05). No statistically significant association was found between intestinal helminth infection and the mean CD4 count (p = 0.79) or the mean viral load (p = 0.98). Conclusion A high prevalence of intestinal helminth infections was observed amongst the study population. Therefore, screening and treatment of helminths should be considered as part of the management of HIV and AIDS in primary health care. PMID:26842519

  20. Characterization of Intestinal Bacteria in Wild and Domesticated Adult Black Tiger Shrimp (Penaeus monodon)

    PubMed Central

    Rungrassamee, Wanilada; Klanchui, Amornpan; Maibunkaew, Sawarot; Chaiyapechara, Sage; Jiravanichpaisal, Pikul; Karoonuthaisiri, Nitsara

    2014-01-01

    The black tiger shrimp (Penaeus monodon) is a marine crustacean of economic importance in the world market. To ensure sustainability of the shrimp industry, production capacity and disease outbreak prevention must be improved. Understanding healthy microbial balance inside the shrimp intestine can provide an initial step toward better farming practice and probiotic applications. In this study, we employed a barcode pyrosequencing analysis of V3-4 regions of 16S rRNA genes to examine intestinal bacteria communities in wild-caught and domesticated P. monodon broodstock. Shrimp faeces were removed from intestines prior to further analysis in attempt to identify mucosal bacterial population. Five phyla, Actinobacteria, Fusobacteria, Proteobacteria, Firmicutes and Bacteroidetes, were found in all shrimp from both wild and domesticated environments. The operational taxonomic unit (OTU) was assigned at 97% sequence identity, and our pyrosequencing results identified 18 OTUs commonly found in both groups. Sequences of the shared OTUs were similar to bacteria in three phyla, namely i) Proteobacteria (Vibrio, Photobacterium, Novosphingobium, Pseudomonas, Sphingomonas and Undibacterium), ii) Firmicutes (Fusibacter), and iii) Bacteroidetes (Cloacibacterium). The shared bacterial members in P. monodon from two different habitats provide evidence that the internal environments within the host shrimp also exerts selective pressure on bacterial members. Intestinal bacterial profiles were compared using denaturing gradient gel electrophoresis (DGGE). The sequences from DGGE bands were similar to those of Vibrio and Photobacterium in all shrimp, consistent with pyrosequencing results. This work provides the first comprehensive report on bacterial populations in the intestine of adult black tiger shrimp and reveals some similar bacterial members between the intestine of wild-caught and domesticated shrimp. PMID:24618668

  1. FSTL3 deletion reveals roles for TGF-β family ligands in glucose and fat homeostasis in adults

    PubMed Central

    Mukherjee, Abir; Sidis, Yisrael; Mahan, Amy; Raher, Michael J.; Xia, Yin; Rosen, Evan D.; Bloch, Kenneth D.; Thomas, Melissa K.; Schneyer, Alan L.

    2007-01-01

    Activin and myostatin are related members of the TGF-β growth factor superfamily. FSTL3 (Follistatin-like 3) is an activin and myostatin antagonist whose physiological role in adults remains to be determined. We found that homozygous FSTL3 knockout adults developed a distinct group of metabolic phenotypes, including increased pancreatic islet number and size, β cell hyperplasia, decreased visceral fat mass, improved glucose tolerance, and enhanced insulin sensitivity, changes that might benefit obese, insulin-resistant patients. The mice also developed hepatic steatosis and mild hypertension but exhibited no alteration of muscle or body weight. This combination of phenotypes appears to arise from increased activin and myostatin bioactivity in specific tissues resulting from the absence of the FSTL3 antagonist. Thus, the enlarged islets and β cell number likely result from increased activin action. Reduced visceral fat is consistent with a role for increased myostatin action in regulating fat deposition, which, in turn, may be partly responsible for the enhanced glucose tolerance and insulin sensitivity. Our results demonstrate that FSTL3 regulation of activin and myostatin is critical for normal adult metabolic homeostasis, suggesting that pharmacological manipulation of FSTL3 activity might simultaneously reduce visceral adiposity, increase β cell mass, and improve insulin sensitivity. PMID:17229845

  2. Insulin signaling and the heat shock response modulate protein homeostasis in the Caenorhabditis elegans intestine during infection.

    PubMed

    Mohri-Shiomi, Akiko; Garsin, Danielle A

    2008-01-01

    During infection, damage can occur to the host as an outcome of both pathogen virulence mechanisms and host defense strategies. Using aggregation of a model polyglutamine-containing protein as an indicator in Caenorhabditis elegans, we show that protein damage occurs specifically at the site of the host-pathogen interaction, the intestine, in response to various bacterial pathogens. We demonstrate that the insulin signaling pathway and the heat shock transcription factor (HSF-1) influence the amount of aggregation that occurs, in addition to heat shock proteins and oxidative stress enzymes. We also show that addition of the antioxidants epigallocatechin gallate and alpha-lipoic acid reduces polyglutamine aggregation. The influence of oxidative stress enzymes and exogenous antioxidants on protein aggregation suggests that reactive oxygen species produced by the host are a source of protein damage during infection. We propose a model in which heat shock proteins and oxidative stress enzymes regulated by insulin signaling and HSF-1 are required for tissue protection during infection, to minimize the effects of protein damage occurring as a result of host-pathogen interactions. PMID:17951251

  3. Administration of Lactobacillus evokes coordinated changes in the intestinal expression profile of genes regulating energy homeostasis and immune phenotype in mice.

    PubMed

    Nerstedt, Annika; Nilsson, Elisabeth C; Ohlson, Kajsa; Håkansson, Janet; Thomas Svensson, L; Löwenadler, Björn; Svensson, Ulla K; Mahlapuu, Margit

    2007-06-01

    Lactic acid bacteria are probiotics widely used in functional food products, with a variety of beneficial effects reported. Recently, intense research has been carried out to provide insight into the mechanism of the action of probiotic bacteria. We have used gene array technology to map the pattern of changes in the global gene expression profile of the host caused by Lactobacillus administration. Affymetrix microarrays were applied to comparatively characterize differences in gene transcription in the distal ileum of normal microflora (NMF) and germ-free (GF) mice evoked by oral administration of two Lactobacillus strains used in fermented dairy products today - Lactobacillus paracasei ssp. paracasei F19 (L. F19) or Lactobacillus acidophilus NCFB 1748. We show that feeding either of the two strains caused very similar effects on the transcriptional profile of the host. Both L. F19 and L. acidophilus NCFB 1748 evoked a complex response in the gut, reflected by differential regulation of a number of genes involved in essential physiological functions such as immune response, regulation of energy homeostasis and host defence. Notably, the changes in intestinal gene expression caused by Lactobacillus were different in the mice raised under GF v. NMF conditions, underlying the complex and dynamic nature of the host-commensal relationship. Differential expression of an array of genes described in this report evokes novel hypothesis of possible interactions between the probiotic bacteria and the host organism and warrants further studies to evaluate the functional significance of these transcriptional changes on the metabolic profile of the host. PMID:17433125

  4. The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration

    PubMed Central

    Shaw, Rachael L.; Kohlmaier, Alexander; Polesello, Cédric; Veelken, Cornelia; Edgar, Bruce A.; Tapon, Nicolas

    2010-01-01

    Intestinal stem cells (ISCs) in the adult Drosophila midgut proliferate to self-renew and to produce differentiating daughter cells that replace those lost as part of normal gut function. Intestinal stress induces the activation of Upd/Jak/Stat signalling, which promotes intestinal regeneration by inducing rapid stem cell proliferation. We have investigated the role of the Hippo (Hpo) pathway in the Drosophila intestine (midgut). Hpo pathway inactivation in either the ISCs or the differentiated enterocytes induces a phenotype similar to that observed under stress situations, including increased stem cell proliferation and expression of Jak/Stat pathway ligands. Hpo pathway targets are induced by stresses such as bacterial infection, suggesting that the Hpo pathway functions as a sensor of cellular stress in the differentiated cells of the midgut. In addition, Yki, the pro-growth transcription factor target of the Hpo pathway, is required in ISCs to drive the proliferative response to stress. Our results suggest that the Hpo pathway is a mediator of the regenerative response in the Drosophila midgut. PMID:21068063

  5. DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport

    PubMed Central

    Bernier-Latmani, Jeremiah; Cisarovsky, Christophe; Demir, Cansaran Saygili; Bruand, Marine; Jaquet, Muriel; Davanture, Suzel; Ragusa, Simone; Siegert, Stefanie; Dormond, Olivier; Benedito, Rui; Radtke, Freddy; Luther, Sanjiv A.; Petrova, Tatiana V.

    2015-01-01

    The small intestine is a dynamic and complex organ that is characterized by constant epithelium turnover and crosstalk among various cell types and the microbiota. Lymphatic capillaries of the small intestine, called lacteals, play key roles in dietary fat absorption and the gut immune response; however, little is known about the molecular regulation of lacteal function. Here, we performed a high-resolution analysis of the small intestinal stroma and determined that lacteals reside in a permanent regenerative, proliferative state that is distinct from embryonic lymphangiogenesis or quiescent lymphatic vessels observed in other tissues. We further demonstrated that this continuous regeneration process is mediated by Notch signaling and that the expression of the Notch ligand delta-like 4 (DLL4) in lacteals requires activation of VEGFR3 and VEGFR2. Moreover, genetic inactivation of Dll4 in lymphatic endothelial cells led to lacteal regression and impaired dietary fat uptake. We propose that such a slow lymphatic regeneration mode is necessary to match a unique need of intestinal lymphatic vessels for both continuous maintenance, due to the constant exposure to dietary fat and mechanical strain, and efficient uptake of fat and immune cells. Our work reveals how lymphatic vessel responses are shaped by tissue specialization and uncover a role for continuous DLL4 signaling in the function of adult lymphatic vasculature. PMID:26529256

  6. Activation of Sox3 Gene by Thyroid Hormone in the Developing Adult Intestinal Stem Cell During Xenopus Metamorphosis

    PubMed Central

    Sun, Guihong; Fu, Liezhen; Wen, Luan

    2014-01-01

    The maturation of the intestine into the adult form involves the formation of adult stem cells in a thyroid hormone (T3)-dependent process in vertebrates. In mammals, this takes place during postembryonic development, a period around birth when the T3 level peaks. Due to the difficulty of manipulating late-stage, uterus-enclosed embryos, very little is known about the development of the adult intestinal stem cells. Interestingly, the remodeling of the intestine during the T3-dependent amphibian metamorphosis mimics the maturation of mammalian intestine. Our earlier microarray studies in Xenopus laevis revealed that the transcription factor SRY (sex-determining region Y)-box 3 (Sox3), well known for its involvement in neural development, was upregulated in the intestinal epithelium during metamorphosis. Here, we show that Sox3 is highly and specifically expressed in the developing adult intestinal progenitor/stem cells. We further show that its induction by T3 is independent of new protein synthesis, suggesting that Sox3 is directly activated by liganded T3 receptor. Thus, T3 activates Sox3 as one of the earliest changes in the epithelium, and Sox3 in turn may facilitate the dedifferentiation of the larval epithelial cells into adult stem cells. PMID:25211587

  7. Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

    PubMed Central

    Mullenders, Jasper; Aranda-Orgilles, Beatriz; Lhoumaud, Priscillia; Keller, Matthew; Pae, Juhee; Wang, Kun; Kayembe, Clarisse; Rocha, Pedro P.; Raviram, Ramya; Gong, Yixiao; Premsrirut, Prem K.; Tsirigos, Aristotelis; Bonneau, Richard; Skok, Jane A.; Cimmino, Luisa; Hoehn, Daniela

    2015-01-01

    The cohesin complex (consisting of Rad21, Smc1a, Smc3, and Stag2 proteins) is critically important for proper sister chromatid separation during mitosis. Mutations in the cohesin complex were recently identified in a variety of human malignancies including acute myeloid leukemia (AML). To address the potential tumor-suppressive function of cohesin in vivo, we generated a series of shRNA mouse models in which endogenous cohesin can be silenced inducibly. Notably, silencing of cohesin complex members did not have a deleterious effect on cell viability. Furthermore, knockdown of cohesin led to gain of replating capacity of mouse hematopoietic progenitor cells. However, cohesin silencing in vivo rapidly altered stem cells homeostasis and myelopoiesis. Likewise, we found widespread changes in chromatin accessibility and expression of genes involved in myelomonocytic maturation and differentiation. Finally, aged cohesin knockdown mice developed a clinical picture closely resembling myeloproliferative disorders/neoplasms (MPNs), including varying degrees of extramedullary hematopoiesis (myeloid metaplasia) and splenomegaly. Our results represent the first successful demonstration of a tumor suppressor function for the cohesin complex, while also confirming that cohesin mutations occur as an early event in leukemogenesis, facilitating the potential development of a myeloid malignancy. PMID:26438359

  8. Congenital intestinal malrotation in adolescent and adult patients: a 12-year clinical and radiological survey.

    PubMed

    Husberg, Britt; Salehi, Karin; Peters, Trevor; Gunnarsson, Ulf; Michanek, Margareta; Nordenskjöld, Agneta; Strigård, Karin

    2016-01-01

    Congenital intestinal malrotation is mainly detected in childhood and caused by incomplete rotation and fixation of the intestines providing the prerequisites for life-threatening volvulus of the midgut. The objective of this study was to evaluate a large cohort of adult patients with intestinal malrotation. Thirty-nine patients, 15-67 years, were diagnosed and admitted to a university setting with congenital intestinal malrotation 2002-2013. The patients were divided into three age groups for stratified evaluation. Medical charts were scrutinized, and clinical outcome of surgery was reviewed. Twelve patients presented as emergency cases, whereas 27 were admitted as elective cases. Diagnosis was established in 33 patients who underwent radiological investigation and in the remaining 6 during surgery. A Ladd's operation was performed in 31 symptomatic patients; a conservative strategy was chosen in eight cases. Volvulus was more common in the younger age group. Twenty-six surgically treated patients were available for telephone interview, 1-12 years after surgery. All patients, except one, regarded their general condition improved to a high degree (n = 18) or with some reservation (n = 7). Twelve patients suffered remaining abdominal pain of a chronic and diffuse character. Due to recurrence of malrotation six patients were reoperated. Symptomatic malrotation occurs in both children and the adult population. Improved awareness and an accurately performed CT scan can reveal the malformation and enable surgical treatment. A Ladd's procedure relieved most patients from their severe complaints even when a history of several years of suffering existed. PMID:27026938

  9. Clinical characteristics of chronic idiopathic intestinal pseudo-obstruction in adults

    PubMed Central

    Mann, S; Debinski, H; Kamm, M

    1997-01-01

    prolonged, and prokinetic drug therapies are not usually helpful. Ongoing management problems include pain relief and nutritional support. 

 Keywords: adult; intestinal; pseudo-obstruction; myopathy; neuropathy PMID:9414977

  10. Current Understanding of the Pathways Involved in Adult Stem and Progenitor Cell Migration for Tissue Homeostasis and Repair.

    PubMed

    Goichberg, Polina

    2016-08-01

    With the advancements in the field of adult stem and progenitor cells grows the recognition that the motility of primitive cells is a pivotal aspect of their functionality. There is accumulating evidence that the recruitment of tissue-resident and circulating cells is critical for organ homeostasis and effective injury responses, whereas the pathobiology of degenerative diseases, neoplasm and aging, might be rooted in the altered ability of immature cells to migrate. Furthermore, understanding the biological machinery determining the translocation patterns of tissue progenitors is of great relevance for the emerging methodologies for cell-based therapies and regenerative medicine. The present article provides an overview of studies addressing the physiological significance and diverse modes of stem and progenitor cell trafficking in adult mammalian organs, discusses the major microenvironmental cues regulating cell migration, and describes the implementation of live imaging approaches for the exploration of stem cell movement in tissues and the factors dictating the motility of endogenous and transplanted cells with regenerative potential. PMID:27209167

  11. Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice

    PubMed Central

    Besnard, Valérie; Matsuzaki, Yohei; Clark, Jean; Xu, Yan; Wert, Susan E.; Ikegami, Machiko; Stahlman, Mildred T.; Weaver, Timothy E.; Hunt, Alan N.; Postle, Anthony D.

