Scientists pinpoint how a common gut bacterium triggers colon cancer

A multi-institutional team led by researchers at the Johns Hopkins Kimmel Cancer Center has solved a question that has puzzled cancer researchers for more than 15 years: how a toxin made by a common gut bacterium first gains entry to the cells of the colon. According to the study, published in Nature, the toxin must first latch onto a host protein called claudin-4 before it can injure colon cells and help set the stage for colorectal cancer (https://doi.org/10.1038/s41586-026-10375-0). The toxin, known as BFT, is produced by Bacteroides fragilis, a bacterium that lives in the guts of up to 20% of healthy people. Certain strains drive inflammation in the colon and promote tumour growth. Earlier work from the same group showed that BFT damages the colon's protective barrier by cutting a protein called E-cadherin, but BFT did not appear to bind E-cadherin directly, suggesting some other molecule first ushered the toxin to its target. To find that missing piece, Maxwell White, an M.D./Ph.D. candidate in the Sears laboratory, led a genome-wide CRISPR screen with the laboratory of Matthew Waldor at Harvard Medical School. By switching off individual genes in colon cells, the team found that removing claudin-4 left BFT unable to attach and left E-cadherin unharmed. 'Once we were able to do the screen, claudin-4 was a clear, resounding top hit,' White said. The finding was a surprise: many scientists had expected the receptor to be a signalling protein, but claudin-4 belongs to a different family, and a review of prior research turned up no other toxin that works the same way. Structural biologists at the Molecular Biology Institute of Barcelona showed that BFT and claudin-4 form a tightly bound one-to-one complex - the first direct physical evidence of the attachment. Senior author Cynthia Sears, M.D., Bloomberg~Kimmel Professor of Cancer Immunotherapy at Johns Hopkins, said understanding how bacterial toxins operate 'can open doors to new approaches for detection and therapy for associated diseases, including diarrhea, colorectal cancer and bloodstream infections.' Working with Min Dong's laboratory at Harvard Medical School, the team built a soluble decoy version of claudin-4 that soaked up BFT in mouse models and protected the animals from toxin-induced colon damage. One challenge remains: the researchers have not yet captured the precise structure of how BFT and claudin-4 fit together, and current AI modelling tools including AlphaFold could not fully resolve the interaction. The work was supported in part by the National Institutes of Health, Cancer Research UK, the Howard Hughes Medical Institute, Janssen Research and Development, and the Bloomberg~Kimmel Institute. Source Reporters corrects errors promptly; contact the desk with amendments.