Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

Diabetologia. 2010 Apr;53(4):741-8. doi: 10.1007/s00125-009-1626-y. Epub 2009 Dec 13.


Aims/hypothesis: Increased exposure to enteric microbes as a result of intestinal barrier disruption is thought to contribute to the development of several intestinal inflammatory diseases; however, it less clear whether such exposure modulates the development of extra-intestinal inflammatory and autoimmune diseases. The goal of this study was to examine the potential role of pathogenic enteric microbes and intestinal barrier dysfunction in the pathogenesis of type 1 diabetes.

Methods: Using NOD mice, we assessed: (1) intrinsic barrier function in mice at different ages by measuring serum levels of FITC-labelled dextran; and (2) the impact on insulitis development of infection by strains of an enteric bacterial pathogen (Citrobacter rodentium) either capable (wild-type) or incapable (lacking Escherichia coli secreted protein F virulence factor owing to deletion of the gene [DeltaespF]) of causing intestinal epithelial barrier disruption.

Results: Here we demonstrate that prediabetic (12-week-old) NOD mice display increased intestinal permeability compared with non-obese diabetes-resistant and C57BL/6 mice. We also found that young (4-week-old) NOD mice infected with wild-type C. rodentium exhibited accelerated development of insulitis in concert with infection-induced barrier disruption. In contrast, insulitis development was not altered in NOD mice infected with the non-barrier-disrupting DeltaespF strain. Moreover, C. rodentium-infected NOD mice demonstrated increased activation and proliferation of pancreatic-draining lymph node T cells, including diabetogenic CD8(+) T cells, compared with uninfected NOD mice.

Conclusions/interpretation: This is the first demonstration that a loss of intestinal barrier integrity caused by an enteric bacterial pathogen results in the activation of diabetogenic CD8(+) T cells and modulates insulitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Infections / complications*
  • Bacterial Infections / microbiology
  • CD8-Positive T-Lymphocytes / immunology
  • Citrobacter rodentium / immunology
  • Citrobacter rodentium / pathogenicity
  • Enterobacteriaceae / immunology
  • Enterobacteriaceae / pathogenicity
  • Enterobacteriaceae Infections / immunology
  • Enterobacteriaceae Infections / pathology
  • Flow Cytometry
  • Gene Rearrangement
  • Hyperinsulinism / microbiology
  • Inflammation / immunology
  • Intestines / microbiology
  • Intestines / physiology
  • Intestines / physiopathology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Prediabetic State / microbiology
  • Prediabetic State / physiopathology
  • Receptors, Antigen, T-Cell / genetics
  • Species Specificity


  • Receptors, Antigen, T-Cell