    2010-01-01

    ATP-binding cassette A3 (ABCA3) is a lipid transport protein required for synthesis and storage of pulmonary surfactant in type II cells in the alveoli. Abca3 was conditionally deleted in respiratory epithelial cells (Abca3Δ/Δ) in vivo. The majority of mice in which Abca3 was deleted in alveolar type II cells died shortly after birth from respiratory distress related to surfactant deficiency. Approximately 30% of the Abca3Δ/Δ mice survived after birth. Surviving Abca3Δ/Δ mice developed emphysema in the absence of significant pulmonary inflammation. Staining of lung tissue and mRNA isolated from alveolar type II cells demonstrated that ∼50% of alveolar type II cells lacked ABCA3. Phospholipid content and composition were altered in lung tissue, lamellar bodies, and bronchoalveolar lavage fluid from adult Abca3Δ/Δ mice. In adult Abca3Δ/Δ mice, cells lacking ABCA3 had decreased expression of mRNAs associated with lipid synthesis and transport. FOXA2 and CCAAT enhancer-binding protein-α, transcription factors known to regulate genes regulating lung lipid metabolism, were markedly decreased in cells lacking ABCA3. Deletion of Abca3 disrupted surfactant lipid synthesis in a cell-autonomous manner. Compensatory surfactant synthesis was initiated in ABCA3-sufficient type II cells, indicating that surfactant homeostasis is a highly regulated process that includes sensing and coregulation among alveolar type II cells. PMID:20190032

  12. Wnt pathway regulation of intestinal stem cells.

    PubMed

    Mah, Amanda T; Yan, Kelley S; Kuo, Calvin J

    2016-09-01

    Wnt signalling is involved in multiple aspects of embryonic development and adult tissue homeostasis, notably via controlling cellular proliferation and differentiation. Wnt signalling is subject to stringent positive and negative regulation to promote proper development and homeostasis yet avoid aberrant growth. Such multi-layer regulation includes post-translational modification and processing of Wnt proteins themselves, R-spondin (Rspo) amplification of Wnt signalling, diverse receptor families, and intracellular and extracellular antagonists and destruction and transcription complexes. In the gastrointestinal tract, Wnt signalling is crucial for development and renewal of the intestinal epithelium. Intestinal stem cells (ISCs) undergo symmetric division and neutral drift dynamics to renew the intestinal epithelium. Sources of Wnts and Wnt amplifers such as R-spondins are beginning to be elucidated as well as their functional contribution to intestinal homeostasis. In this review we focus on regulation of ISCs and intestinal homeostasis by the Wnt/Rspo pathway, the potential cellular sources of Wnt signalling regulators and highlight potential future areas of study. PMID:27581568

  13. Rac1 drives intestinal stem cell proliferation and regeneration

    PubMed Central

    Myant, Kevin B; Scopelliti, Alessandro; Haque, Sara; Vidal, Marcos; Sansom, Owen J; Cordero, Julia B

    2013-01-01

    Adult stem cells are responsible for maintaining the balance between cell proliferation and differentiation within self-renewing tissues. The molecular and cellular mechanisms mediating such balance are poorly understood. The production of reactive oxygen species (ROS) has emerged as an important mediator of stem cell homeostasis in various systems. Our recent work demonstrates that Rac1-dependent ROS production mediates intestinal stem cell (ISC) proliferation in mouse models of colorectal cancer (CRC). Here, we use the adult Drosophila midgut and the mouse small intestine to directly address the role of Rac1 in ISC proliferation and tissue regeneration in response to damage. Our results demonstrate that Rac1 is necessary and sufficient to drive ISC proliferation and regeneration in an ROS-dependent manner. Our data point to an evolutionarily conserved role of Rac1 in intestinal homeostasis and highlight the value of combining work in the mammalian and Drosophila intestine as paradigms to study stem cell biology. PMID:23974108

  14. Intestinal barrier: Molecular pathways and modifiers.

    PubMed

    Jeon, Min Kyung; Klaus, Christina; Kaemmerer, Elke; Gassler, Nikolaus

    2013-11-15

    The gastrointestinal tract is frequently challenged by pathogens/antigens contained in food and water and the intestinal epithelium must be capable of rapid regeneration in the event of tissue damage. Disruption of the intestinal barrier leads to a number of immune-mediated diseases, including inflammatory bowel disease, food allergy, and celiac disease. The intestinal mucosa is composed of different types of epithelial cells in specific barrier functions. Epithelial cells control surface-associated bacterial populations without disrupting the intestinal microflora that is crucial for host health. They are also capable of modulating mucosal immune system, and are thus essential in maintaining homeostasis in the gut. Thus, the regulation of intestinal epithelial homeostasis is crucial for the maintenance of the structure of the mucosa and the defensive barrier functions. Recent studies have demonstrated that multiple molecular pathways are involved in the regulation of intestinal epithelial cell polarity. These include the Wnt, Notch, Hippo, transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) and Hedgehog pathways, most of which were identified in lower organisms where they play important roles during embryogenesis. These pathways are also used in adult organisms to regulate multiple self-renewing organs. Understanding the interactions between these molecular mechanisms and intestinal barrier function will therefore provide important insight into the pathogenesis of intestinal-based immune-mediated diseases. PMID:24244877

  15. Xenobiotic Effects on Intestinal Stem Cell Proliferation in Adult Honey Bee (Apis mellifera L) Workers

    PubMed Central

    Forkpah, Cordelia; Dixon, Luke R.; Fahrbach, Susan E.; Rueppell, Olav

    2014-01-01

    The causes of the current global decline in honey bee health are unknown. One major group of hypotheses invokes the pesticides and other xenobiotics to which this important pollinator species is often exposed. Most studies have focused on mortality or behavioral deficiencies in exposed honey bees while neglecting other biological functions and target organs. The midgut epithelium of honey bees presents an important interface between the insect and its environment. It is maintained by proliferation of intestinal stem cells throughout the adult life of honey bees. We used caged honey bees to test multiple xenobiotics for effects on the replicative activity of the intestinal stem cells under laboratory conditions. Most of the tested compounds did not alter the replicative activity of intestinal stem cells. However, colchicine, methoxyfenozide, tetracycline, and a combination of coumaphos and tau-fluvalinate significantly affected proliferation rate. All substances except methoxyfenozide decreased proliferation rate. Thus, the results indicate that some xenobiotics frequently used in apiculture and known to accumulate in honey bee hives may have hitherto unknown physiological effects. The nutritional status and the susceptibility to pathogens of honey bees could be compromised by the impacts of xenobiotics on the maintenance of the midgut epithelium. This study contributes to a growing body of evidence that more comprehensive testing of xenobiotics may be required before novel or existing compounds can be considered safe for honey bees and other non-target species. PMID:24608542

  16. [An adult with mechanical ileus in association with non-rotation of the intestine].

    PubMed

    Andriessen, M J G; Koop, K A; Consten, E C J

    2005-05-01

    A mechanical ileus was considered in the differential diagnosis of a 28-year-old man who presented to the Emergency Clinic with acute, severe, painful cramps in the lower abdomen of 2 hours' duration, without radiation and with an urge to move constantly. An emergency laparotomy was then performed, revealing non-rotation of the intestine; the last segment ofthe small intestine was pinched off by a strangulation. Several strangulations were cleaved, after which the symptoms disappeared. Non-rotation, a form of malrotation, is a congenital anomaly of intestinal rotation. In adults, non-rotation is a rare diagnosis with a variable presentation. Surgical intervention is necessary in both the acute and the more chronic presentation. The chronic presentation is usually discovered by chance in patients who have had aspecific recurrent abdominal complaints for a long time; if malrotation is suspected, additional investigation, for example by means of a gastrointestinal contrast study, is necessary before resorting to surgery. In the acute situation, immediate surgery is the only proper decision. Surgical intervention comprises reduction of the volvulus, inspection of the mesenteric bands (Ladd's bands) that run from the coecum to the lateral peritoneum and compress the duodenum, and an appendectomy: the Ladd procedure. PMID:15909395

  17. Ileal duplication mimicking intestinal intussusception: a congenital condition rarely reported in adult.

    PubMed

    Li, Bing-Lu; Huang, Xin; Zheng, Chao-Ji; Zhou, Jiao-Lin; Zhao, Yu-Pei

    2013-10-14

    Intestinal duplication is an uncommon congenital condition in young adults. A 25-year-old man complained of chronic, intermittent abdominal pain for 3 years following previous appendectomy for the treatment of suspected appendicitis. Abdominal discomfort and pain, suggestive of intestinal obstruction, recurred after operation. A tubular mass was palpable in the right lower quadrant. Computed tomography enterography scan identified suspicious intestinal intussusception, while Tc-99m pertechnetate scintigraphy revealed a cluster of strip-like abnormal radioactivity in the right lower quadrant. On exploratory laparotomy, a tubular-shaped ileal duplication cyst was found arising from the mesenteric margin of the native ileal segment located 15 cm proximal to the ileocecal valve. Ileectomy was performed along with the removal of the duplication disease, and the end-to-end anastomosis was done to restore the gastrointestinal tract continuity. Pathological examination showed ileal duplication with ectopic gastric mucosa. The patient experienced an eventless postoperative recovery and remained asymptomatic within 2 years of postoperative follow-up. PMID:24151372

  18. Intestine-specific Deletion of Sirt1 in Mice Impairs DCoH2–HNF1α–FXR Signaling and Alters Systemic Bile Acid Homeostasis

    PubMed Central

    Kazgan, Nevzat; Metukuri, Mallikarjuna R.; Purushotham, Aparna; Lu, Jing; Rao, Anuradha; Lee, Sangkyu; Pratt-Hyatt, Matthew; Lickteig, Andrew; Csanaky, Ivan; Zhao, Yingming; Dawson, Paul A.; Li, Xiaoling

    2014-01-01

    Background & Aims Sirtuin 1 (SIRT1), the most conserved mammalian NAD+-dependent protein deacetylase, is an important metabolic sensor in many tissues. However, little is known about its role in the small intestine, which absorbs and senses nutrients. We investigated the functions of intestinal Sirt1 in systemic bile acid and cholesterol metabolism in mice. Methods Sirt1 was specifically deleted from intestines of mice using the Flox-villin-Cre system (Sirt1 iKO mice). Intestinal and heptic tissues were collected, and bile acid absorption was analyzed using the everted gut sac experiment. Systemic bile acid metabolism was studied in Sirt1 iKO and Flox control mice placed on standard diets, diets containing 0.5% cholic acid or 1.25% cholesterol, or lithogenic diets. Results Sirt1 iKO mice had reduced intestinal Fxr signaling via Hnf1a compared with controls, which reduced expression of the bile acid transporter genes Asbt and Mcf2l (encodes Ost) and absorption of ileal bile acids. Sirt1 regulated Hnf1α–Fxr signaling partially through Dcoh2, which increases dimerization of Hnf1α. Sirt1 was found to deacetylate DCoH2, promoting its interaction with Hnf1α and inducing DNA binding by Hnf1α. Intestine-specific deletion of Sirt1 increased hepatic bile acid biosynthesis, reduced hepatic accumulation of bile acids, and protected animals from liver damage from high-bile acid diets. Conclusions Intestinal Sirt1, a key nutrient sensor, is required for ileal bile acid absorption and systemic bile acid homeostasis in mice. We delineated the mechanism of metabolic regulation of Hnf1α–Fxr signaling. Reagents designed to inhibit intestinal SIRT1 might be developed to treat bile acid-related diseases such as cholestasis. PMID:24389307

  19. Diagnosis and treatment of intestinal intussusception in adults: a rare experience for surgeons

    PubMed Central

    Ciftci, Fatih

    2015-01-01

    Aim: We evaluated the aetiological factors, diagnoses and treatment outcomes of adult cases of invagination of the intestine, or intussusception. We elucidated the role of ultrasonography (USG), computed tomography (CT) and other techniques in the diagnosis of such cases. Patients and Methods: Six patients with sufficient medical data, all of whom were followed-up and treated for intussusception at Safa Hospital, General Surgery Clinic, Istanbul, Turkey, between July 2008 and December 2013, were enrolled. Results: The site of intussusception was the small bowel in five cases. The aetiopathology was benign in 5 (83.3%) cases and included inflammatory fibroid polyp (IFP) and adhesion. The malignant case was adenocarcinoma. The bowel segments involved were ileoileal in five cases and ileocolic in one case. Conclusions: USG and CT aided with the diagnosis. Although more rare in adults than in children, cases of ileus presenting with acute abdominal disorder, particularly those with an uncertain diagnosis, should be considered possible intussusception cases. PMID:26309690

  20. Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis

    PubMed Central

    Bozec, Aline; Hannemann, Nicole

    2016-01-01

    Considering that adipose tissue (AT) is an endocrine organ, it can influence whole body metabolism. Excessive energy storage leads to the dysregulation of adipocytes, which in turn induces abnormal secretion of adipokines, triggering metabolic syndromes such as obesity, dyslipidemia, hyperglycemia, hyperinsulinemia, insulin resistance and type 2 diabetes. Therefore, investigating the molecular mechanisms behind adipocyte dysregulation could help to develop novel therapeutic strategies. Our protocol describes methods for evaluating the molecular mechanism affected by hypoxic conditions of the AT, which correlates with adipocyte apoptosis in adult mice. This protocol describes how to analyze AT in vivo through gene expression profiling as well as histological analysis of adipocyte differentiation, proliferation and apoptosis during hypoxia exposure, ascertained through staining of hypoxic cells or HIF-1α protein. Furthermore, in vitro analysis of adipocyte differentiation and its responses to various stimuli completes the characterization of the molecular pathways behind possible adipocyte dysfunction leading to metabolic syndromes. PMID:27284940

  1. Survival of Lactobacillus casei strain Shirota in the intestines of healthy Chinese adults.

    PubMed

    Wang, Ran; Chen, Shanbin; Jin, Junhua; Ren, Fazheng; Li, Yang; Qiao, Zhenxing; Wang, Yue; Zhao, Liang

    2015-05-01

    Lactobacillus casei strain Shirota (LcS) is a widely used probiotic strain with health benefits. In this study, the survival of LcS in the intestines of healthy Chinese adults was assessed and the effects of LcS on stool consistency, stool SCFAs and intestinal microbiota evaluated. Subjects consumed 100 mL per day of a probiotic beverage containing 1.0 × 10(8) CFU/mL of LcS for 14 days. LcS were enumerated using a culture method and the colony identity confirmed by ELISA. Fourteen days after ingestion, the amount of LcS recovered from fecal samples was between 6.86 ± 0.80 and 7.17 ± 0.57 Log10 CFU/g of feces (mean ± SD). The intestinal microbiotas were analyzed by denaturing gradient gel electrophoresis. Principal component analysis showed that consuming LcS significantly changed fecal microbiota profiles. According to redundancy analysis, the amounts of 25 bacterial strains were significantly correlated with LcS intake (P < 0.05), 11 of them positively and fourteen negatively. Concentrations of acetic acid and propionic acid in feces were significantly lower during the ingestion period than during the baseline period (P < 0.05). These results confirm that LcS can survive passage through the gastrointestinal tract of Chinese people; however, they were found to have little ability to persist once their consumption had ceased. Furthermore, consumption of probiotic beverages containing LcS can modulate the composition of the intestinal microbiota on a long-term basis, resulting in decreased concentrations of SCFAs in the gut. PMID:25707300

  2. Acute and Chronic Effects of Dietary Lactose in Adult Rats Are not Explained by Residual Intestinal Lactase Activity

    PubMed Central

    van de Heijning, Bert J. M.; Kegler, Diane; Schipper, Lidewij; Voogd, Eline; Oosting, Annemarie; van der Beek, Eline M.

    2015-01-01

    Neonatal rats have a high intestinal lactase activity, which declines around weaning. Yet, the effects of lactose-containing products are often studied in adult animals. This report is on the residual, post-weaning lactase activity and on the short- and long-term effects of lactose exposure in adult rats. Acutely, the postprandial plasma response to increasing doses of lactose was studied, and chronically, the effects of a 30% lactose diet fed from postnatal (PN) Day 15 onwards were evaluated. Intestinal lactase activity, as assessed both in vivo and in vitro, was compared between both test methods and diet groups (lactose vs. control). A 50%–75% decreased digestive capability towards lactose was observed from weaning into adulthood. Instillation of lactose in adult rats showed disproportionally low increases in plasma glucose levels and did not elicit an insulin response. However, gavages comprising maltodextrin gave rise to significant plasma glucose and insulin responses, indicative of a bias of the adult GI tract to digest glucose polymers. Despite the residual intestinal lactase activity shown, a 30% lactose diet was poorly digested by adult rats: the lactose diet rendered the animals less heavy and virtually devoid of body fat, whereas their cecum tripled in size, suggesting an increased bacterial fermentation. The observed acute and chronic effects of lactose exposure in adult rats cannot be explained by the residual intestinal lactase activity assessed. PMID:26184291

  3. Acute and Chronic Effects of Dietary Lactose in Adult Rats Are not Explained by Residual Intestinal Lactase Activity.

    PubMed

    van de Heijning, Bert J M; Kegler, Diane; Schipper, Lidewij; Voogd, Eline; Oosting, Annemarie; van der Beek, Eline M

    2015-07-01

    Neonatal rats have a high intestinal lactase activity, which declines around weaning. Yet, the effects of lactose-containing products are often studied in adult animals. This report is on the residual, post-weaning lactase activity and on the short- and long-term effects of lactose exposure in adult rats. Acutely, the postprandial plasma response to increasing doses of lactose was studied, and chronically, the effects of a 30% lactose diet fed from postnatal (PN) Day 15 onwards were evaluated. Intestinal lactase activity, as assessed both in vivo and in vitro, was compared between both test methods and diet groups (lactose vs. control). A 50%-75% decreased digestive capability towards lactose was observed from weaning into adulthood. Instillation of lactose in adult rats showed disproportionally low increases in plasma glucose levels and did not elicit an insulin response. However, gavages comprising maltodextrin gave rise to significant plasma glucose and insulin responses, indicative of a bias of the adult GI tract to digest glucose polymers. Despite the residual intestinal lactase activity shown, a 30% lactose diet was poorly digested by adult rats: the lactose diet rendered the animals less heavy and virtually devoid of body fat, whereas their cecum tripled in size, suggesting an increased bacterial fermentation. The observed acute and chronic effects of lactose exposure in adult rats cannot be explained by the residual intestinal lactase activity assessed. PMID:26184291

  4. The Osa-containing SWI/SNF chromatin-remodeling complex regulates stem cell commitment in the adult Drosophila intestine

    PubMed Central

    Zeng, Xiankun; Lin, Xinhua; Hou, Steven X.

