Leaky Gut and Autoimmune Diseases
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Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on the role of impaired intestinal barrier function on autoimmune pathogenesis. 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 non-self antigens. Zonulin is the only physiologic modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the zonulin pathway is deregulated in genetically susceptible individuals, autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing the zonulin-dependent intestinal barrier function. Both animal models and recent clinical evidence support this new paradigm and provide the rationale for innovative approaches to prevent and treat autoimmune diseases.
KeywordsAntigens Autoimmunity Gut permeability Immune response Tight junctions Zonulin
Work presented in this review was supported in parts by grants from the National Institutes of Health Grants DK-48373 and DK-078699 to AF.
- 3.Fasano A (2001) Pathological and therapeutic implications of macromolecule passage through the tight junction. In Tight Junctions. CRC Press, Inc, Boca Raton, pp 697–722Google Scholar
- 9.Madara JL, Trier JS (1980) Structural abnormalities of jejunal epithelial cell membranes in celiac sprue. Lab Inves 43:254–261Google Scholar
- 14.Mojibian M, Chakir H, Lefebvre DE, Crookshank JA, Sonier B, Keely E, Scott FW (2009) Diabetes-specific HLA-DR-restricted proinflammatory T-cell response to wheat polypeptides in tissue transglutaminase antibody-negative patients with type 1 diabetes. Diabetes 58:1789–1796PubMedCrossRefGoogle Scholar
- 22.Cereijido M (1992) Evolution of ideas on the tight junction. In Tight Junction. CRC Press, Inc., Boca Raton, p 1Google Scholar
- 35.Fasano A (2001) Pathological and therapeutical implications of macromolecule passage through the tight junction. In Tight junctions. CRC Press, Inc., Boca Raton, pp 697–722Google Scholar
- 50.Wendling D, Bidet A, Guidet M (1992) Evaluation de la perméabilité intestinale au cours de la spondylarthrite ankylosante par le test au 51Cr-EDTA. Rev Esp Reumatol 19:253–256Google Scholar