A molecular decoy blocked toxin damage as scientists finally discover how a common bacterium can trigger colon cancer
A toxin’s missing first step
For nearly two decades, researchers have known that some Bacteroides fragilis bacteria produce a toxin that can damage the colon and promote tumors. They had not established how the toxin first attaches to intestinal cells.
The new study, published in Nature, identifies claudin-4 as the protein that B. fragilis toxin, or BFT, uses to dock on colon cells. Researchers from Johns Hopkins institutions and Harvard Medical School took part in the work.
How the toxin damages cells
B. fragilis can live in the intestines of up to 20% of healthy people. Its presence alone does not mean a person will develop cancer, but certain strains produce BFT, which can disrupt the colon’s protective lining, cause inflammation and encourage tumor growth.
Earlier research found that BFT breaks down E-cadherin, a protein that helps neighboring cells stay connected. The new findings show that the toxin must first bind to claudin-4 before it can attack E-cadherin.
A genome-wide search
To find the toxin’s docking point, the team used CRISPR to switch off genes in colon epithelial cells and test which were needed for BFT to bind and cause damage. Maxwell White, an M.D./Ph.D. candidate in Cynthia Sears’ laboratory, led the screening effort with Matthew Waldor’s laboratory at Harvard Medical School.
The gene that produces claudin-4 stood out. When researchers disabled it, BFT could no longer attach to the cells or attack E-cadherin. Claudin-4 normally helps form tight junctions, seals between cells that support the intestinal barrier.
Key points
- Claudin-4 is the docking point BFT uses to attach to colon cells.
- After binding to claudin-4, BFT can attack E-cadherin and weaken the protective lining.
- A molecular decoy protected mice from BFT’s harmful effects.
- B. fragilis occurs in the intestines of up to 20% of healthy people, but its presence alone does not mean cancer will develop.