    2013-01-01

    The proportion of stem cells versus differentiated progeny is well balanced to maintain tissue homeostasis, which in turn depends on the balance of the different signaling pathways involved in stem cell self-renewal versus lineage-specific differentiation. In a screen for genes that regulate cell lineage determination in the posterior midgut, we identified that the Osa-containing SWI/SNF (Brahma) chromatin-remodeling complex regulates Drosophila midgut homeostasis. Mutations in subunits of the Osa-containing complex result in intestinal stem cell (ISC) expansion as well as enteroendocrine (EE) cell reduction. We further demonstrated that Osa regulates ISC self-renewal and differentiation into enterocytes by elaborating Notch signaling, and ISC commitment to differentiation into EE cells by regulating the expression of Asense, an EE cell fate determinant. Our data uncover a unique mechanism whereby the commitment of stem cells to discrete lineages is coordinately regulated by chromatin-remodeling factors. PMID:23942514

  5. A rare presentation of midgut malrotation as an acute intestinal obstruction in an adult: Two case reports and literature review

    PubMed Central

    Singh, Shailendra; Das, Anupam; Chawla, A.S.; Arya, S.V.; Chaggar, Jasneet

    2012-01-01

    INTRODUCTION Midgut malrotation is a congenital anomaly presenting mainly in the childhood. Its presentation as an acute intestinal obstruction is extremely rare in adults usually recognized intra-operatively, therefore a high index of suspicion is always required when dealing with any case of acute intestinal obstruction. PRESENTATION OF CASE We report two cases of young adults who presented with symptoms of acute intestinal obstruction and were diagnosed intra-operatively as cecal volvulus and paraduodenal hernia, respectively, caused by midgut malrotation. Post-operative CT scan confirmed these findings. DISCUSSION Malrotation of the intestinal tract is a product of an aberrant embryology. The presentation of intestinal malrotation in adults is rare (0.2–0.5%). Contrast enhanced CT can show the abnormal anatomic location of a right sided small bowel, a left-sided colon and an abnormal relationship of the superior mesenteric vein (SMV) situated to the left of the superior mesenteric artery (SMA) instead of to the right. CONCLUSION Anomalies like midgut malrotation can present as an operative surprise and awareness regarding these anomalies can help surgeons deal with these conditions. PMID:23123419

  6. Intestinal establishment and reproduction of adult Trichinella spp. in single and mixed species infections in foxes (Vulpes vulpes).

    PubMed

    Webster, Pia; Kapel, Christian M O

    2005-06-30

    Intestinal establishment and reproduction of adult Trichinella spiralis, Trichinella nativa, Trichinella britovi and Trichinella pseudospiralis were examined as single species or mixed species infections in foxes. This is the first study of intestinal dynamics of Trichinella spp. in a carnivore model and the results suggest that the intestinal phase is relatively short as only very few worms were recovered 10 days post-inoculation (dpi). In mixed species infection with equal doses of T. nativa and T. spiralis, molecular typing demonstrated that 64% of the intestinal worms and 78% of the muscle larvae were T. nativa. Conversely, T. spiralis dominated in the mixed species infections with T. pseudospiralis, constituting 66% of the intestinal worms and 94% of the muscle larvae. Although, the individual recoveries of intestinal worms were only up to 5.6% on day 1, and up to 1.5% on day 4 post-infection, the muscle larvae establishment was comparable to other fox studies. Infectivity, measured as muscle larvae burden did not differ among the four species of Trichinella, which is in contrast to other models with mice, rats, pigs or herbivores. Although statistically significant differences in intestinal worm burdens were found for some days, no distinct species were recovered in consistently higher numbers than the others. PMID:15925724

  7. Transport of Particles in Intestinal Mucus under Simulated Infant and Adult Physiological Conditions: Impact of Mucus Structure and Extracellular DNA

    PubMed Central

    Macierzanka, Adam; Mackie, Alan R.; Bajka, Balazs H.; Rigby, Neil M.; Nau, Françoise; Dupont, Didier

    2014-01-01

    The final boundary between digested food and the cells that take up nutrients in the small intestine is a protective layer of mucus. In this work, the microstructural organization and permeability of the intestinal mucus have been determined under conditions simulating those of infant and adult human small intestines. As a model, we used the mucus from the proximal (jejunal) small intestines of piglets and adult pigs. Confocal microscopy of both unfixed and fixed mucosal tissue showed mucus lining the entire jejunal epithelium. The mucus contained DNA from shed epithelial cells at different stages of degradation, with higher amounts of DNA found in the adult pig. The pig mucus comprised a coherent network of mucin and DNA with higher viscosity than the more heterogeneous piglet mucus, which resulted in increased permeability of the latter to 500-nm and 1-µm latex beads. Multiple-particle tracking experiments revealed that diffusion of the probe particles was considerably enhanced after treating mucus with DNase. The fraction of diffusive 500-nm probe particles increased in the pig mucus from 0.6% to 64% and in the piglet mucus from ca. 30% to 77% after the treatment. This suggests that extracellular DNA can significantly contribute to the microrheology and barrier properties of the intestinal mucus layer. To our knowledge, this is the first time that the structure and permeability of the small intestinal mucus have been compared between different age groups and the contribution of extracellular DNA highlighted. The results help to define rules governing colloidal transport in the developing small intestine. These are required for engineering orally administered pharmaceutical preparations with improved delivery, as well as for fabricating novel foods with enhanced nutritional quality or for controlled calorie uptake. PMID:24755941

  8. Binding kinetics of Clostridium difficile toxins A and B to intestinal brush border membranes from infant and adult hamsters

    SciTech Connect

    Rolfe, R.D. )

    1991-04-01

    This study was undertaken to determine if the relative resistance of neonates and infants to Clostridium difficile-associated intestinal disease can be related to age-dependent differences in intestinal receptors for C. difficile toxins A and B. Brush border membranes (BBMs) from the small intestines of adult and infant hamsters were examined for their ability to bind radiolabeled toxins A and B. (125I)toxin A bound to both infant and adult hamster BBMs at physiological temperature, whereas (125I)toxin B did not bind to the BBMs under any of the conditions examined. The number of (125I)toxin A molecules bound at saturation was approximately 4 x 10(10) per micrograms of membrane protein for adult BBMs and 1 x 10(11) per micrograms of membrane protein for infant BBMs. Scatchard plot analysis suggested the presence of a single class of toxin A binding sites on both infant and adult hamster BBMs. Maximal binding capacity and Kd values were 0.63 pmol/mg of protein and 66.7 nM, respectively, for the infant BBMs, and 0.24 pmol/mg of protein and 27 nM, respectively, for the adult BBMs. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analyses of extracted BBM proteins revealed differences in the proteins of infant and adult BBMs. However, there were not any detectable differences in the protein bands which bound (125I)toxin A between infant and adult hamsters. The results from these investigations indicate that differences in the binding kinetics of toxins A and/or B to infant and adult hamster BBMs do not account for the observed differences in their susceptibility to C. difficile-associated intestinal disease.

  9. Fibroblast growth factor 10 alters the balance between goblet and Paneth cells in the adult mouse small intestine.

    PubMed

    Al Alam, Denise; Danopoulos, Soula; Schall, Kathy; Sala, Frederic G; Almohazey, Dana; Fernandez, G Esteban; Georgia, Senta; Frey, Mark R; Ford, Henri R; Grikscheit, Tracy; Bellusci, Saverio

    2015-04-15

    Intestinal epithelial cell renewal relies on the right balance of epithelial cell migration, proliferation, differentiation, and apoptosis. Intestinal epithelial cells consist of absorptive and secretory lineage. The latter is comprised of goblet, Paneth, and enteroendocrine cells. Fibroblast growth factor 10 (FGF10) plays a central role in epithelial cell proliferation, survival, and differentiation in several organs. The expression pattern of FGF10 and its receptors in both human and mouse intestine and their role in small intestine have yet to be investigated. First, we analyzed the expression of FGF10, FGFR1, and FGFR2, in the human ileum and throughout the adult mouse small intestine. We found that FGF10, FGFR1b, and FGFR2b are expressed in the human ileum as well as in the mouse small intestine. We then used transgenic mouse models to overexpress Fgf10 and a soluble form of Fgfr2b, to study the impact of gain or loss of Fgf signaling in the adult small intestine. We demonstrated that overexpression of Fgf10 in vivo and in vitro induces goblet cell differentiation while decreasing Paneth cells. Moreover, FGF10 decreases stem cell markers such as Lgr5, Lrig1, Hopx, Ascl2, and Sox9. FGF10 inhibited Hes1 expression in vitro, suggesting that FGF10 induces goblet cell differentiation likely through the inhibition of Notch signaling. Interestingly, Fgf10 overexpression for 3 days in vivo and in vitro increased the number of Mmp7/Muc2 double-positive cells, suggesting that goblet cells replace Paneth cells. Further studies are needed to determine the mechanism by which Fgf10 alters cell differentiation in the small intestine. PMID:25721301

  10. Cardiac-Specific Disruption of GH Receptor Alters Glucose Homeostasis While Maintaining Normal Cardiac Performance in Adult Male Mice.

    PubMed

    Jara, Adam; Liu, Xingbo; Sim, Don; Benner, Chance M; Duran-Ortiz, Silvana; Qian, Yanrong; List, Edward O; Berryman, Darlene E; Kim, Jason K; Kopchick, John J

    2016-05-01

    GH is considered necessary for the proper development and maintenance of several tissues, including the heart. Studies conducted in both GH receptor null and bovine GH transgenic mice have demonstrated specific cardiac structural and functional changes. In each of these mouse lines, however, GH-induced signaling is altered systemically, being decreased in GH receptor null mice and increased in bovine GH transgenic mice. Therefore, to clarify the direct effects GH has on cardiac tissue, we developed a tamoxifen-inducible, cardiac-specific GHR disrupted (iC-GHRKO) mouse line. Cardiac GH receptor was disrupted in 4-month-old iC-GHRKO mice to avoid developmental effects due to perinatal GHR gene disruption. Surprisingly, iC-GHRKO mice showed no difference vs controls in baseline or postdobutamine stress test echocardiography measurements, nor did iC-GHRKO mice show differences in longitudinal systolic blood pressure measurements. Interestingly, iC-GHRKO mice had decreased fat mass and improved insulin sensitivity at 6.5 months of age. By 12.5 months of age, however, iC-GHRKO mice no longer had significant decreases in fat mass and had developed glucose intolerance and insulin resistance. Furthermore, investigation via immunoblot analysis demonstrated that iC-GHRKO mice had appreciably decreased insulin stimulated Akt phosphorylation, specifically in heart and liver, but not in epididymal white adipose tissue. These changes were accompanied by a decrease in circulating IGF-1 levels in 12.5-month-old iC-GHRKO mice. These data indicate that whereas the disruption of cardiomyocyte GH-induced signaling in adult mice does not affect cardiac function, it does play a role in systemic glucose homeostasis, in part through modulation of circulating IGF-1. PMID:27035649

  11. Ontogeny of Intestinal Epithelial Innate Immune Responses

    PubMed Central

    Hornef, Mathias W.; Fulde, Marcus

    2014-01-01

    Emerging evidence indicates that processes during postnatal development might significantly influence the establishment of mucosal host-microbial homeostasis. Developmental and adaptive immunological processes but also environmental and microbial exposure early after birth might thus affect disease susceptibility and health during adult life. The present review aims at summarizing the current understanding of the intestinal epithelial innate immune system and its developmental and adaptive changes after birth. PMID:25346729

  12. Thyroid hormone activates Wnt/β-catenin signaling involved in adult epithelial development during intestinal remodeling in Xenopus laevis.

    PubMed

    Hasebe, Takashi; Fujimoto, Kenta; Kajita, Mitsuko; Ishizuya-Oka, Atsuko

    2016-08-01

    During amphibian intestinal remodeling, thyroid hormone (TH) induces some larval epithelial cells to dedifferentiate into adult stem cells, which newly generate the absorptive epithelium analogous to the mammalian epithelium. To clarify molecular mechanisms underlying adult epithelial development, we here focus on TH response genes that are associated with the canonical Wnt pathway. Our quantitative reverse transcription plus polymerase chain reaction and immunohistochemical analyses indicate that all of the genes examined, including β-catenin, c-Myc and secreted frizzle-related protein 2 (SFRP2), are up-regulated in Xenopus laevis intestine during both natural and TH-induced metamorphosis. Moreover, immunoreactivity for nuclear β-catenin becomes detectable in adult stem cells from the start of their appearance and then increases in intensity in adult epithelial primordia derived from the stem cells, which actively proliferate and coexpress Wnt target genes c-Myc and LGR5. These expression profiles strongly suggest the involvement of the canonical Wnt pathway in the maintenance and/or proliferation of adult stem/progenitor cells. More importantly, by using organ cultures of the tadpole intestine, we have experimentally shown that the addition of exogenous SFRP2 protein to the culture medium promotes cell proliferation of the adult epithelial primordia, whereas inhibition of endogenous SFRP2 by its antibody suppresses their proliferation. The inhibition of SFRP2 suppresses larval epithelial changes in shape from simple columnar to stem-cell-like roundish cells, resulting in the failure of epithelial dedifferentiation. Thus, TH-up-regulated SFRP2 in the postembryonic intestine promotes adult stem cell development, possibly by acting as an agonist of both canonical and non-canonical Wnt signaling. PMID:27068920

  13. Spatiotemporally Regulated Ablation of Klf4 in Adult Mouse Corneal Epithelial Cells Results in Altered Epithelial Cell Identity and Disrupted Homeostasis

    PubMed Central

    Delp, Emili E.; Swamynathan, Sudha; Kao, Winston W.; Swamynathan, Shivalingappa K.

    2015-01-01

    Purpose. In previous studies, conditional disruption of Klf4 in the developing mouse ocular surface from embryonic day 10 resulted in corneal epithelial fragility, stromal edema, and loss of conjunctival goblet cells, revealing the importance of Klf4 in ocular surface maturation. Here, we use spatiotemporally regulated ablation of Klf4 to investigate its functions in maintenance of adult corneal epithelial homeostasis. Methods. Expression of Cre was induced in ternary transgenic (Klf4LoxP/LoxP/Krt12rtTA/rtTA/Tet-O-Cre) mouse corneal epithelium by doxycycline administered through intraperitoneal injections and drinking water, to generate corneal epithelium–specific deletion of Klf4 (Klf4Δ/ΔCE). Corneal epithelial barrier function was tested by fluorescein staining. Expression of selected Klf4-target genes was determined by quantitative PCR (QPCR), immunoblotting, and immunofluorescent staining. Results. Klf4 was efficiently ablated within 5 days of doxycycline administration in adult Klf4Δ/ΔCE corneal epithelium. The Klf4Δ/ΔCE corneal epithelial barrier function was disrupted, and the basal cells were swollen and rounded after 15 days of doxycycline treatment. Increased numbers of cell layers and Ki67-positive proliferating cells suggested deregulated Klf4Δ/ΔCE corneal epithelial homeostasis. Expression of tight junction proteins ZO-1 and occludin, desmosomal Dsg and Dsp, basement membrane laminin-332, and corneal epithelial–specific keratin-12 was decreased, while that of matrix metalloproteinase Mmp9 and noncorneal keratin-17 increased, suggesting altered Klf4Δ/ΔCE corneal epithelial cell identity. Conclusions. Ablation of Klf4 in the adult mouse corneas resulted in the absence of characteristic corneal epithelial cell differentiation, disrupted barrier function, and squamous metaplasia, revealing that Klf4 is essential for maintenance of the adult corneal epithelial cell identity and homeostasis. PMID:26047041

  14. Th17 Cells Coordinate with Th22 Cells in Maintaining Homeostasis of Intestinal Tissues and both are Depleted in SIV-Infected Macaques

    PubMed Central

    Xu, Huanbin; Wang, Xiaolei; Veazey, Ronald S.

