Colibactin-driven colon cancer requires adhesin-mediated epithelial binding

Area of Science:

• Microbiology
• Oncology
• Genetics

Background:

• Bacteria are implicated in colorectal cancer (CRC) development.
• pks+ Escherichia coli produces colibactin, a genotoxin causing DNA damage in host cells.
• The mechanism by which colibactin accesses host cells to cause harm is unclear.

Purpose of the Study:

• To investigate the role of bacterial adhesion in pks+ E. coli-mediated CRC development.
• To identify bacterial factors involved in adhesion and genotoxicity.
• To explore therapeutic strategies targeting bacterial adhesion.

Main Methods:

• Utilized a ZEB2-transgenic mouse model of invasive CRC.
• Investigated the role of type 1 pilus adhesin FimH and F9 pilus adhesin FmlH in bacterial adhesion.
• Tested a pharmacological FimH inhibitor to block bacterial adhesion.
• Analyzed allelic switching of FimH in pks+ E. coli and probiotic strains.

Main Results:

• Bacterial adhesion to host epithelial cells, mediated by FimH and FmlH, is critical for the oncogenic potential of pks+ E. coli.
• Blocking bacterial adhesion with an FimH inhibitor reduced colibactin genotoxicity and CRC exacerbation.
• FimH allelic switching influenced pks+ E. coli genotoxicity and could confer gain-of-function to probiotic strains.
• Adhesin-mediated binding facilitates colibactin production near host cells, promoting DNA damage and CRC.

Conclusions:

• Bacterial adhesins like FimH and FmlH are key mediators of pks+ E. coli-induced CRC.
• Targeting bacterial adhesion presents a promising therapeutic strategy for CRC prevention.
• Anti-adhesive therapies could mitigate colibactin-induced DNA damage, particularly in high-risk individuals.