Roles of gut microbiota-mediated nutrient competition and metabolite inhibition in the intestinal colonisation of CRE.
The intestine is the primary colonisation site for carbapenem-resistant Enterobacteriaceae (CRE) and serves as a reservoir of CRE that cause invasive infections (e.g. bloodstream infections). Antibiotics disrupt colonisation resistance mediated by the gut microbiota, promoting the expansion of CRE within the intestine. We used ex vivo faecal cultures to measure the impact of antibiotics (that promote CRE intestinal colonisation) on the faecal microbiota from healthy human donors. We demonstrated that antibiotics decreased the abundance of gut commensals (including Bifidobacteriaceae and Bacteroidales) in human faecal microbiota, resulting in an enrichment of nutrients and a depletion of microbial metabolites. The nutrient utilisation abilities, nutrient preferences, and metabolite inhibition susceptibilities of carbapenem-resistant Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae strains were measured. Nutrients (which were elevated with antibiotics) acted as carbon and nitrogen sources to support CRE growth, where CRE showed an ordered preference for specific nutrients. These nutrients were also increased in faeces from antibiotic-treated mice but decreased following intestinal colonisation with carbapenem-resistant E. coli. Microbial metabolites (which decreased with antibiotics) were inhibitory towards CRE growth in vitro. Carbapenem-resistant E. coli growth was decreased in faecal samples from mice treated with a mixture of inhibitory metabolites compared with PBS-treated mice. These findings demonstrate that killing gut commensals with antibiotics disrupts colonisation resistance by enriching nutrients that support CRE growth and depleting metabolites that inhibit CRE growth. These results support the development of new microbiome therapeutics to prevent CRE intestinal colonisation, which would also prevent the subsequent development of invasive CRE infections.