The role of mucoprotectants in the management of gastrointestinal disorders

Introduction: The intestinal barrier controls the absorption of nutrients and water whilst helping to prevent the entry of toxins and pathogenic micro-organisms from the lumen into the tissues. Deficiencies in the barrier are associated with various gastrointestinal and extra digestive disorders.

Areas covered: This review provides an overview of the relationship between increased intestinal permeability and disease, and considers the role of mucosal protectants (mucoprotectants) in restoring normal intestinal barrier function, with a particular focus on diarrheal disorders.

Expert commentary: Impairment of the intestinal barrier characterizes a variety of diseases, and there is ongoing interest in the development of pharmacological approaches targeting the reduction of intestinal permeability. These include corticosteroids, aminosalicylates and anti-tumor necrosis factor-α (TNF-α), which act by reducing inflammation; probiotics, which modulate the production of mucin and epithelial tight junction proteins; and mucoprotectants, which form a protective film over the epithelium. Recently, preclinical and clinical data highlight, the ability of new mucoprotectants, such as gelatin tannate and xyloglucan, to protect the intestinal mucosa and to exert anti-diarrheal effects. In the future the ability of these substances to enhance the intestinal barrier may extend their use in the management of a variety of gastro-intestinal diseases associated with ‘leaky gut’.     

Effects of Inhibition of PAF,ICAM-1 and PECAM-1 on Gut Barrier Failure Caused by Intestinal Ischemia and Reperfusion

Background: The role of cell adhesion molecules and transmigration of PMNs through the endothelial barrier is probably essential in intestinal ischemia and reperfusion (I/R)-induced gut barrier dysfunction. Although cytokines are released in I/R, it is unclear whether cytokines directly increase permeability or if this phenomenon requires both expression of cell adhesion molecules and PMN adhesion-activation. Endothelial barrier dysfunction plays an important role in the pathogenesis of multiple organ dysfunction syndrome, inducing gut barrier failure, but the mechanisms are not fully understood. The purpose of this study was to evaluate the potential therapeutic value of inhibition of platelet activating factor (PAF), intercellular adhesion molecule-1 (ICAM-1), and platelet endothelial cell adhesion molecule-1 (PECAM1) in gut barrier dysfunction induced by intestinal I/R. Methods:     

Gut microbiota derived metabolites contribute to intestinal barrier maturation at the suckling-to-weaning transition

ABSTRACT

In suckling mammals, the onset of solid food ingestion is coincident with the maturation of the gut barrier. This ontogenic process is driven by the colonization of the intestine by the microbiota. However, the mechanisms underlying the microbial regulation of the intestinal development in early life are not fully understood. Here, we studied the co-maturation of the microbiota (composition and metabolic activity) and of the gut barrier at the suckling-to-weaning transition by using a combination of experiments in vivo (suckling rabbit model), ex vivo (Ussing chambers) and in vitro (epithelial cell lines and organoids). The microbiota composition, its metabolic activity, para-cellular epithelial permeability and the gene expression of key components of the gut barrier shifted sharply at the onset of solid food ingestion in vivo, despite milk was still predominant in the diet at that time. We found that cecal content sterile supernatant (i.e. containing a mixture of metabolites) obtained after the onset of solid food ingestion accelerated the formation of the epithelial barrier in Caco-2 cells in vitro and our results suggested that these effects were driven by the bacterial metabolite butyrate. Moreover, the treatment of organoids with cecal content sterile supernatant partially replicated in vitro the effects of solid food ingestion on the epithelial barrier in vivo. Altogether, our results show that the metabolites produced by the microbiota at the onset of solid food ingestion contribute to the maturation of the gut barrier at the suckling-to-weaning transition. Targeting the gut microbiota metabolic activity during this key developmental window might therefore be a promising strategy to promote intestinal homeostasis.     

