Bacteroides Fragilis enterotoxin engagement of the colonic epithelium is associated with early YAP1 activation and colon tumorigenesis

Enterotoxigenic Bacteroides fragilis (ETBF) promotes colonic inflammation and tumorigenesis, but the epithelial signaling events linking toxin (BFT2)-induced junctional injury to tumor development remain incompletely defined. Here, wild-type BFT2, but not catalytically inactive BFT2, induced E-cadherin loss and nuclear accumulation of active YAP1 in colonic epithelial cells. Deletion of BFT receptors, CLAUDINs 3 and 4 mitigated BFT-associated E-cadherin loss and YAP1 nuclear translocation, supporting a model in which BFT epithelial targeting is linked to early YAP1 activation. In ETBF-colonized Min mice, epithelial YAP1 activation was rapid and transient, whereas STAT3 and NF-kB activation persisted after colonization. Nevertheless, conditional deletion of epithelial Yap1 was sufficient to abrogate colon tumor formation without altering ETBF colonization or abolishing IL-17 colitis. Transcriptomic analyses further associated epithelial Yap1 deficiency with reduced regenerative epithelial programs and increased secretory-cell differentiation signatures. Together, these findings support a model in which BFT engagement of CLAUDINs and toxin catalytic activity are associated with epithelial YAP1 activation, and epithelial YAP1 contributes to ETBF-associated colon tumorigenesis in Min mice