Precision microbiome restoration of bile acid-mediated resistance to Clostridium difficile

Abstract

The gastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute to health, including colonization resistance against intestinal pathogens ¹ . Many antibiotics destroy intestinal microbial communities and increase susceptibility to intestinal pathogens ² . Among these, Clostridium difficile, a major cause of antibiotic-induced diarrhea, greatly increases morbidity and mortality in hospitalized patients ³ . Which intestinal bacteria provide resistance to C. difficile infection and their in vivo inhibitory mechanisms remain unclear. 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. Mathematical modeling augmented by microbiota analyses of hospitalized patients identified resistance-associated bacteria common to mice and humans. Using these platforms, we determined that Clostridium scindens, a bile acid 7-dehydroxylating intestinal bacterium, is associated with resistance to C. difficile infection and, upon administration, enhances resistance to infection in a secondary bile acid-dependent fashion. Using a workflow involving mouse models, clinical studies, metagenomic analyses and mathematical modeling, we identified a probiotic candidate that corrects a clinically relevant microbiome deficiency. These findings have implications for rational design of targeted antimicrobials as well as microbiome-based diagnostics and therapeutics for individuals at risk for C. difficile infection.