{
  "abstract": "Background Host-gut microbiota metabolic interactions, such as the dysregulation of bile acid (BA) metabolism, are implicated in the pathogenesis of ulcerative colitis (UC), but the underlying mechanisms of certain metabolites remain ambiguous. This study aims to investigate the mechanisms of BA metabolism in the pathogenesis of UC, providing new insights for the prevention and treatment.Methods Fecal samples of UC patients were collected for targeted metabolomics analyses to explore alterations in BA. Metagenomic analysis was employed to identify potential microbial contributors to the reduced production of hyodeoxycholic acid (HDCA). Single-cell sequencing was performed to investigate the mechanisms by which HDCA alleviates colitis. Flow cytometry and immunofluorescence were utilized to assess the infiltration of macrophage subpopulations. Seahorse analysis was conducted to evaluate macrophage energy metabolism, while JC-1 staining and electron microscopy were used to assess mitochondrial changes. Finally, Cut&Tag assays were applied to investigate the role of mitochondrial metabolite acetyl-CoA as a donor for histone acetylation.Results Metabolomic analysis of the multicenter clinical cohort revealed an impaired BA homeostasis in UC with a significant deficiency of HDCA, which was inversely correlated with the severity of UC ( IDDF2026-ABS-0084 Figure 1). Given that secondary BAs are primarily metabolized by gut microbiota, we utilized metagenomic analysis and identified R. callidus as a potential microbial contributor to HDCA generation. Supplementation with R. callidus ameliorated DSS-induced colitis and HDCA production. ScRNA-seq indicated that HDCA induced the heterogeneity of macrophages in the intestinal immune microenvironment and elevated infiltration of metabolically rewired Mrc1+ subpopulation with immunosuppressive features (IDDF2026-ABS-0084 Figure 2). 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, modulating epigenetic transcription and supporting the phenotypic shift of macrophages (IDDF2026-ABS-0084 Figure 3).Conclusions These findings uncover a unique mechanism of gut microbiota-derived HDCA regulating metabolism, providing a therapeutic potential for UC.Abstract IDDF2026-ABS-0084 Figure 1Abstract IDDF2026-ABS-0084 Figure 2Abstract IDDF2026-ABS-0084 Figure 3",
  "authors": [
    {
      "affiliations": [
        "Tianjin Medical University General Hospital, China"
      ],
      "name": "Yaping An"
    },
    {
      "affiliations": [
        "Tianjin Medical University General Hospital, China"
      ],
      "name": "Hailong Cao"
    }
  ],
  "title": "IDDF2026-ABS-0084 Microbial metabolite hyodeoxycholic acid induces macrophage immunometabolic reprogramming and alleviates ulcerative colitis",
  "uid": "1097b0cf-dee7-5202-992c-418b1ac6dab3"
}