Human Gut Commensal Bacteroides fragilis Suppresses Mucin Production and Alters Microbiota Composition Resulting in Accelerated Type 1 Diabetes in Mice.

Abstract

Type 1 diabetes (T1D) in humans is associated with a higher Bacteroidetes:Firmicutes ratio and a higher abundance of Bacteroides genus members. Bacteroides fragilis (BF) is an integral component of the human colonic commensal microbiota. Here, we show that gut colonisation 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-monocolonised parents not only showed rapid disease progression compared to germ-free (GF) controls but also preserved accelerated disease onset and higher disease incidence upon conventionalisation, 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-colonised SPF mice, the presence of BF alone could significantly impact the acquisition of microbial communities upon conventionalisation of gnotobiotic mice. Bulk RNAseq analysis of colon tissues revealed profound differences in the gene expression pattern of GF and BF-monocolonised mice as well as their conventionalised 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-colonised mice. Overall, these studies demonstrate that early life acquisition of BF-like distal gut commensals could have profound modulatory effects on the eventual overall gut physiology, microbiota structure, immune function, and β-cell specific autoimmune outcomes under genetic susceptibility.