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Diabetologia
Published in: Diabetologia 4/2010

01-04-2010 | Article

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

Authors: A. S. Lee, D. L. Gibson, Y. Zhang, H. P. Sham, B. A. Vallance, J. P. Dutz

Published in: Diabetologia | Issue 4/2010

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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.
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Metadata
Title
Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice
Authors
A. S. Lee
D. L. Gibson
Y. Zhang
H. P. Sham
B. A. Vallance
J. P. Dutz
Publication date
01-04-2010
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 4/2010
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-009-1626-y

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