Understanding the role of gut microbiota in protecting the host against intestinal colonisation by vancomycin-resistant enterococci
File(s)
Author(s)
King, Olivia
Type
Thesis
Abstract
The gut is the primary reservoir for vancomycin-resistant Enterococcus (VRE), a multidrug-resistant pathogen which can cause severe infections, including endocarditis, bloodstream, intra-abdominal, and urinary tract infections. Broad-spectrum antibiotics kill members of the gut microbiota essential for maintaining colonisation resistance against VRE in the intestine. It was hypothesised that antibiotics disrupt microbiota-mediated colonisation resistance which can be restored through the reintroduction of key members of the gut microbiota to reestablish nutrient competition and/or metabolite inhibition against VRE. This study aimed to identify how antibiotic treatment impacted microbiota diversity and density, nutrient and microbial metabolite availability, and VRE colonisation. Faecal cultures were used to test the effects of antibiotic treatment and VRE intestinal colonisation on changes in microbiota taxa (16S rRNA gene sequencing), nutrients and microbial metabolites (1H-NMR spectroscopy). Faecal microbiota treated with broad-spectrum antibiotics which promote VRE colonisation caused a reduction in the abundance of the Bacteroidaceae, Bifidobacteriaceae, and Coriobacteriaceae families. These antibiotics caused an increase in nutrient availability and a decrease in the production of microbial metabolites. This study showed that nutrients elevated following antibiotic treatment supported high levels of VRE growth. These findings were supported by longitudinal culturing of faecal microbiota using an artificial gut model, which showed persistent growth of vancomycin-resistant E. faecium in vancomycin-treated faecal cultures. Administration of faecal microbiota transplants to antibiotic-treated faecal cultures reestablished colonisation resistance and restricted vancomycin-resistant E. faecium growth. A commensal consortium designed to deplete nutrients utilised by VRE was able to successfully restrict VRE growth in both in vitro cultures and in vivo mouse model of intestinal colonisation. These findings demonstrate that antibiotic-mediated killing of gut commensals promoted VRE intestinal colonisation by increasing the availability of nutrients that support VRE growth, and that this can be reversed by reintroducing key commensals to the microbiota that compete with VRE to use nutrients.
Version
Open Access
Date Issued
2024-01-08
Date Awarded
2024-05-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
McDonald, Julie
Publisher Department
Department of Infectious Disease
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)