BCAA-producing Clostridium symbiosum promotes colorectal tumorigenesis through the modulation of host cholesterol metabolism

Identification of potential bacterial players in colorectal tumorigenesis has been a focus of intense research. Herein, we find that Clostridium symbiosum (C. symbiosum) is selectively enriched in tumor tissues of patients with colorectal cancer (CRC) and associated with higher colorectal adenoma recurrence after endoscopic polypectomy. The tumorigenic effect of C. symbiosum is observed in multiple murine models. Single-cell transcriptome profiling along with functional assays demonstrates that C. symbiosum promotes the proliferation of colonic stem cells and enhances cancer stemness. Mechanistically, C. symbiosum intensifies cellular cholesterol synthesis by producing branched-chain amino acids (BCAAs), which sequentially activates Sonic hedgehog signaling. Low dietary BCAA intake or blockade of cholesterol synthesis by statins could partially abrogate the C. symbiosum-induced cell proliferation in vivo and in vitro. Collectively, we reveal C. symbiosum as a bacterial driver of colorectal tumorigenesis, thus identifying a potential target in CRC prediction, prevention, and treatment. [Display omitted] •Elevated level of C. symbiosum is clinically relevant to CRA recurrence and CRC•C. symbiosum intensifies colorectal cancer stemness and promotes tumorigenesis•C. symbiosum-derived BCAAs enhance host cholesterol synthesis through mTORC1 signaling•Cholesterol biosynthesis enhanced by C. symbiosum activates hedgehog signaling Ren et al. identify C. symbiosum as an oncogenic player in colorectal cancer. Multi-omics study deciphers the metabolic contribution of C. symbiosum to reprogramming colorectal cholesterol metabolism and regulating stem cell homeostasis via bacteria-derived branched-chain amino acids. These findings reveal potential metabolism-based host-microbe interactions and therapeutic approaches against colorectal cancer.