Microbiota-mediated defense against antibiotic-resistant infections
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 faecium (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. 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 identified a probiotic candidate that corrects the microbiome deficiency responsible for susceptibility to C. difficile infection. Using a similar strategy, we demonstrated that oxygen-tolerant members of the microbiota are ineffective at eliminating VRE while administration of obligate anaerobic commensal bacteria to mice results in a billion-fold reduction in the density of intestinal VRE colonization. We have identified specific bacterial species, including Blautia producta and Clostridium bolteae, which prevent intestinal colonization with VRE and lead to its clearance from the gut. Our studies indicate that obligate anaerobic bacteria that can be retrieved from the commensal microbiota enable clearance of intestinal VRE colonization and provide resistance to C. difficile infection. These bacterial species may provide novel approaches to prevent the spread of highly antibiotic-resistant bacteria.
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