{
  "abstract": "Background Protective gut commensals and their metabolites against colorectal cancer (CRC) remain underdefined. A clearer delineation of these beneficial microbes and bioactive compounds is needed to inform prevention strategies and microbiome-based therapies. Our study aims to elucidate the key metabolites and associated pathways through which Agathobacter rectalis (Ar) suppresses the progression of colorectal cancer.Methods We analyzed fecal metagenomes from CRC patients and controls across multiple cohorts. Using Apcmin/+ mice, organoids, in vitro models, and multi-omics, we assessed the effects of (Ar) and its metabolite EGC. Molecular assays, including docking, Cellular Thermal Shift Assay, and co-immunoprecipitation, confirmed that EGC impacts CRC by directly binding SREBF2, regulating its intracellular translocation and modulating the SREBF2–cholesterol/MAPK signaling pathways.Results Fecal Ar was significantly reduced in CRC across cohorts. Ar suppressed colon tumorigenesis in Apcmin/+ mice, significantly reducing tumor number and volume compared to E. coli and PBS controls. Metabolomics revealed decreased fecal cholesterol and enrichment of lipid/cholesterol pathways by Ar treatment. Ar-conditioned supernatant inhibited CRC cell growth, clonogenicity, migration, and cell-cycle progression. Liquid Chromatography-Mass Spectrometry identified (-)-epigallocatechin (EGC) as a heat- and protease-resistant Ar-derived metabolite absent in control bacteria. EGC recapitulated the anti-CRC effects of Ar in vitro and in vivo without overt toxicity, with differential abundant metabolites also enriched in lipid/cholesterol pathways. Transcriptomic analysis revealed that EGC treatment suppressed SREBP signaling, cholesterol metabolism and MAPK pathways. EGC reduced nuclear SREBF2 and impaired its transcriptional activity, downregulated expression of cholesterol synthesis/metabolism genes (FDPS and PCSK9), and suppressed MAPK signaling. Molecular docking suggested that EGC may bind to either precursor SREBF2 (pSREBF2) or SCAP. Subsequent CETSA experiments confirmed that EGC binds to and stabilizes pSREBF2. Furthermore, co-immunoprecipitation demonstrated that EGC reduces the interaction between pSREBF2 and SCAP, indicating that EGC’s binding to pSREBF2 inhibits its binding to SCAP and subsequent activation by cleavage.Conclusions Ar suppresses colorectal tumorigenesis by disrupting SREBF2 activation, suppressing cholesterol metabolism and MAPK signaling through its metabolite EGC ( IDDF2026-ABS-0426 Figure 1). This microbe–metabolite axis supports the potential of Ar/EGC-based interventions targeting cholesterol metabolism in CRC.Abstract IDDF2026-ABS-0426 Figure 1",
  "authors": [
    {
      "affiliations": [
        "The Chinese University of Hong Kong, Hong Kong"
      ],
      "name": "Jiawei Lu"
    },
    {
      "affiliations": [
        "The Chinese University of Hong Kong, Hong Kong"
      ],
      "name": "Yuting Sun"
    },
    {
      "affiliations": [
        "The Chinese University of Hong Kong, Hong Kong"
      ],
      "name": "Yao Zeng"
    },
    {
      "affiliations": [
        "The Chinese University of Hong Kong, Hong Kong"
      ],
      "name": "Effie Lau"
    },
    {
      "affiliations": [
        "The Chinese University of Hong Kong, Hong Kong"
      ],
      "name": "Silin Ye"
    },
    {
      "affiliations": [
        "The Chinese University of Hong Kong, Hong Kong"
      ],
      "name": "Jessie Qiaoyi Liang"
    }
  ],
  "title": "IDDF2026-ABS-0426 Agathobacter rectalis suppresses colorectal tumorigenesis via regulating cholesterol metabolism through its metabolite (−)-epigallocatechin",
  "uid": "0dd31660-a820-5244-8b05-bcc49713ade7"
}