Scientists finally discover how a common gut bacterium can trigger colon cancer
Scientists at Johns Hopkins have uncovered a crucial missing link between a common gut bacterium and colorectal cancer, solving a mystery that has puzzled researchers for nearly two decades. The bacterium, Bacteroides fragilis, produces a toxin that damages the colon’s protective lining, triggers chronic inflammation, and promotes tumor formation.
Key points
- Johns Hopkins-led researchers identified claudin-4 as the receptor that the Bacteroides fragilis toxin BFT must bind to before it can damage colon cells.
- A soluble molecular decoy carrying claudin-4 sequences intercepted BFT and protected mice from toxin-induced damage.
- The discovery explains a step unknown since 2009, when the same team linked BFT to colon tumor formation, but human prevention of colorectal cancer remains untested.
Researchers led by Johns Hopkins Kimmel Cancer Center, its Bloomberg~Kimmel Institute for Cancer Immunotherapy and the Johns Hopkins University School of Medicine have identified the missing step in how a common gut bacterium's toxin attacks the colon. The findings, published in Nature, name a protein called claudin-4 as the docking point for the toxin BFT, produced by Bacteroides fragilis.
The bacterium can be found in the intestines of up to 20 percent of healthy people, and its presence does not mean cancer will develop. Certain strains make BFT, which damages the colon's lining and encourages tumor growth; a 2009 study by the same team linked the toxin to colon tumors in mice.
How the receptor was found
Maxwell White, an M.D./Ph.D. candidate in Cynthia Sears' laboratory, led a genome-wide CRISPR screen with Matthew Waldor's laboratory at Harvard Medical School. The team switched off genes in colon epithelial cells to see which were needed for the toxin to attach and cause damage. Claudin-4, which helps seal the junctions between cells, stood out; when its gene was disabled, BFT could not bind and could not attack E-cadherin.
Sears said the receptor's identity was unexpected, since claudin-4 maintains cell connections rather than acting mainly as a signaling receptor. Collaborators at the Molecular Biology Institute of Barcelona showed BFT and claudin-4 form a tightly bound complex in laboratory experiments.
It took a while to get the assay working and validate the approach, but once we were able to do the screen, claudin-4 was a clear, resounding top hit
— Maxwell White
Decoy protects mice
The team built a molecular decoy, a soluble protein carrying claudin-4 sequences, to draw BFT away from colon cells. In experiments with Min Dong's laboratory at Harvard Medical School, the decoys intercepted the toxin and protected mice from BFT-induced damage.
White said the approach could be refined with small molecules or other biologics. The researchers have not captured the exact three-dimensional structure of the interaction, and mouse experiments did not establish that the strategy prevents colorectal cancer in people.
