Abstract
Human gut colonization by multi-drug resistant Enterobacterales (MDR-E) poses a risk for subsequent infections. Because of the collateral damage antibiotics cause to the microbiota, microbiome-based interventions aimed at promoting decolonization have garnered interest. In this study, we evaluate the strain-specific potential of 430 commensal Escherichia coli isolates to inhibit the growth of an MDR E. coli strain. Comparative analyses using in vitro, ex vivo, and mouse models reveal that only a subset of commensal strains can facilitate gut decolonization. Bioinformatic and experimental analyses of the antagonism among representative strains demonstrate that both direct and indirect carbohydrate competition contribute to niche exclusion between E. coli strains. Finally, the combination of a protective E. coli strain with a Klebsiella oxytoca strain enhances the inhibitory potential against metabolically diverse MDR E. coli strains and additional MDR-E species, highlighting that rationally designed metabolically complementary approaches can contribute to developing next-generation probiotics with broad-spectrum activity.