Researchers have identified how a toxin released by a common gut bacterium breaches colon cell defenses, resolving a longstanding scientific puzzle. The findings reveal a novel mechanism by which the toxin, produced by Bacteroides fragilis, triggers cellular damage linked to colorectal cancer, offering potential pathways for therapeutic intervention.
The study, led by scientists at the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins University School of Medicine, was published in Nature. It details how the toxin, termed BFT, must first bind to a host protein named claudin-4 before it can harm colon cells. This discovery addresses a critical gap in understanding how the toxin initiates its pathogenic effects.
“This breakthrough marks a significant step forward in deciphering bacterial toxin interactions,” says senior author Cynthia Sears, M.D., Bloomberg-Kimmel Professor of Cancer Immunotherapy. “These insights could lead to innovative strategies for diagnosing and treating conditions like colorectal cancer, chronic inflammation, and systemic infections.”
Claudin-4 Identified as Key Receptor for Toxin Entry
Building on prior work linking B. fragilis to colon tumors, the team explored how BFT—a protease toxin—targets cells. Earlier research indicated that BFT disrupts E-cadherin, a protein crucial for maintaining colon barrier integrity, but the mechanism of entry remained unclear. To pinpoint the missing receptor, researchers conducted a genome-wide CRISPR screen in colon epithelial cells, systematically inactivating genes to assess their role in toxin activity.
Claudin-4 emerged as the critical factor. When its gene was disrupted, BFT lost the ability to bind to cells, leaving E-cadherin intact. “Identifying claudin-4 as the receptor was unexpected,” notes Maxwell White, an M.D./Ph.D. candidate who spearheaded the experiments. “Most protease toxins attack their targets directly, so this indirect mechanism was a surprise.”
Molecular Decoy Blocks Toxin Damage in Animal Models
Collaborating with structural biologists at the Molecular Biology Institute of Barcelona, the team confirmed that BFT forms a stable one-to-one complex with claudin-4 using biophysical methods. To test therapeutic potential, they designed a soluble claudin-4 decoy that mimics the receptor’s toxin-binding regions. In mouse trials, this decoy neutralized BFT, preventing colon injury.
“This strategy could be refined using drugs or biologics with improved pharmacological profiles,” White adds. The researchers are now exploring the decoy approach’s broader applications for combating toxin-mediated diseases.
Unresolved Structural Details and Ongoing Investigations
While the study validates claudin-4 as a receptor, the precise three-dimensional structure of the toxin-receptor complex remains to be fully characterized. Current AI tools, including AlphaFold, have yet to resolve the interaction, highlighting the need for advanced structural analysis.
Additional contributors include Jason Chen, Shaoguang Wu, Abby L. Geis, and Jessica Queen (Johns Hopkins), and Hailong Zhang, Karthik Hullahalli, and Jie Zhang (Harvard Medical School). Funding was provided by the Bloomberg-Kimmel Institute, the National Institutes of Health (grants R01 AI042347, R01 NS080833, R01 NS117626, R01 AI170835, R01 AI189789), Cancer Research UK, Janssen Research and Development, and the Howard Hughes Medical Institute. Sears discloses royalty payments through UpToDate, managed under Johns Hopkins’ conflict-of-interest policies.
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