A consortium of 7 commensal bacteria accelerate the gut microbiota recovery to enhance ecological barrier against Vancomycin-Resistant Enterococci

Background: The gastrointestinal tract is a reservoir of opportunistic pathogens or pathobionts, which benefit from dysbiosis to proliferate in fragilised patients. Vancomycin-resistant Enterococcus (VRE) frequently originate from the gastrointestinal tract, where their proliferation precedes dissemination in the bloodstream, and may lead to systemic infection. Understanding the mechanisms responsible for resistance to intestinal colonisation by VRE is essential for infection control. We aimed to identify commensal bacteria to enhance resistance to colonisation or ecological barrier against VRE.Results: We performed a longitudinal analysis of the gut microbiota composition and VRE carriage levels during microbiota recovery in mice colonised with VRE after antibiotic-induced dysbiosis. By combining biological data and mathematical modelling, we identified 15 molecular species (OTUs) that correlate negatively with VRE carriage. Six strains representative of these OTUs have been collected and used in mixture with a seventh strain (Mix7) in two different mice lines challenged with VRE. Among the seven strains, three belonged to Lachnospiraceae, one to Muribaculaceae (Muribaculum intestinale YL27-DSM 28989), one to Ruminococcaceae and two to Lactobacillaceae. We found that Mix7 allows a reduction of VRE carriage and a better gut microbiota recovery. Differences in the effect of Mix7 between mice were observed with responder and non-responder mice. These differences were associated with variation in composition during recovery and initial microbiota, and constitute potential biomarkers for predicting response to Mix7. In a mouse model of alternative stable state of dysbiosis, response to Mix7 was associated with higher concentrations of short-chain fatty acids (acetate, propionate, butyrate) and a number of metabolites including bile acids, mirroring the recovery of the microbiota to a return to initial state. Furthermore, Muribaculum intestinale YL27 is required in vivo for Mix7 effect in the presence of at least one of the other six strains. None of the supernatant of the 7 strains, alone or in combination, inhibits VRE growth in vitro. Interestingly, 5 strains belong to species shared between human and mice, and the other two have human functional equivalents.Conclusions: We show that supplementation with a mixture of commensal bacterial strains identified through mathematical modelling improves the ecological barrier effect against VRE by mechanisms dependent on the recovery and initial composition of the microbiota. Ultimately, this work will allow to move towards a personalised medicine by targeting patients at risk and likely to respond to supplementation with commensal strains, providing new live biotherapeutic products and biomarkers for predicting response to supplementation.