Eric Pamer

– Abstract –

Microbiota-mediated defense against intestinal infection

Infections caused by antibiotic-resistant bacteria generally begin with colonization of mucosal surfaces, in particular the intestinal epithelium. The intestinal microbiota provides resistance to infection with highly antibiotic-resistant bacteria, including Vancomycin Resistant Enterococcus (VRE), Klebsiella pneumoniae and Clostridium difficile, the major cause of hospitalization-associated diarrhea. Metagenomic sequencing of the murine and human microbiota following treatment with different antibiotics is beginning to identify bacterial taxa that are associated with resistance to VRE and C. difficile infection.  We demonstrate that reintroduction of a diverse intestinal microbiota to densely VRE colonized mice eliminates VRE from the intestinal tract.  While oxygen-tolerant members of the microbiota are ineffective at eliminating VRE, administration of obligate anaerobic commensal bacteria to mice results in a billion-fold reduction in the density of intestinal VRE colonization.  Recent studies have identified specific bacterial species, including Blautia producta and Clostridium bolteae that prevent intestinal colonization with VRE. By treating mice with different antibiotics that result in distinct microbiota changes and lead to varied susceptibility to C. difficile, we correlated loss of specific bacterial taxa with development of infection. Using a workflow involving mouse models, clinical studies, metagenomic analyses and mathematical modeling, we have identified a probiotic candidate that corrects a clinically relevant microbiome deficiency.  Our studies indicate that obligate anaerobic bacteria enable clearance of intestinal VRE colonization and may provide novel approaches to prevent the spread of highly antibiotic-resistant bacteria.