Article

Diabetologia

, Volume 53, Issue 4, pp 741-748

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

  • A. S. LeeAffiliated withDepartment of Medicine, University of British ColumbiaDepartment of Dermatology and Skin Science, University of British Columbia
  • , D. L. GibsonAffiliated withDepartment of Paediatrics, Division of Gastroenterology, University of British Columbia, British Columbia Children’s Hospital
  • , Y. ZhangAffiliated withDepartment of Medicine, University of British ColumbiaDepartment of Dermatology and Skin Science, University of British Columbia
  • , H. P. ShamAffiliated withDepartment of Paediatrics, Division of Gastroenterology, University of British Columbia, British Columbia Children’s Hospital
  • , B. A. VallanceAffiliated withDepartment of Paediatrics, Division of Gastroenterology, University of British Columbia, British Columbia Children’s Hospital Email author 
  • , J. P. DutzAffiliated withDepartment of Medicine, University of British ColumbiaDepartment of Dermatology and Skin Science, University of British Columbia Email author 

Abstract

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 [ΔespF]) 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 ΔespF 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.

Keywords

Citrobacter rodentium ΔespF Citrobacter rodentium Enteric bacterial infection Gut barrier disruption Insulitis Intestinal barrier NOD mice Type 1 diabetes