Abstract
Accumulating evidence supports that the intestinal microbiome is involved in Type 1 diabetes (T1D) pathogenesis through the gut-pancreas nexus. Our aim was to determine whether the intestinal microbiota in the non-obese diabetic (NOD) mouse model played a role in T1D through the gut. To examine the effect of the intestinal microbiota on T1D onset, we manipulated gut microbes by: (1) the fecal transplantation between non-obese diabetic (NOD) and resistant (NOR) mice and (2) the oral antibiotic and probiotic treatment of NOD mice. We monitored diabetes onset, quantified CD4+T cells in the Peyer’s patches, profiled the microbiome and measured fecal short-chain fatty acids (SCFA). The gut microbiota from NOD mice harbored more pathobionts and fewer beneficial microbes in comparison with NOR mice. Fecal transplantation of NOD microbes induced insulitis in NOR hosts suggesting that the NOD microbiome is diabetogenic. Moreover, antibiotic exposure accelerated diabetes onset in NOD mice accompanied by increased T-helper type 1 (Th1) and reduced Th17 cells in the intestinal lymphoid tissues. The diabetogenic microbiome was characterized by a metagenome altered in several metabolic gene clusters. Furthermore, diabetes susceptibility correlated with reduced fecal SCFAs. In an attempt to correct the diabetogenic microbiome, we administered VLS#3 probiotics to NOD mice but found that VSL#3 colonized the intestine poorly and did not delay diabetes. We conclude that NOD mice harbor gut microbes that induce diabetes and that their diabetogenic microbiome can be amplified early in life through antibiotic exposure. Protective microbes like VSL#3 are insufficient to overcome the effects of a diabetogenic microbiome.
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Acknowledgements
BAV holds the Children with Intestinal and Liver Disorders (CHILD) Foundation Chair in Pediatric Gastroenterology. BAV is also the Canada Research Chair (Tier 2) in Pediatric Gastroenterology. JPD is a senior scientist at the Child and Family Research Institute. This work was supported by operating grants to BAV from the Canadian Institutes for Health Research, to JPD and BAV from Juvenile Diabetes Research Foundation, to JPD and DLG from the Child and Family Research Institute Diabetes Catalyst Grant from the Canuck’s Foundation and to DLG from VSL#3 Pharmaceuticals and Natural Sciences and Engineering Research Council.
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Brown, K., Godovannyi, A., Ma, C. et al. Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice. ISME J 10, 321–332 (2016). https://doi.org/10.1038/ismej.2015.114
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DOI: https://doi.org/10.1038/ismej.2015.114
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