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.

结直肠肿瘤发生中潜在细菌的鉴定一直是深入研究的焦点。在此，我们发现共生梭菌（ C.symbiosum ）选择性地富集于结直肠癌（CRC）患者的肿瘤组织中，并且与内镜息肉切除术后较高的结直肠腺瘤复发相关。在多种小鼠模型中观察到C. symbiosum的致瘤作用。单细胞转录组分析和功能分析表明， C. symbiosum促进结肠干细胞的增殖并增强癌症干细胞性。从机制上讲， C. symbiosum通过产生支链氨基酸 (BCAA) 来强化细胞胆固醇合成，从而依次激活 Sonic Hedgehog 信号传导。低膳食 BCAA 摄入量或用他汀类药物阻断胆固醇合成可以部分消除C. symbiosum诱导的体内和体外细胞增殖。总的来说，我们揭示了共生梭菌是结直肠肿瘤发生的细菌驱动因素，从而确定了结直肠癌预测、预防和治疗的潜在靶点。