Starring role of toll-like receptor-4 activation in the gut-liver axis

Since the introduction of the term “gut-liver axis”, many studies have focused on the functional links of intestinal microbiota, barrier function and immune responses to liver physiology. Intestinal and extra-intestinal diseases alter microbiota composition and lead to dysbiosis, which aggravates impaired intestinal barrier function via increased lipopolysaccharide translocation. The subsequent increased passage of gut-derived product from the intestinal lumen to the organ wall and bloodstream affects gut motility and liver biology. The activation of the toll-like receptor 4 (TLR-4) likely plays a key role in both cases. This review analyzed the most recent literature on the gut-liver axis, with a particular focus on the role of TLR-4 activation. Findings that linked liver disease with dysbiosis are evaluated, and links between dysbiosis and alterations of intestinal permeability and motility are discussed. We also examine the mechanisms of translocated gut bacteria and/or the bacterial product activation of liver inflammation and fibrogenesis via activity on different hepatic cell types.     

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

BackgroundNecroptosis is an inflammatory form of programmed cell death requiring receptor-interacting protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL).AimsThe aim of this study is to examine in depth in vitro and ex vivo the contribution of necroptosis to intestinal inflammation.MethodsIn vitro: we used an intestinal cell line, HCT116RIP3, produced in our laboratory and overexpressing RIP3. Ex vivo: intestinal mucosal biopsies were taken from patients with inflammatory bowel disease (IBD) (20 with Crohn’s disease; 20 with ulcerative colitis) and from 20 controls.ResultsRIP3-induced necroptosis triggers MLKL activation, increases cytokine/alarmin expression (IL-8, IL-1β, IL-33, HMGB1), NF-kBp65 translocation and NALP3 inflammasome assembly. It also affects membrane permeability by altering cell–cell junctional proteins (E-cadherin, Occludin, Zonulin-1). Targeting necroptosis through Necrostatin-1 significantly reduces intestinal inflammation in vitro and in cultured intestinal explants from IBD.ConclusionWe show for the first time in vitro and ex vivo that RIP3-driven necroptosis seriously affects intestinal inflammation by increasing pMLKL, activating different cytokines and alarmins, and altering epithelial permeability. The inhibition of necroptosis causes a significant decrease of all these effects. These data strongly support the view that targeting necroptosis may represent a promising new option for the treatment of inflammatory enteropathies.     

Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function

BACKGROUND & AIMS: Toll-like receptors (TLRs) represent a class of transmembrane pattern recognition receptors essential for microbial recognition and control of innate immune responses. Commensal bacteria play an important role in maintaining tolerance and active stability of the intestinal epithelial barrier by suppressing intestinal inflammation, yet the mechanisms of action are unknown. The aim of this study was to determine the functional relevance of TLR2 to control tight junction (TJ)-associated intestinal epithelial barrier integrity to balance mucosal homeostasis against inflammatory stress-induced damage. METHODS: TLR2 ligand (synthetic Pam(3)Cys-SK4 [PCSK])-induced activation of signaling cascades and TJ-associated distribution was assessed by using Western blotting and confocal microscopy combined with functional transfection and inhibitor studies in model intestinal epithelial cell (IEC) lines (IEC-6, Caco-2) or primary IEC cultured short-term ex vivo. DSS colitis was induced by standard protocol in wild-type, TLR2-/-, and MyD88-/- mice. Spontaneous apoptosis was assessed by terminal deoxinucleotidyl-transferase-mediated dUTP-biotin nick end-labeling. RESULTS: Data from in vitro and ex vivo models of intestinal epithelial cells revealed that TLR2 stimulation effectively preserves TJ-associated barrier assembly against stress-induced damage through promotion of PI3K/Akt-mediated cell survival via MyD88. Furthermore, in vivo studies underscored that TLR2-mediated TJ regulation critically determines susceptibility to intestinal injury and inflammation. Inflammatory stress in mice deficient of TLR2 or MyD88 induced early TJ-associated disruption interrelated with anti-apoptotic failure of the intestinal epithelial barrier. Oral treatment of colitis with the TLR2 ligand PCSK significantly suppressed mucosal inflammation and apoptosis by efficiently restoring TJ-associated integrity of the intestinal epithelium in vivo. CONCLUSION: TLR2 may provide a target to pharmacologically modulate mucosal injury and intestinal inflammation.     

