Klebsiella oxytoca causes colonization resistance against multidrug-resistant K. pneumoniae in the gut via cooperative carbohydrate competition

Gut colonization with multidrug-resistant (MDR) bacteria enhances the risk of bloodstream infections in susceptible individuals. We demonstrate highly variable degrees of ex vivo colonization resistance against a carbapenem-resistant Klebsiella pneumoniae strain in human feces samples and subsequently isolate diverse K. oxytoca strains from protected donors. Several of these K. oxytoca strains reduce gut colonization of MDR K. pneumoniae strains in antibiotic-treated and gnotobiotic mouse models. Comparative analysis of K. oxytoca strains coupled with CRISPR-Cas9-mediated deletion of casA, a protein essential for utilization of selected beta-glucosides, identified competition for specific carbohydrates as key in promoting colonization resistance. In addition to direct competition between K. oxytoca and K. pneumoniae, cooperation with additional commensals is required to reestablish full colonization resistance and gut decolonization. Finally, humanized microbiota mice generated from K. pneumoniae-susceptible donors are protected by K. oxytoca administration, demonstrating the potential of commensal K. oxytoca strains as next-generation probiotics. [Display omitted] •Ex vivo colonization resistance against K. pneumoniae is variable between individuals•Diverse commensal Klebsiella oxytoca strains are isolated from protected individuals•K. oxytoca establishes colonization resistance against of K. pneumoniae in vivo•Cooperation with commensal bacteria restricts nutrient availability in the gut Gut colonization with multidrug-resistant enterobacteria increases risk of bloodstream infections. Osbelt et al. characterize the ability of human stools to inhibit growth of multidrug-resistant Klebsiella pneumoniae. Commensal Klebsiella oxytoca strains were identified in protected human donors, which in cooperation with other commensals outcompete K. pneumoniae through beta-glucoside utilization in mice.