Intestinal barrier function: Molecular regulation and disease pathogenesis
ABSTRACT The intestinal epithelium is a single-cell layer that constitutes the largest and most important barrier against the external environment. It acts as a selectively permeable barrier, permitting the absorption of nutrients, electrolytes, and water while maintaining an effective defense against intraluminal toxins, antigens, and enteric flora. The epithelium maintains its selective barrier function through the formation of complex protein-protein networks that mechanically link adjacent cells and seal the intercellular space. The protein networks connecting epithelial cells form 3 adhesive complexes: desmosomes, adherens junctions, and tight junctions. These complexes consist of transmembrane proteins that interact extracellularly with adjacent cells and intracellularly with adaptor proteins that link to the cytoskeleton. Over the past decade, there has been increasing recognition of an association between disrupted intestinal barrier function and the development of autoimmune and inflammatory diseases. In this review we summarize the evolving understanding of the molecular composition and regulation of intestinal barrier function. We discuss the interactions between innate and adaptive immunity and intestinal epithelial barrier function, as well as the effect of exogenous factors on intestinal barrier function. Finally, we summarize clinical and experimental evidence demonstrating intestinal epithelial barrier dysfunction as a major factor contributing to the predisposition to inflammatory diseases, including food allergy, inflammatory bowel diseases, and celiac disease.
- SourceAvailable from: Guillermo Tellez
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- "Other enteric changes associated with stress include gut motility, permeability , and alterations to ion, fluid, and mucus secretion (Alverdy and Aoys, 1991; Karavolos et al., 2008). These changes have been linked to mast cells which are important effectors of the brain-gut axis and translate stress signals into the release of a wide range of neurotransmitters and pro-inflammatory cytokines, with dramatic effects on gastrointestinal physiology (Groschwitz and Hogan, 2009; Bailey et al., 2011; Lamprecht and Frauwallner, 2012). Studies have shown that dexamethasone can modulate enteric tight junction integrity in mammary tissue and also at the blood-brain barrier, but reports regarding gastrointestinal tight junctions are rare (Boivin et al., 2007; Tenenbaum et al., 2008). "
ABSTRACT: We have previously shown that intestinal barrier function can be adversely affected by poorly digested diets or feed restriction, resulting in increased intestinal inflammation-associated permeability. Three experiments were conducted in broilers to evaluate the effect of dexamethasone (DEX) treatment on systemic fluorescein isothiocyanate-dextran (FITC-D; 3-5 kDa) levels, indicative of increased gut epithelial leakage. Experiment 1 compared DEX injections of 1 mg/kg, once per day on d 3, 5, and 9, with feed administration at 0.57, 1.7, or 5.1 ppm d 4 to 10, with FITC-D serum concentrations 2.5 h after gavage with 4.16 mg/kg FITC-D. All DEX treatments resulted in marked (2 to 6X; P < 0.05) increased serum FITC-D levels. Feed DEX administration resulted in greater (P < 0.05) gut permeability than injection at any dose, with numerically optimal effects at the lowest dose tested. In experiments 2 and 3, chicks were randomly assigned to a starter ration containing either control (CON) or DEX treated feed (0.57 ppm/kg; d 3 to 10 experiment 2, d 4 to 10 experiment 3). At d 10, all chicks were treated by oral gavage with FITC-D and serum samples were obtained as described above. Samples of the liver were aseptically collected, homogenized, diluted 1:4 wt/vol in sterile saline, and serial dilutions were plated on tryptic soy agar to evaluate total numbers of aerobic bacteria in the liver as an index of bacterial translocation (BT). In both experiments, FITC-D absorption was significantly enhanced (P < 0.05) in DEX-treated chicks, again indicating increased paracellular leakage across the gut epithelium associated with dissolution of tight junctions. Experiment 2 differential cell counts showed an increased heterophil/lymphocyte ratio, and immune organ (spleen and bursa of Fabricius) weights for experiments 2 and 3 were decreased (P < 0.05) from controls. In experiments 2 and 3, dietary DEX administration resulted in numerically (experiment 2) or significantly (P < 0.05) increased enteric BT to the liver, supporting the observation that dietary DEX causes a stress-like inflammatory GI response, which may contribute to subclinical or clinical disease, and may be a useful model for ongoing disease mitigation research related to stress-related diseases of GIT origin. © 2015 Poultry Science Association Inc.Poultry Science 07/2015; DOI:10.3382/ps/pev211 · 1.67 Impact Factor
- "Intestinal epithelial cells (IECs) participating in mucosal barrier function are conventional enterocytes, goblet cells, entero-endocrine cells and Paneth cells. The luminal secretion of mucins and non-specific antimicrobial peptides by goblet cells and Paneth cells, respectively, establishes a physical and biochemical barrier to microbial contact with the epithelial surface and underlying immune cells  . The mucosal barriers (membrane and mucus) provide the first line of defense and directly communicate with microbiota in the gut . "
Article: Mode of delivery and gut microbiotaItalian Journal of Pediatrics 10/2014; 40(Suppl 2):A17-A17. DOI:10.1186/1824-7288-40-S2-A17 · 1.52 Impact Factor
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- "Intestinal epithelium maintains its selective barrier function through the formation of network of tight junction proteins such as claudins and ZO-1. These proteins interact intracellularly with adaptor proteins that link to the actin cytoskeleton  and maintenance of intestinal barrier function is dependent on the expression of tight junction protein associated with cytoskeletal protein fraction or the detergent insoluble protein fraction . When Caco-2 cells were exposed to LPS, there was 26% and 17% decrease in detergent insoluble actin-associated ZO-1 (P = 0.01) and claudin 1 expression (P = 0.05) respectively. "
ABSTRACT: Association between circulating lipopolysaccharide (LPS) and metabolic diseases (such as Type 2 Diabetes and atherosclerosis) has shifted the focus from Western diet-induced changes in gut microbiota per se to release of gut bacteria-derived products into circulation as the possible mechanism for the chronic inflammatory state underlying the development of these diseases. Under physiological conditions, an intact intestinal barrier prevents this release of LPS underscoring the importance of examining and modulating the direct effects of Western diet on intestinal barrier function. In the present study we evaluated two strategies, namely selective gut decontamination and supplementation with oral curcumin, to modulate Western-diet (WD) induced changes in intestinal barrier function and subsequent development of glucose intolerance and atherosclerosis. LDLR-/- mice were fed WD for 16 weeks and either received non-absorbable antibiotics (Neomycin and polymyxin) in drinking water for selective gut decontamination or gavaged daily with curcumin. WD significantly increased intestinal permeability as assessed by in vivo translocation of FITC-dextran and plasma LPS levels. Selective gut decontamination and supplementation with curcumin significantly attenuated the WD-induced increase in plasma LPS levels (3.32 vs 1.90 or 1.51 EU/ml, respectively) and improved intestinal barrier function at multiple levels (restoring intestinal alkaline phosphatase activity and expression of tight junction proteins, ZO-1 and Claudin-1). Consequently, both these interventions significantly reduced WD-induced glucose intolerance and atherosclerosis in LDLR-/- mice. Activation of macrophages by low levels of LPS (50 ng/ml) and its exacerbation by fatty acids is likely the mechanism by which release of trace amounts of LPS into circulation due to disruption of intestinal barrier function induces the development of these diseases. These studies not only establish the important role of intestinal barrier function, but also identify oral supplementation with curcumin as a potential therapeutic strategy to improve intestinal barrier function and prevent the development of metabolic diseases.PLoS ONE 09/2014; 9(9):e108577. DOI:10.1371/journal.pone.0108577 · 3.23 Impact Factor