Scientists Crack How a Common Gut Toxin Breaches the Colon, Then Build a Decoy to Block It

Researchers at Johns Hopkins Medicine have solved a mystery that has puzzled scientists for more than 15 years: exactly how a toxin made by a common gut bacterium breaks into colon cells and begins the damage that can lead to colorectal cancer. Just as important, they used that discovery to design a molecular decoy that blocked the toxin in mice.

The toxin, known as BFT, is produced by certain strains of Bacteroides fragilis, a bacterium found in the guts of up to 20% of healthy people. Most of the time it causes no harm. But some strains promote chronic inflammation and tumor growth in the colon, and researchers have long struggled to explain how the toxin first gains a foothold on the cells lining the gut.

Using a genomewide CRISPR screen, a technique that systematically switches off genes one at a time to see which ones matter, the team identified the toxin's point of entry. BFT latches onto a receptor called claudin-4 on the surface of colon cells. That binding gives the toxin access to the cells' protective barrier, where it cleaves a protein called E-cadherin that normally helps hold the barrier together, opening the door to inflammation and, over time, cancer.

The work was led by Dr. Cynthia Sears, with M.D.-Ph.D. candidate Maxwell White directing the screening effort. The team collaborated with Matthew Waldor at Harvard Medical School and structural biologists F. Xavier Gomis-Rüth and Ulrich Eckhard at the Molecular Biology Institute in Barcelona, whose work helped pin down how the toxin and receptor fit together. The findings were published in the journal Nature.

Having found the weak point, the researchers went a step further. They engineered a soluble version of claudin-4, essentially a free-floating copy of the receptor, to act as a decoy. When introduced in mouse models, the decoy intercepted the toxin before it could reach the real receptors on colon cells, preventing the damage that BFT would otherwise cause.

The results are early and confined to animal studies, but they point toward a potential new strategy for preventing inflammation-driven colorectal cancer, particularly in people who carry harmful strains of B. fragilis. Colorectal cancer is one of the most common cancers worldwide, and cases among younger adults have been rising for reasons scientists are still working to understand. A therapy that could neutralize a cancer-promoting toxin before it acts, the researchers said, might eventually help protect vulnerable patients or manage the infections associated with the disease.