title: Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: A S
authors.initials: AS
authors.lastname: Lee
authors.forename: D L
authors.initials: DL
authors.lastname: Gibson
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: H P
authors.initials: HP
authors.lastname: Sham
authors.forename: B A
authors.initials: BA
authors.lastname: Vallance
authors.forename: J P
authors.initials: JP
authors.lastname: Dutz
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000150:complications* / Q000382:microbiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D044082:Citrobacter rodentium / Q000276:immunology / Q000472:pathogenicity; D004755:Enterobacteriaceae / Q000276:immunology / Q000472:pathogenicity; D004756:Enterobacteriaceae Infections / Q000276:immunology / Q000473:pathology; D005434:Flow Cytometry; D015321:Gene Rearrangement; D006946:Hyperinsulinism / Q000382:microbiology; D007249:Inflammation / Q000276:immunology; D007422:Intestines / Q000382:microbiology / Q000502:physiology / Q000503:physiopathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011236:Prediabetic State / Q000382:microbiology / Q000503:physiopathology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013045:Species Specificity
chemical_list: D011948:Receptors, Antigen, T-Cell