Plate Nº 29 · recorded October 31, 2026
Health & Medicine ResearchReported finding
Johns Hopkins Team Finds the Docking Point a Gut Toxin Uses to Attack the Colon
After two decades of failed searches, Johns Hopkins researchers identified claudin-4 as the receptor a colon-damaging bacterial toxin needs, and built a decoy that protected mice.
By James Calloway4 min read770 words
In brief
- The study, published in Nature on October 31, 2026, identifies claudin-4 as the receptor for B. fragilis toxin (BFT).
- Bacteroides fragilis lives in up to 20% of healthy people's intestines; some strains produce the tumor-promoting toxin.
- A 2009 Nature Medicine study by the same senior author first linked the toxin to colon tumor formation.
- A soluble molecular decoy carrying claudin-4 sequences intercepted the toxin and protected mice from BFT-induced damage.
- The mouse studies showed protection against tissue damage, not yet prevention of colorectal cancer in humans.
After nearly two decades of failed attempts, researchers have identified the exact protein that a diarrhea- and cancer-linked gut toxin uses to latch onto colon cells. The culprit-docking station, described October 31, 2026, in Nature, is a protein called claudin-4, and blocking it protected mice from the toxin's damage.
The study comes from a team 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, with collaborators at Harvard Medical School and the Molecular Biology Institute of Barcelona. The National Institutes of Health partially funded the work.
"We've made several attempts over time to identify the receptor, so this is an exciting moment," said senior author Cynthia Sears, M.D., Bloomberg~Kimmel Professor of Cancer Immunotherapy at Johns Hopkins. "Understanding how bacterial toxins work can open doors to new approaches for detection and therapy for associated diseases, including diarrhea, colorectal cancer and bloodstream infections."
What was the mystery?
The story centers on Bacteroides fragilis, a bacterium found in the intestines of up to 20% of healthy people. Presence doesn't equal cancer risk. But certain strains produce B. fragilis toxin, or BFT, which disrupts the colon's protective lining, drives chronic inflammation, and encourages tumor growth.
Sears and colleagues showed in a landmark 2009 Nature Medicine study that the toxin promotes colon tumor development in mice. Later work revealed BFT slices apart E-cadherin, a protein that glues neighboring cells together and maintains the colon's barrier.
One problem nagged at researchers. The toxin didn't attach to E-cadherin directly. Something else, they suspected, helped it reach its target. Repeated attempts to find that something failed. For years.
How did CRISPR crack it?
Maxwell White, an M.D./Ph.D. candidate in Sears' lab, led a genome-wide CRISPR screen in collaboration with Matthew Waldor's laboratory at Harvard Medical School. The method is brute force: switch off genes one by one in colon epithelial cells, the cells lining the intestine, and see which one the toxin needs.
One gene stood out. It makes claudin-4, a protein that forms tight junctions, the seals between cells that control what passes through the intestinal barrier. Disable the gene, and BFT could no longer bind. No binding, no E-cadherin damage.
"Once we were able to do the screen, claudin-4 was a clear, resounding top hit," White said. "That was an exciting moment."
The result surprised the team. They had expected BFT to dock onto a signaling protein, such as a G protein-coupled receptor, which works like a communication switch on the cell surface. Claudin-4 is different; it's structural, not a signaling switch. And BFT, a protease (an enzyme that cuts proteins), appears unusual in needing a separate receptor at all. The researchers found no other known toxin using the same mechanism.
Working with structural biologists F. Xavier Gomis-Rüth and Ulrich Eckhard in Barcelona, the team confirmed BFT and claudin-4 form a tightly bound complex in lab experiments, pairing one toxin molecule with one receptor molecule.
Can a decoy stop the toxin?
Here's the clever part. If the toxin needs claudin-4, why not offer it a fake? The researchers built a soluble molecular decoy carrying claudin-4 sequences, designed to attract BFT without letting it attack the colon lining.
In mouse experiments with Min Dong's Harvard lab, including Kang Wang and colleagues, BFT bound to the decoys instead of colon cells. The mice were protected from toxin-induced damage. The strategy intercepts the toxin's first move rather than repairing damage afterward.
"This approach could be iterated upon with small molecules or other biologics that have better pharmacological properties," White said. Small molecules are compounds that can become drugs; biologics are treatments made from biological materials, such as proteins.
What does this change for cancer prevention?
Honest answer: not yet proven. The mouse experiments showed protection against tissue damage, not against colorectal cancer itself. The researchers haven't captured the exact three-dimensional structure of the toxin-receptor pair, and even AlphaFold, the AI protein-folding tool, couldn't fully resolve it. Human safety and efficacy studies remain ahead.
Still, the discovery closes a question open since 2009 and opens a target: interrupt a harmful process before it starts. Additional contributors included Jason Chen, Shaoguang Wu, Abby L. Geis, and Jessica Queen of Johns Hopkins, and Hailong Zhang, Karthik Hullahalli, and Jie Zhang of Harvard. Funding also came from Janssen Research and Development, Cancer Research UK, and the Howard Hughes Medical Institute.
via tandfonline.com (Original)
More from James Calloway
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Staff writer covering regulation, policy and their impact on general science news at SciBeat.
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