    2014-01-01

    Th17 and Th22 cells are thought to function as innate regulators of mucosal antimicrobial responses, tissue inflammation and mucosal integrity, yet their role in persistent SIV infection is still unclear. Here we compared Th17 and Th22 cells in their phenotype, effector/cytokine function, and frequency in blood and intestinal mucosal tissues, and correlate levels with mucosal damage in SIV-infected rhesus macaques. We found that Th17/Th22 cells share similar features in that both highly produce TNF-α and IL-2 and express CCR5 in intestinal tissues; yet very few show cytotoxic functions, as evidenced by lack of IFN-γ and granzyme B production. Further, Th17/Th22 cells display distinct tissue-specific distributions. Both Th17 and Th22 cells and cytokine secretion were significantly depleted in both blood and intestine in chronically SIV-infected macaques. The frequency of Th17 and Th22 cells in the intestine positively correlated with percentages of intestinal CD4+ T cells and negatively with damage to intestinal mucosa, and plasma viral loads in SIV infection. These findings indicate Th17 and Th22 cells share considerable functions, and may coordinate in innate mucosal immune responses, and their regional loss in the intestine may be associated with local mucosal immune dysfunction in persistent HIV/SIV infection. PMID:25364618

  15. Polycomb complex PRC1 as gatekeeper of intestinal stem cell identity.

    PubMed

    Léveillé, Nicolas; Vermeulen, Louis

    2016-01-01

    Intestinal stem cells (ISCs) are adult multipotent cells essential for the maintenance of intestinal epithelial homeostasis. Wnt signaling activity ensures that the pool of ISCs at the basis of the intestinal crypts is preserved. Dysregulation of the Wnt pathway is often observed in cancer and supports malignant progression. Chiacchiera and colleagues recently demonstrated the implication of the polycomb complex PRC1 in the regulation of the Wnt pathway in adult ISCs. The authors show that PRC1 maintains intestinal homeostasis by repressing the expression of ZICs, a family of transcription factors inactivating the β-catenin/TCF complex. Importantly, interfering with PRC1 activity completely inhibits the formation of Wnt-dependent tumors. These findings reveal a new layer of epigenetic regulation of the Wnt pathway and open novel opportunities for cancer stem cell targeted therapy. PMID:27488310

  16. Polycomb complex PRC1 as gatekeeper of intestinal stem cell identity

    PubMed Central

    Léveillé, Nicolas

    2016-01-01

    Intestinal stem cells (ISCs) are adult multipotent cells essential for the maintenance of intestinal epithelial homeostasis. Wnt signaling activity ensures that the pool of ISCs at the basis of the intestinal crypts is preserved. Dysregulation of the Wnt pathway is often observed in cancer and supports malignant progression. Chiacchiera and colleagues recently demonstrated the implication of the polycomb complex PRC1 in the regulation of the Wnt pathway in adult ISCs. The authors show that PRC1 maintains intestinal homeostasis by repressing the expression of ZICs, a family of transcription factors inactivating the β-catenin/TCF complex. Importantly, interfering with PRC1 activity completely inhibits the formation of Wnt-dependent tumors. These findings reveal a new layer of epigenetic regulation of the Wnt pathway and open novel opportunities for cancer stem cell targeted therapy. PMID:27488310

  17. Effect of in ovo administration of an adult-derived microbiota on establishment of the intestinal microbiome in chickens.

    PubMed

    Pedroso, Adriana A; Batal, Amy B; Lee, Margie D

    2016-05-01

    OBJECTIVE To determine effects of in ovo administration of a probiotic on development of the intestinal microbiota of 2 genetic lineages (modern and heritage) of chickens. SAMPLE 10 newly hatched chicks and 40 fertile eggs to determine intestinal microbiota at hatch, 900 fertile eggs to determine effects of probiotic on hatchability, and 1,560 chicks from treated or control eggs. PROCEDURES A probiotic competitive-exclusion product derived from adult microbiota was administered in ovo to fertile eggs of both genetic lineages. Cecal contents and tissues were collected from embryos, newly hatched chicks, and chicks. A PCR assay was used to detect bacteria present within the cecum of newly hatched chicks. Fluorescence in situ hybridization and vitality staining were used to detect viable bacteria within intestines of embryos. The intestinal microbiota was assessed by use of 16S pyrosequencing. RESULTS Microscopic evaluation of embryonic cecal contents and tissues subjected to differential staining techniques revealed viable bacteria in low numbers. Development of the intestinal microbiota of broiler chicks of both genetic lineages was enhanced by in ovo administration of adult microbiota. Although the treatment increased diversity and affected composition of the microbiota of chicks, most bacterial species present in the probiotic were transient colonizers. However, the treatment decreased the abundance of undesirable bacterial species within heritage lineage chicks. CONCLUSIONS AND CLINICAL RELEVANCE In ovo inoculation of a probiotic competitive-exclusion product derived from adult microbiota may be a viable method of managing development of the microbiota and reducing the prevalence of pathogenic bacteria in chickens. PMID:27111019

  18. Systematic literature review on self-reported quality of life in adult intestinal transplantation.

    PubMed

    Ceulemans, Laurens J; Lomme, Céline; Pirenne, Jacques; De Geest, Sabina

    2016-04-01

    Quality of life (QoL) gains importance in intestinal transplantation (ITx). This systematic review aimed to summarize all evidence on self-reported QoL in adult ITx. PubMed, EMBASE, CCTR, CINAHL, and PsycINFO were searched until October 2014. Structured data abstraction was performed and methodological quality was assessed using a standardized checklist. Nine eligible studies were identified addressing one or more study-aims: (i) QoL comparison pre- and post-ITx (n=4); (ii) QoL follow-up post-ITx (n=1); and (iii) QoL comparison between ITx and home parenteral nutrition (HPN) patients (n=6), healthy subjects (n=1), general population (n=1). Assessments indicated sub-optimal methodology throughout, e.g., retrospective (n=2) and cross-sectional (n=7) study designs, non-probabilistic sampling with inadequate matching of ITx subjects, non-standard terminology, lack of operational definitions and variety in assessment instruments. Still, despite these inconsistencies, this review produced three encouraging findings: (i) post-ITx QoL improved versus pre-ITx (anxiety, sleep, social support, leisure); (ii) post-ITx QoL improved with longer follow-up (anxiety, impulsiveness/control); and (iii) QoL between ITx and HPN patients was similar for most domains yet ITx patients excelled for energy, social functioning and travel ability. Although results are encouraging, QoL research in adult ITx is scarce and needs methodological improvement by implementing prospective multicenter studies, adequate QoL conceptualization and appropriate measurements. PMID:27066940

  19. [Clinical aspects and therapy of intestinal non-rotation in adults].

    PubMed

    von Flüe, M; Bailleux, A; Stähelin, F; Vogt, B

    1990-06-01

    The intestinal non-rotation is a rare fetal disorder of the gut torsion. Its manifestation is very rarely seen in the adult, either in form of a volvulus of the midgut or ileocecal with an acute onset, or as chronic recurrent abdominal pain. Each diagnostic or therapeutic delay increases the risk of strangulation and may end as an abdominal disaster. We describe three own cases and we try to elucidate the diagnostic and therapeutic problems. Our proceeding: In the acute symptomatic form the explorative laparotomy with a consequent staging of the abdominal situs is the safest way to get an exact diagnosis. Therapeutically the procedure described by LADD is the best torsion prophylaxis; the ascending colon is sawn to the descending colon. Due to a paratopia, the appendectomy is recommended. In the chronic forms the contrast enema and the gastrointestinal barium study are the main diagnostic procedures. In the operation described by Fitzgerald and the ascending colon and the mesentery of the small bowel are--after incision of the common mesentery--fixed at their anatomical site. PMID:2228684

  20. Meckel's diverticulum--a rare cause of intestinal obstruction in adults.

    PubMed

    Bălălău, C; Bacalbaşa, N; Motofei, I; Popa, Fl; Voiculescu, S; Scăunaşu, R V

    2015-01-01

    Although many people have Meckel's diverticulum, only some experience any symptoms, most under the age of 10. In adults it is usually asymptomatic but approximately 4% develop complications. Meckel's diverticulum is usually diagnosed in the first years of life and after that the risk of the complications decreases with increasing age, with no predictive factors for the development of complications. We describe the case of a 34-year-old man admitted in the emergency department with diffuse abdominal pain, nausea, flatulence and lack of transit for feces and gas. The patient had been previously operated for peritonitis due to a perforated ulcer. Clinical examination and paraclinical investigations (abdominal radiography and ultrasound) suggested the diagnosis of intestinal obstruction, probably produced by adhesions due to previous abdominal intervention. The diverticulum was resected using a linear stapler and the patient recovered without any complications. Small bowel obstruction due to Meckel's diverticulitis may be caused by entangled loop of small bowel around a fibrous cord, intussusception, volvulus, or incarceration within a hernia sac. The discovery of a Meckel's diverticulum complication in a mid thirties patient represented an intra-operatory surprise and is the peculiarity of the case. PMID:25970960

  1. Organ-Specific and Size-Dependent Ag Nanoparticle Toxicity in Gills and Intestines of Adult Zebrafish.

    PubMed

    Osborne, Olivia J; Lin, Sijie; Chang, Chong Hyun; Ji, Zhaoxia; Yu, Xuechen; Wang, Xiang; Lin, Shuo; Xia, Tian; Nel, André E

    2015-10-27

    We studied adult zebrafish to determine whether the size of 20 and 110 nm citrate-coated silver nanoparticles (AgC NPs) differentially impact the gills and intestines, known target organs for Ag toxicity in fish. Following exposure for 4 h, 4 days, or 4 days plus a 7 day depuration period, we obtained different toxicokinetic profiles for different particle sizes, as determined by Ag content of the tissues. Ionic AgNO3 served as a positive control. The gills showed a significantly higher Ag content for the 20 nm particles at 4 h and 4 days than the 110 nm particles, while the values were more similar in the intestines. Both particle types were retained in the intestines even after depuration. These toxicokinetics were accompanied by striking size-dependent differences in the ultrastructural features and histopathology in the target organs in response to the particulates. Ag staining of the gills and intestines confirmed prominent Ag deposition in the basolateral membranes for the 20 nm but not for the 110 nm particles. Furthermore, it was possible to link the site of tissue deposition to disruption of the Na(+)/K(+) ion channel, which is also localized to the basolateral membrane. This was confirmed by a reduction in ATPase activity and immunohistochemical detection of the α subunit of this channel in both target organs, with the 20 nm particles causing significantly higher inhibition and disruption than the larger size particles or AgNO3. These results demonstrate the importance of particle size in determining the hazardous impact of AgNPs in the gills and intestines of adult zebrafish. PMID:26327297

  2. Intestinal steroidogenesis.

    PubMed

    Bouguen, Guillaume; Dubuquoy, Laurent; Desreumaux, Pierre; Brunner, Thomas; Bertin, Benjamin

    2015-11-01

    Steroids are fundamental hormones that control a wide variety of physiological processes such as metabolism, immune functions, and sexual characteristics. Historically, steroid synthesis was considered a function restricted to the adrenals and the gonads. In the past 20 years, a significant number of studies have demonstrated that steroids could also be synthesized or metabolized by other organs. According to these studies, the intestine appears to be a major source of de novo produced glucocorticoids as well as a tissue capable of producing and metabolizing sex steroids. This finding is based on the detection of steroidogenic enzyme expression as well as the presence of bioactive steroids in both the rodent and human gut. Within the intestinal mucosa, the intestinal epithelial cell layer is one of the main cellular sources of steroids. Glucocorticoid synthesis regulation in the intestinal epithelial cells is unique in that it does not involve the classical positive regulator steroidogenic factor-1 (SF-1) but a closely related homolog, namely the liver receptor homolog-1 (LRH-1). This local production of immunoregulatory glucocorticoids contributes to intestinal homeostasis and has been linked to pathophysiology of inflammatory bowel diseases. Intestinal epithelial cells also possess the ability to metabolize sex steroids, notably estrogen; this mechanism may impact colorectal cancer development. In this review, we contextualize and discuss what is known about intestinal steroidogenesis and regulation as well as the key role these functions play both in physiological and pathological conditions. PMID:25560486

  3. Adaptive homeostasis.

    PubMed

    Davies, Kelvin J A

    2016-06-01

    Homeostasis is a central pillar of modern Physiology. The term homeostasis was invented by Walter Bradford Cannon in an attempt to extend and codify the principle of 'milieu intérieur,' or a constant interior bodily environment, that had previously been postulated by Claude Bernard. Clearly, 'milieu intérieur' and homeostasis have served us well for over a century. Nevertheless, research on signal transduction systems that regulate gene expression, or that cause biochemical alterations to existing enzymes, in response to external and internal stimuli, makes it clear that biological systems are continuously making short-term adaptations both to set-points, and to the range of 'normal' capacity. These transient adaptations typically occur in response to relatively mild changes in conditions, to programs of exercise training, or to sub-toxic, non-damaging levels of chemical agents; thus, the terms hormesis, heterostasis, and allostasis are not accurate descriptors. Therefore, an operational adjustment to our understanding of homeostasis suggests that the modified term, Adaptive Homeostasis, may be useful especially in studies of stress, toxicology, disease, and aging. Adaptive Homeostasis may be defined as follows: 'The transient expansion or contraction of the homeostatic range in response to exposure to sub-toxic, non-damaging, signaling molecules or events, or the removal or cessation of such molecules or events.' PMID:27112802

  4. N-Glycans on secretory component: mediators of the interaction between secretory IgA and gram-positive commensals sustaining intestinal homeostasis.

    PubMed

    Mathias, Amandine; Corthésy, Blaise

    2011-09-01

    Human beings live in symbiosis with billions of microorganisms colonizing mucosal surfaces. The understanding of the mechanisms underlying this fine-tuned intestinal balance has made significant processes during the last decades. We have recently demonstrated that the interaction of SIgA with Gram-positive bacteria is essentially based on Fab-independent, glycan-mediated recognition. Results obtained using mouse hybridoma- and colostrum-derived secretory IgA (SIgA) consistently show that N-glycans present on secretory component (SC) play a crucial role in the process. Natural coating may involve specific Gram-positive cell wall components, which may explain selective recognition at the molecular level. More widely, the existence of these complexes is involved in the modulation of intestinal epithelial cell (IEC) responses in vitro and the formation of intestinal biofilms. Thus, SIgA may act as one of the pillars in homeostatic maintenance of the microbiota in the gut, adding yet another facet to its multiple roles in the mucosal environment. PMID:22067937

  5. [Adult Case of Invagination Due to Small Intestinal Metastases of Malignant Melanoma].

    PubMed

    Ikeda, Atsushi; Kanazawa, Akifumi; Miura, Yoshiyuki; Hosoda, Yohei; Esaki, Hidekazu; Inoue, Naoya; Awane, Masaaki; Tsunekawa, Shoji; Taki, Yoshiro; Imamura, Masayuki

    2015-11-01

    An 84-year-old woman was diagnosed with malignant melanoma after resection of a nasal cavity tumor in February 2008. In April 2010, she underwent small bowel resection because of ileus due to small intestinal metastases. She was diagnosed with ileus again in October 2010. Computed tomography (CT) and 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed invagination of the small intestine and small intestinal metastases. We performed a palliative small bowel resection. She had a good postoperative course and was discharged 2 weeks after surgery. Oral intake was possible for 6 months until her death. PMID:26805140

  6. Tegumental ultrastructure of adult Quinqueserialis quinqueserialis (Trematoda: Notocotylidae): an intestinal parasite of muskrat (Ondatra zibethicus).

