Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China.
Chinese Academy of Sciences Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
Cell Host Microbe. 2024 Sep 11;32(9):1519-1535.e7. doi: 10.1016/j.chom.2024.07.012. Epub 2024 Aug 5.
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.
鉴定结直肠肿瘤发生过程中的潜在细菌“参与者”一直是研究的重点。在此，我们发现共生梭菌（C. symbiosum）在结直肠癌（CRC）患者的肿瘤组织中选择性富集，并与内镜息肉切除术后结直肠腺瘤复发率升高相关。共生梭菌在多种小鼠模型中均表现出致瘤作用。单细胞转录组谱分析和功能实验表明，共生梭菌促进结肠干细胞的增殖并增强癌症干性。其机制是通过产生支链氨基酸（BCAAs）来增强细胞胆固醇合成，从而依次激活 Sonic hedgehog 信号通路。低膳食 BCAA 摄入或他汀类药物抑制胆固醇合成可部分阻断共生梭菌在体内和体外诱导的细胞增殖。综上所述，我们揭示了共生梭菌是结直肠肿瘤发生的细菌驱动因素，从而为 CRC 的预测、预防和治疗确定了一个潜在靶点。
