Gut bacteria toxin needs claudin‑4 to attack colon cells

Scientists at Johns Hopkins have solved how the toxin from the gut bacterium Bacteroides fragilis damages the colon lining and promotes tumors. The toxin, called BFT, can cut a protein that keeps cells together, but researchers had not known how it first attaches to intestinal cells. Using a genome‑wide CRISPR screen, they discovered that BFT requires the cell‑surface protein claudin‑4 to latch onto colon cells. "We've made several attempts over time to identify the receptor, so this is an exciting moment," says senior author Cynthia Sears.

Revealing the missing receptor

The CRISPR screen identified claudin‑4 as the key docking point for BFT. When the gene for claudin‑4 was disabled in colon epithelial cells, the toxin could no longer bind and could not damage E‑cadherin, the protein that forms the protective barrier. Claudin‑4 normally helps neighboring cells form tight junctions, sealing gaps in the intestinal lining. The finding shows that BFT must first attach to claudin‑4 before it can cut the barrier and trigger chronic inflammation that can lead to tumor growth.

Because claudin‑4 is required for the toxin’s attack, the team built a soluble protein carrying parts of claudin‑4 to lure the toxin away. In mice, the decoy intercepted BFT and protected the colon from toxin‑induced damage. The experiments, done with collaborators at Harvard Medical School, suggest a possible new approach to preventing bacterial damage linked to colorectal cancer, though they did not show that the strategy prevents the cancer itself.