For more than 15 years, researchers knew a common gut bacterium could trigger colon cancer, but they could not explain how its toxin got inside cells. Scientists at Johns Hopkins Medicine have now solved that puzzle, and they built a decoy that stopped the toxin in mice.
The discovery centers on Bacteroides fragilis, a bacterium found in up to 20% of healthy people. Certain strains of this microbe produce a toxin called BFT that drives chronic inflammation and tumor growth in the colon. The new study, published in Nature, reveals that BFT must first latch onto a host protein called claudin-4 before it can damage colon cells.
A Hidden Receptor Gives the Toxin Access
Earlier work from the same lab showed that BFT causes harm by cutting a protective protein called E-cadherin, which maintains the colon's barrier. But the toxin did not bind directly to E-cadherin, leaving a missing step in the process. Researchers suspected another molecule was helping BFT get close enough to strike.
To find that missing link, Maxwell White, an M.D./Ph.D. candidate in the lab of senior author Cynthia Sears, led a genomewide CRISPR screen. The team systematically disabled individual genes in colon epithelial cells to see which ones the toxin needed to work. One protein stood out: claudin-4. When claudin-4 was removed, BFT could no longer attach to the cells, and E-cadherin remained unharmed.
A Decoy That Blocks the Toxin
Once the receptor was identified, the team designed a molecular decoy that mimics claudin-4. In animal models, this decoy intercepted BFT before it could reach real colon cells, preventing damage. The approach could lead to new therapies that stop inflammation and tumor formation before they start.
The research was supported by the National Institutes of Health and involved collaboration with the laboratory of Matthew Waldor at Harvard Medical School. Sears called the finding an exciting moment after years of attempts to identify the receptor.
Understanding how bacterial toxins enter cells opens doors for detecting and treating associated diseases, including diarrhea, colorectal cancer, and bloodstream infections. The decoy strategy now offers a concrete path toward blocking one of the hidden triggers of colon cancer.
