For nearly two decades, a bacterial toxin that could injure the colon kept one secret: how it first found its footing on the cells it harmed. A team at Johns Hopkins now reports that the missing key is claudin-4, a protein whose ordinary work is sealing the spaces between neighboring cells, and that a decoy built from it can draw the toxin away from living tissue. The finding does not yet tell us whether such a shield can keep cancer at bay, but it reveals how a quiet passenger of the gut might be made to lose its grip.
Johns Hopkins Team Identifies Claudin-4 as Receptor for Gut Bacterial Toxin Linked to Colon Cancer
Claudin-4 was a clear, resounding top hit.
Mark
Why does finding a receptor matter so much here?
Mimi
Because the toxin's damage was known but its first step wasn't. Without the docking point, there was nothing specific to block. Now there is.
Mark
Was claudin-4 what people expected?
Mimi
No. Sears expected a signaling receptor. Claudin-4 is a structural protein that helps seal cells together, so the toxin is using the barrier's own parts as a handle.
Luke
And the evidence for that is solid?
Mimi
The CRISPR screen flagged it as the top hit, disabling the gene stopped binding, and lab experiments with the Barcelona team showed a tight one-to-one complex.
Mark
So the decoy works?
Luke
In mice, against toxin-induced damage. The study did not show it prevents colorectal cancer, and nothing is shown in humans yet.
Mark
Is the structure known?
Luke
Not experimentally. The exact 3D fit hasn't been captured, and AlphaFold couldn't fully resolve it either.
Mimi
That's why the team talks about small molecules or other biologics next. The decoy is a proof of concept, not a finished drug.
Le Pouls
- A toxin from a common gut bacterium has long been known to damage the colon, yet its point of entry remained unseen.
- Researchers searched the genome gene by gene until one protein, claudin-4, stood out as the toxin's docking point.
- The discovery overturned expectations, since the receptor turned out to be a cell-sealing structure rather than a signaling molecule.
- A decoy carrying claudin-4 pulled the toxin away from colon cells and shielded mice from its damage.
- The protection stops short of cancer prevention, and the path toward a safe human blocker remains open and untested.
For nearly two decades, a bacterial toxin that could injure the colon kept one secret: how it first found its footing on the cells it harmed. A team at Johns Hopkins now reports that the missing key is claudin-4, a protein whose ordinary work is sealing the spaces between neighboring cells, and that a decoy built from it can draw the toxin away from living tissue. The finding does not yet tell us whether such a shield can keep cancer at bay, but it reveals how a quiet passenger of the gut might be made to lose its grip.
For close to twenty years, scientists knew what a toxin from Bacteroides fragilis did to the colon, but not how it got a grip on the cells in the first place. A team at Johns Hopkins now reports in Nature that the answer is claudin-4, a protein that helps neighboring cells form the tight seals that guard what passes between them.
The bacterium lives in the intestines of up to a fifth of healthy people, and carrying it does not mean cancer will follow. Certain strains, however, make a toxin called BFT that breaks down the cell-holding protein E-cadherin, weakens the colon's lining, drives inflammation, and encourages tumors. Earlier work had tied this toxin to colorectal cancer, but the molecule guiding it to cells had eluded every search.
Maxwell White, a graduate student in Cynthia Sears' laboratory, led a genome-wide screen with colleagues at Harvard, switching off genes one at a time in colon cells. When the claudin-4 gene was disabled, the toxin could no longer attach or do harm. The result surprised the team, who had expected a signaling receptor, and the finding was confirmed through structural work in Barcelona showing the two molecules bind tightly.
If the toxin needs claudin-4 to latch on, the researchers reasoned, a substitute might lure it away. They built a soluble decoy carrying claudin-4 sequences and tested it in mice. The toxin attached to the decoy instead of the colon, and the animals were protected from damage.
The work has limits. The three-dimensional shape of the toxin-receptor pair has not been fully captured, the mice were shielded from tissue damage rather than cancer itself, and safety in humans is unknown. The next steps are mapping that structure and searching for a better blocker, possibly a small molecule or another biologic.