    PubMed

    Naem, Soraya; Smythe, Ashleigh B

    2015-07-01

    Ten adult Quinqueserialis quinqueserialis specimens were removed from the intestine of a naturally infected muskrat, and scanning electron microscopy was used to study the morphological characteristics of the trematodes. The mature trematode, which was easy to recognize by the monostome holdfast organ, with no anterior cone, measured 2200-2500 μm in length by 900-1050 μm in width. The body was elongated and tapering at the anterior end, but the posterior end was rounded, and in some specimens was slightly truncated. The mouth opening lay at the anterior end and was surrounded by the oral sucker, which was round, small to medium in size, and subterminal. The tegument of the rim and inside of the oral sucker was smooth and had two types of papillae, domed and rosette papillae. Around the oral sucker, tegument was covered with sharp, pointed spines. The common genital pore was located on the median line of the body, posterior to the oral sucker. The cirrus had smooth tegument at the base and was armed with numerous conical spines throughout its length. The ventral surface was concave and provided with five distinct longitudinal rows of ventral papillae, which extended from the anterior to the posterior end of the body. Each row consisted of 15 to 20 papillae, making 81 to 88 papillae in all. These papillae were variable in size. In most specimens, the papillae were simple knob-like structures, but in some cases, they appeared to be bi- or trifurcate. The tegument at the base of each ventral papilla showed minute spiny pattern, but it was smooth or folded on top and had small rosette and ciliated papillae. Tegument at the edges of the worm was smooth in the mid-parts, spiny on lateral parts, and included rosette papillae. The dorsal surface of the worm was smooth and slightly convex, and the tegument was provided with two large domed papillae in one third of the anterior end of the dorsal part, few thick spines in the mid-part, and excretory pore at the level just

  7. The Short isoform of the CEACAM1 receptor in intestinal T cells regulates mucosal immunity and homeostasis via Tfh cell induction

    PubMed Central

    Chen, Lanfen; Chen, Zhangguo; Baker, Kristi; Halvorsen, E lizabeth M.; da Cunha, Andre Pires; Flak, Magdalena B.; Gerber, Georg; Huang, Yu-Hwa; Hosomi, Shuhei; Arthur, J anelle C.; Dery, Ken J.; Nagaishi, Takashi; Beauchemin, Nicole; Holmes, Kathryn V.; Ho, Joshua W. K.; Shively, John E.; Jobin, Christian; Onderdonk, Andrew B.; Bry, Lynn; Weiner, Howard L.; Higgins, Darren E.; Blumberg, Richard S.

    2012-01-01

    Summary Carcinoembryonic antigen cell adhesion molecule like I (CEACAM1) is expressed on activated T cells and signals through either a long (L) cytoplasmic tail containing immune receptor tyrosine based inhibitory motifs, which provide inhibitory function, or a short (S) cytoplasmic tail with an unknown role. Previous studies on peripheral T cells show that CEACAM1-L isoforms predominate with little to no detectable CEACAM1-S isoforms in mouse and human. We show here that this was not the case in tissue resident T cells of intestines and gut associated lymphoid tissues which demonstrated predominant expression of CEACAM1-S isoforms relative to CEACAM1-L isoforms in human and mouse. This tissue resident predominance of CEACAM1-S expression was determined by the intestinal environment where it served a stimulatory function leading to the regulation of T cell subsets associated with generation of secretory IgA immunity, the regulation of mucosal commensalism, and defense of the barrier against enteropathogens. PMID:23123061

  8. Coffee Consumption, Newly Diagnosed Diabetes, and Other Alterations in Glucose Homeostasis: A Cross-Sectional Analysis of the Longitudinal Study of Adult Health (ELSA-Brasil)

    PubMed Central

    Yarmolinsky, James; Mueller, Noel T.; Duncan, Bruce B.; Bisi Molina, Maria del Carmen; Goulart, Alessandra C.; Schmidt, Maria Inês

    2015-01-01

    Introduction Observational studies have reported fairly consistent inverse associations between coffee consumption and risk of type 2 diabetes, but this association has been little investigated with regard to lesser degrees of hyperglycemia and other alterations in glucose homeostasis. Additionally, the association between coffee consumption and diabetes has been rarely investigated in South American populations. We examined the cross-sectional relationships of coffee intake with newly diagnosed diabetes and measures of glucose homeostasis, insulin sensitivity, and insulin secretion, in a large Brazilian cohort of middle-aged and elderly individuals. Methods We used baseline data from 12,586 participants of the Longitudinal Study of Adult Health (ELSA-Brasil). Logistic regression analyses were performed to examine associations between coffee consumption and newly diagnosed diabetes. Analysis of covariance was used to assess coffee intake in relation to two-hour glucose from an oral glucose tolerance test, fasting glucose, glycated hemoglobin, fasting and –2-hour postload insulin and measures of insulin sensitivity. Results We found an inverse association between coffee consumption and newly diagnosed diabetes, after adjusting for multiple covariates [23% and 26% lower odds of diabetes for those consuming coffee 2–3 and >3 times per day, respectively, compared to those reporting never or almost never consuming coffee, (p = .02)]. An inverse association was also found for 2-hour postload glucose [Never/almost never: 7.57 mmol/L, ≤1 time/day: 7.48 mmol/L, 2-3 times/day: 7.22 mmol/L, >3 times/day: 7.12 mol/L, p<0.0001] but not with fasting glucose concentrations (p = 0.07). Coffee was additionally associated with 2-hour postload insulin [Never/almost never: 287.2 pmol/L, ≤1 time/day: 280.1 pmol/L, 2–3 times/day: 275.3 pmol/L, >3 times/day: 262.2 pmol/L, p = 0.0005) but not with fasting insulin concentrations (p = .58). Conclusion Our present study provides

  9. Effect of dietary lysine on growth, intestinal enzymes activities and antioxidant status of sub-adult grass carp (Ctenopharyngodon idella).

    PubMed

    Li, Xue-Yin; Tang, Ling; Hu, Kai; Liu, Yang; Jiang, Wei-Dan; Jiang, Jun; Wu, Pei; Chen, Gang-Fu; Li, Shu-Hong; Kuang, Sheng-Yao; Feng, Lin; Zhou, Xiao-Qiu

    2014-06-01

    The dietary lysine requirement of sub-adult grass carp (460 ± 1.5 g) was assessed by feeding diets supplemented with grade levels of lysine (6.6, 8.5, 10.8, 12.9, 15.0 and 16.7 g kg(-1) diet) for 56 days. The test diets (28% CP) contained fish meal, casein and gelatin as sources of intact protein, supplemented with crystalline amino acids. Weight gain (WG), feed intake and feed efficiency were significantly improved with increasing levels of lysine up to 12.9 g kg(-1) diet and thereafter declined (P < 0.05). Quadratic regression analysis of WG at 95% maximum response indicated lysine requirement was 10.9 g kg(-1) diet. Activities of trypsin, chymotrypsin, lipase, Na(+), K(+)-ATPase and alkaline phosphatase in intestine, creatine kinase activity in proximal and mid-intestine responded similar to WG (P < 0.05). In addition, lipid and protein oxidation decreased with increasing levels of lysine up to certain values and increased thereafter (P < 0.05); the anti-hydroxyl radical capacity, dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase (GST) activities and glutathione content were increased with increasing dietary lysine levels up to certain values in the detected tissues, except for hepatopancreatic GST. Requirement estimated on the basis of malondialdehyde content in intestine and hepatopancreas was 10.6 and 9.53 g lysine kg(-1) diet, respectively. PMID:24174167

  10. Effects of Rice Bran Oil on the Intestinal Microbiota and Metabolism of Isoflavones in Adult Mice

    PubMed Central

    Tamura, Motoi; Hori, Sachiko; Hoshi, Chigusa; Nakagawa, Hiroyuki

    2012-01-01

    This study examined the effects of rice bran oil (RBO) on mouse intestinal microbiota and urinary isoflavonoids. Dietary RBO affects intestinal cholesterol absorption. Intestinal microbiota seem to play an important role in isoflavone metabolism. We hypothesized that dietary RBO changes the metabolism of isoflavonoids and intestinal microbiota in mice. Male mice were randomly divided into two groups: those fed a 0.05% daidzein with 10% RBO diet (RO group) and those fed a 0.05% daidzein with 10% lard control diet (LO group) for 30 days. Urinary amounts of daidzein and dihydrodaidzein were significantly lower in the RO group than in the LO group. The ratio of equol/daidzein was significantly higher in the RO group (p < 0.01) than in the LO group. The amount of fecal bile acids was significantly greater in the RO group than in the LO group. The composition of cecal microbiota differed between the RO and LO groups. The occupation ratios of Lactobacillales were significantly higher in the RO group (p < 0.05). Significant positive correlation (r = 0.591) was observed between the occupation ratios of Lactobacillales and fecal bile acid content of two dietary groups. This study suggests that dietary rice bran oil has the potential to affect the metabolism of daidzein by altering the metabolic activity of intestinal microbiota. PMID:22949864

  11. The cardiac stem cell compartment is indispensable for myocardial cell homeostasis, repair and regeneration in the adult.

    PubMed

    Nadal-Ginard, Bernardo; Ellison, Georgina M; Torella, Daniele

    2014-11-01

    Resident cardiac stem cells in embryonic, neonatal and adult mammalian heart have been identified by different membrane markers and transcription factors. However, despite a flurry of publications no consensus has been reached on the identity and actual regenerative effects of the adult cardiac stem cells. Intensive research on the adult mammalian heart's capacity for self-renewal of its muscle cell mass has led to a consensus that new cardiomyocytes (CMs) are indeed formed throughout adult mammalian life albeit at a disputed frequency. The physiological significance of this renewal, the origin of the new CMs, and the rate of adult CM turnover are still highly debated. Myocyte replacement, particularly after injury, was originally attributed to differentiation of a stem cell compartment. More recently, it has been reported that CMs are mainly replaced by the division of pre-existing post-mitotic CMs. These latter results, if confirmed, would shift the target of regenerative therapy toward boosting mature CM cell-cycle re-entry. Despite this controversy, it is documented that the adult endogenous c-kit(pos) cardiac stem cells (c-kit(pos) eCSCs) participate in adaptations to myocardial stress, and, when transplanted into the myocardium, regenerate most cardiomyocytes and microvasculature lost in an infarct. Nevertheless, the in situ myogenic potential of adult c-kit(pos) cardiac cells has been questioned. To revisit the regenerative potential of c-kit(pos) eCSCs, we have recently employed experimental protocols of severe diffuse myocardial damage in combination with several genetic murine models and cell transplantation approaches showing that eCSCs are necessary and sufficient for CM regeneration, leading to complete cellular, anatomical, and functional myocardial recovery. Here we will review the available data on adult eCSC biology and their regenerative potential placing it in the context of the different claimed mechanisms of CM replacement. These data are in

  12. mTOR disruption causes intestinal epithelial cell defects and intestinal atrophy postinjury in mice.

    PubMed

    Sampson, Leesa L; Davis, Ashley K; Grogg, Matthew W; Zheng, Yi

    2016-03-01

    Intestinal stem cells (ISCs) drive small intestinal epithelial homeostasis and regeneration. Mechanistic target of rapamycin (mTOR) regulates stem and progenitor cell metabolism and is frequently dysregulated in human disease, but its physiologic functions in the mammalian small intestinal epithelium remain poorly defined. We disrupted the genes mTOR, Rptor, Rictor, or both Rptor and Rictor in mouse ISCs, progenitors, and differentiated intestinal epithelial cells (IECs) using Villin-Cre. Mutant tissues and wild-type or heterozygous littermate controls were analyzed by histologic immunostaining, immunoblots, and proliferation assays. A total of 10 Gy irradiation was used to injure the intestinal epithelium and induce subsequent crypt regeneration. We report that mTOR supports absorptive enterocytes and secretory Paneth and goblet cell function while negatively regulating chromogranin A-positive enteroendocrine cell number. Through additional Rptor, Rictor, and Rptor/Rictor mutant mouse models, we identify mechanistic target of rapamycin complex 1 as the major IEC regulatory pathway, but mechanistic target of rapamycin complex 2 also contributes to ileal villus maintenance and goblet cell size. Homeostatic adult small intestinal crypt cell proliferation, survival, and canonical wingless-int (WNT) activity are not mTOR dependent, but Olfm4(+) ISC/progenitor population maintenance and crypt regeneration postinjury require mTOR. Overall, we conclude that mTOR regulates multiple IEC lineages and promotes stem and progenitor cell activity during intestinal epithelium repair postinjury. PMID:26631481

  13. Secreted adhesion molecules of Strongyloides venezuelensis are produced by oesophageal glands and are components of the wall of tunnels constructed by adult worms in the host intestinal mucosa.

    PubMed

    Maruyama, H; El-Malky, M; Kumagai, T; Ohta, N

    2003-02-01

    The parasitic female of Strongyloides venezuelensis keeps invading the epithelial layer of the host intestinal mucosa. Upon invasion, it adheres to the surface of the intestinal epithelial cells with adhesion molecules secreted from the mouth. It has been demonstrated that S. venezuelensis are expelled from the intestine because mucosal mast cells inhibit the attachment of adult worms to the mucosal surface. In the present study, we generated specific antibodies against secreted adhesion molecules to investigate their function in vivo, because these molecules have been demonstrated only in vitro in spite of the importance in the infection processes. A mouse monoclonal antibody specific to S. venezuelensis adhesion molecules inhibited the attachment of adult worms to plastic dishes and the binding of adhesion molecules to rat intestinal epithelial cells. Immunohistochemical study revealed that adhesion molecules were produced by oesophageal glands and were continuously secreted in vivo to line the wall of the tunnels formed by adult worms in the intestinal mucosa. Our findings indicate that adhesion molecules play essential roles in the infection processes of S. venezuelensis in the host intestine. PMID:12636354

  14. The resist diabetes trial: Rationale, design, and methods of a hybrid efficacy/effectiveness intervention trial for resistance training maintenance to improve glucose homeostasis in older prediabetic adults.

    PubMed

    Marinik, Elaina L; Kelleher, Sarah; Savla, Jyoti; Winett, Richard A; Davy, Brenda M

    2014-01-01

    Advancing age is associated with reduced levels of physical activity, increased body weight and fat, decreased lean body mass, and a high prevalence of type 2 diabetes (T2D). Resistance training (RT) increases muscle strength and lean body mass, and reduces risk of T2D among older adults. The Resist Diabetes trial will determine if a social cognitive theory (SCT)-based intervention improves RT maintenance in older, prediabetic adults, using a hybrid efficacy/effectiveness approach. Sedentary, overweight/obese (BMI: 25-39.9 kg/m(2)) adults aged 50-69 (N = 170) with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) completed a supervised 3-month RT (2×/wk) initiation phase and were then randomly assigned (N = 159; 94% retention) to one of two 6-month maintenance conditions: SCT or standard care. The SCT intervention consisted of faded contacts compared to standard care. Participants continue RT at an approved, self-selected community facility during maintenance. A subsequent 6-month period involves no contact for both conditions. Assessments occur at baseline and months 3 (post-initiation), 9 (post-intervention), and 15 (six months after no contact). Primary outcomes are prediabetes indices (i.e., impaired fasting and 2-hour glucose concentration) and strength. Secondary measures include insulin sensitivity, beta-cell responsiveness, and disposition index (oral glucose and C-peptide minimal model); adherence; body composition; and SCT measures. Resist Diabetes is the first trial to examine the effectiveness of a high fidelity SCT-based intervention for maintaining RT in older adults with prediabetes to improve glucose homeostasis. Successful application of SCT constructs for RT maintenance may support translation of our RT program for diabetes prevention into community settings. PMID:24252311

  15. The Resist Diabetes trial: Rationale, design, and methods of a hybrid efficacy/effectiveness intervention trial for resistance training maintenance to improve glucose homeostasis in older prediabetic adults

    PubMed Central

    Marinik, Elaina L.; Kelleher, Sarah; Savla, Jyoti; Winett, Richard A.; Davy, Brenda M.

    2014-01-01

    Advancing age is associated with reduced levels of physical activity, increased body weight and fat, decreased lean body mass, and a high prevalence of type 2 diabetes (T2D). Resistance training (RT) increases muscle strength and lean body mass, and reduces risk of T2D among older adults. The Resist Diabetes trial will determine if a social cognitive theory (SCT)-based intervention improves RT maintenance in older, prediabetic adults, using a hybrid efficacy/effectiveness approach. Sedentary, overweight/obese (BMI 25-39.9 kg/m2) adults aged 50-69 (N=170) with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) completed a supervised 3-month RT (2x/wk) Initiation Phase and were then randomly assigned (n=159; 94% retention) to one of two 6-month maintenance conditions: SCT or Standard care. The SCT intervention consisted of faded contacts compared to Standard care. Participants continue RT at an approved, self-selected community facility during maintenance. A subsequent 6-month period involves no contact for both conditions. Assessments occur at baseline and months 3 (post-initiation), 9 (post-intervention), and 15 (six months after no contact). Primary outcomes are prediabetes indices (i.e., impaired fasting and 2-hour glucose concentration) and strength. Secondary measures include insulin sensitivity, beta-cell responsiveness, and disposition index (oral glucose and C-peptide minimal model); adherence; body composition; and SCT measures. Resist Diabetes is the first trial to examine the effectiveness of a high fidelity SCT-based intervention for maintaining RT in older adults with prediabetes to improve glucose homeostasis. Successful application of SCT constructs for RT maintenance may support translation of our RT program for diabetes prevention into community settings. PMID:24252311

  16. Intestinal lactase (beta-galactosidase) and other glycosidase activities in suckling and adult tammar wallabies (Macropus eugenii).

