Surface expression of antitoxin on engineered bacteria neutralizes genotoxic colibactin in the gut

Area of Science:

• Microbiology
• Genetics
• Cancer Research

Background:

• Colibactin, a gut bacteria metabolite from pks+ isolates, is linked to genotoxicity and cancer.
• Current therapeutics do not directly target colibactin.
• Understanding colibactin's genotoxic mechanisms is crucial for developing interventions.

Purpose of the Study:

• To engineer bacteria to express the colibactin self-resistance protein (ClbS) on their surface.
• To evaluate the efficacy of surface-displayed ClbS in protecting against colibactin-induced genotoxicity.
• To assess the therapeutic potential of engineered bacteria in preclinical models of colitis and colon cancer.

Main Methods:

• Engineered Escherichia coli by fusing ClbS with outer membrane protein A (ClbS-OmpA).
• Tested the engineered bacteria's ability to reduce DNA damage and cell cycle arrest in human cell lines and organoids.
• Evaluated the mitigation of intestinal damage in a mouse colitis model.
• Assessed the suppression of tumorigenesis in mouse models of colon cancer.

Main Results:

• Surface display of ClbS-OmpA effectively shielded host cells from colibactin's genotoxic effects.
• Engineered bacteria outperformed D-serine in reducing colibactin-induced DNA damage and cell cycle arrest.
• The engineered strains mitigated intestinal damage in colitis models and suppressed tumor formation in cancer models.

Conclusions:

• Surface display of bacterial proteins offers a viable strategy to inhibit bacterial genotoxins in the gut.
• Engineered bacteria expressing ClbS represent a promising starting point for novel therapeutics against colibactin-induced pathologies.
• This approach could be extended to target other cancer-causing bacterial metabolites.