Scientists Solve 15-Year Mystery of How Gut Bacteria Can Trigger Colon Cancer

What if a harmful gut bacterium could be stopped before it damages the colon and potentially contributes to cancer? Scientists have identified a previously unknown mechanism through which a bacterial toxin attacks intestinal cells and developed an experimental strategy to block its effects.

Published in the journal Nature, the study conducted by researchers at the Johns Hopkins Kimmel Cancer Center and collaborating institutions investigated how certain strains of the gut bacterium Bacteroides fragilis contribute to intestinal inflammation and colorectal cancer.

Although Bacteroides fragilis can naturally occur in the human intestine, some strains produce a toxin known as BFT, which damages the intestinal lining and has been linked to tumour development.

Researchers used genome-wide CRISPR gene-editing technology to identify the cellular proteins required for the toxin to attach to colon cells.

The findings revealed that a protein called claudin-4 acts as an essential receptor for BFT.

Claudin-4 normally helps maintain tight connections between intestinal cells, protecting the colon's barrier.

However, researchers discovered that BFT attaches to claudin-4 before damaging another protein called E-cadherin, which helps hold neighbouring cells together.

Importantly, when scientists disabled the gene responsible for claudin-4, the toxin could no longer attach to colon cells or damage E-cadherin.

The team subsequently developed a soluble protein designed to imitate the toxin-binding region of claudin-4.

This molecular decoy intercepted BFT before it could attach to intestinal cells.

Experiments in mice demonstrated that the decoy successfully protected against toxin-induced intestinal damage.

Researchers suggested that this approach could eventually support the development of treatments designed to block harmful bacterial toxins before they disrupt the intestinal barrier.

However, the protective effects have so far been demonstrated in laboratory and animal experiments, and the study did not establish that the treatment prevents colorectal cancer.

REFERENCE: Maxwell T. White, et al.; A pro-carcinogenic bacterial toxin binds claudin-4 to cleave E-cadherin. Nature, 2026; 654 (8118): 504 DOI: 10.1038/s41586-026-10375-0