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

Dig Dis Sci. 2019 Jul;64(7):1748-1758. doi: 10.1007/s10620-019-05646-y.

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.

Keywords: Antigen trafficking; Autoimmunity; Gut permeability; Inflammation; Tight junctions; Zonulin.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Celiac Disease / drug therapy*
  • Celiac Disease / immunology
  • Celiac Disease / metabolism
  • Cholera Toxin / antagonists & inhibitors
  • Cholera Toxin / metabolism
  • Gastrointestinal Agents / therapeutic use*
  • Glutens / immunology*
  • Haptoglobins
  • Humans
  • Intercellular Junctions / drug effects*
  • Intercellular Junctions / immunology
  • Intercellular Junctions / metabolism
  • Intestinal Absorption / drug effects*
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Intestine, Small / drug effects*
  • Intestine, Small / immunology
  • Intestine, Small / metabolism
  • Oligopeptides / adverse effects
  • Oligopeptides / therapeutic use*
  • Permeability
  • Protein Precursors

Substances

  • AT-1001
  • Gastrointestinal Agents
  • Haptoglobins
  • Oligopeptides
  • Protein Precursors
  • zonulin
  • Glutens
  • Cholera Toxin