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.
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.
Authors: Li Wen; Ruth E Ley; Pavel Yu Volchkov; Peter B Stranges; Lia Avanesyan; Austin C Stonebraker; Changyun Hu; F Susan Wong; Gregory L Szot; Jeffrey A Bluestone; Jeffrey I Gordon; Alexander V Chervonsky Journal: Nature Date: 2008-09-21 Impact factor: 49.962
Authors: Camilla H F Hansen; Christian S Larsen; Henriette O Petersson; Line F Zachariassen; Andreas Vegge; Charlotte Lauridsen; Witold Kot; Łukasz Krych; Dennis S Nielsen; Axel K Hansen Journal: Diabetologia Date: 2019-05-28 Impact factor: 10.122
Authors: Martin A Kriegel; Esen Sefik; Jonathan A Hill; Hsin-Jung Wu; Christophe Benoist; Diane Mathis Journal: Proc Natl Acad Sci U S A Date: 2011-06-27 Impact factor: 11.205
Authors: Vit Neuman; Ondrej Cinek; David P Funda; Tomas Hudcovic; Jaroslav Golias; Lenka Kramna; Lenka Petruzelkova; Stepanka Pruhova; Zdenek Sumnik Journal: Diabetologia Date: 2019-04-25 Impact factor: 10.122
Authors: J T J Visser; K Lammers; A Hoogendijk; M W Boer; S Brugman; S Beijer-Liefers; A Zandvoort; H Harmsen; G Welling; F Stellaard; N A Bos; A Fasano; J Rozing Journal: Diabetologia Date: 2010-09-19 Impact factor: 10.122