A commensal-encoded genotoxin drives restriction of Vibrio cholerae colonization and host gut microbiome remodeling

Members of complex microbial communities that reside in environments such as the mammalian gut have evolved mechanisms of interspecies competition, which may be directed at resident microbial and host cells. While previous work has focused mainly on metabolic or niche competition, few specific intermicrobial targeting mechanisms have been elucidated in the mammalian gut. Here, we show that a genotoxin produced by commensal Escherichia coli, colibactin, which was previously shown to induce DNA damage in host intestinal cells, is also able to target via a contact-dependent mechanism a variety of enteric pathogens and commensals, including the important human diarrheal pathogen Vibrio cholerae. We find that colibactin-mediated killing depends on accumulation of intracellular reactive oxygen species, leading to DNA damage and loss of target cell fitness. We also show that the presence of colibactin is associated with cholera outcomes in a large human metagenomic dataset and that colibactin can shape the microbiome by species-specific targeting of a common human gut-associated microbe Bacteroides fragilis, suggesting that genotoxin-mediated mechanisms may have broad effects in the complex polymicrobial interactions that shape commensal microbial communities and their effects on host health and disease.