Bacterial translocation in patients with liver cirrhosis: physiology,clinical consequences,and practical implications

Introduction: The gut liver axis is an operative unit that works to protect the human body against potentially harmful substances and microorganisms, maintaining the homeostasis of the immune system. Liver cirrhosis profoundly alters this complex system. The intestine becomes more permeable allowing the translocation of bacteria, bacterial products and fragments into the portal circulation, triggering an abnormal local and systemic inflammatory response and a condition of perpetual immunologic alarm. This immune-inflammatory disorder related to dysbiosis is involved in the development of liver damage and liver cirrhosis complications and increases intestinal permeability in a vicious circle.

Areas covered: The most relevant studies on bacterial translocation, the mechanism of intestinal barrier dysfunction and its consequences in patients with liver cirrhosis have been revised through a PubMed search. Data have been discussed with particular regard to their significance in clinical practice.

Expert commentary: The assessment of bacterial translocation and intestinal permeability is not currently used in clinical practice but may be useful to stratify patients’ prognosis.     

The intestinal barrier: a fundamental role in health and disease

Introduction: The gastrointestinal mucosa constitutes a critical barrier where millions of microbes and environmental antigens come in close contact with the host immune system. Intestinal barrier defects have been associated with a broad range of diseases and therefore denote a new therapeutic target.

Areas covered: This review is based on an extensive literature search in PubMed of how the intestinal barrier contributes to health and as a trigger for disease. It discusses the anatomy of the intestinal barrier and explains the available methods to evaluate its function. Also reviewed is the importance of diet and lifestyle factors on intestinal barrier function, and three prototypes of chronic diseases (inflammatory bowel disease, celiac disease and nonalcoholic fatty liver disease) that have been linked to barrier defects are discussed.

Expert commentary: The intestinal barrier has been investigated by various methods, but correlation of results across studies is difficult, representing a major shortcoming in the field. New upcoming techniques and research on the effect of barrier-restoring therapeutics may improve our current understanding of the gut barrier, and provide a step forward towards personalised medicine.     

Psychological stress exacerbates NSAID-induced small bowel injury by inducing changes in intestinal microbiota and permeability via glucocorticoid receptor signaling

Background

Nonsteroidal anti-inflammatory drugs (NSAIDs) are popular painkillers, but they have serious side effects, not only in the upper gastrointestinal tract but also in the small intestine. It is well known that psychological stress may exacerbate various gastrointestinal diseases. The aim of this study was to determine whether psychological stress exacerbates NSAID enteropathy and to determine the possible underlying mechanisms for this.

Methods

Experiment 1: mice were exposed to water avoidance stress (WAS) or sham stress for 1 h per day for 8 consecutive days, and then enteropathy was induced by indomethacin. Experiment 2: cecal contents from stress (−) or (+) mice were transplanted into mice that had received antibiotics and in which NSAID enteropathy had been induced without WAS. Experiment 3: mifepristone, a glucocorticoid receptor antagonist, was injected before WAS for 8 days. Small intestinal injury, mRNA expression of TNFα, intestinal permeability, and the microbial community were assessed.

Results

Psychological stress exacerbated NSAID enteropathy and increased intestinal permeability. Psychological stress induced changes in the ileal microbiota that were characterized by increases in the total number of bacteria and the proportion of Gram-negative bacteria. The increased susceptibility to NSAIDs and intestinal permeability due to WAS was transferable via cecal microbiota transplantation. The increased permeability and aggravation of NSAID enteropathy caused by WAS were blocked by the administration of mifepristone.

Conclusions

This study demonstrated a relationship between NSAID enteropathy and psychological stress, and showed the utility of studying the intestinal microbiota in order to elucidate the pathophysiology of NSAID enteropathy. It also showed the impact of stress on the intestinal microbiota and the mucosal barrier in gastrointestinal diseases.

