A 20-Year Mystery: How a Gut Bacterium Breaches the Colon's Defenses
Scientists have long known that a common gut bacterium, Bacteroides fragilis, can produce a toxin that damages the colon's protective lining, triggers chronic inflammation and promotes tumor formation. But for nearly two decades, they could not explain a critical question: how does the toxin first attach to intestinal cells and begin its attack?
Now, researchers at Johns Hopkins have uncovered that missing step—and revealed a surprising vulnerability that could lead to new ways of protecting the colon. The findings were published in Nature.
Key Finding: Claudin-4 Is the Toxin's Docking Point
The research was led by scientists at the Johns Hopkins Kimmel Cancer Center, its Bloomberg~Kimmel Institute for Cancer Immunotherapy, and the Johns Hopkins University School of Medicine. They identified a protein called claudin-4 as the essential docking point for the B. fragilis toxin, known as BFT.
Claudin-4 normally helps neighboring cells form tight junctions—the seals that limit the movement of substances between cells and help maintain the intestinal barrier.
Using CRISPR gene-editing technology, the team systematically switched off genes in colon epithelial cells to see which ones were necessary for the toxin to attach and cause damage. One gene stood out dramatically: the one producing claudin-4. When it was disabled, BFT could no longer bind to colon cells and was unable to attack E-cadherin, another protein that helps hold cells together.
An Unexpected Mechanism: A Receptor Before the Target
What surprised the scientists was that claudin-4 is not a typical signaling receptor such as a G protein-coupled receptor. Instead, it is a structural protein that maintains physical connections between cells. This means BFT uses an unusual attack strategy: although it belongs to a class of enzymes called proteases that cut other proteins, it must first latch onto claudin-4 before it can reach and damage E-cadherin.
The Johns Hopkins team collaborated with structural biologists F. Xavier Gomis-Rüth and Ulrich Eckhard at the Molecular Biology Institute of Barcelona. Using techniques that measure molecular interactions, they showed that BFT and claudin-4 form a tightly bound complex, with each toxin molecule pairing with one receptor molecule—direct physical evidence of the connection.
A Molecular Decoy That Blocks the Toxin in Mice
If BFT needs claudin-4 to attach to colon cells, perhaps a substitute could lure the toxin away from its intended target.
The team developed a molecular decoy: a soluble protein carrying sequences from claudin-4, designed to attract BFT without allowing it to attack the colon's protective lining. Working with Min Dong's laboratory at Harvard Medical School, including Kang Wang and colleagues, they tested the approach in mice.
The results were encouraging. Instead of binding to claudin-4 receptors on colon cells, BFT attached to the decoy proteins. By intercepting the toxin, the decoys successfully protected the mice from BFT-induced damage. The finding suggests it may be possible to interfere with the toxin's first step rather than trying to repair damage after it occurs.
What Does This Mean for the Public?
- B. fragilis is not rare: The bacterium can be found in the intestines of up to 20% of healthy people, but not all strains produce the toxin, and carrying the bacterium does not mean someone will develop cancer.
- Toxin-producing strains are linked to colorectal cancer risk: Certain strains produce BFT, which can disrupt the intestinal barrier and cause chronic inflammation—an important risk factor for colorectal cancer.
- Possible future directions: Identifying the receptor and developing molecular decoys offers new research avenues for detection, prevention and treatment of colorectal cancer, but this work is still at an early stage and not yet available in the clinic.
- Everyday gut care: A balanced diet, adequate dietary fiber, regular sleep and attention to gut health remain the foundation of colon health.
The team notes that the approach could be further optimized with small molecules or other biologics to improve pharmacological properties. For people interested in gut health, following research progress while maintaining good daily health habits is the more practical approach.
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