Agathobacter rectalis suppresses colorectal tumorigenesis via an epigallocatechin-SREBF2 axis controlling cholesterol metabolism.

Beneficial effects of the gut commensal Agathobacter rectalis (Ar) are reported in diseases, yet its role in colorectal cancer (CRC) remains unclear. Here, metagenomic analysis revealed consistent fecal Ar depletion across CRC cohorts. In Apc min/+ mice, Ar inhibited colon tumorigenesis, reducing tumor number and volume versus E. coli and PBS controls. LC-MS/MS metabolomics showed decreased fecal cholesterol and altered lipid/cholesterol pathways after Ar treatment.

In vitro, Ar-conditioned medium suppressed CRC cell growth, clonogenicity, migration, and cell cycle progression. LC-MS/MS identified (-)-epigallocatechin (EGC) as an Ar-derived metabolite absent in control bacteria. EGC recapitulated Ar-mediated anti-CRC effects in vitro and in vivo, with metabolic changes linked to lipid/cholesterol pathways. Transcriptomics showed that EGC suppressed SREBP signaling, cholesterol metabolism, and MAPK pathways.

Mechanistically, EGC reduced nuclear SREBF2 and its transcriptional activity, downregulated cholesterol synthesis/metabolism genes, including FDPS and PCSK9, and suppressed MAPK signaling. Molecular docking suggested that EGC may bind pSREBF2 or SCAP. Cellular thermal shift assay revealed that EGC interacts with and stabilizes pSREBF2, but not SCAP. Co-immunoprecipitation demonstrated that EGC reduces pSREBF2-SCAP interaction, thereby inhibiting SCAP-mediated SREBF2 cleavage activation.

Together, these findings define an Ar-EGC microbe-metabolite axis and support Ar/EGC-based interventions targeting cholesterol metabolism in CRC.