Reviews and feature articleIntestinal barrier function: Molecular regulation and disease pathogenesis
Section snippets
AJs
AJs (also known as zonula adherens) are protein complexes on the lateral membrane that occur at points of cell-cell contact (Fig 2). They are formed by interactions between transmembrane proteins, intracellular adaptor proteins, and the cytoskeleton. The major AJs are formed by cadherin-catenin interactions. E-cadherins (calcium-dependent adhesion molecules) are type I single-transmembrane-spanning glycoproteins that possess an intracellular C-terminus and extracellular N-terminus. The
TJ formation in the gastrointestinal (GI) tract
The intestinal epithelium forms the largest and most important barrier between our internal and external environments. The barrier is maintained by the expression of AJs and TJs, including cadherins, claudins, occludin, and JAM proteins, which seal together adjacent cells and provide cytoskeletal anchorage (Fig 3).41 Expression of junctional proteins in the intestine is highly regulated and dependent on the intestinal compartment (small or large intestine), villus/crypt localization, and cell
Cytokine mediated
In vitro and in vivo animal studies have demonstrated that intestinal permeability is regulated by multiple factors, including exogenous factors, epithelial apoptosis, cytokines, and immune cells (Fig 4). Immune-induced intestinal barrier dysfunction is thought to be critical in the predisposition to and exacerbation of numerous autoimmune and inflammatory conditions, including inflammatory bowel disease (IBD), food allergy, celiac disease, and diabetes.103 For example, IFN-γ and TNF-α, which
Alcohol
Chronic alcohol consumption has been shown to be associated with increased intestinal permeability, inhibition of vitamin and nutrient transport, and a reduction in sodium and water absorption.134, 135 Experimental analyses suggest involvement of the byproduct of ethanol metabolism, acetaldehyde, and nitric oxide (NO) in alcohol-mediated barrier dysfunction. High levels of acetaldehyde have been detected in the intestines of rats after ethanol administration and elevated levels were associated
Summary
Dysregulation of the intestinal barrier has been associated with chronic immune diseases, including food allergy, IBD, and celiac disease. Whether intestinal epithelial barrier function is a primary causative factor in the predisposition to disease development remains unclear; however, clinical and experimental evidence supports a role for intestinal epithelial barrier dysfunction in disease pathogenesis. Recent experimental studies have identified a role for a number of exogenous factors,
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Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD
Supported in part by a Crohn's Colitis Foundation of America Career Development Award, an American Heart Association Grant-in-Aid, and National Institutes of Health grants R01 (AI 073553), F30 (DK082113), and T32 (GM063483).