Scientists at Johns Hopkins have uncovered how a common gut bacterium may contribute to colorectal cancer, solving a long-standing mystery about how bacterial toxins damage the colon. The breakthrough identifies a protein called claudin-4 as the key receptor that allows the toxin to attach to colon cells and initiate damage.
The findings, published in the journal Nature, could help researchers develop new strategies to prevent toxin-related intestinal damage and potentially reduce cancer-associated risks. However, the experimental treatment has so far been tested in mice, and its effectiveness in humans remains unknown.
Gut Bacterium Linked to Colon Cancer
The research focuses on Bacteroides fragilis, a bacterium found in the intestines of some healthy people. While its presence does not automatically indicate cancer, certain strains produce a toxin known as B. fragilis toxin (BFT), which can damage the colon’s protective lining.
Previous research established that the toxin can trigger inflammation and contribute to tumor formation. Scientists, however, had struggled to understand how BFT first attaches to intestinal cells before damaging them.
The new study, led by researchers at the Johns Hopkins Kimmel Cancer Center and collaborating institutions, identifies claudin-4 as the missing link.
Claudin-4 Identified as the Toxin’s Receptor
Researchers used CRISPR gene-editing technology to investigate which proteins allow the bacterial toxin to interact with colon cells.
The screening process identified claudin-4, a protein that helps maintain tight junctions between neighboring cells and supports the intestinal barrier.
When researchers disabled the gene responsible for producing claudin-4, the toxin could no longer attach to the colon cells. This prevented it from reaching and damaging another important protein, E-cadherin, which helps maintain the protective structure of the colon lining.
The discovery explains how the toxin gains access to its target and provides researchers with a potential point of intervention.
Molecular Decoy Successfully Protects Mice
Building on the discovery, scientists developed a molecular decoy designed to attract the bacterial toxin before it can bind to colon cells.
The decoy contains a soluble version of claudin-4. In laboratory and animal experiments, the toxin attached to the decoy instead of the cells lining the colon.
Researchers reported that the strategy successfully protected mice from toxin-induced colon damage.
The result offers a promising direction for future research into treatments that block bacterial toxins before they harm intestinal tissue. Scientists are now exploring whether other molecular approaches could provide more effective and practical ways to prevent the toxin’s activity.
What the Discovery Means for Colorectal Cancer
The findings provide a clearer understanding of how toxin-producing gut bacteria can contribute to inflammation and processes associated with colorectal cancer.
By identifying claudin-4 as the toxin’s receptor, researchers have uncovered a potential target for future diagnostic and therapeutic development.
However, the study does not establish that the molecular decoy prevents cancer in humans. Further research is needed to determine whether the approach can safely block the toxin in people and whether doing so can reduce cancer risk.
Researchers also noted that the precise three-dimensional structure of the toxin-receptor interaction remains unresolved, leaving important questions for future investigation.
Study Published in Nature
The research was led by scientists from Johns Hopkins, with collaborators from Harvard Medical School and the Molecular Biology Institute of Barcelona.
The study, titled “A pro-carcinogenic bacterial toxin binds claudin-4 to cleave E-cadherin,” was published in Nature.
The researchers say the discovery could support new approaches to understanding and addressing diseases associated with bacterial toxins, including intestinal inflammation, colorectal cancer and other toxin-related conditions.
