Bacteroides fragilis toxin promotes gall bladder cancer in mice

Enterotoxigenic Bacteroides fragilis (ETBF), which secretes B. fragilis toxin (BFT) and has been associated with colorectal cancer, can be enriched in patients with gall bladder cancer (GBC). Whether and how ETBF contributes to GBC is unclear. Here we confirm, through analysis of patient samples, that ETBF is enriched in GBC tumours, while experiments in mice show that ETBF colonizes the gall bladder. In vitro and in patient-derived organoids, ETBF promoted GBC proliferation. ETBF also promoted tumour growth in a BFT-dependent manner in a mouse GBC allograft model. Mechanistically, the tumorigenic activity of BFT was dependent on the ETBF surface protein, membrane-bound lytic murein transglycosylase D (MltD), which interacts with the host receptor protein, transmembrane serine protease 13 (TMPRSS13). This interaction activated JAK2–STAT3 signalling to promote tumorigenesis. BFT also activated NF-κB signalling, which increased CXCL1 secretion, leading to myeloid-derived suppressor cell recruitment and angiogenesis in the tumour microenvironment. Taken together, these findings uncover mechanisms through which ETBF facilitates GBC development, with potential promise as therapeutic targets to limit GBC progression. Binding between bacterial membrane-bound lytic murein transglycosylase D (MltD) and host transmembrane serine protease 13 (TMPRSS13) potentiates the tumorigenic effects of Bacteroides fragilis toxin through JAK2–STAT3 signalling and myeloid-derived suppressor cell recruitment in gall bladder cancer.