Antibiotic-resistant bacteria are an increasing problem in hospitalized patients and commonly cause infections following broad-spectrum antibiotic administration. Among these, Vancomycin-resistant Enterococcus (VRE) is one of the most common causes of bloodstream infections. Commensal microbes that colonize mucosal surfaces provide defense against infection by physically occupying niches and competing for nutrients. In addition, commensal microbes also condition the intestinal mucosa to resist bacterial invasion by inducing expression of antimicrobial molecules. Clinical use of antibiotics profoundly alters the commensal flora by killing subsets of microbes that are normal intestinal inhabitants. The downstream effects of antibiotic-induced microbial depletion on mucosal innate immune defenses include decreased expression of RegIIIγ, a bactericidal C-type lectin that is secreted by intestinal epithelial cells. RegIIIγ kills VRE in the ileum of mice and decreased expression of RegIIIγ during antibiotic treatment increases susceptibility to VRE colonization (Figure 1). Our laboratory has demonstrated that oral administration of lipopolysaccharide (LPS), a ligand for TLR4, or systemic administration of flagellin, a ligand for TLR5, reverses antibiotic-induced down-regulation of RegIIIγ and enhances resistance to colonization with VRE (Figure 2).
To begin to define the commensal bacterial species that confer resistance to VRE colonization, we transplanted fecal microbiota from antibiotic-naïve mice to mice that had intestinal domination by VRE.
In order to begin to associate specific bacterial species with clearance of VRE from the gut, we reconstituted mice with fractionated fecal microbiota obtained from antibiotic-naïve mice and correlated microbiota composition, determined by next generation sequencing of 16S rRNA genes, with clearance of VRE. Figure 4 demonstrates that the presence of Barnesiella in the colon correlates with resistance to VRE colonization of the gut.
Ongoing studies in our laboratory are focusing on the development of bacterial consortia that provide high-level resistance to VRE, and to determine mechanisms of microbiota-mediated resistance to VRE colonization beyond the role of RegIIIγ.