In vivo commensal control of Clostridioides difficile virulence

Summary We define multiple mechanisms by which commensals protect against or worsen Clostridioides difficile infection. Leveraging new systems-level models we show how metabolically distinct species of Clostridia modulate the pathogen’s colonization, growth, and virulence to impact host survival. Gnotobiotic mice colonized with the amino acid fermenter Paraclostridium bifermentans survived infection while mice colonized with the butyrate- producer, Clostridium sardiniense, more rapidly succumbed. Systematic in vivo analyses revealed how each commensal altered the gut nutrient environment, modulating the pathogen’s metabolism, regulatory networks, and toxin production. Oral administration of P. bifermentans rescued conventional mice from lethal C. difficile infection via mechanisms identified in specifically colonized mice. Our findings lay the foundation for mechanistically informed therapies to counter C. difficile infections using systems biologic approaches to define host-commensal-pathogen interactions in vivo .