Bacteroides fragilis promotes chemoresistance in colorectal cancer, and its elimination by phage VA7 restores chemosensitivity
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<sup>Min/+</sup>- 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.
Authors
- Kai Yuan (ORCID: https://orcid.org/0000-0003-3692-1648)
- Yang Sun (ORCID: https://orcid.org/0000-0003-3271-1491)
- Sunny H. Wong (ORCID: https://orcid.org/0000-0002-3354-9310)
- Chuanfa Liu (ORCID: https://orcid.org/0000-0001-5140-6041)
- Mingxu Xie (ORCID: https://orcid.org/0000-0003-3394-4465)
- Joseph J.�Y. Sung (ORCID: https://orcid.org/0000-0003-3125-5199)
- Pingmei Huang (ORCID: https://orcid.org/0000-0002-4893-8159)
- William Ka Kei Wu (ORCID: https://orcid.org/0000-0002-5662-5240)
- Nick Lung-Ngai Ting
- Yanqiang Ding (ORCID: https://orcid.org/0000-0002-7740-6696)
- Lanqing Ma
- Weixun Li (ORCID: https://orcid.org/0000-0001-5644-4223)
- Luyao Wang (ORCID: https://orcid.org/0000-0001-6470-5059)
- Qing Li (ORCID: https://orcid.org/0000-0003-3370-471X)
- Yiran Li (ORCID: https://orcid.org/0000-0001-7922-7766)
- Yujie Liu (ORCID: https://orcid.org/0000-0003-3910-511X)
- Jun Qing Yu (ORCID: https://orcid.org/0000-0001-5008-2153)
- Yinglei Miao (ORCID: https://orcid.org/0000-0001-8193-5198)
- Weixin Liu (ORCID: https://orcid.org/0000-0002-1650-0371)
- Xinyue Zhang (ORCID: https://orcid.org/0000-0002-5027-6596)
- Xiao Ding (ORCID: https://orcid.org/0000-0002-5205-5957)
- Chi Chun Wong (ORCID: https://orcid.org/0000-0003-4520-2688)
- Lanping Jiang (ORCID: https://orcid.org/0009-0006-3201-3799)
- Xiang Gao
- Yufeng Lin (ORCID: https://orcid.org/0000-0003-2370-7589)
Institutions
- Shandong University (CN)
- Sun Yat-sen University (CN)
- Nanyang Technological University (SG)
- Chinese University of Hong Kong (HK)
- Kunming Medical University (CN)
- First Affiliated Hospital of Kunming Medical University (CN)
- Sun Yat-sen University Cancer Center (CN)
- State Key Laboratory of Microbial Technology
Publication Details
- Journal
- Cell Host & Microbe
- Published
- 2025-05-29
- DOI
- https://doi.org/10.1016/j.chom.2025.05.004
- Citations
- 27
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 21.76