Gut Microbiome Modulates Th17 Immune Responses and Impacts Sex-Based Differences in a Model of Crohn’s Disease-like Ileitis 4826

Abstract Description Sex-based differences in IBD patients have been reported, with females (F) experiencing earlier onset and heightened disease vs. males (M). Similarly, specific pathogen-free (SPF)-raised SAMP1/YitFc (SAMP) mice, an established model of Crohn’s disease, display earlier onset and increased disease severity in F vs. -M. These differences were abrogated in germ-free (GF) SAMP. To determine potential mechanisms of how the gut microbiome may influence sexual dimorphism in SAMP, cells from draining mesenteric lymph nodes (MLNs) of SPF vs. GF SAMP were immunophenotyped by FACS, and cells activated in vitro, with supernatants assayed using a Luminex-based Th1/Th2/Th17/Th22/Treg panel. Our results showed that the increased frequency of CD4+Foxp3+ Tregs in SPF SAMP-M vs. -F is abolished in GF SAMP, and while a predominant Th17 (vs. Th1 and Th2) profile is observed in SPF SAMP-F vs. -M, these differences are not detected in GF SAMP. Initial experiments investigating the cellular source of IL-17 indicate that the ratio of either Th17 cells or IL-17-producing Tregs to conventional Tregs is greater in SPF SAMP-F vs. –Ms. Furthermore, no differences are detected in absolute numbers of gut mucosal Th17-producing αβ+ T cells, while a trend towards expansion of IL-17A/F-expressing γδ+ T cells is observed in SPF SAMP-F vs. -M. Our findings suggest that sexual dimorphism in ileitis-prone SAMP is dependent on the gut microbiome that may preferentially drive Th17 immune responses in SAMP-F vs.-M. Funding Sources We acknowledge support from the Crohn’s & Colitis Foundation: CRIA SRA #882725 (RDP/TTP) and the NIH/NCI: administrative supplement for Research on Sex/Gender Differences, R01 DK042191 (/TTP) and research supplement to Promote Diversity in Health-Related Research, R01 DK125293 (HLW/TTP). Topic Categories Mucosal and Regional Immunology (MUC)