产生 BCAA 的共生梭菌通过调节宿主胆固醇代谢促进结直肠肿瘤发生。
BCAA-producing Clostridium symbiosum promotes colorectal tumorigenesis through the modulation of host cholesterol metabolism.
发表日期：2024 Aug 01
作者：
Yi-Meng Ren, Zi-Yan Zhuang, Yuan-Hong Xie, Peng-Jie Yang, Tian-Xue Xia, Yi-Le Xie, Zhu-Hui Liu, Zi-Ran Kang, Xiao-Xu Leng, Shi-Yuan Lu, Lu Zhang, Jin-Xian Chen, Jia Xu, En-Hao Zhao, Zheng Wang, Ming Wang, Yun Cui, Juan Tan, Qiang Liu, Wei-Hong Jiang, Hua Xiong, Jie Hong, Ying-Xuan Chen, Hao-Yan Chen, Jing-Yuan Fang
来源：
Cell Host & Microbe
摘要：
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) 在结直肠癌 (CRC) 患者的肿瘤组织中选择性富集，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 可以促进结肠干细胞的增殖并增强癌症干性。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 hump 信号传导。低膳食 BCAA 摄入量或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 C. symbiosum 作为结直肠肿瘤发生的细菌驱动因素，从而确定了 CRC 预测、预防和治疗的潜在靶点。版权所有 © 2024 Elsevier Inc. 保留所有权利。
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.Copyright © 2024 Elsevier Inc. All rights reserved.