Claudin-4 as the molecular gateway to Bacteroides fragilis toxin-driven oncogenesis: implications for the microbiome–cancer targetome

Enterotoxigenic Bacteroides fragilis (ETBF) is among the best-characterised microbial oncobionts implicated in colorectal cancer (CRC), exerting its entire carcinogenic programme through a single zinc-dependent metalloprotease, the B. fragilis toxin (BFT; fragilysin). BFT initiates oncogenesis by cleaving the E-cadherin ectodomain on colonic epithelial cells, triggering barrier disruption, mucosal T helper Type 17 inflammation and Wnt/β-catenin activation. Despite several years of investigation, the epithelial receptor mediating this initiating event remained unknown, constraining both mechanistic understanding and therapeutic development. A landmark study by White et al. resolved this by identifying claudin-4 as the primary BFT receptor via a genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) knockout screen. Receptor binding is not merely permissive but mechanistically instructive. Claudin-4 anchors BFT at the plasma membrane, positioning its active site to access a sterically constrained, membrane-proximal E-cadherin cleavage site inaccessible to a freely diffusing protease. This converges with the tetraspanin-guided substrate positioning described for the mammalian sheddase ADAM10, an unexpected parallel between a bacterially encoded ADAM xenolog and its mammalian counterpart. This structural specificity establishes a potentially druggable interface. Proof-of-concept claudin-4 blockade using a soluble claudin-4 analogue (CLN4sol) attenuates BFT-mediated colonic injury in vivo, and the precedent set by zolbetuximab, an approved antibody against the related family member claudin-18.2, substantially de-risks pursuing claudin-4 therapeutically. The claudin-4–BFT interface represents a genuine druggable node at the microbiome–cancer interface, with direct implications for microbiome-informed chemoprevention of CRC.