Receptor-guided proteolysis at the host-gut microbiota interface: insights from the Bacteroides fragilis toxin-claudin-4 axis

Enterotoxigenic Bacteroides fragilis (ETBF) is a colorectal cancer-associated bacterium whose pathogenicity depends largely on B. fragilis toxin (BFT), a secreted metalloprotease that cleaves E-cadherin and disrupts epithelial barrier integrity. Despite decades of investigation, the epithelial receptor for BFT has remained unknown. White, Wang et al. recently identify claudin-4 as the long-sought receptor for BFT and demonstrate that claudin-4 binding enables BFT-mediated cleavage of cell-surface E-cadherin. This work establishes a receptor-guided bacterial proteolysis mechanism linking toxin recognition, epithelial junctional injury and pro-carcinogenic inflammation. Importantly, a soluble claudin-4 analogue attenuates BFT-induced epithelial damage in vitro and in vivo, highlighting the therapeutic potential of targeting host-pathogen interactions rather than bacterial viability itself ¹. Nevertheless, how luminal BFT accesses basolateral junctions, whether additional receptor components participate in toxin recognition, and how the BFT-claudin-4 axis contributes to chronic ETBF-associated tumorigenesis remain unresolved. Addressing these questions may facilitate the development of precision anti-virulence therapies for ETBF-mediated diarrheal disease, sepsis and colorectal cancer.