Loss of gut barrier integrity triggers activation of islet-reactive T cells and autoimmune diabetes

Proc Natl Acad Sci U S A. 2019 Jul 23;116(30):15140-15149. doi: 10.1073/pnas.1814558116. Epub 2019 Jun 10.


Low-grade intestinal inflammation and alterations of gut barrier integrity are found in patients affected by extraintestinal autoimmune diseases such as type 1 diabetes (T1D), but a direct causal link between enteropathy and triggering of autoimmunity is yet to be established. Here, we found that onset of autoimmunity in preclinical models of T1D is associated with alterations of the mucus layer structure and loss of gut barrier integrity. Importantly, we showed that breakage of the gut barrier integrity in BDC2.5XNOD mice carrying a transgenic T cell receptor (TCR) specific for a beta cell autoantigen leads to activation of islet-reactive T cells within the gut mucosa and onset of T1D. The intestinal activation of islet-reactive T cells requires the presence of gut microbiota and is abolished when mice are depleted of endogenous commensal microbiota by antibiotic treatment. Our results indicate that loss of gut barrier continuity can lead to activation of islet-specific T cells within the intestinal mucosa and to autoimmune diabetes and provide a strong rationale to design innovative therapeutic interventions in "at-risk" individuals aimed at restoring gut barrier integrity to prevent T1D occurrence.

Keywords: autoimmune diabetes; gut inflammation; microbiota.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteria / classification
  • Bacteria / genetics
  • Bacteria / immunology
  • Blood Glucose / immunology
  • Blood Glucose / metabolism
  • Colitis / chemically induced
  • Colitis / immunology*
  • Colitis / pathology
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / pathology
  • Disease Models, Animal
  • Female
  • Gastrointestinal Microbiome / immunology*
  • Gene Expression
  • Humans
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / microbiology
  • Intestinal Mucosa / pathology
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Permeability
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Sodium Dodecyl Sulfate / administration & dosage
  • Survival Analysis
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology
  • Transgenes


  • Blood Glucose
  • Receptors, Antigen, T-Cell
  • Sodium Dodecyl Sulfate