Ding Xiao, Ting Nick Lung-Ngai, Wong Chi Chun, Huang Pingmei, Jiang Lanping, Liu Chuanfa, Lin Yufeng, Li Shiyu, Liu Yujie, Xie Mingxu, Liu Weixin, Yuan Kai, Wang Luyao, Zhang Xinyue, Ding Yanqiang, Li Qing, Sun Yang, Miao Yinglei, Ma Lanqing, Gao Xiang, Li Weixun, Wu William K K, Sung Joseph J Y, Wong Sunny Hei, Yu Jun
Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
Department of Oncology, Cancer Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Cell Host Microbe. 2025 Jun 11;33(6):941-956.e10. doi: 10.1016/j.chom.2025.05.004. Epub 2025 May 29.
Chemoresistance is a main cause of colorectal cancer (CRC) treatment failure. We identified that Bacteroides fragilis is enriched in patients with CRC resistant to chemotherapy in two independent cohorts, and its abundance is associated with poor survival. Consistently, administration of B. fragilis to CRC xenografts and Apc- and AOM/DSS-induced CRC mice all significantly attenuated the antitumor efficacy of 5-FU and OXA. Mechanistically, B. fragilis colonized colon tumors and mediated its effect via its surface protein SusD/RagB binding to the Notch1 receptor in CRC cells, leading to activation of the Notch1 signaling pathway and the induction of epithelial-to-mesenchymal transition (EMT)/stemness to suppress chemotherapy-induced apoptosis. Either deletion of SusD/RagB or blockade of Notch1 signaling abrogated B. fragilis-mediated chemoresistance. Finally, B. fragilis-targeting phage VA7 selectively suppressed B. fragilis and restored chemosensitivity in preclinical CRC mouse models. Our findings have offered insights into the potential of precise gut microbiota manipulation for the clinical management of CRC.
化疗耐药是结直肠癌（CRC）治疗失败的主要原因。我们在两个独立队列中发现，脆弱拟杆菌在对化疗耐药的CRC患者中富集，其丰度与较差的生存率相关。同样，将脆弱拟杆菌接种到CRC异种移植瘤以及Apc和AOM/DSS诱导的CRC小鼠中，均显著减弱了5-氟尿嘧啶和奥沙利铂的抗肿瘤疗效。从机制上讲，脆弱拟杆菌定殖于结肠肿瘤，并通过其表面蛋白SusD/RagB与CRC细胞中的Notch1受体结合来介导其作用，导致Notch1信号通路激活以及上皮-间质转化（EMT）/干性诱导，从而抑制化疗诱导的细胞凋亡。删除SusD/RagB或阻断Notch1信号通路均可消除脆弱拟杆菌介导的化疗耐药。最后，靶向脆弱拟杆菌的噬菌体VA7在临床前CRC小鼠模型中选择性抑制了脆弱拟杆菌并恢复了化疗敏感性。我们的研究结果为精确操纵肠道微生物群用于CRC临床管理的潜力提供了见解。
