Johns Hopkins team finds the receptor a cancer-linked gut-bacteria toxin uses to attack the colon lining

Some strains of the gut bacterium Bacteroides fragilis — found in up to 20% of healthy people, according to Johns Hopkins — make a toxin called BFT that damages the colon’s lining, drives inflammation and has been linked to colon tumours in animal studies since 2009. How the toxin first latches onto cells was unknown. A laboratory and mouse study published in Nature now proposes an answer.

What the researchers found

• Using a genome-wide CRISPR screen in colon epithelial cells, a team from Johns Hopkins and Harvard found that switching off the gene for claudin-4, a tight-junction protein, stopped BFT from binding.
• Without that binding, the toxin could not cleave E-cadherin, the protein that holds neighbouring cells together.
• Biophysical tests with colleagues in Barcelona showed BFT and claudin-4 form a tight one-to-one complex. The authors say they found no other known toxin that works this way.
• A soluble decoy protein carrying claudin-4 sequences intercepted the toxin and protected mice from BFT-induced damage.

“Claudin-4 was a clear, resounding top hit,” said first author Maxwell White.

Limitations

This is preclinical research in cells and mice. The decoy protected mouse tissue from toxin damage but was not shown to prevent colorectal cancer, and it has not been tested in people. The exact 3D structure of the BFT–claudin-4 complex has not yet been solved. Funders included the NIH, HHMI, Cancer Research UK and Janssen. Anyone with concerns about bowel cancer risk or screening should talk to their doctor.