Microbiome-mediated fructose depletion restricts murine gut colonization by vancomycin-resistant Enterococcus

Abstract

Multidrug-resistant organisms (MDRO) are a major threat to public health. MDRO infections, including those caused by vancomycin-resistant Enterococcus (VRE), frequently begin by colonization of the intestinal tract, a crucial step that is impaired by the intestinal microbiota. However, the specific members of the microbiota that suppress MDRO colonization and the mechanisms of such protection are largely unknown. Here, using metagenomics and mouse models that mimic the patients’ exposure to antibiotics, we identified commensal bacteria associated with protection against VRE colonization. We further found a consortium of five strains that was sufficient to restrict VRE gut colonization in antibiotic treated mice. Transcriptomics in combination with targeted metabolomics and in vivo assays indicated that the bacterial consortium inhibits VRE growth through nutrient depletion, specifically by reducing the levels of fructose, a carbohydrate that boosts VRE growth in vivo. Finally, in vivo RNA-seq analysis of each strain of the consortium in combination with ex vivo and in vivo assays demonstrated that a single bacterium (Olsenella sp.) could recapitulate the effect of the consortium. Our results indicate that nutrient depletion by specific commensals can reduce VRE intestinal colonization, which represents a novel non-antibiotic based strategy to prevent infections caused by this multidrug-resistant organism.

Promiscuous, persistent and problematic: insights into current enterococcal genomics to guide therapeutic strategy

“…An underrepresentation of carbohydrate utilising genes in the microbiota of participants favoured colonisation, whereas establishment was prevented through competitive exclusion by phylogenetically related resident microbes, suggesting colonisation was determined by niche and resource availability [ 239 ]. Interestingly, these findings align with competitive exclusion of VRE mentioned previously [ 226 ]. These findings suggest WGS could be a tool for predicting engraftment of probiotics based on the carrier state of the subject's microbiota and if a functional niche is vacant.…”

“…A recent study uncovered that fructose depletion restricts VRE colonisation using a commensal bacterial consortium [ 226 ]. Subsequent downstream analysis using RNA-seq identified an Olsenella sp.…”

“…Subsequent downstream analysis using RNA-seq identified an Olsenella sp. that could reproduce the effect of the consortium and protect from vancomycin induced susceptibility to VRE in a mouse model [ 226 ]. Olsenella treated mice saw a 2-log reduction in VRE from CFU counts of faeces [ 226 ].…”

“…that could reproduce the effect of the consortium and protect from vancomycin induced susceptibility to VRE in a mouse model [ 226 ]. Olsenella treated mice saw a 2-log reduction in VRE from CFU counts of faeces [ 226 ]. Identifying anti-pathogenic microbes in a microbiota through 16s rRNA sequencing with a computational workflow is an emerging field of study but has yet to be applied at WGS resolution [ 227 ].…”

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

“…One approach is to identify gut commensals that negatively correlate with pathogen growth. Isaac et al treated mice with antibiotics with different spectra of activity and measured the amount of VRE in faecal samples [113]. Spearman correlation analysis was used to identify specific bacterial taxa that negatively correlated with VRE colonization.…”