In situ neutralization of the genotoxicity of pathogenic gut bacteria with the polyketide synthase island

The gut microbiota produce beneficial and deleterious metabolites to influence host physiology, with colibactin from pks ⁺ bacteria one of the most studied metabolites associated with host genotoxicity and tumorigenesis. However, no FDA-approved therapeutics target colibactin. Interestingly, pks ⁺ bacteria protect themselves from colibactin through ClbS, an intracellular enzyme inactivating colibactin. Building on this defense mechanism, we displayed ClbS on the surface of engineered bacteria to shield the host from the genotoxic effects across multiple pks ⁺ isolates. This approach outperformed direct ClbS secretion from engineered bacteria and a small molecule inhibitor against colibactin biosynthesis in cell lines and colon organoids. Furthermore, our strategy inhibited pks ⁺ E. coli in vivo , mitigated intestinal DNA damage, and suppressed tumorigenesis in mouse models of colon cancer. This work demonstrates the feasibility of inhibiting bacterial genotoxins in the gut with translational potential and offers a new avenue to understand the roles of microbial metabolites in host diseases.