Klebsiella oxytoca inhibits Salmonella infection through multiple microbiota-context-dependent mechanisms. The study shows that K. oxytoca provides colonization resistance (CR) against Salmonella Typhimurium in different microbiota settings. In vitro, the antimicrobial activity against various Salmonella strains depends on tilimycin production and is induced by simple carbohydrates. In vivo, CR against Salmonella depends on toxin production in germ-free mice, while it is largely toxin-independent in mice with residual microbiota. This is linked to the relative levels of toxin-inducing carbohydrates in vivo. Dulcitol utilization is essential for toxin-independent CR in gnotobiotic mice. The study demonstrates that nutrient availability is key to both toxin-dependent and substrate-driven competition between K. oxytoca and Salmonella. The human microbiota provides CR by preventing or reducing the severity of infections through mechanisms such as competition for nutrients, metabolites, and environmental niches, as well as production of inhibitory or toxic compounds. Members of the Klebsiella oxytoca species complex (KoSC) provide CR against their more pathogenic counterparts through overlapping metabolic niches in the gut. KoSC strains can confer CR against MDR Klebsiella pneumoniae strains through competition for specific beta-glucosidic sugars. While these studies provided mechanistic insight in mouse models, carriage of specific strains of KoSC could also lower the risk for bacteraemia in cancer and haematopoietic cell transplantation patients as well as neonates. The contribution of KoSC strains to CR might be especially relevant when the prevalence and population densities of these bacteria are high. KoSC strains are prevalent colonizers in infants but maintain a relatively low abundance in homeostatic conditions. KoSC members may expand after antibiotic disruption of the microbiota due to the availability of additional metabolic niches. However, upon expansion, KoSC strains may also pose a threat to the host due to strain-specific sets of virulence factors. KoSC strains can produce enterotoxins, namely, tilimycin and tilivalline, while also contributing to colonization resistance (CR). The relationship between these seemingly contradictory roles is not well understood. The study shows that K. oxytoca provides CR against S. Typhimurium in different microbiota settings via distinct toxin-dependent and -independent mechanisms. The availability of simple carbohydrates links both mechanisms as toxicity predominates with high sugar availability, while microbial competition contributes when carbohydrates are scarce. These findings show that KoSC members can contribute via distinct mechanisms to CR against S. Typhimurium. The study also shows that the til PAI correlates with inhibition, and toxin production is essential for the inhibition. The contribution of toxin production is microbiota-dependent. The study shows that the availability of sugars is crucial for toxin production in vitro. The study also shows that the protective phenotype observed in vivo is due to toxin production. The study showsKlebsiella oxytoca inhibits Salmonella infection through multiple microbiota-context-dependent mechanisms. The study shows that K. oxytoca provides colonization resistance (CR) against Salmonella Typhimurium in different microbiota settings. In vitro, the antimicrobial activity against various Salmonella strains depends on tilimycin production and is induced by simple carbohydrates. In vivo, CR against Salmonella depends on toxin production in germ-free mice, while it is largely toxin-independent in mice with residual microbiota. This is linked to the relative levels of toxin-inducing carbohydrates in vivo. Dulcitol utilization is essential for toxin-independent CR in gnotobiotic mice. The study demonstrates that nutrient availability is key to both toxin-dependent and substrate-driven competition between K. oxytoca and Salmonella. The human microbiota provides CR by preventing or reducing the severity of infections through mechanisms such as competition for nutrients, metabolites, and environmental niches, as well as production of inhibitory or toxic compounds. Members of the Klebsiella oxytoca species complex (KoSC) provide CR against their more pathogenic counterparts through overlapping metabolic niches in the gut. KoSC strains can confer CR against MDR Klebsiella pneumoniae strains through competition for specific beta-glucosidic sugars. While these studies provided mechanistic insight in mouse models, carriage of specific strains of KoSC could also lower the risk for bacteraemia in cancer and haematopoietic cell transplantation patients as well as neonates. The contribution of KoSC strains to CR might be especially relevant when the prevalence and population densities of these bacteria are high. KoSC strains are prevalent colonizers in infants but maintain a relatively low abundance in homeostatic conditions. KoSC members may expand after antibiotic disruption of the microbiota due to the availability of additional metabolic niches. However, upon expansion, KoSC strains may also pose a threat to the host due to strain-specific sets of virulence factors. KoSC strains can produce enterotoxins, namely, tilimycin and tilivalline, while also contributing to colonization resistance (CR). The relationship between these seemingly contradictory roles is not well understood. The study shows that K. oxytoca provides CR against S. Typhimurium in different microbiota settings via distinct toxin-dependent and -independent mechanisms. The availability of simple carbohydrates links both mechanisms as toxicity predominates with high sugar availability, while microbial competition contributes when carbohydrates are scarce. These findings show that KoSC members can contribute via distinct mechanisms to CR against S. Typhimurium. The study also shows that the til PAI correlates with inhibition, and toxin production is essential for the inhibition. The contribution of toxin production is microbiota-dependent. The study shows that the availability of sugars is crucial for toxin production in vitro. The study also shows that the protective phenotype observed in vivo is due to toxin production. The study shows