     

Recombinant angiopoietin-like protein 4 attenuates intestinal barrier structure and function injury after ischemia/reperfusion

BACKGROUNDIntestinal barrier breakdown, a frequent complication of intestinal ischemia-reperfusion (I/R) including dysfunction and the structure changes of the intestine, is characterized by a loss of tight junction and enhanced permeability of the intestinal barrier and increased mortality. To develop effective and novel therapeutics is important for the improvement of outcome of patients with intestinal barrier deterioration. Recombinant human angiopoietin-like protein 4 (rhANGPTL4) is reported to protect the blood-brain barrier when administered exogenously, and endogenous ANGPTL4 deficiency deteriorates radiation-induced intestinal injury. AIMTo identify whether rhANGPTL4 may protect intestinal barrier breakdown induced by I/R.METHODSIntestinal I/R injury was elicited through clamping the superior mesenteric artery for 60 min followed by 240 min reperfusion. Intestinal epithelial (Caco-2) cells and human umbilical vein endothelial cells were challenged by hypoxia/ reoxygenation to mimic I/R in vitro.RESULTSIndicators including fluorescein isothiocyanate-conjugated dextran (4 kilodaltons; FD-4) clearance, ratio of phosphorylated myosin light chain/total myosin light chain, myosin light chain kinase and loss of zonula occludens-1, claudin-2 and VE-cadherin were significantly increased after intestinal I/R or cell hypoxia/reoxygenation. rhANGPTL4 treatment significantly reversed these indicators, which were associated with inhibiting the inflammatory and oxidative cascade, excessive activation of cellular autophagy and apoptosis and improvement of survival rate. Similar results were observed in vitro when cells were challenged by hypoxia/reoxygenation, whereas rhANGPTL4 reversed the indicators close to normal level in Caco-2 cells and human umbilical vein endothelial cells significantly.CONCLUSIONrhANGPTL4 can function as a protective agent against intestinal injury induced by intestinal I/R and improve survival via maintenance of intestinal barrier structure and functions.     

Nitric Oxide-Mediated Intestinal Injury Is Required for Alcohol-Induced Gut Leakiness and Liver Damage

Background: Alcoholic liver disease (ALD) requires endotoxemia and is commonly associated with intestinal barrier leakiness. Using monolayers of intestinal epithelial cells as an in vitro barrier model, we showed that ethanol‐induced intestinal barrier disruption is mediated by inducible nitric oxide synthase (iNOS) upregulation, nitric oxide (NO) overproduction, and oxidation/nitration of cytoskeletal proteins. We hypothesized that iNOS inhibitors [NG‐nitro‐l ‐arginine methyl ester (l ‐NAME), l ‐N⁶‐(1‐iminoethyl)‐lysine (l ‐NIL)] in vivo will inhibit the above cascade and liver injury in an animal model of alcoholic steatohepatitis (ASH). Methods: Male Sprague–Dawley rats were gavaged daily with alcohol (6 g/kg/d) or dextrose for 10 weeks ± l ‐NAME, l ‐NIL, or vehicle. Systemic and intestinal NO levels were measured by nitrites and nitrates in urine and tissue samples, oxidative damage to the intestinal mucosa by protein carbonyl and nitrotyrosine, intestinal permeability by urinary sugar tests, and liver injury by histological inflammation scores, liver fat, and myeloperoxidase activity. Results: Alcohol caused tissue oxidation, gut leakiness, endotoxemia, and ASH. l ‐NIL and l ‐NAME, but not the d ‐enantiomers, attenuated all steps in the alcohol‐induced cascade including NO overproduction, oxidative tissue damage, gut leakiness, endotoxemia, hepatic inflammation, and liver injury. Conclusions: The mechanism we reported for alcohol‐induced intestinal barrier disruption in vitro — NO overproduction, oxidative tissue damage, leaky gut, endotoxemia, and liver injury — appears to be relevant in vivo in an animal model of alcohol‐induced liver injury. That iNOS inhibitors attenuated all steps of this cascade suggests that prevention of this cascade in alcoholics will protect the liver against the injurious effects of chronic alcohol and that iNOS may be a useful target for prevention of ALD.     

