In vivocommensal control ofClostridioides difficilevirulence

SummaryWe define multiple mechanisms by which commensals protect against or worsenClostridioides difficileinfection. Leveraging new systems-level models we show how metabolically distinct species ofClostridiamodulate the pathogen’s colonization, growth, and virulence to impact host survival. Gnotobiotic mice colonized with the amino acid fermenterParaclostridium bifermentanssurvived infection while mice colonized with the butyrate- producer,Clostridium sardiniense,more rapidly succumbed. Systematicin vivoanalyses revealed how each commensal altered the gut nutrient environment, modulating the pathogen’s metabolism, regulatory networks, and toxin production. Oral administration ofP. bifermentansrescued conventional mice from lethalC. difficileinfection via mechanisms identified in specifically colonized mice. Our findings lay the foundation for mechanistically informed therapies to counterC. difficileinfections using systems biologic approaches to define host-commensal-pathogen interactionsin vivo.Graphical Abstract