Abstract
Vancomycin-resistant Enterococcus faecium (VREfm) is an emerging antibiotic-resistant pathogen. Strain-level investigations are beginning to reveal the molecular mechanisms used by VREfm to colonize regions of the human bowel. However, the role of commensal bacteria during VREfm colonization, in particular following antibiotic treatment, remains largely unknown. We employed amplicon 16S rRNA gene sequencing and metabolomics in a murine model system to try and investigate functional roles of the gut microbiome during VREfm colonization. First-order taxonomic shifts between Bacteroidetes and Tenericutes within the gut microbial community composition were detected both in response to pretreatment using ceftriaxone and to subsequent VREfm challenge. Using neural networking approaches to find cooccurrence profiles of bacteria and metabolites, we detected key metabolome features associated with butyric acid during and after VREfm colonization. These metabolite features were associated with Bacteroides, indicative of a transition toward a preantibiotic naive microbiome. This study shows the impacts of antibiotics on the gut ecosystem and the progression of the microbiome in response to colonization with VREfm. Our results offer insights toward identifying potential nonantibiotic alternatives to eliminate VREfm through metabolic reengineering to preferentially select for Bacteroides IMPORTANCE This study demonstrates the importance and power of linking bacterial composition profiling with metabolomics to find the interactions between commensal gut bacteria and a specific pathogen. Knowledge from this research will inform gut microbiome engineering strategies, with the aim of translating observations from animal models to human-relevant therapeutic applications.
Highlights
Vancomycin-resistant Enterococcus faecium (VREfm) is an emerging antibiotic-resistant pathogen
Males) were monitored and fecal samples were collected over a 14-day period with two intervention time points including (i) ceftriaxone treatment administered at 0.5g/liter in drinking water across a 2-day period, and (ii) colonization with 1 ϫ 106 VREfm ST796 per mouse postantibiotic treatment at a single time point
In this study of the murine gut ecosystem, we employed a mouse model of gastrointestinal tract colonization that replicates the shift in bacterial composition when patients enter the health care system, develop an imbalance in their microbiome as a result of pretreatment, and are subsequently colonized with a hospital superbug [14]
Summary
Vancomycin-resistant Enterococcus faecium (VREfm) is an emerging antibiotic-resistant pathogen. B. producta—a colonizer of the colon—reduces VREfm growth in vivo by secreting a lantibiotic [6] These observations raise the intriguing possibility that metabolic traits act in concert between pathogen and select gut commensals to confer mutual benefits during pathogen persistence. These findings highlight the greater risk posed to immunocompromised patients when colonized with VREfm. For instance, allogeneic hematopoietic cell transplantation patients have gastrointestinal tracts that are dominated by VREfm as a result of losing a large portion of the intestinal commensal microbiota upon receiving broad-spectrum antibiotics as pretreatment [7]. This research provides support for engineering the metabolic potential of the gut microbiome using, for example, prebiotics as a nonantibiotic alternative for treating multidrug-resistant bacterial infections
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