Partially hydrolyzed guar gum attenuates non-alcoholic fatty liver disease in mice through the gut-liver axis

BACKGROUNDThe gut-liver axis has attracted much interest in the context of chronic liver disease pathogenesis. Prebiotics such as dietary fibers were shown to attenuate non-alcoholic fatty liver disease (NAFLD) by modulating gut microbiota. Partially hydrolyzed guar gum (PHGG), a water-soluble dietary fiber, has been reported to alleviate the symptoms of various intestinal diseases and metabolic syndromes. However, its effects on NAFLD remain to be fully elucidated.AIMTo determine whether treatment with PHGG attenuates NAFLD development in mice through the gut-liver axis.METHODSSeven-week-old male C57BL/6J mice with increased intestinal permeability were fed a control or atherogenic (Ath) diet (a mouse model of NAFLD) for 8 wk, with or without 5% PHGG. Increased intestinal permeability was induced through chronic intermittent administration of low-dose dextran sulfate sodium. Body weight, liver weight, macroscopic findings in the liver, blood biochemistry [aspartate aminotransferase (AST) and alanine aminotransferase (ALT), total cholesterol, triglyceride, free fatty acids, and glucose levels], liver histology, myeloperoxidase activity in liver tissue, mRNA expression in the liver and intestine, serum endotoxin levels in the portal vein, intestinal permeability, and microbiota and short-chain fatty acid (SCFA) profiles in the cecal samples were investigated.RESULTSMice with increased intestinal permeability subjected to the Ath diet showed significantly increased serum AST and ALT levels, liver fat accumulation, liver inflammatory (tumor necrosis factor-α and monocyte chemotactic protein-1) and fibrogenic (collagen 1a1 and α smooth muscle actin) marker levels, and liver myeloperoxidase activity, which were significantly attenuated by PHGG treatment. Furthermore, the Ath diet combined with increased intestinal permeability resulted in elevated portal endotoxin levels and activated toll-like receptor (TLR) 4 and TLR9 expression, confirming that intestinal permeability was significantly elevated, as observed by evaluating the lumen-to-blood clearance of fluorescein isothiocyanate-conjugated dextran. PHGG treatment did not affect fatty acid metabolism in the liver. However, it decreased lipopolysaccharide signaling through the gut-liver axis. In addition, it significantly increased the abundance of cecal Bacteroides and Clostridium subcluster XIVa. Treatment with PHGG markedly increased the levels of SCFAs, particularly, butyric acid, acetic acid, propionic acid, and formic acid, in the cecal samples.CONCLUSIONPHGG partially prevented NAFLD development in mice through the gut-liver axis by modulating microbiota and downstream SCFA profiles.     

Human tissue transglutaminase ELISA and an old study: a revision of the blood donor screening study for coeliac disease in the USA

Objective. Growing evidence indicates that innate immunity, including toll-like receptor (TLR) signalling, plays a role in inflammatory bowel disease (IBD). This may also apply in the case of TLR-8, which has recently been shown to reverse the immunosuppressive function of regulatory T cells. However, the role of TLR-8 in IBD is currently unknown, and therefore we investigated the expression of TLR-8 and its natural antagonist, Tollip, in normal and inflamed human gut, and examined whether the receptor is functionally active. Methods. TLR-8 and Tollip mRNA expression were measured in colonic epithelial cells (CEC) and lamina propria mononuclear cells (LPMNC) by quantitative polymerase chain reaction. TLR-8 protein expression was visualized in whole biopsy specimens by indirect immunofluorescence microscopy. Cellular localization of TLR-8 protein was assessed by immuno-electron microscopy. IL-8 secretion was measured by ELISA after stimulation with TLR-8 ligand. Results. TLR-8 mRNA and protein expression were substantially up-regulated in CEC from inflamed mucosa from patients with ulcerative colitis (～350-fold, p<0.01) and Crohn's disease (～45-fold, p<0.05) compared to controls. TLR-8 proteins resided on the luminal surface membrane and in intracellular organelles. Tollip was not increased in CEC from IBD patients. CEC from normal mucosa responded to TLR-8 stimulation by secreting IL-8. TLR-8 was expressed only on the mRNA level in LPMNC with no differences between IBD patients and controls. Conclusion. Expression of TLR-8, but not Tollip, is highly up-regulated in the colonic epithelium from patients with active IBD. Since the receptor is functionally active, our data suggest that TLR-8 signalling is important in the pathogenesis of IBD.     

