Intestinal barrier function: Molecular regulation and disease pathogenesis

Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 08/2009; 124(1):3-20; quiz 21-2. DOI: 10.1016/j.jaci.2009.05.038
Source: PubMed


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.

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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). "
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    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; 94(9). DOI:10.3382/ps/pev211 · 1.67 Impact Factor
    • "Signaling through the zonulin receptor causes remodeling of the cytoskeleton and down-regulation of ZO-1 and occludin [45]. This disassembly of the tight junctions results in enhanced gut permeability [43] [45]. The detrimental effect of zonulin on the gut barrier function was confirmed by Watts and coworkers. "
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    ABSTRACT: Type 1 Diabetes (T1D) is a multifactorial, immune-mediated disease, which is characterized by the progressive destruction of autologous insulin-producing beta cells in the pancreas. The risk of developing T1D is determined by genetic, epigenetic and environmental factors. In the past few decades there has been a continuous rise in the incidence of T1D, which cannot be explained by genetic factors alone. Changes in our lifestyle that include diet, hygiene, and antibiotic usage have already been suggested to be causal factors for this rising T1D incidence. Only recently have microbiota, which are affected by all these factors, been recognized as key environmental factors affecting T1D development. In this review we will summarize current knowledge on the impact of gut microbiota on T1D development and give an outlook on the potential to design new microbiota-based therapies in the prevention and treatment of T1D. Copyright © 2015. Published by Elsevier Inc.
    Clinical Immunology 06/2015; 159(2). DOI:10.1016/j.clim.2015.05.013 · 3.67 Impact Factor
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    • "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 [32] [33]. The mucosal barriers (membrane and mucus) provide the first line of defense and directly communicate with microbiota in the gut [34]. "
    Italian 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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