Microbial competition regulates a gradual switch from toxin production to metabolic exclusion in a prevalent human gut commensal

The Klebsiella oxytoca species complex (KoSC) is a crucial component of the human microbiome and particularly prevalent during infancy and childhood. KoSC strains can produce two enterotoxic natural products, tilimycin and tilivalline, while also contributing to colonization resistance (CR) against pathogenic Enterobacteriaceae. The relationship between these seemingly contradictory roles has remained underexplored. In this study, we demonstrate that K. oxytoca provides CR against Salmonella Typhimurium infections. Genetic disruption of toxin production showed that tilimycin exhibits antimicrobial activity against various Salmonella strains in vitro. Notably, CR against Salmonella depended on toxin production in germfree mice, while it was largely toxin-independent in mice with a residual microbiota. Further, we found that availability of abundant carbohydrate availability induced toxin production, and that nutrient competition not only limited toxin production but was also critical for CR. Thus, mutual interactions occurring between KoSC members and the microbiota impact both gut community composition and function.