Abdominal paracentesis drainage attenuates intestinal inflammation in rats with severe acute pancreatitis by inhibiting the HMGB1-mediated TLR4 signaling pathway

BACKGROUND Our previous studies confirmed that abdominal paracentesis drainage(APD)attenuates intestinal mucosal injury in rats with severe acute pancreatitis(SAP),and improves administration of enteral nutrition in patients with acute pancreatitis(AP).However,the underlying mechanisms of the beneficial effects of APD remain poorly understood.AIM To evaluate the effect of APD on intestinal inflammation and accompanying apoptosis induced by SAP in rats,and its potential mechanisms.METHODS SAP was induced in male adult Sprague-Dawley rats by 5%sodium taurocholate.Mild AP was induced by intraperitoneal injections of cerulein(20μg/kg body weight,six consecutive injections).Following SAP induction,a drainage tube connected to a vacuum ball was placed into the lower right abdomen of the rats to build APD.Morphological changes,serum inflammatory mediators,serum and ascites high mobility group box protein 1(HMGB1),intestinal barrier function indices,apoptosis and associated proteins,and toll-like receptor 4(TLR4)signaling molecules in intestinal tissue were assessed.RESULTS APD significantly alleviated intestinal mucosal injury induced by SAP,as demonstrated by decreased pathological scores,serum levels of D-lactate,diamine oxidase and endotoxin.APD reduced intestinal inflammation and accompanying apoptosis of mucosal cells,and normalized the expression of apoptosis-associated proteins in intestinal tissues.APD significantly suppressed activation of the intestinal TLR4 signaling pathway mediated by HMGB1,thus exerting protective effects against SAP-associated intestinal injury.CONCLUSION APD improved intestinal barrier function,intestinal inflammatory response and accompanying mucosal cell apoptosis in SAP rats.The beneficial effects are potentially due to inhibition of HMGB1-mediated TLR4 signaling.     

Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease

Emerging data have shown a close association between compositional changes in gut microbiota and the development of nonalcoholic fatty liver disease (NAFLD). The change in gut microbiota may alter nutritional absorption and storage. In addition, gut microbiota are a source of Toll-like receptor (TLR) ligands, and their compositional change can also increase the amount of TLR ligands delivered to the liver. TLR ligands can stimulate liver cells to produce proinflammatory cytokines. Therefore, the gut-liver axis has attracted much interest, particularly regarding the pathogenesis of NAFLD. The abundance of the major gut microbiota, including Firmicutes and Bacteroidetes, has been considered a potential underlying mechanism of obesity and NAFLD, but the role of these microbiota in NAFLD remains unknown. Several reports have demonstrated that certain gut microbiota are associated with the development of obesity and NAFLD. For instance, a decrease in Akkermansia muciniphila causes a thinner intestinal mucus layer and promotes gut permeability, which allows the leakage of bacterial components. Interventions to increase Akkermansia muciniphila improve the metabolic parameters in obesity and NAFLD. In children, the levels of Escherichia were significantly increased in nonalcoholic steatohepatitis (NASH) compared with those in obese control. Escherichia can produce ethanol, which promotes gut permeability. Thus, normalization of gut microbiota using probiotics or prebiotics is a promising treatment option for NAFLD. In addition, TLR signaling in the liver is activated, and its downstream molecules, such as proinflammatory cytokines, are increased in NAFLD. To data, TLR2, TLR4, TLR5, and TLR9 have been shown to be associated with the pathogenesis of NAFLD. Therefore, gut microbiota and TLRs are targets for NAFLD treatment.     

Roseburia intestinalis inhibits oncostatin M and maintains tight junction integrity in a murine model of acute experimental colitis

Objective: Levels of oncostatin M (OSM) and the composition of gut microbiota predict responses to anti-TNF agents used for IBD therapy. Here, the aim was to investigate the effects of Roseburia intestinalis, a gut microbiota, on OSM and on intestinal barrier in colitis.

