IBD-associated Bacteroides fragilis strains drive dysregulated tolerogenic immunity and pro-inflammatory responses 3416

Abstract Description The gut microbiota plays a central role in maintaining immune homeostasis, balancing tolerogenic and pro-inflammatory responses crucial for intestinal health. Among gut bacteria, Bacteroides fragilis is a keystone species known to promote immune tolerance by inducing IL-10 production in Foxp3+ regulatory T cells (Tregs), protecting against experimental colitis. However, its role in inflammatory bowel disease (IBD) is less clear, particularly how strains adapt to the inflamed gut environment. We hypothesize that IBD-associated B. fragilis strains undergo adaptations that compromise their anti-inflammatory potential. In this study, we demonstrate that healthy-derived strains enhance IL-10 production in colonic Tregs, while IBD-associated strains exhibit pro-inflammatory properties. Specifically, we observed increased secretion of Th17-skewing cytokines (e.g., IL-6 and IL-23) by dendritic cells and the induction of IL-17A-producing CD4+RORgt+ T cells in colonic lamina propria during steady-state conditions. Additionally, IBD-associated strains exacerbate inflammation during chemically induced colitis. These findings demonstrate how strain-level variation among commensals influences immune regulation, contributing to dysbiosis and disease progression in IBD. This highlights the need to consider strain-specific functionality in microbiome-based therapeutic strategies. Funding Sources M.C.T is supported by T32 DK007202 (NIDDK), the National Academies of Sciences, Engineering and Medicine through the Predoctoral Fellowship of the Ford Foundation, and the Howard Hughes Medical Institute (HHMI) Graduate Fellowships grant (GT15123) Topic Categories Mucosal and Regional Immunology (MUC)