Gut Bacterium Toxin Uses Claudin-4 to Attack Colon Cells, Study Finds

Scientists at Johns Hopkins Medicine have identified how a toxin made by a common gut bacterium latches onto colon cells, solving a puzzle that has stood since the toxin was first linked to colon tumours in 2009. The study, published in the journal Nature, found that the toxin docks onto a protein called claudin-4. The team also designed a molecular decoy that protected mice from the toxin’s damage.

The work centres on Bacteroides fragilis, a bacterium found in the intestines of up to 20% of healthy people, according to Johns Hopkins. Most people who carry it never develop cancer, but certain strains produce a toxin known as B. fragilis toxin, or BFT, which can damage the lining of the colon, drive chronic inflammation and encourage tumours to grow.

What Did the Johns Hopkins Study Find?

Researchers had known for years that BFT breaks down E-cadherin, a protein that holds neighbouring cells together and keeps the colon’s protective barrier intact. But the toxin did not seem to attach to E-cadherin directly, which suggested another molecule was helping it reach its target. Repeated attempts to find that molecule had failed.

To solve it, Maxwell White, an MD-PhD candidate in the laboratory of senior author Cynthia Sears, led a genome-wide CRISPR screen with Matthew Waldor’s laboratory at Harvard Medical School. The team switched off genes one by one in colon lining cells to see which were needed for the toxin to bind. “Once we were able to do the screen, claudin-4 was a clear, resounding top hit,” White said.

When the gene for claudin-4 was disabled, BFT could no longer attach to colon cells, and without that first step it could not attack E-cadherin. “We’ve made several attempts over time to identify the receptor, so this is an exciting moment,” Sears said.

What Is Claudin-4?

Claudin-4 is a protein that helps form tight junctions, the seals between neighbouring cells that control what passes through the gut lining. Its identity surprised the team, who had expected the toxin to use a signalling receptor, such as a G protein-coupled receptor.

The discovery also points to an unusual attack strategy. BFT is a protease, an enzyme that cuts other proteins. Most proteases act directly on their targets, but BFT appears to need a separate receptor before it can reach E-cadherin. The researchers said they could not find another toxin known to work in the same way. Structural biologists F. Xavier Gomis-Rüth and Ulrich Eckhard at the Molecular Biology Institute of Barcelona helped confirm that each toxin molecule binds tightly to one claudin-4 molecule.

How Does the Molecular Decoy Work?

If the toxin needs claudin-4 to attach, a look-alike might lure it away. The team built a soluble protein carrying sequences from claudin-4 and tested it in mice with Min Dong’s laboratory at Harvard Medical School. Instead of binding to the colon’s own cells, BFT attached to the decoy, and the mice were protected from toxin-induced damage.

“This approach could be iterated upon with small molecules or other biologics that have better pharmacological properties,” White said. The team is now exploring which approaches are most likely to block the toxin effectively.

Does This Mean Colon Cancer Can Be Prevented?

Not yet. The researchers are clear that the mouse experiments showed protection against tissue damage, but they did not show that the decoy prevents colorectal cancer. Further studies are needed to see whether the strategy is safe and effective in people.

The exact three-dimensional structure of the toxin and receptor bound together has also not been captured experimentally, and even AI tools such as AlphaFold could not fully resolve it. Knowing that structure could help scientists design better blockers.

Even so, the finding gives researchers a specific target at the very first step of the toxin’s attack, rather than trying to repair damage afterwards. The authors say it could also inform work on other conditions linked to the toxin, including diarrhoea and bloodstream infections.

Why Does This Matter for Colorectal Cancer?

Colorectal cancer is one of the most common cancers worldwide, and cases among younger adults have been rising in many countries. Researchers increasingly see the gut microbiome as part of the picture, alongside diet, genetics and lifestyle. New treatments are also changing care, such as the immunotherapy recently approved for some rectal cancers, while a high-fibre diet remains one of the main ways people can support gut health; see our guide to how much fibre you need a day.

The study was funded by the Bloomberg~Kimmel Institute for Cancer Immunotherapy, Janssen Research and Development, Cancer Research UK, the US National Institutes of Health and the Howard Hughes Medical Institute.

Featured image: Bacteroides fragilis growing on fastidious anaerobe agar, by Nathan Reading / Wikimedia Commons, CC BY 2.0.

Sources

• ScienceDaily (Johns Hopkins Medicine) — Scientists finally discover how a common gut bacterium can trigger colon cancer (31 October 2026).
• Nature — A pro-carcinogenic bacterial toxin binds claudin-4 to cleave E-cadherin (2026).
• Johns Hopkins Medicine — Solving a 15-year mystery: how gut bacteria toxin invades colon cells (2026).