Microbiome acetate biosynthesis orchestrates anti-inflammatory gut T cell maintenance and expansion via epithelial cell antigen presentation 3953

Abstract Description Complex crosstalk between resident microbes and the intestinal epithelium contributes to balancing required inflammatory and anti-inflammatory immune responses in the gut. However, the specific microbiome metabolites that promote epithelial cell anti-inflammatory signalling to local T cells remain poorly characterized. Using functional annotation of microbial genes in the gut microbiome, we discovered a causal relationship between bacterial acetate biosynthesis and epithelial antigen presentation on MHC class II. This epithelial antigen presentation is required for induction, maintenance, and proliferation of anti-inflammatory CD4+CD8aa+ double-positive intraepithelial lymphocytes (dpIELs). Acetate supplementation induced epithelial antigen processing and MHC II expression and differentiation of dpIELs in germ-free mice. In the absence of epithelial MHC II, the dpIEL transcriptional program is completely lost, and gut T cell profiles skew towards effector and inflammation-associated phenotypes. Multi-cohort meta-analysis of matched microbiomes and biopsy transcriptomes from Crohn’s disease patients confirmed that bacterial acetate biosynthesis and dpIELs transcriptional signatures correlate with lower disease severity. This study links a specific microbiome metabolic output with a key epithelial function that contributes to modulating intestinal inflammation. Funding Sources Supported by Wellcome Trust and the Royal Society 206245/Z/17/Z and Wellcome Trust 302351/Z/23/Z. Topic Categories Mucosal and Regional Immunology (MUC)