Antibiotics promote intestinal growth of carbapenem-resistantEnterobacteriaceaeby enriching nutrients and depleting microbial metabolites

Abstract

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.

Role of the gut microbiota in nutrient competition and protection against intestinal pathogen colonization

“…Broad-spectrum antibiotics cause significant decreases in the abundance and diversity of a wide range of gut commensals, thus reducing competition for nutrients [6,78]. These nutrient-defined intestinal niches can then be exploited by pathogens, such as C. difficile, CRE and S. Typhimurium [37,38,57,79,80].…”

“…It is also important to consider that there may be differences in the preferences that bacteria have for particular available nutrients, which will impact the development of microbiome therapeutics. Different species of Enterobacteriaceae have different nutrient utilization profiles in aerobic and anaerobic environments and also have a different order of nutrient preference [79, 128]. These results suggest that microbiome therapeutics should include multiple gut commensals that are able to outcompete pathogens for all available nutrients that could support pathogen growth to fully occupy all available nutrient niches in the gut and effectively restore colonization resistance.…”

“…According to the nutrient niche theory, Enterobacteriaceae growth is limited in the healthy gut microbiota due to competition for nutrient sources with other gut commensals. Enterobacteriaceae can also be suppressed by production of SCFA and other metabolites produced by gut commensals [39, 79, 82]. However, antibiotics disrupt colonization resistance and allow for the expansion of pathogens () [83].…”

“…Restoring colonization resistance (or preventing the initial loss of colonization resistance) is vital to restrict the growth of MDR pathogens in the intestine following antibiotic treatment [ 86 ]. We recently demonstrated that broad-spectrum antibiotics (which promote intestinal colonization by CRE) altered the nutrient landscape in the gut by increasing the availability of various monosaccharides, disaccharides and amino acids [ 79 ]. These enriched nutrients were used as carbon and nitrogen sources to support CRE growth both in vitro and in vivo .…”