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Breaking Down Barriers: How Understanding Celiac Disease Pathogenesis Informed the Development of Novel Treatments

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Abstract

For decades, the pathogenesis of a variety of human diseases has been attributed to increased intestinal paracellular permeability even though scientific evidence supporting this hypothesis has been tenuous. Nevertheless, during the past decade, there have been a growing number of publications focused on human genetics, the gut microbiome, and proteomics, suggesting that loss of mucosal barrier function, particularly in the gastrointestinal tract, may substantially affect antigen trafficking, ultimately causing chronic inflammation, including autoimmunity, in genetically predisposed individuals. The gut mucosa works as a semipermeable barrier in that it permits nutrient absorption and also regulates immune surveillance while retaining potentially harmful microbes and environmental antigens within the intestinal lumen. Celiac disease (CD), a systemic, immune-mediated disorder triggered by gluten in genetically susceptible individuals, is associated with altered gut permeability. Pre-clinical and clinical studies have shown that gliadin, a prolamine component of gluten that is implicated in CD pathogenesis, is capable to disassembling intercellular junctional proteins by upregulating the zonulin pathway, which can be inhibited by the zonulin antagonist larazotide acetate. In this review, we will focus on CD as a paradigm of chronic inflammatory diseases in order to outline the contribution of gut paracellular permeability toward disease pathogenesis; moreover, we will summarize current evidence derived from available clinical trials of larazotide acetate in CD.

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Authors and Affiliations

  1. Pediatric Gastroenterology and Liver Unit, Department of “Maternal-and-Child Health” and Urology, Sapienza University of Rome, Rome, Italy

    Francesco Valitutti

  2. Mucosal Immunology and Biology Research Center, Center for Celiac Research and Treatment and Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, 175 Cambridge Street, CPZS – 574, Boston, MA, 02114, USA

    Alessio Fasano

  3. European Biomedical Research Institute of Salerno, Salerno, Italy

    Alessio Fasano

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Correspondence to Alessio Fasano.

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Dr. Fasano is co-founder and stock holder of Alba Therapeutics, a company developing treatments complementary to the gluten-free diet by exploiting gut permeability; Dr. Valitutti has no conflict of interest.

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Valitutti, F., Fasano, A. Breaking Down Barriers: How Understanding Celiac Disease Pathogenesis Informed the Development of Novel Treatments. Dig Dis Sci 64, 1748–1758 (2019). https://doi.org/10.1007/s10620-019-05646-y

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