Researchers Solve 15-Year Mystery Behind Cancer-Causing Gut Toxin

Key Points:

• Researchers at Johns Hopkins and collaborators have identified that the gut bacterium Bacteroides fragilis toxin (BFT) binds to the host receptor claudin-4 to damage colon cells, clarifying a long-standing mystery about how BFT promotes colorectal cancer.
• Using a genomewide CRISPR screen, the team found that removing claudin-4 prevents BFT from attaching to colon epithelial cells and disrupting E-cadherin, a protein critical for maintaining the colon's protective barrier.
• Structural and biophysical analyses confirmed a strong one-to-one binding between BFT and claudin-4, an unexpected mechanism since claudin-4 is not a typical signaling receptor for toxins.
• The researchers developed a soluble claudin-4 decoy protein that successfully blocked BFT binding and prevented colon damage in mouse models, suggesting a potential therapeutic strategy.
• Although the receptor interaction was confirmed, the precise structural details remain unresolved, with current AI tools unable to fully model the BFT-claudin-4 complex; further studies are ongoing to explore molecular inhibitors.