| Summary: | Accumulating evidence supports the idea that intestinal microbes are involved in the pathogenesis of type 1 diabetes (T1D) through the gut-pancreas nexus. While it has been hypothesized that a “leaky” gut could facilitate exposure to microbial antigens and accelerate diabetes onset, the role of the microbiota and their effect on intestinal inflammation and barrier function have not been well studied. Our aim was to determine if the intestinal microbiota in the non-obese diabetic (NOD) mouse model plays a causal role in diabetes onset through a leaky and inflamed gut. To examine the effect of the intestinal microbiota on the onset of T1D we manipulated gut microbes by: 1) fecal transplantation between diabetic susceptible (NOD) and resistant (NOR) mice and 2) antibiotic and probiotic treatment of NOD mice. We monitored diabetes onset, determined microbial community structure using high throughput sequencing, examined intestinal inflammation by qPCR, barrier function using FITC-dextran, and quantified testosterone and insulin auto-antibodies in the sera. We found that fecal transplantation of NOD microbes induced insulitis in the NOR host supporting the idea that the microbiome from NOD mice is “diabetogenic” or diabetes-inducing. Furthermore, peri-natal antibiotic exposure resulted in accelerated diabetes onset in NOD mice accompanied by the production of insulin auto-antibodies, independent of a leaky gut. Neither transplantation of microbes from NOR mice nor probiotics (VSL3) were able to reverse diabetes progression in NOD mice. Antibiotic treatment resulted in lower diversity and decreased levels of several commensal microbes. The microbiota of vancomycin-treated NOD mice were enriched in pathobionts like Enterobacteriaceae and depleted of beneficial microbes like segmented filamentous bacteria (SFB). This corresponded with increased colonic inflammation, the loss of Th17 associated cytokines and decreased testosterone. Despite accelerated diabetes, neomycin-treated NOD mice contained SFB and had similar Th17-associated cytokines and serum testosterone levels as untreated NODs, indicating that SFB alone is not sufficient to protect against the effects of the diabetogenic microbiome. We conclude that NOD mice harbor gut microbes that induce diabetes which cannot be overcome by the presence of protective microbes like SFB or addition of probiotics and that antibiotics accelerate diabetes by augmenting the diabetogenic microbiome. === Irving K. Barber School of Arts and Sciences (Okanagan) === Biology, Department of (Okanagan) === Graduate
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