Gut decolonization of multidrug-resistant Escherichia coli clinical isolates via cooperative niche exclusion

Human gut colonization with multi-drug resistant Enterobacteriaceae (MDR-E) is a risk factor for subsequent infection. Due to the collateral damage of antibiotics on the microbiota, microbiome-based interventions to promote decolonization have received high interest. Here, we assessed the strain-specific potential of 430 commensal Escherichia coli isolates to inhibit the growth of a MDR E. coli strain. The comparative analyses in-vitro, ex-vivo, and mouse models revealed that only a subset of commensal strains could promote gut decolonization. Bioinformatic and experimental analysis of the antagonism for representative strains demonstrated the contribution of direct and indirect carbohydrate competition to niche exclusion between E. coli strains. Lastly, the combination of a protective E. coli strain with a Klebsiella oxytoca strain expanded the gut decolonization potential to metabolically diverse MDR E. coli strains and additional MDR-E species demonstrating that rational metabolically complementary design is crucial to developing next-generation probiotics with broad-spectrum activity.