    PubMed

    Walcott, P J; Messer, M

    1980-10-01

    The activities of various glycosidases in homogenates of the small intestinal mucosa of two adult and 18 suckling tammar wallabies (M. eugenii) aged from 6 to 50 weeks were investigated. Lactase (beta-D-galactosidase), beta-N-acetylglucosaminidase, alpha-L-fucosidase and neuraminidase activities were high during the first 34 weeks post partum and then declined to very low levels. Maltase, isomaltase, sucrase and trehalase activities were very low or absent during the first 34 weeks, and then increased. The lactase activity was unusual in being greater in the distal than the middle or proximal thirds of the intestine, and in its low pH optimum (pH 4.6), inhibition by p-chloromercuribenzene sulfonate but not by Tris, and lack of cellobiase activity. These properties are those of a lysosomal acid beta-galactosidase rather than of a brush border neutral lactase. The maltase activity had the characteristics of a lysosomal acid alpha-glucosidase early in lactation and of a brush border neutral maltase in adult animals. The significance of these findings is discussed in relation to changes in dietary carbohydrates during weaning and to the mode of digestion of milk carbohydrates by the pouch young. PMID:6783021

  17. Quinoa extract enriched in 20-hydroxyecdysone affects energy homeostasis and intestinal fat absorption in mice fed a high-fat diet.

    PubMed

    Foucault, Anne-Sophie; Even, Patrick; Lafont, René; Dioh, Waly; Veillet, Stanislas; Tomé, Daniel; Huneau, Jean-François; Hermier, Dominique; Quignard-Boulangé, Annie

    2014-04-10

    In a previous study, we have demonstrated that a supplementation of a high-fat diet with a quinoa extract enriched in 20-hydroxyecdysone (QE) or pure 20-hydroxyecdysone (20E) could prevent the development of obesity. In line with the anti-obesity effect of QE, we used indirect calorimetry to examine the effect of dietary QE and 20E in high-fat fed mice on different components of energy metabolism. Mice were fed a high-fat (HF) diet with or without supplementation by QE or pure 20E for 3 weeks. As compared to mice maintained on a low-fat diet, HF feeding resulted in a marked physiological shift in energy homeostasis, associating a decrease in global energy expenditure (EE) and an increase in lipid utilization as assessed by the lower respiratory quotient (RQ). Supplementation with 20E increased energy expenditure while food intake and activity were not affected. Furthermore QE and 20E promoted a higher rate of glucose oxidation leading to an increased RQ value. In QE and 20E-treated HFD fed mice, there was an increase in fecal lipid excretion without any change in stool amount. Our study indicates that anti-obesity effect of QE can be explained by a global increase in energy expenditure, a shift in glucose metabolism towards oxidation to the detriment of lipogenesis and a decrease in dietary lipid absorption leading to reduced dietary lipid storage in adipose tissue. PMID:24534167

  18. Epithelial-connective tissue interactions induced by thyroid hormone receptor are essential for adult stem cell development in the Xenopus laevis intestine

    PubMed Central

    Hasebe, Takashi; Buchholz, Daniel R.; Shi, Yun-Bo; Ishizuya-Oka, Atsuko

    2012-01-01

    In the amphibian intestine during metamorphosis, stem cells appear and generate the adult absorptive epithelium, analogous to the mammalian one, under the control of thyroid hormone (TH). We have previously shown that the adult stem cells originate from differentiated larval epithelial cells in the Xenopus laevis intestine. To clarify whether TH signaling in the epithelium alone is sufficient for inducing the stem cells, we have now performed tissue recombinant culture experiments, using transgenic X. laevis tadpoles that express a dominant positive TH receptor (dpTR) under a control of heat shock promoter. Wild-type (Wt) or dpTR transgenic (Tg) larval epithelium (Ep) was isolated from the tadpole intestine, recombined with homologous or heterologous non-epithelial tissues (non-Ep), and then cultivated in the absence of TH with daily heat shocks to induce transgenic dpTR expression. Adult epithelial progenitor cells expressing sonic hedgehog became detectable on day 5 in both the recombinant intestine of Tg Ep and Tg non-Ep (Tg/Tg) and that of Tg Ep and Wt non-Ep (Tg/Wt). However, in Tg/Wt intestine, they did not express other stem cell markers such as Musashi-1 and never generated the adult epithelium expressing a marker for absorptive epithelial cells. Our results indicate that, while it is unclear why some larval epithelial cells dedifferentiate into adult progenitor/stem cells, TR-mediated gene expression in the surrounding tissues other than the epithelium is required for them to develop into adult stem cells, suggesting the importance of TH-inducible epithelial-connective tissue interactions in establishment of the stem cell niche in the amphibian intestine. PMID:21280164

  19. Rapamycin preserves gut homeostasis during Drosophila aging.

    PubMed

    Fan, Xiaolan; Liang, Qing; Lian, Ting; Wu, Qi; Gaur, Uma; Li, Diyan; Yang, Deying; Mao, Xueping; Jin, Zhihua; Li, Ying; Yang, Mingyao

    2015-11-01

    Gut homeostasis plays an important role in maintaining the overall body health during aging. Rapamycin, a specific inhibitor of mTOR, exerts prolongevity effects in evolutionarily diverse species. However, its impact on the intestinal homeostasis remains poorly understood. Here, we demonstrate that rapamycin can slow down the proliferation rate of intestinal stem cells (ISCs) in the aging guts and induce autophagy in the intestinal epithelium in Drosophila. Rapamycin can also significantly affect the FOXO associated genes in intestine and up-regulate the negative regulators of IMD/Rel pathway, consequently delaying the microbial expansion in the aging guts. Collectively, these findings reveal that rapamycin can delay the intestinal aging by inhibiting mTOR and thus keeping stem cell proliferation in check. These results will further explain the mechanism of healthspan and lifespan extension by rapamycin in Drosophila. PMID:26431326

  20. Rapamycin preserves gut homeostasis during Drosophila aging

    PubMed Central

    Lian, Ting; Wu, Qi; Gaur, Uma; Li, Diyan; Yang, Deying; Mao, Xueping; Jin, Zhihua; Li, Ying; Yang, Mingyao

    2015-01-01

    Gut homeostasis plays an important role in maintaining the overall body health during aging. Rapamycin, a specific inhibitor of mTOR, exerts prolongevity effects in evolutionarily diverse species. However, its impact on the intestinal homeostasis remains poorly understood. Here, we demonstrate that rapamycin can slow down the proliferation rate of intestinal stem cells (ISCs) in the aging guts and induce autophagy in the intestinal epithelium in Drosophila. Rapamycin can also significantly affect the FOXO associated genes in intestine and up-regulate the negative regulators of IMD/Rel pathway, consequently delaying the microbial expansion in the aging guts. Collectively, these findings reveal that rapamycin can delay the intestinal aging by inhibiting mTOR and thus keeping stem cell proliferation in check. These results will further explain the mechanism of healthspan and lifespan extension by rapamycin in Drosophila. PMID:26431326

  1. Osmotic Homeostasis

    PubMed Central

    Zeidel, Mark L.

    2015-01-01

    Alterations in water homeostasis can disturb cell size and function. Although most cells can internally regulate cell volume in response to osmolar stress, neurons are particularly at risk given a combination of complex cell function and space restriction within the calvarium. Thus, regulating water balance is fundamental to survival. Through specialized neuronal “osmoreceptors” that sense changes in plasma osmolality, vasopressin release and thirst are titrated in order to achieve water balance. Fine-tuning of water absorption occurs along the collecting duct, and depends on unique structural modifications of renal tubular epithelium that confer a wide range of water permeability. In this article, we review the mechanisms that ensure water homeostasis as well as the fundamentals of disorders of water balance. PMID:25078421

  2. European Society of Coloproctology consensus on the surgical management of intestinal failure in adults.

    PubMed

    Vaizey, C J; Maeda, Y; Barbosa, E; Bozzetti, F; Calvo, J; Irtun, Ø; Jeppesen, P B; Klek, S; Panisic-Sekeljic, M; Papaconstantinou, I; Pascher, A; Panis, Y; Wallace, W D; Carlson, G; Boermeester, M

    2016-06-01

    Intestinal failure (IF) is a debilitating condition of inadequate nutrition due to an anatomical and/or physiological deficit of the intestine. Surgical management of patients with acute and chronic IF requires expertise to deal with technical challenges and make correct decisions. Dedicated IF units have expertise in patient selection, operative risk assessment and multidisciplinary support such as nutritional input and interventional radiology, which dramatically improve the morbidity and mortality of this complex condition and can beneficially affect the continuing dependence on parenteral nutritional support. Currently there is little guidance to bridge the gap between general surgeons and specialist IF surgeons. Fifteen European experts took part in a consensus process to develop guidance to support surgeons in the management of patients with IF. Based on a systematic literature review, statements were prepared for a modified Delphi process. The evidence for each statement was graded using Oxford Centre for Evidence-Based Medicine Levels of Evidence. The current paper contains the statements reflecting the position and practice of leading European experts in IF encompassing the general definition of IF surgery and organization of an IF unit, strategies to prevent IF, management of acute IF, management of wound, fistula and stoma, rehabilitation, intestinal and abdominal reconstruction, criteria for referral to a specialist unit and intestinal transplantation. PMID:26946219

  3. Xylitol affects the intestinal microbiota and metabolism of daidzein in adult male mice.

    PubMed

    Tamura, Motoi; Hoshi, Chigusa; Hori, Sachiko

    2013-01-01

    This study examined the effects of xylitol on mouse intestinal microbiota and urinary isoflavonoids. Xylitol is classified as a sugar alcohol and used as a food additive. The intestinal microbiota seems to play an important role in isoflavone metabolism. Xylitol feeding appears to affect the gut microbiota. We hypothesized that dietary xylitol changes intestinal microbiota and, therefore, the metabolism of isoflavonoids in mice. Male mice were randomly divided into two groups: those fed a 0.05% daidzein with 5% xylitol diet (XD group) and those fed a 0.05% daidzein-containing control diet (CD group) for 28 days. Plasma total cholesterol concentrations were significantly lower in the XD group than in the CD group (p < 0.05). Urinary amounts of equol were significantly higher in the XD group than in the CD group (p < 0.05). The fecal lipid contents (% dry weight) were significantly greater in the XD group than in the CD group (p < 0.01). The cecal microbiota differed between the two dietary groups. The occupation ratios of Bacteroides were significantly greater in the CD than in the XD group (p < 0.05). This study suggests that xylitol has the potential to affect the metabolism of daidzein by altering the metabolic activity of the intestinal microbiota and/or gut environment. Given that equol affects bone health, dietary xylitol plus isoflavonoids may exert a favorable effect on bone health. PMID:24336061

  4. Xylitol Affects the Intestinal Microbiota and Metabolism of Daidzein in Adult Male Mice

    PubMed Central

    Tamura, Motoi; Hoshi, Chigusa; Hori, Sachiko

    2013-01-01

    This study examined the effects of xylitol on mouse intestinal microbiota and urinary isoflavonoids. Xylitol is classified as a sugar alcohol and used as a food additive. The intestinal microbiota seems to play an important role in isoflavone metabolism. Xylitol feeding appears to affect the gut microbiota. We hypothesized that dietary xylitol changes intestinal microbiota and, therefore, the metabolism of isoflavonoids in mice. Male mice were randomly divided into two groups: those fed a 0.05% daidzein with 5% xylitol diet (XD group) and those fed a 0.05% daidzein-containing control diet (CD group) for 28 days. Plasma total cholesterol concentrations were significantly lower in the XD group than in the CD group (p < 0.05). Urinary amounts of equol were significantly higher in the XD group than in the CD group (p < 0.05). The fecal lipid contents (% dry weight) were significantly greater in the XD group than in the CD group (p < 0.01). The cecal microbiota differed between the two dietary groups. The occupation ratios of Bacteroides were significantly greater in the CD than in the XD group (p < 0.05). This study suggests that xylitol has the potential to affect the metabolism of daidzein by altering the metabolic activity of the intestinal microbiota and/or gut environment. Given that equol affects bone health, dietary xylitol plus isoflavonoids may exert a favorable effect on bone health. PMID:24336061

  5. Molecular background and physiological consequences of altered peripheral serotonin homeostasis in adult rats perinatally treated with tranylcypromine.

    PubMed

    Blazevic, S; Erjavec, I; Brizic, M; Vukicevic, S; Hranilovic, D

    2015-08-01

    Serotonin (5-hydroxytryptamine, 5-HT) is a biologically active molecule present in mammals in the brain and peripheral tissues where it exerts many physiological functions. Developmental exposure to 5-HT-enhancing agents has been reported to induce long-lasting changes in the brain, but the long-term effects of perinatal 5-HT enhancement on 5-HT balance and function in the peripheral compartment have not been explored. Perinatal treatment of rats with monoamine oxidase (MAO) inhibitor tranylcypromine (TCP), leads to persistent imbalance in central (increased 5-HT degradation and decreased 5-HT concentrations in the brain) and peripheral (increased platelet and decreased plasma 5-HT concentrations) 5-HT homeostasis. In this study, we explored the molecular background of peripheral 5-HT imbalance, and its possible consequences on bone remodeling and hematopoiesis. Jejunum, liver and blood samples were collected from TCP- and saline-treated rats on post-natal day 70. Relative mRNA levels for tryptophan hydroxylase 1 (TPH1) and MAO A were analyzed using quantitative RT-PCR, femoral trabecular bone parameters were measured using microcomputed tomography, while peripheral blood cell number was determined by cell counter. TCP-treated rats displayed significant decrease in expression of Tph1, and significant increase in percentage of bone volume, trabecular number, connectivity density, and leukocyte number. In addition, significant negative correlation was observed between relative concentrations of TPH1 mRNA and trabecular bone parameters. Our results: a) show that perinatal exposure to tranylcypromine leads to long-lasting compensatory decrease in Tph1 expression in the peripheral compartment, accompanied with alterations in bone remodeling and hematopoiesis, b) suggest that peripheral and central 5HT compartment use different strategies to compensate for 5-HT imbalances of the same cause, and c) indicate dominant role of peripheral over central 5-HT in the regulation

  6. TGF-β Is Required for Vascular Barrier Function, Endothelial Survival and Homeostasis of the Adult Microvasculature

    PubMed Central

    Maharaj, Arindel S. R.; Sekiyama, Eiichi; Maldonado, Angel E.; D'Amore, Patricia A.

    2009-01-01

    Pericyte-endothelial cell (EC) interactions are critical to both vascular development and vessel stability. We have previously shown that TGF-β signaling between EC and mural cells participates in vessel stabilization in vitro. We therefore investigated the role of TGF-β signaling in maintaining microvessel structure and function in the adult mouse retinal microvasculature. TGF-β signaling was inhibited by systemic expression of soluble endoglin (sEng) and inhibition was demonstrated by reduced phospho-smad2 in the adult retina. Blockade of TGF-β signaling led to increased vascular and neural cell apoptosis in the retina, which was associated with decreased retinal function, as measured by electroretinogram (ERG). Perfusion of the inner retinal vasculature was impaired and was accompanied by defective autoregulation and loss of capillary integrity. Fundus angiography and Evans blue permeability assay revealed a breakdown of the blood-retinal-barrier that was characterized by decreased association between the tight junction proteins zo-1 and occludin. Inhibition of TGF-β signaling in cocultures of EC and 10T1/2 cells corroborated the in vivo findings, with impaired EC barrier function, dissociation of EC from 10T1/2 cells, and endothelial cell death, supporting the role of EC-mesenchymal interactions in TGF-β signaling. These results implicate constitutive TGF-β signaling in maintaining the integrity and function of the adult microvasculature and shed light on the potential role of TGF-β signaling in vasoproliferative and vascular degenerative retinal diseases. PMID:19340291

  7. Use of computed tomography to evaluate the intestinal tract of adult llamas.

    PubMed

    Van Hoogmoed, L; Roberts, G; Snyder, J R; Yarbrough, T; Harmon, F

    1998-01-01

    In the llama, signs of colic are obscure and may be exhibited as persistent sternal recumbency and anorexia even in the presence of a surgical lesion. Diagnostic methods for evaluation of abdominal disorders are limited. As a result, surgical intervention may be prolonged and increase the risk of mortality and postoperative complications. The objective of this study was to determine the feasibility of computed tomography to evaluate the llama intestinal tract. Eighteen hours prior to the computed tomography scan, six llamas were given barium sulfate (15%) via an orogastric tube. Following induction of general anesthesia, the llamas were positioned in sternal recumbency, and 10 mm contiguous slices were obtained from the diaphragm to the tuber ischiadicum. Structures that were consistently identified included the first, second, and third compartments (C1, 2, and 3), small intestine, spiral colon, and ascending colon. C1 was easily identified in the cranial aspect of the abdomen due to its large size relative to the other compartments and characteristic saccules. C2 was located cranial, ventral, and to the right of C1, while C3 was visualized as a tubular structure to the right and ventral to C1 and C2, C3 was traced caudally until it turned dorsally and continued cranially to a dilated ampulla in the right cranial abdomen delineating the entrance to the small intestine. The spiral colon was identified consistently in the left ventral caudal abdomen. Structures that could not be conclusively identified included the cecum and mesenteric lymph nodes. Computed tomography allowed a consistent evaluation of the major intestinal structures associated with colic in the llama. Thus, computed tomography is a potentially valuable noninvasive diagnostic tool to effectively evaluate the abdominal cavity and differentiate medical from surgical lesions in the llama. PMID:9548138

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

    PubMed

    Packer, Nicholas; Hoffman-Goetz, Laurie

    2012-06-01

    Aging is associated with increased intestinal inflammation and elevated risk of chronic diseases including inflammatory bowel diseases and colon cancer; many epidemiologic studies show that regular exercise reduces risk. This study examined the effects of long-term voluntary exercise on inflammatory mediators expressed in the intestine of older (15-16 months), healthy C57BL/6 mice. Animals were assigned to four months of freewheel running (WR; n = 20) or to a "sedentary" no wheel running (NWR; n = 20) control group. Intestinal lymphocytes were harvested and analysed for expression of (1) pro-inflammatory (TNF-α, IL-1β) and pleiotropic (IL-6) cytokines, and (2) pro-(caspase-3/-7) and anti-(Bcl-2) apoptotic proteins. Training was confirmed by skeletal muscle enzyme activity; stress was assessed by plasma 8-iso-PGF(2α) and corticosterone. The WR mice had a lower expression of TNF-α, caspase-7, and 8-isoprostanes (p < .05) compared to sedentary controls, suggesting that long-term exercise may "protect" the bowel by reducing inflammatory cytokine and apoptotic protein expression. PMID:22647663

  9. Hepatocyte nuclear factor 4α is required for cell differentiation and homeostasis in the adult mouse gastric epithelium.

