Enterococci enhance Clostridioides difficile Pathogenesis

Enteric pathogens are exposed to a dynamic polymicrobial environment in the gastrointestinal tract(1). This microbial community has been shown to be important during infection, but there are few examples illustrating how microbial interactions can influence virulence of invading pathogens(2). Here, we show that expansion of a group of antibiotic-resistant, opportunistic pathogens in the gut, the enterococci, enhances fitness and pathogenesis of C. difficile. Through a parallel process of nutrient restriction and cross-feeding, enterococci shape the metabolic environment in the gut and reprogram C. difficile metabolism. Enterococci provide fermentable amino acids, including leucine and ornithine, which increase C. difficile fitness in the antibiotic perturbed gut. Parallel depletion of arginine by enterococci through arginine catabolism provides a metabolic cue for C. difficile that facilitates increased virulence. Evidence of microbial interaction between these two pathogenic organisms is observed in multiple mouse models of infection and C. difficile-infected patients. These findings provide mechanistic insights into the role that pathogenic microbiota have in susceptibility to and severity of C. difficile infection.