For close to two decades, a toxin made by a common gut bacterium had a gap in its story. Researchers knew what the toxin did to the colon. They did not know how it got a grip on the cells to begin with. A team at Johns Hopkins now reports in Nature that it has found the answer: a protein called claudin-4.
The bacterium is Bacteroides fragilis, which lives in the intestines of up to 20% of healthy people. Carrying it does not mean a person will develop cancer. But certain strains make a toxin, known as BFT, that disrupts the colon's protective lining, drives inflammation, and encourages tumors. In a landmark 2009 study in Nature Medicine, Cynthia Sears and her colleagues showed that the toxin could promote colon tumors, tying toxin-producing gut bacteria to chronic inflammation and colorectal cancer.
Earlier work also showed that BFT breaks down E-cadherin, a protein that holds neighboring cells together and maintains the colon's barrier. Once it is cut apart, the barrier weakens, and harmful substances and bacteria can interfere with surrounding tissue. The puzzle was that BFT did not seem to attach to E-cadherin directly. Researchers suspected another molecule was guiding it there, but repeated attempts to find that molecule failed.
The team, from the Johns Hopkins Kimmel Cancer Center, its Bloomberg~Kimmel Institute for Cancer Immunotherapy, and the School of Medicine, turned to CRISPR gene editing. Maxwell White, an M.D./Ph.D. candidate in Sears' laboratory, led a genome-wide screen with Matthew Waldor's laboratory at Harvard Medical School. They switched off genes one by one in colon epithelial cells, the cells lining the colon, to see which were needed for the toxin to attach and do harm. One gene stood out: the one that produces claudin-4, a protein that helps neighboring cells form tight junctions, the seals that limit what passes between them. With that gene disabled, BFT could not bind the cells and could not attack E-cadherin. White said it took time to get the assay working and validated, but once the screen ran, claudin-4 was a "clear, resounding top hit."
The result surprised the researchers. Sears and others had expected a signaling receptor, such as a G protein-coupled receptor. Claudin-4 instead maintains the physical connections between cells. BFT is a protease, an enzyme that cuts proteins, and most proteases act directly on their targets. BFT appears to need a separate receptor first. When the team reviewed earlier literature, they found no other toxin known to work this way.
To confirm the two molecules bind, the Hopkins group worked with structural biologists F. Xavier Gomis-Rüth and Ulrich Eckhard at the Molecular Biology Institute of Barcelona. In laboratory experiments, BFT and claudin-4 formed a tightly bound complex, one toxin molecule to one receptor molecule.
The discovery also suggested a countermeasure. If BFT needs claudin-4 to latch on, a substitute might draw it away. The team built a decoy: a soluble protein carrying claudin-4 sequences, designed to attract the toxin without letting it attack the colon lining. Working with Min Dong's laboratory at Harvard Medical School, including Kang Wang and colleagues, they tested it in mice. BFT attached to the decoy instead of colon-cell claudin-4, and the mice were protected from BFT-induced damage. White said the approach could be iterated with small molecules or other biologics with better pharmacological properties, and the team is exploring which would work best.
Limits remain. The researchers have not captured an experimental three-dimensional structure of how BFT and claudin-4 fit together, and even AlphaFold has not fully resolved it. The mouse experiments showed protection against tissue damage, not prevention of colorectal cancer, and whether the decoy approach is safe and effective in humans is untested. Sears said understanding how bacterial toxins work could open new routes to detection and therapy for diarrhea, colorectal cancer, and bloodstream infections. The next steps are the structure and the search for a better blocker.
Citations marquantes
Claudin-4 was a clear, resounding top hit.— Maxwell White, M.D./Ph.D. candidate, Johns Hopkins
Understanding how bacterial toxins work can open doors to new approaches for detection and therapy for associated diseases.— Cynthia Sears, M.D., senior author
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