The impact of Parabacteroides distasonis colonization on the microbiome, metabolome, immune responses in SPF mice and diabetes onset in germ-free mice 4785

Abstract Description 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. Environmental factors and the gut microbiome are thought to contribute to T1D development. Insulin B:9-23 is a primary autoantigen in T1D. We previously showed Parabacteroides distasonis (Pd) protein hypoxanthine phosphoribosyl transferase (HPRT), an insulin peptide mimic, cross-reacted with insulin B:9-23-specific human T-cells. Orally gavaging non-obese diabetic (NOD) female mice with Pd accelerated diabetes onset and did not stimulate intraepithelial lymphocytes. We hypothesize Pd is accelerating T1D onset via molecular mimicry. Though the effects of Pd on gut permeability, gut microbiome composition, cytokines, insulin-specific T-cells and in germ-free conditions were unknown. Pd-colonized NOD mice had decreased IL-15, unaltered gut alpha diversity but Pd stimulated insulin B:9-23-specific mouse T-cells (n = 8-9/group). To assess the impact of Pd in the absence of other gut microbes, germ-free NOD mice were orally gavaged with Pd once after weaning. Germ-free NOD Pd-colonized mice had more severe insulitis but gut permeability and the serum metabolite composition did not change compared to the saline-treated mice. Our findings further support our hypothesis that Pd accelerates T1D onset via insulin molecular mimicry. Funding Sources Beatson Foundation 2023-003, Start-up funds, NIH NIDDK DK132674 Topic Categories Basic Autoimmunity (BA)