    PubMed

    Moore, Benjamin D; Khurana, Shradha S; Huh, Won Jae; Mills, Jason C

    2016-08-01

    We have previously shown that the sequential transcription factors Xbp1→Mist1 (Bhlha15) govern the ultrastructural maturation of the secretory apparatus in enzyme-secreting zymogenic chief cells (ZCs) in the gastric unit. Here we sought to identify transcriptional regulators upstream of X-box binding protein 1 (XBP1) and MIST1. We used immunohistochemistry to characterize Hnf4α(flox/flox) adult mouse stomachs after tamoxifen-induced deletion of Hnf4α We used qRT-PCR, Western blotting, and chromatin immunoprecipitation to define the molecular interaction between hepatocyte nuclear factor 4 alpha (HNF4α) and Xbp1 in mouse stomach and human gastric cells. We show that HNF4α protein is expressed in pit (foveolar) cells, mucous neck cells, and zymogenic chief cells (ZCs) of the corpus gastric unit. Loss of HNF4α in adult mouse stomach led to reduced ZC size and ER content, phenocopying previously characterized effects of Xbp1 deletion. However, HNF4α(Δ/Δ) stomachs also exhibited additional phenotypes including increased proliferation in the isthmal stem cell zone and altered mucous neck cell migration, indicating a role of HNF4α in progenitor cells as well as in ZCs. HNF4α directly occupies the Xbp1 promoter locus in mouse stomach, and forced HNF4α expression increased abundance of XBP1 mRNA in human gastric cancer cells. Finally, as expected, loss of HNF4α caused decreased Xbp1 and Mist1 expression in mouse stomachs. We show that HNF4α regulates homeostatic proliferation in the gastric epithelium and is both necessary and sufficient for the upstream regulation of the Xbp1→Mist1 axis in maintenance of ZC secretory architecture. PMID:27340127

  10. Suppression of c-Kit signaling induces adult neurogenesis in the mouse intestine after myenteric plexus ablation with benzalkonium chloride

    PubMed Central

    Tamada, Hiromi; Kiyama, Hiroshi

    2016-01-01

    Adult neurogenesis rarely occurs in the enteric nervous system (ENS). In this study, we demonstrated that, after intestinal myenteric plexus (MP) ablation with benzalkonium chloride (BAC), adult neurogenesis in the ENS was significantly induced in c-kit loss-of-function mutant mice (W/Wv). Almost all neurons and fibers in the MP disappeared after BAC treatment. However, 1 week after ablation, substantial penetration of nerve fibers from the non-damaged area was observed in the MP, longitudinal muscle and subserosal layers in both wildtype and W/Wv mice. Two weeks after BAC treatment, in addition to the penetrating fibers, a substantial number of ectopic neurons appeared in the subserosal and longitudinal muscle layers of W/Wv mice, whereas only a few ectopic neurons appeared in wildtype mice. Such ectopic neurons expressed either excitatory or inhibitory intrinsic motor neuron markers and formed ganglion-like structures, including glial cells, synaptic vesicles and basal lamina. Furthermore, oral administration of imatinib, an inhibitor of c-Kit and an anticancer agent for gastrointestinal stromal tumors, markedly induced appearance of ectopic neurons after BAC treatment, even in wildtype mice. These results suggest that adult neurogenesis in the ENS is negatively regulated by c-Kit signaling in vivo. PMID:27572504

  11. Suppression of c-Kit signaling induces adult neurogenesis in the mouse intestine after myenteric plexus ablation with benzalkonium chloride.

    PubMed

    Tamada, Hiromi; Kiyama, Hiroshi

    2016-01-01

    Adult neurogenesis rarely occurs in the enteric nervous system (ENS). In this study, we demonstrated that, after intestinal myenteric plexus (MP) ablation with benzalkonium chloride (BAC), adult neurogenesis in the ENS was significantly induced in c-kit loss-of-function mutant mice (W/W(v)). Almost all neurons and fibers in the MP disappeared after BAC treatment. However, 1 week after ablation, substantial penetration of nerve fibers from the non-damaged area was observed in the MP, longitudinal muscle and subserosal layers in both wildtype and W/W(v) mice. Two weeks after BAC treatment, in addition to the penetrating fibers, a substantial number of ectopic neurons appeared in the subserosal and longitudinal muscle layers of W/W(v) mice, whereas only a few ectopic neurons appeared in wildtype mice. Such ectopic neurons expressed either excitatory or inhibitory intrinsic motor neuron markers and formed ganglion-like structures, including glial cells, synaptic vesicles and basal lamina. Furthermore, oral administration of imatinib, an inhibitor of c-Kit and an anticancer agent for gastrointestinal stromal tumors, markedly induced appearance of ectopic neurons after BAC treatment, even in wildtype mice. These results suggest that adult neurogenesis in the ENS is negatively regulated by c-Kit signaling in vivo. PMID:27572504

  12. A method for high purity intestinal epithelial cell culture from adult human and murine tissues for the investigation of innate immune function

    PubMed Central

    Graves, Christina L.; Harden, Scott W.; LaPato, Melissa; Nelson, Michael; Amador, Byron; Sorenson, Heather; Frazier, Charles J.; Wallet, Shannon M.

    2015-01-01

    Intestinal epithelial cells (IECs) serve as an important physiologic barrier between environmental antigens and the host intestinal immune system. Thus, IECs serve as a first line of defense and may act as sentinel cells during inflammatory insults. Despite recent renewed interest in IEC contributions to host immune function, the study of primary IEC has been hindered by lack of a robust culture technique, particularly for small intestinal and adult tissues. Here, a novel adaptation for culture of primary IEC is described for human duodenal organ donor tissue as well as duodenum and colon of adult mice. These epithelial cell cultures display characteristic phenotypes and are of high purity. In addition, the innate immune function of human primary IEC, specifically with regard to Toll-like receptor (TLR) expression and microbial ligand responsiveness, is contrasted with a commonly used intestinal epithelial cell line (HT-29). Specifically, TLR expression at the mRNA level and production of cytokine (IFNγ and TNFα) in response to TLR agonist stimulation is assessed. Differential expression of TLRs as well as innate immune responses to ligand stimulation is observed in human-derived cultures compared to that of HT-29. Thus, use of this adapted method to culture primary epithelial cells from adult human donors and from adult mice will allow for more appropriate studies of IECs as innate immune effectors. PMID:25193428

  13. Maternal flaxseed oil intake during lactation changes body fat, inflammatory markers and glucose homeostasis in the adult progeny: role of gender dimorphism.

    PubMed

    Guarda, Deysla Sabino; de Moura, Egberto Gaspar; Carvalho, Janaíne Cavalcanti; Reis, Adelina Martha Dos; Soares, Patricia Novaes; Lisboa, Patricia Cristina; Figueiredo, Mariana Sarto

    2016-09-01

    We evaluated maternal flaxseed oil intake during lactation on body composition, lipid profile, glucose homeostasis and adipose tissue inflammation in male and female progeny at adulthood. Lactating rats were divided into the following: control 7% soybean oil (C), hyper 19% soybean oil (HS) and hyper 17% flaxseed oil+2% soybean oil (HF). Weaned pups received a standard diet. Offspring were killed in PN180. Male HF presented higher visceral adipose tissue (VAT) and triacylglycerol, and female HF showed insulin resistance. Both male and female HF had hyperleptinemia, and only male HF had hyperprolactinemia. In VAT, male HF presented lower PPAR-γ expressions and higher TNF-α, IL-6, IL-1β and IL-10 expressions; in subcutaneous adipose tissue (SAT), they presented lower PPAR-γ and TNF-α expressions. Female HF presented higher leptin, as well as lower adiponectin, TNF-α, IL-6 and IL-1β expressions in VAT and lower TNF-α in SAT. Flaxseed oil during lactation leads to gender-specific effects with more adiposity and dyslipidemia in male and insulin resistance in female. Higher prolactin and inflammatory cytokines in male could play a role in these gender differences. We suggest that the use of flaxseed oil during lactation increases metabolic syndrome risk in the adult progeny. PMID:27469994

  14. The role of miR-126 in embryonic angiogenesis, adult vascular homeostasis, and vascular repair and its alterations in atherosclerotic disease.

    PubMed

    Chistiakov, Dimitry A; Orekhov, Alexander N; Bobryshev, Yuri V

    2016-08-01

    Expression of microRNA (miR)-126 is enriched in endothelial cells (ECs) and endothelial progenitor cells (EPCs). MiR-126 is considered a master regulator of physiological angiogenesis. In embryonic vasculogenesis, this miRNA is involved in induction of angiogenic signaling, supports differentiation of embryonic stem cells to EPCs and ECs, and promotes EC maturation. However, in mature ECs and adult EPCs, miR-126 contributes to vascular homeostasis by inhibiting angiogenesis and maintaining the quiescent endothelial phenotype associated with increased vascular integrity and inhibited proliferation and motility. In a case of vessel injury and/or hypoxia, miR-126 up-regulation activates EPCs and ECs and contributes to vascular healing and neovessel formation. Indeed, miR-126 exhibits vasculoprotective and atheroprotective properties. The promising regenerative and proangiogenic potential of this miRNA will be helpful for development of cardioprotective strategies and cardiovascular repair therapies of myocardial infarction, heart failure, and other cardiovascular pathology. PMID:27180261

  15. Appendicitis and abscess in an adult patient with intestinal nonrotation: Case report.

    PubMed

    Assenza, M; Reali, C; Valesini, L; Marenga, G; Bartolucci, P; Rossi, D; Modini, C

    2015-01-01

    The aim of the article is showing a particular case of midgut nonrotation. It is a congenital defect of the bowel development, during which fails the rotation of 270° around the vascular pedicle. This anomaly causes a different intestinal arrangement: the small bowel is located in the right side of abdominal cavity while the large bowel is situated in the left side. We present a case of acute appendicitis and abscess treated successfully with urgent surgical intervention in a patient completely asymptomatic for nonrotation. Nonrotation may lead to acute symptoms, vague abdominal pain or may remain asymptomatic throughout all life and be discovered only accidentally. Radiological exams and laparoscopy can help to make a correct diagnosis. A conservative treatment could be preferred in asymptomatic patients and Ladd's surgical procedure should be performed in selected cases. PMID:25945440

  16. Cocoa Flavonoid-Enriched Diet Modulates Systemic and Intestinal Immunoglobulin Synthesis in Adult Lewis Rats

    PubMed Central

    Massot-Cladera, Malen; Franch, Àngels; Castellote, Cristina; Castell, Margarida; Pérez-Cano, Francisco J.

    2013-01-01

    Previous studies have reported that a diet containing 10% cocoa, a rich source of flavonoids, has immunomodulatory effects on rats and, among others effects, is able to attenuate the immunoglobulin (Ig) synthesis in both systemic and intestinal compartments. The purpose of the present study was focused on investigating whether these effects were attributed exclusively to the flavonoid content or to other compounds present in cocoa. To this end, eight-week-old Lewis rats were fed, for two weeks, either a standard diet or three isoenergetic diets containing increasing proportions of cocoa flavonoids from different sources: one with 0.2% polyphenols from conventional defatted cocoa, and two others with 0.4% and 0.8% polyphenols, respectively, from non-fermented cocoa. Diet intake and body weight were monitored and fecal samples were obtained throughout the study to determine fecal pH, IgA, bacteria proportions, and IgA-coated bacteria. Moreover, IgG and IgM concentrations in serum samples collected during the study were quantified. At the end of the dietary intervention no clear changes of serum IgG or IgM concentrations were quantified, showing few effects of cocoa polyphenol diets at the systemic level. However, in the intestine, all cocoa polyphenol-enriched diets attenuated the age-related increase of both fecal IgA and IgA-coated bacteria, as well as the proportion of bacteria in feces. As these effects were not dependent on the dose of polyphenol present in the diets, other compounds and/or the precise polyphenol composition present in cocoa raw material used for the diets could be key factors in this effect. PMID:23966108

  17. Intestinal Lesions Are Associated with Altered Intestinal Microbiome and Are More Frequent in Children and Young Adults with Cystic Fibrosis and Cirrhosis

    PubMed Central

    Flass, Thomas; Tong, Suhong; Frank, Daniel N.; Wagner, Brandie D.; Robertson, Charles E.; Kotter, Cassandra Vogel; Sokol, Ronald J.; Zemanick, Edith; Accurso, Frank; Hoffenberg, Edward J.; Narkewicz, Michael R.

    2015-01-01

    Background and Aims Cirrhosis (CIR) occurs in 5–7% of cystic fibrosis (CF) patients. We hypothesized that alterations in intestinal function in CF contribute to the development of CIR. Aims: Determine the frequency of macroscopic intestinal lesions, intestinal inflammation, intestinal permeability and characterize fecal microbiome in CF CIR subjects and CF subjects with no liver disease (CFnoLIV). Methods 11 subjects with CFCIR (6 M, 12.8 yrs ± 3.8) and 19 matched with CFnoLIV (10 M, 12.6 yrs ± 3.4) underwent small bowel capsule endoscopy, intestinal permeability testing by urinary lactulose: mannitol excretion ratio, fecal calprotectin determination and fecal microbiome characterization. Results CFCIR and CFnoLIV did not differ in key demographics or CF complications. CFCIR had higher GGT (59±51 U/L vs 17±4 p = 0.02) and lower platelet count (187±126 vs 283±60 p = 0.04) and weight (-0.86 ± 1.0 vs 0.30 ± 0.9 p = 0.002) z scores. CFCIR had more severe intestinal mucosal lesions on capsule endoscopy (score ≥4, 4/11 vs 0/19 p = 0.01). Fecal calprotectin was similar between CFCIR and CFnoLIV (166 μg/g ±175 vs 136 ± 193 p = 0.58, nl <120). Lactulose:mannitol ratio was elevated in 27/28 subjects and was slightly lower in CFCIR vs CFnoLIV (0.08±0.02 vs 0.11±0.05, p = 0.04, nl ≤0.03). Small bowel transit time was longer in CFCIR vs CFnoLIV (195±42 min vs 167±68 p<0.001, nl 274 ± 41). Bacteroides were decreased in relative abundance in CFCIR and were associated with lower capsule endoscopy score whereas Clostridium were more abundant in CFCIR and associated with higher capsule endoscopy score. Conclusions CFCIR is associated with increased intestinal mucosal lesions, slower small bowel transit time and alterations in fecal microbiome. Abnormal intestinal permeability and elevated fecal calprotectin are common in all CF subjects. Disturbances in intestinal function in CF combined with changes in the microbiome may contribute to the development of

  18. Conjugated Linoleic Acid Supplementation under a High-Fat Diet Modulates Stomach Protein Expression and Intestinal Microbiota in Adult Mice

    PubMed Central

    Chaplin, Alice; Parra, Pilar; Serra, Francisca; Palou, Andreu

    2015-01-01

    The gastrointestinal tract constitutes a physiological interface integrating nutrient and microbiota-host metabolism. Conjugated linoleic acids (CLA) have been reported to contribute to decreased body weight and fat accretion. The modulation by dietary CLA of stomach proteins related to energy homeostasis or microbiota may be involved, although this has not been previously analysed. This is examined in the present study, which aims to underline the potential mechanisms of CLA which contribute to body weight regulation. Adult mice were fed either a normal fat (NF, 12% kJ content as fat) or a high-fat (HF, 43% kJ content as fat) diet. In the latter case, half of the animals received daily oral supplementation of CLA. Expression and content of stomach proteins and specific bacterial populations from caecum were analysed. CLA supplementation was associated with an increase in stomach protein expression, and exerted a prebiotic action on both Bacteroidetes/Prevotella and Akkermansia muciniphila. However, CLA supplementation was not able to override the negative effects of HF diet on Bifidobacterium spp., which was decreased in both HF and HF+CLA groups. Our data show that CLA are able to modulate stomach protein expression and exert a prebiotic effect on specific gut bacterial species. PMID:25915857

  19. Intussusception causing postoperative intestinal obstruction following free jejunum transfer in adults: two case reports and review of the literature.

