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

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-weekold) 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.

Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice

“…46,47). Breach of the gastrointestinal barrier with subsequent leakage of potentially immunogenic dietary components has been proposed to promote T1D in NOD mice (48) and is a well-established trigger of celiac disease, an anti-gliadin-directed autoimmune disorder that frequently accompanies T1D in humans (49,50). Moreover, we previously demonstrated that gut irritation in NOD mice alters the priming of diabetogenic islet-derived self-antigens in the PLNs (31).…”

Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity?

“…In recent T1D and CD investigations, intestinal microbiota have received attention as possible modulators of disease development. [27][28][29][30] However, one could ask whether the detection of serum antibodies against antigens of a particular commensal bacteria reflects its presence and involvement in immune reactions at the intestinal level. Although it is possible that we detected antibodies induced by antigens that originated from other microorganisms, we are still confident that a portion of the detected antibodies was directed against B. adolescentis itself or other Bifidobacterium spp.…”

“…[22][23][24] In experimentally induced diabetes in rats or mice, changes in intestinal permeability are also detected before the onset of diabetes; increased intestinal permeability in these cases has been shown to be dependent on increased zonulin expression, which regulates tight junctions in the intestinal mucosa. [25][26][27] Additionally, mucosal biopsy, fecal microbiota and serological studies have indicated that the composition of intestinal microbiota may influence the immune mechanisms that participate in the development of CD 28,29 and T1D. 27,29,30 Consistent with these studies, recent investigations have stressed the importance of Bifidobacteria species and strains in the modulation of immune reactivity at the intestinal mucosa level.…”

“…[25][26][27] Additionally, mucosal biopsy, fecal microbiota and serological studies have indicated that the composition of intestinal microbiota may influence the immune mechanisms that participate in the development of CD 28,29 and T1D. 27,29,30 Consistent with these studies, recent investigations have stressed the importance of Bifidobacteria species and strains in the modulation of immune reactivity at the intestinal mucosa level. 31 In particular, Bifidobacterium adolescentis has recently received attention because this bacterium is more prevalent in patients with allergic disorders compared to non-allergic subjects, thus indicating that it might be connected to the development of immune dysfunction.…”

Lessons from the mouse: potential contribution of bystander lymphocyte activation by viruses to human type 1 diabetes

“…Virus infections are hypothesised to contribute to diabetes development by three distinct but not mutually exclusive general mechanisms: pancreatic infection, T cell molecular mimicry and bystander activation. Increased intestinal inflammation and permeability have also been implicated in diabetes development [4], and certain bacterial infections and intestinal microbiota may modulate diabetes in these ways [10,11]. Here we briefly discuss the potential roles of pancreatic infection and molecular mimicry, which have been extensively reviewed previously [12,13].…”