Audrey Randall: No financial relationships to disclose
Introduction/Rationale: Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of pancreatic, insulin-producing beta cells by autoreactive T-cells. T1D incidence is increasing worldwide but it is poorly understood what activates autoreactive T-cells. Over 90% of anti-insulin mouse CD4 T-cells target amino acids 9-23 of the insulin B chain (insB:9-23). The gut microbiome is thought to contribute to T1D development. We previously showed Parabacteroides distasonis (Pd) peptide HPRT:4-18 cross-reacted with insulin B:9-23-specific mice and patient T-cells. We hypothesize Pd accelerates diabetes onset via molecular mimicry.
Methods: Specific pathogen-free non-obese diabetic (NOD) mice were oral gavaged with saline, live Pd or heat-inactivated Pd. Germ-free NOD mice were orally gavaged with Pd. Insulitis, gut microbiome diversity and the serum metabolome were assessed.
Results: Live but not-heat inactivated Pd increased severe insulitis. Gut permeability and metabolites were unaltered with minimal changes in gut microbiome diversity. Germ-free Pd-colonized mice had more severe insulitis but gut permeability and metabolite composition did not change compared to the saline-treated mice.
Conclusion: The findings further support our hypothesis that Pd accelerates T1D onset via insulin molecular mimicry. To further test the molecular mimicry hypothesis, NOD mice are orally gavaged with engineered Escherichia coli which secretes wild-type or mutant HPRT, containing the insB:9-23 mimic.