    PubMed

    Matsumoto, Akira; Watanabe, Masayuki; Shigaki, Hironobu; Okumura, Yasuhiro; Nishida, Koujiro; Mine, Shinji; Yamada, Kazuhiko; Yanaga, Katsuhiko; Sano, Takeshi

    2015-12-01

    Intussusception is a rare cause of postoperative intestinal obstruction in adults. We experienced two cases of bowel obstruction due to the jejuno-jejunal intussusception after harvest of a free jejunum graft for reconstruction after cervical esophagectomy. Bowel obstruction occurred early in the postoperative course, and reoperations were needed in both cases. In both case, the anastomotic site was resected and re-anastomosed in a side-to-side fashion. Recurrence of intussusception has not been observed. In the literature, such a complication has been documented in two case series and a case report. The reported incidence of postoperative intussusception of the case series was 2.8% and 7.4%, respectively. The jejuno-jejunal anastomoses were performed with end-to-end fashion by two layered hand-sewn suture (Albert-Lembert method) in all cases reported. In order to prevent the occurrence of postoperative intussusception, we recommend to harvest a free jejunal graft as far from the Treitz ligament as possible and to avoid reconstruction by an Albert-Lembert end-to-end anastomosis. PMID:26943396

  20. Prevalence and Predictors of Intestinal Helminth Infections Among Human Immunodeficiency Virus Type 1–Infected Adults in an Urban African Setting

    PubMed Central

    Modjarrad, Kayvon; Zulu, Isaac; Redden, David T.; Njobvu, Lungowe; Freedman, David O.; Vermund, Sten H.

    2009-01-01

    Sub-Saharan Africa is disproportionately burdened by intestinal helminth and human immunodeficiency virus (HIV)-1 infection. Recent evidence suggests detrimental immunologic effects from concomitant infection with the two pathogens. Few studies, however, have assessed the prevalence of and predictors for intestinal helminth infection among HIV-1–infected adults in urban African settings where HIV infection rates are highest. We collected and analyzed sociodemographic and parasitologic data from 297 HIV-1–infected adults (mean age = 31.1 years, 69% female) living in Lusaka, Zambia to assess the prevalence and associated predictors of helminth infection. We found at least one type of intestinal helminth in 24.9% of HIV-infected adults. Thirty-nine (52.7%) were infected with Ascaris lumbricoides, and 29 (39.2%) were infected with hookworm. More than 80% were light-intensity infections. A recent visit to a rural area, food shortage, and prior history of helminth infection were significant predictors of current helminth status. The high helminth prevalence and potential for adverse interactions between helminths and HIV suggests that helminth diagnosis and treatment should be part of routine HIV care. PMID:16222025

  1. Candidate Genes from Molecular Pathways Related to Appetite Regulatory Neural Network and Adipocyte Homeostasis and Obesity: the Coronary Artery Risk Development in Young Adults (CARDIA) Study

    PubMed Central

    Friedlander, Yechiel; Li, Guo; Fornage, Myriam; Williams, O. Dale; Lewis, Cora E.; Schreiner, Pamela; Pletcher, Mark J.; Enquobahrie, Daniel; Williams, Michelle; Siscovick, David S.

    2010-01-01

    Background Appetite regulatory neural network and adipocyte homeostasis molecular pathways are critical to long-term weight maintenance. Genetic variation in these pathways may explain variability of obesity in the general population. Aims The associations of four genes in these pathways (leptin (LEP), leptin receptor (LEPR), neuropeptide Y2 receptor (NPY2R) and peptide YY (PYY)) with obesity-related phenotypes were examined among participants in the CARDIA Study. Participants were 18-30 years old upon recruitment (1985-86). Weight, BMI and waist circumference were measured at baseline and at years 2, 5, 7, 10, 15, and 20. Genotyping was conducted using tag SNPs that characterize the common pattern of genetic variation in these genes. Race-specific linear regression models were used to examine associations of the various SNPs with obesity-related measurements, controlling for sex and age. The overall association based on the 7 repeated anthropometric measurements was tested with GEE. False discovery rate was used to adjust for multiple testing. Results In African-Americans, SNPs across the LEP gene demonstrated significant overall associations with obesity-related phenotypes. The associations between rs17151919 in LEP gene with weight tended to increase with time (SNP × time interaction p=0.0193). The difference in weight levels associated with each additional minor allele ranged from 2.6 kg at entry to 4.8 kg at year 20. Among African-American men, the global tests indicated that SNPs across the NPY2R gene were also associated with waist circumference measurements (p=0.0462). In Caucasians, SNPs across the LEP gene also tended to be associated with weight measurements (p=0.0471) and rs11684664 in PYY gene was associated with obesity-related phenotypes (p= 0.010-0.026) in women only. Conclusions Several SNPs in the LEP, NPY2R and PYY but not the LEPR genes were associated with obesity-related phenotypes in young adults. The associations were more prominent for the

  2. Purslane Extract and Glucose Homeostasis in Adults with Type 2 Diabetes: A Double-Blind, Placebo-Controlled Clinical Trial of Efficacy and Safety.

    PubMed

    Wainstein, Julio; Landau, Zohar; Bar Dayan, Yosefa; Jakubowicz, Daniela; Grothe, Torsten; Perrinjaquet-Moccetti, Tania; Boaz, Mona

    2016-02-01

    Purslane extract (PE) is derived from Portulaca oleracea L., a medicinal plant used in traditional medicine for its antidiabetic properties. This randomized, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of PE in improving glucose control, blood pressure, and lipid profile in adults with type 2 diabetes mellitus (T2DM) treated with a single oral hypoglycemic agent at baseline. Subjects were randomized to treatment with three capsules of PE/day or a matched placebo. Change from baseline to the week 12 end-of-follow-up visit measures of glucose homeostasis, hemodynamics, and lipid profile was compared by treatment assignment. In addition, these measures were evaluated in a subgroup of "responders," defined as patients whose week 12 HbA1c was lower than baseline values, regardless of treatment assignment. This group was further assessed in subgroups of baseline oral hypoglycemic treatment. A total of 63 participants were treated with either PE (n = 31, 11 females, mean age 52.4 ± 7.9 years) or matched placebo (n = 32, 11 females, mean age 58.3 ± 10.8 years). In the total cohort, systolic blood pressure declined significantly more in the PE group than the placebo group: -7.5 ± 5.0 versus -0.01 ± 0.3 mmHg, P < .0001. In the responders' subgroup, HbA1c declined significantly more in the PE group than the placebo group: -0.8% ± 0.4% versus -0.6% ± 0.5%, P = .03. Few adverse events were reported. These were mild and did not differ by treatment assignment. PE appears to be a safe, adjunct treatment for T2DM, significantly reducing systolic blood pressure in the total cohort and HbA1c in the subgroup of responders. PMID:26854844

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

    PubMed Central

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

    2015-01-01

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

  4. Intestinal stem cell response to injury: lessons from Drosophila.

    PubMed

    Jiang, Huaqi; Tian, Aiguo; Jiang, Jin

    2016-09-01

    Many adult tissues and organs are maintained by resident stem cells that are activated in response to injury but the mechanisms that regulate stem cell activity during regeneration are still poorly understood. An emerging system to study such problem is the Drosophila adult midgut. Recent studies have identified both intrinsic factors and extrinsic niche signals that control the proliferation, self-renewal, and lineage differentiation of Drosophila adult intestinal stem cells (ISCs). These findings set up the stage to interrogate how niche signals are regulated and how they are integrated with cell-intrinsic factors to control ISC activity during normal homeostasis and regeneration. Here we review the current understanding of the mechanisms that control ISC self-renewal, proliferation, and lineage differentiation in Drosophila adult midgut with a focus on the niche signaling network that governs ISC activity in response to injury. PMID:27137186

  5. Neonate Intestinal Immune Response to CpG Oligodeoxynucleotide Stimulation

    PubMed Central

    Lacroix-Lamandé, Sonia; Rochereau, Nicolas; Mancassola, Roselyne; Barrier, Mathieu; Clauzon, Amandine; Laurent, Fabrice

    2009-01-01

    Background The development of mucosal vaccines is crucial to efficiently control infectious agents for which mucosae are the primary site of entry. Major drawbacks of these protective strategies are the lack of effective mucosal adjuvant. Synthetic oligodeoxynucleotides that contain several unmethylated cytosine-guanine dinucleotide (CpG-ODN) motifs are now recognized as promising adjuvants displaying mucosal adjuvant activity through direct activation of TLR9-expressing cells. However, little is known about the efficacy of these molecules in stimulating the intestinal immune system in neonates. Methodology/Principal Findings First, newborn mice received CpG-ODN orally, and the intestinal cytokine and chemokine response was measured. We observed that oral administration of CpG-ODN induces CXC and CC chemokine responses and a cellular infiltration in the intestine of neonates as detected by immunohistochemistry. We next compared the efficiency of the oral route to intraperitoneal administration in stimulating the intestinal immune responses of both adults and neonates. Neonates were more responsive to TLR9-stimulation than adults whatever the CpG-ODN administration route. Their intestinal epithelial cells (IECs) indirectly responded to TLR9 stimulation and contributed to the CXC chemokine response, whereas other TLR9-bearing cells of the lamina-propria produced CC chemokines and Th1-type cytokines. Moreover, we showed that the intestine of adult exhibited a significantly higher level of IL10 at homeostasis than neonates, which might be responsible for the unresponsiveness to TLR9-stimulation, as confirmed by our findings in IL10-deficient mice. Conclusions/Significance This is the first report that deciphers the role played by CpG-ODN in the intestine of neonates. This work clearly demonstrates that an intraperitoneal administration of CpG-ODN is more efficient in neonates than in adults to stimulate an intestinal chemokine response due to their lower IL-10

  6. Cdk4 functions in multiple cell types to control Drosophila intestinal stem cell proliferation and differentiation.

    PubMed

    Adlesic, Mojca; Frei, Christian; Frew, Ian J

    2016-01-01

    The proliferation of intestinal stem cells (ISCs) and differentiation of enteroblasts to form mature enteroendocrine cells and enterocytes in the Drosophila intestinal epithelium must be tightly regulated to maintain homeostasis. We show that genetic modulation of CyclinD/Cdk4 activity or mTOR-dependent signalling cell-autonomously regulates enterocyte growth, which influences ISC proliferation and enteroblast differentiation. Increased enterocyte growth results in higher numbers of ISCs and defective enterocyte growth reduces ISC abundance and proliferation in the midgut. Adult midguts deficient for Cdk4 show severe disruption of intestinal homeostasis characterised by decreased ISC self-renewal, enteroblast differentiation defects and low enteroendocrine cell and enterocyte numbers. The ISC/enteroblast phenotypes result from a combination of cell autonomous and non-autonomous requirements for Cdk4 function. One non-autonomous consequence of Cdk4-dependent deficient enterocyte growth is high expression of Delta in ISCs and Delta retention in enteroblasts. We postulate that aberrant activation of the Delta-Notch pathway is a possible partial cause of lost ISC stemness. These results support the idea that enterocytes contribute to a putative stem cell niche that maintains intestinal homeostasis in the Drosophila anterior midgut. PMID:26879465

  7. Cdk4 functions in multiple cell types to control Drosophila intestinal stem cell proliferation and differentiation

    PubMed Central

    Adlesic, Mojca; Frei, Christian; Frew, Ian J.

    2016-01-01

    ABSTRACT The proliferation of intestinal stem cells (ISCs) and differentiation of enteroblasts to form mature enteroendocrine cells and enterocytes in the Drosophila intestinal epithelium must be tightly regulated to maintain homeostasis. We show that genetic modulation of CyclinD/Cdk4 activity or mTOR-dependent signalling cell-autonomously regulates enterocyte growth, which influences ISC proliferation and enteroblast differentiation. Increased enterocyte growth results in higher numbers of ISCs and defective enterocyte growth reduces ISC abundance and proliferation in the midgut. Adult midguts deficient for Cdk4 show severe disruption of intestinal homeostasis characterised by decreased ISC self-renewal, enteroblast differentiation defects and low enteroendocrine cell and enterocyte numbers. The ISC/enteroblast phenotypes result from a combination of cell autonomous and non-autonomous requirements for Cdk4 function. One non-autonomous consequence of Cdk4-dependent deficient enterocyte growth is high expression of Delta in ISCs and Delta retention in enteroblasts. We postulate that aberrant activation of the Delta–Notch pathway is a possible partial cause of lost ISC stemness. These results support the idea that enterocytes contribute to a putative stem cell niche that maintains intestinal homeostasis in the Drosophila anterior midgut. PMID:26879465

  8. Oral Immunization with Cholera Toxin Provides Protection against Campylobacter jejuni in an Adult Mouse Intestinal Colonization Model

    PubMed Central

    Albert, M. John; Mustafa, Abu Salim; Islam, Anjum; Haridas, Shilpa

    2013-01-01

    ABSTRACT Immunity to Campylobacter jejuni, a major diarrheal pathogen, is largely Penner serotype specific. For broad protection, a vaccine should be based on a common antigen(s) present in all strains. In our previous study (M. J. Albert, S. Haridas, D. Steer, G. S. Dhaunsi, A. I. Smith, and B. Adler, Infect. Immun. 75:3070–3073, 2007), we demonstrated that antibody to cholera toxin (CT) cross-reacted with the major outer membrane proteins (MOMPs) of all Campylobacter jejuni strains tested. In the current study, we investigated whether immunization with CT protects against intestinal colonization by C. jejuni in an adult mouse model and whether the nontoxic subunit of CT (CT-B) is the portion mediating cross-reaction. Mice were orally immunized with CT and later challenged with C. jejuni strains (48, 75, and 111) of different serotypes. Control animals were immunized with phosphate-buffered saline. Fecal shedding of challenge organisms was studied daily for 9 days. Serum and fecal antibody responses were studied by enzyme-linked immunosorbent assay (ELISA) and immunoblotting. The cross-reactivity of rabbit CT-B antibody to MOMP was studied by immunoblotting. The reactivity of 21 overlapping 30-mer oligopeptides (based on MOMP’s sequence) against rabbit CT antibody was tested by ELISA. Test animals produced antibodies to CT and MMP in serum and feces and showed resistance to colonization, the vaccine efficacies being 49% (for strain 48), 37% (for strain 75), and 34% (for strain 111) (P, ≤0.05 to ≤0.001). One peptide corresponding to a variable region of MOMP showed significant reactivity. CT-B antibody cross-reacted with MOMP. Since CT-B is a component of oral cholera vaccines, it might be possible to control C. jejuni diarrhea with these vaccines. PMID:23653448

  9. Calcium homeostasis and bone metabolic responses to high-protein diets during energy deficit in healthy young adults: a randomized control trial

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Although consuming dietary protein above current recommendations during energy deficit enhances blood lipid profiles and preserves lean body mass, concerns have been raised regarding effects of high-protein diets on bone health. To determine whether calcium homeostasis and bone turnover are affected...

  10. Intestinal failure: Pathophysiological elements and clinical diseases

    PubMed Central

    Ding, Lian-An; Li, Jie-Shou

    2004-01-01

    There are two main functions of gastrointestinal tract, digestion and absorption, and barrier function. The latter has an important defensive effect, which keeps the body away from the invading and damaging of bacteria and endotoxin. It maintains the systemic homeostasis. Intestinal dysfunction would happen when body suffers from diseases or harmful stimulations. The lesser dysfunction of GI tract manifests only disorder of digestion and absorption, whereas the more serious intestinal disorders would harm the intestinal protective mechanism, or intestinal barrier function, and bacterial/endotoxin translocation, of intestinal failure (IF) would ensue. This review disscussed the theory of the intestinal failure, aiming at attracting recognition and valuable comments by clinicians. PMID:15052668