Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice.
Diabetologia
; 53(4): 741-8, 2010 Apr.
Article
em En
| MEDLINE
| ID: mdl-20012858
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 [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.
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Base de dados:
MEDLINE
Assunto principal:
Infecções Bacterianas
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article