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Mechanisms of Disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases

Nature Clinical Practice Gastroenterology & Hepatology volume 2, pages 416–422 (2005)Cite this article

Abstract

The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and electrolytes, and to water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to nonself-antigens. When the finely tuned trafficking of macromolecules is dysregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on molecular mimicry and/or the bystander effect, and suggests that the autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing intestinal barrier function. Understanding the role of the intestinal barrier in the pathogenesis of gastrointestinal disease is an area of translational research that encompasses many fields and is currently receiving a great deal of attention. This review is timely given the increased interest in the role of a 'leaky gut' in the pathogenesis of gastrointestinal diseases and the advent of novel treatment strategies, such as the use of probiotics.

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Figure 1: Proposed role of abnormal intestinal permeability in the pathogenesis of celiac disease.

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Acknowledgements

Work by the authors was supported in parts by grants from the National Institutes of Health: DK-48373 and DK-66630 (AF) and AI/DK49316 (TSD).

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Authors and Affiliations

  1. Mucosal Biology Research Center and the Center for Celiac Research,

    Alessio Fasano & Terez Shea-Donohue

  2. Mucosal Biology Research Center, at the University of Maryland School of Medicine, Baltimore, MD, USA

    Alessio Fasano & Terez Shea-Donohue

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  1. Alessio Fasano
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Correspondence to Alessio Fasano.

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Competing interests

AF has economic interests in Alba Therapeutics, a company that works on the treatment of autoimmune diseases, including type 1 diabetes and celiac disease.

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Fasano, A., Shea-Donohue, T. Mechanisms of Disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Rev Gastroenterol Hepatol 2, 416–422 (2005). https://doi.org/10.1038/ncpgasthep0259

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