Reviews and feature article
Intestinal barrier function: Molecular regulation and disease pathogenesis

https://doi.org/10.1016/j.jaci.2009.05.038Get rights and content

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.

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).

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