Gut colonization by Bacteroides fragilis at juvenile age alters microbiota composition and accelerates type 1 diabetes progression in non-obese diabetic mice

Abstract

Type 1 diabetes (T1D) in humans is associated with higher Bacteroidetes : Firmicutes ratio and higher abundance of Bacteroides genus members. Bacteroides fragilis (BF) is an integral component of the human colonic commensal microbiota. Here, we show that gut colonization of specific pathogen-free (SPF) non-obese diabetic (NOD) mice by BF at a juvenile age induces a pro-inflammatory immune response and accelerated disease progression. NOD mice born to BF-monocolonized parents not only showed rapid disease progression compared to germ-free (GF) controls but also preserved accelerated disease onset and higher disease incidence upon conventionalization, suggesting that BF contributes to a pro-inflammatory response and autoimmunity in T1D. Interestingly, we found that while gut microbiota composition was different in control and BF-colonized SPF mice, presence of BF alone could significantly impact the acquisition of microbial communities upon conventionalization of gnotobiotic mice. Bulk RNAseq analysis of colon tissues revealed profound differences in the gene expression pattern of GF and BF-monocolonized mice as well as their conventionalized counterparts, shedding light on the probable mechanisms contributing to accelerated disease onset in mice that are exposed to BF. We found that mucin production is downregulated and the abundance of mucin degraders such as Akkermansia muciniphila is profoundly lower in BF-colonized mice that are conventionalized. Overall, these studies demonstrate that early life acquisition of BF-like distal gut commensals could have profound modulatory effects on the eventual overall gut microbiota structure, immune function, and {beta}-cell specific autoimmune outcomes under genetic susceptibility.