Type 1 diabetes (T1D) is caused by autoimmune destruction of pancreatic β-cells. The insulin B-chain 9-23 (insB9-23) peptide is a critical epitope in triggering T1D. In our previous study, we showed that Parabacteroides distasonis, a human gut commensal, contains an insB9-23 mimic in its hprt protein (residues 4-18). This mimic (hprt4-18) peptide activates insB9-23-specific T cells, and P. distasonis colonization enhanced diabetes in NOD mice. However, the impact of the P. distasonis colonization on inflammation, gut microbiome, intestinal immune cells, gut permeability, cytokine, and serum metabolome profiles remained unknown. Here, we investigated these effects using specific pathogen-free (SPF) and germ-free (GF) female NOD mice. P. distasonis colonization minimally impacted gut microbiome composition, altering only 28 ASVs. In P. distasonis-colonized mice, there was a reduction in T-helper, T-effector, and B-cell populations in the intraepithelial lymphocytes, indicating a potential decrease in immune activation. Furthermore, P. distasonis colonization did not alter serum metabolome and circulating cytokine profiles (except for a decrease in IL-15) and gut permeability gene expressions. P. distasonis colonization in GF NOD mice induced severe insulitis without affecting gut permeability. Interestingly, mice gavaged with heat-inactivated (HI) P. distasonis did not affect insulitis scores or immune cell composition. These findings support our hypothesis that P. distasonis functions as a gut commensal, exerting no effect on the gut microbiome, metabolome, gut permeability, intestinal immune cell composition, or nonspecific immune activation. Instead, P. distasonis appears to trigger an insB9-23-specific immune response, potentially accelerating T1D onset in NOD mice through molecular mimicry.

Boston College Biology Department Chestnut Hill Massachusetts USA

BPGbio Inc Framingham Massachusetts USA

Laboratory of Gnotobiology Institute of Microbiology of the Czech Academy of Sciences Novy Hradek Czech Republic

Medical College of Wisconsin Department of Pediatrics Division of Endocrinology McGee Diabetes Research Center Milwaukee Wisconsin USA

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