Figures (1)  Tables (1)

    • Figure 1. 

      Claudin-4 is the receptor that enables B. fragilis toxin to cleave E-cadherin and drive colorectal oncogenesis. (1) Enterotoxigenic B. fragilis (ETBF) secretes the metalloprotease B. fragilis toxin (BFT; fragilysin). (2) BFT binds claudin-4 on colonic epithelial cells, positioning its active site at the membrane. (3) This directs BFT to a membrane-proximal but otherwise inaccessible cleavage site in the E-cadherin ectodomain, releasing the soluble E-cadherin ectodomain. (4) Loss of E-cadherin adhesion disrupts barrier integrity and drives a pro-carcinogenic cascade of increased permeability, Th17 inflammation, Wnt/β-catenin activation and proliferation. Blocking the claudin-4–BFT interaction with the soluble claudin-4 analogue (CLN4sol), prevents E-cadherin cleavage and attenuates BFT-mediated epithelial injury, marking the interface as a druggable node at the microbiome–cancer interface. Created in BioRender. https://BioRender.com/ibajvho

    • AreaCurrent evidenceKnowledge gapTranslational/future opportunity
      BFT receptor biologyClaudin-4 is the primary epithelial receptor for BFT; claudin-3 provides partial functional redundancyThe structural basis of native BFT/claudin-4 recognition remains unresolvedStructural definition of the interaction could guide selective inhibitors
      E-cadherin cleavageClaudin-4 positions BFT to access a membrane-proximal E-cadherin cleavage siteThe full repertoire of BFT substrates remains unclearDefine additional claudin-4-dependent epithelial substrates
      Epithelial barrier injuryBFT-mediated E-cadherin cleavage promotes epithelial shedding and barrier disruptionThe consequences of chronic/repeated toxin exposure remain poorly definedLong-term organoid and chronic colonisation models
      Inflammation and oncogenic signallingETBF/BFT is associated with Th17 inflammation, Wnt/β-catenin activation and epithelial proliferationThe contribution of the claudin-4/BFT axis to tumour initiation versus progression is unresolvedGenetically engineered and tumour-prone in vivo models
      Claudin-4 in CRCClaudin-4 expression is dysregulated in colorectal cancerWhether tumour-associated changes in claudin-4 alter susceptibility to BFT is unknownPatient-derived tissues/organoids and molecular stratification
      Therapeutic blockadeSoluble CLN4sol reduces BFT-mediated epithelial injury in an acute murine modelLong-term efficacy, selectivity and safety have not been establishedInterface-selective antibodies, peptides or soluble receptor mimetics
      SafetyClaudin-4 has important physiological epithelial barrier functionsSystemic blockade could disrupt normal tight junction biologySelective blockade of BFT binding without interfering with physiological claudin-4
      Precision preventionETBF is associated with colorectal neoplasia and represents a potentially identifiable microbial risk factorAppropriate patient populations and predictive biomarkers remain undefinedIntegrate stool ETBF/BFT profiling with tissue biomarkers and CRC surveillance
      BFT, B. fragilis toxin; CLN4sol, soluble claudin-4 analogue; CRC, colorectal cancer; ETBF, enterotoxigenic B. fragilis.

      Table 1. 

      From claudin-4 receptors' discovery to therapeutic translation: current evidence, knowledge gaps and future priorities.