A gut commensal, Parabacteroides distasonis, and molecular mimicry in type 1 diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of pancreatic, insulin-producing beta cells by autoreactive T-cells. The trigger(s) of T1D are unclear and genetics alone cannot explain the recent increase in T1D diagnoses. The gut microbiome is thought to play a key role in T1D pathogenesis. Molecular mimicry is an autoimmunity mechanism where host-like microbial proteins trigger immune responses. Insulin is a key autoantigen in T1D autoimmunity, and insulin B-chain amino acids 9-23 (insB:9-23) is an important T-cell epitope. We previously identified a peptide mimic, amino acids 4-18 of hypoxanthine phosphoribosyl transferase (HPRT:4-18) of Parabacteroides distasonis (Pd). HPRT:4-18 cross-reacted with insB:9-23-specific human and non-obese diabetic (NOD) mice T-cells. We hypothesize HPRT:4-18 is required to accelerate diabetes via insB:9-23 molecular mimicry. Orally gavaging NOD mice (n=40 mice/group) and germ-free NOD mice (n=6-8 mice/group) with P. distasonis (Pd) accelerated diabetes compared to the saline-treated mice. The Pd-colonized mice had significantly more splenic CD8 and naïve T-cells, dendritic cells and macrophages but fewer FOXP3 cells (n=3-6 mice/group). Pd colonization did not alter gut permeability and among the intestinal intraepithelial lymphocytes (IELs), there were fewer naïve, central and effector T-cells. The findings indicate Pd decreases intestinal inflammation and induces pancreatic autoimmunity.