A research team led by Johns Hopkins Medicine has identified how the toxin BFT, produced by the common gut bacterium Bacteroides fragilis, gains access to colon cells to cause damage. The findings, published in the journal Nature, resolve a 15-year mystery regarding the initial steps of this process, which is linked to inflammation and the development of colorectal cancer.

The study reveals that BFT must first bind to a host protein known as claudin-4 before it can compromise the protective barrier of the colon. Previously, researchers understood that BFT causes chronic inflammation by cleaving E-cadherin, a protein essential for maintaining cellular integrity, but the mechanism by which the toxin reached its target remained unknown. Using a genomewide CRISPR screen, the team identified claudin-4 as the essential receptor required for the toxin to attach to cells.

"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," said senior author Cynthia Sears, M.D., of the Johns Hopkins Kimmel Cancer Center.

To test the potential for therapeutic intervention, the researchers developed a soluble version of the claudin-4 protein. This decoy molecule successfully intercepted the toxin in mouse models, preventing it from binding to colon cells and thereby protecting the tissue from damage. While the team has confirmed the binding interaction through biophysical techniques, they noted that further research is needed to determine the precise structural fit between the toxin and the receptor, as current AI modeling tools have not yet fully resolved the interaction.

The research was supported by organizations including the National Institutes of Health, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, and the Howard Hughes Medical Institute.

Source: Johns Hopkins Medicine