For nearly two decades, researchers have known that a toxin from the gut bacterium Bacteroides fragilis can promote colon tumors without understanding how the toxin gets into colon cells. A Johns Hopkins team has now identified the docking point, a tight-junction protein called claudin-4, and published the work in the journal Nature.
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The discovery turns a long-standing correlation into a mechanism that can be attacked. It also produced a first experimental decoy that shielded mice from the toxin’s damage.
Claudin-4 as the receptor for the Bacteroides fragilis toxin
Some strains of B. fragilis make a toxin, abbreviated BFT, that is a protease: an enzyme that cuts other proteins. Its known target is E-cadherin, the protein that holds neighboring colon cells together and keeps the lining a barrier. Cutting it opens that barrier, triggers chronic inflammation and, in earlier work, promoted tumors. A 2009 study in Nature Medicine from senior author Cynthia Sears and colleagues had already shown that BFT can promote colon tumors. What nobody could explain was why BFT, which did not appear to bind E-cadherin directly, reached its target at all.
Maxwell White, an M.D./Ph.D. candidate in Sears’s lab, ran a genome-wide CRISPR screen in colon epithelial cells to look for a missing partner. He described claudin-4 as a clear, resounding top hit. Disabling the claudin-4 gene stopped the toxin from binding the cells, so it could not attack E-cadherin. The finding is laid out in the Johns Hopkins publication record and in the Nature paper, which appeared online on April 22, 2026.
The sequence matters for reading the biology. Without claudin-4, BFT cannot dock; with it, the toxin cleaves the outer portion of E-cadherin, the barrier loosens, inflammation follows and cell proliferation rises. Other Johns Hopkins authors on the paper include Kang Wang, Jason Chen, Shaoguang Wu, Abby Geis and Jessica Queen, with structural work from F. Xavier Gomis-Ruth and Ulrich Eckhard in Barcelona.
A receptor-dependent protease and a one-to-one complex
Most proteases do not need a separate receptor to reach their substrate, and the team could not find another toxin known to work this way. Collaborators at the Molecular Biology Institute of Barcelona measured how BFT and claudin-4 interact and found a tightly bound complex with one toxin molecule paired to one receptor molecule. Harvard Medical School groups, led by Matthew Waldor on the CRISPR work and Min Dong on the mouse experiments, contributed to the study.
Sears said the group had made several attempts over the years to find the receptor, which made the result an exciting moment. The exact three-dimensional shape of the pairing remains unsolved: AlphaFold and other AI tools have not fully resolved it, and no experimental structure has been captured yet.
A claudin-4 decoy tested in mice
The therapeutic idea follows directly. The researchers built a soluble decoy protein carrying claudin-4 sequences and tested it in living mice. BFT bound the decoy instead of the claudin-4 on colon cells, and the mice were protected from toxin-induced tissue damage. The university news release posted May 7, 2026 states the same result and its limits.
Those limits matter. The mouse experiment showed protection against tissue damage, not prevention of colorectal cancer, and the safety and effectiveness of a decoy in people are unknown. White said the approach could be iterated with small molecules or other biologics that have better pharmacological properties, so the decoy is a proof of principle and not a candidate drug.
Colon cancer prevention after the Hopkins toxin finding
B. fragilis is found in up to 20 percent of healthy people, according to a 1995 study cited in the ScienceDaily write-up, and only certain strains carry the toxin gene. Most carriers will never develop colon cancer, so a bacterium that is common and a cancer that is not are being linked through a specific toxin rather than through simple presence.
The authors suggest that blocking the toxin could support colorectal cancer prevention and treatment of acute infection with toxin-producing strains. Nothing here replaces screening. The National Cancer Institute notes that colorectal cancer often begins as a polyp in the colon or rectum, and that finding and removing polyps can prevent the disease. A toxin blocker would be a second line of defense for people who carry the bacterium, and the work so far does not show whether it would reduce cancer in humans.
The funding list includes several National Institutes of Health grants, the Bloomberg~Kimmel Institute, Janssen Research and Development, Cancer Research UK and the Howard Hughes Medical Institute. The next experiment the team has flagged is deciding which molecular approach blocks BFT best, a question that has to be answered before any human trial can be designed. The approach also has to prove it can reach the colon lining at useful doses, since a decoy that works in a mouse experiment can still fail on delivery in people.
This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.
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