期刊
DIABETOLOGIA
卷 53, 期 4, 页码 741-748出版社
SPRINGER
DOI: 10.1007/s00125-009-1626-y
关键词
Citrobacter rodentium; Delta espF Citrobacter rodentium; Enteric bacterial infection; Gut barrier disruption; Insulitis; Intestinal barrier; NOD mice; Type 1 diabetes
资金
- Juvenile Diabetes Research Foundation
- Michael Smith Foundation of Health Research (MSFHR)
- Canadian Association of Gastroenterology/AstraZeneca/CIHR
- MSFHR
- Vallance laboratories
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. 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 [Delta espF]) of causing intestinal epithelial barrier disruption. 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 Delta espF 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. 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.
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