2. Academic Validation
  3. Bacteroides fragilis promotes chemoresistance in colorectal cancer, and its elimination by phage VA7 restores chemosensitivity

Bacteroides fragilis promotes chemoresistance in colorectal cancer, and its elimination by phage VA7 restores chemosensitivity

  • Cell Host Microbe. 2025 Jun 11;33(6):941-956.e10. doi: 10.1016/j.chom.2025.05.004.
Xiao Ding 1,  Nick Lung-Ngai Ting 1,  Chi Chun Wong 1,  Pingmei Huang 1,  Lanping Jiang 1,  Chuanfa Liu 1,  Yufeng Lin 1,  Shiyu Li 1,  Yujie Liu 1,  Mingxu Xie 1,  Weixin Liu 1,  Kai Yuan 1,  Luyao Wang 1,  Xinyue Zhang 2,  Yanqiang Ding 1,  Qing Li 1,  Yang Sun 3,  Yinglei Miao 3,  Lanqing Ma 3,  Xiang Gao 4,  Weixun Li 4,  William K K Wu 5,  Joseph J Y Sung 6,  Sunny Hei Wong 6,  Jun Yu 7
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Oncology, Cancer Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3 Department of Gastroenterology, the First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Disease, Yunnan Geriatric Medical Center, Kunming, Yunnan, China.
  • 4 State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China.
  • 5 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 Anaesthesia and Intensive Care, Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 6 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
  • 7 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. Electronic address: junyu@cuhk.edu.hk.
PMID: 40446807 DOI: 10.1016/j.chom.2025.05.004
Abstract

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 APCMin/+- 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.

Keywords

5-fluorouracil; Bacteroides fragilis; Notch1; chemoresistance; colorectal cancer; humanized gnotobiotic mice; microbiome; microbiota; oxaliplatin; phage therapy.

Figures
Products
Inhibitors & Agonists
Other Products