Microbial metabolite hyodeoxycholic acid induces macrophage immunometabolic reprogramming and alleviates ulcerative colitis.

Host-gut microbiota metabolic interactions are implicated in the pathogenesis of ulcerative colitis (UC), but the underlying mechanisms of certain metabolites remain ambiguous. Here, we revealed an impaired bile acid homeostasis in UC with a significant deficiency of hyodeoxycholic acid (HDCA), which was inversely correlated with the severity of UC. Ruminococcus callidus was linked to altered HDCA generation, and colonization of R. callidus increased HDCA concentrations via bile salt hydrolase. Single-cell RNA sequencing (ScRNA-seq) indicated that HDCA reshaped the intestinal macrophage landscape by enriching a metabolically rewired Mrc1+ macrophage subpopulation with immunosuppressive features. Mechanistically, HDCA enhanced PPARγ-mediated fatty acid metabolism reprogramming to alleviate inflammation, which was blunted in myeloid PPARγ-deficient mice. HDCA triggered fatty acid oxidation to promote ATP citrate lyase-dependent histone acetylation, supporting epigenetics-mediated gene regulation and the phenotypic modification of macrophages. These findings uncover a unique mechanism of gut microbiota-derived HDCA regulating metabolism, providing therapeutic potential for UC.