Scientists have identified the molecular gateway that allows a dangerous bacterial toxin to attack colon cells, marking a breakthrough that could lead to new ways to prevent colorectal cancer before it starts. Researchers from Johns Hopkins University and collaborating institutions discovered that a toxin produced by the common bacterium Bacteroides fragilis requires a specific protein called claudin-4 to breach the colon's protective barrier and cause cancer-linked damage.
The finding, published in Nature, solves a puzzle that has frustrated cancer researchers since the early 2000s. While scientists knew that the toxin, abbreviated as BFT, damaged colon cells by attacking a protein called E-cadherin, they could not explain how the toxin initially reached its target. BFT did not appear to attach directly to E-cadherin, suggesting an intermediary step had been missed.
Bacteroides fragilis lives harmlessly in roughly one in five healthy people. But certain strains of the bacterium produce BFT, which triggers chronic inflammation in the colon and promotes tumor growth. Previous research from Johns Hopkins showed that the toxin's assault on E-cadherin weakens the intestinal wall, opening the door to further damage.
To identify the missing link, Maxwell White, an M.D./Ph.D. candidate at Johns Hopkins, led a genome-wide screening effort using CRISPR technology. The team systematically disabled genes in colon cells one by one to pinpoint which ones were essential for the toxin to work. Claudin-4 emerged as the clear winner. When researchers removed this protein, BFT lost its ability to attach to cells and could not harm E-cadherin.
The discovery surprised the research team. Most toxins of this type bind directly to their targets, not through an intermediary receptor. Many had expected claudin-4's role to belong to a signaling protein, a different class of molecules altogether. A review of prior research found no other toxin that operates in this manner.
Working with structural biologists in Barcelona, the Johns Hopkins team used biophysical techniques to confirm that BFT and claudin-4 form a tight, one-to-one binding complex. Testing in mouse models confirmed the finding in living systems. The researchers then created a soluble decoy version of claudin-4 that trapped the toxin before it could reach real colon cells. This molecular trap successfully protected mice from BFT-induced damage.
The approach offers a potential new therapeutic strategy. Researchers are now exploring how to develop small molecules or other drugs that could block the toxin in people, either by disrupting the BFT-claudin-4 interaction or by removing excess claudin-4 from the colon surface. Senior researcher Cynthia Sears, a Bloomberg Kimmel Professor of Cancer Immunotherapy at Johns Hopkins, noted that understanding how bacterial toxins operate can unlock detection and treatment options for colorectal cancer and related diseases.
One technical challenge remains. Despite the breakthroughs, researchers have not yet captured a detailed three-dimensional image showing exactly how the toxin and claudin-4 fit together at the molecular level. Advanced artificial intelligence tools, including AlphaFold, have been unable to resolve that final piece of the puzzle, though the hunt continues.
Author Jessica Williams: "This is exactly the kind of fundamental discovery that can reshape how we think about cancer prevention: instead of waiting to treat tumors, blocking a single bacterial protein interaction might stop the whole cascade before it begins."
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