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

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 Apc Min/+ - 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. • B. fragilis is enriched in non-responders of patients with CRC to chemotherapy • B. fragilis compromises 5-FU/OXA efficacy in CRC cells and in mouse models • B. fragilis surface SusD/RagB binds to host receptor Notch1, inducing chemoresistance • Phage VA7 eliminates B. fragilis and restores chemosensitivity of CRC in mice Ding et al. identify Bacteroides fragilis as a bacterial pathogen that promotes colorectal cancer (CRC) chemoresistance by activating host Notch1 signaling through its surface protein SusD/RagB. Targeting B. fragilis with a phage therapy restores chemotherapy sensitivity in CRC mouse models.