Methods: In the murine model of 3% dextran sulfate sodium (DSS)-induced colitis, we tested disease activity index (DAI), colon length, histological score and expression of tight junction (TJ) proteins (ZO-1, occludin and claudin-1), OSM, TNF-α and TLR5. In addition, a cellular model was used to examine the role of R. intestinalis during secretion of OSM by lipopolysaccharide (LPS)-induced bone marrow-derived macrophages (BMDMs) isolated from wild-type (WT) and TLR5 knockout (TLR5 KO) mice. Furthermore, we evaluated the impact of OSM on expressions of TJ proteins by Caco-2 cells.

Results: R. intestinalis in DSS-induced colitis decreased DAI score (p?<?.001), colon length shortening (6.46?±?0.36?cm vs 5.65 ± 0.47 cm, p?=?.022), histological score (2.667?±?1.15 vs 5.33 ± 1.14, p?=?.018) and increased expression of TJ proteins (p?<?.05). In addition, R. intestinalis reduced expression of OSM (p?<?.05) and TNF-α (p?<?.05), while increasing expression of TLR5 (p?<?.05). Furthermore, R. intestinalis reduced secretion of OSM (p?<?.05) by LPS-induced BMDMs isolated from WT and TLR5 KO mice. Moreover, OSM downregulated expression of TJ proteins (p?<?.05) by Caco-2 cells in a concentration-dependent manner.

Conclusions: These results indicate that R. intestinalis attenuates inflammation in IBD by decreasing secretion of OSM and by promoting intestinal barrier function. Taken together, the data provide insight into the role of the gut microbiota in patients with IBD who are resistant to anti-TNF therapy.     

Structural and functional alterations of the gastrointestinal tract following radiation-induced injury in the rhesus monkey

A severe and debilitating diarrhea is a dose-limiting toxic result for patients receiving abdominal radiation or chemotherapy. To correlate changes in intestinal structure and function, nonhuman primates were exposed to 9.5 Gy total abdominal x-irradiation. Diarrhea and weight loss were correlated with intestinal crypt and villus histology, in vivo assessed intestinal permeability, and ex vivo functional studies performed in Ussing chamber assays before and at 7, 14, and 35 days after irradiation. Peak gut structural damage occurred early and paralleled functional changes of the intestinal mucosa, including increased epithelial permeability (both in vivo and ex vivo), activation of secretory pathways, decreased nutrient absorption, diarrhea, and weight loss. Recovery of gut integrity and epithelial resistance began thereafter, in spite of incomplete histological recovery. Our integrated approach allowed a comprehensive study of the relationship between postirradiation tissue injury and changes in function over time in the gastrointestinal tract of the nonhuman primate.     

In vivo influence of nicotine on human basal and NSAID-induced gut barrier function

BACKGROUND: Smoking reduces the non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal permeability increase in healthy people. It also affects inflammatory bowel disease that is associated with a disturbed gut barrier function. To assess the role of nicotine on barrier function, its influence on basal and NSAID-induced intestinal permeability was studied in healthy volunteers. METHODS: Thirty-one healthy non-smoker subjects performed permeability tests with 51Cr-EDTA and sugar markers (sucrose, lactulose, mannitol, sucralose) before and during 2 weeks of nicotine patch application, and with and without indomethacin intake, respectively. Since smoking has been described as affecting motility, transit measurements were also done with the sodium[13C]-octanoate and lactose-[13C]-ureide breath tests before and during nicotine exposure. Correlations between permeability markers were checked and the influence of gastrointestinal transit was assessed. RESULTS: Nicotine did not affect barrier function in vivo, nor gastric emptying, small-bowel transit time or orocaecal transit. 51Cr-EDTA and lactulose correlated in basal 0-6 h permeability testing (r = 0.529, P < 0.0001), as did 6-24 h excretion of 51Cr-EDTA and sucralose (r = 0.474, P < 0.001); 97% and 90% of the subjects had a permeability increase after indomethacin intake for 0-6 h and 6-24 h excretion of Cr-EDTA, respectively. This population proportion is 63% for lactulose/mannitol and 83% for sucralose. CONCLUSIONS: Short-term exposure to nicotine does not alter normal basal or NSAID-induced gut barrier function or transit. 51Cr-EDTA and the respective sugar markers correlate well in in vivo permeability testing in healthy humans. The radioactive test detects more NSAID-induced permeability increase than does the lactulose/mannitol ratio permeability test.