Commensal-pathogen dynamics structure disease outcomes duringClostridioides difficilecolonization

Abstract

AbstractGastrointestinal colonization byClostridioides difficileis common in healthcare settings and ranges in clinical presentation from asymptomatic carriage to lethalC. difficileinfection (CDI). We used a systems biology approach to investigate why patients colonized withC. difficilehave a range of outcomes. Microbiota-humanization of germ-free mice with fecal samples from toxigenic C. difficile carriers revealed a spectrum of virulence among clade 1 lineages and identified commensalBlautiaassociated with markers of non-pathogenic colonization. Using gnotobiotic mice engrafted with defined human microbiota, we observed strain-specific CDI severity across clade 1 strains. Yet, mice engrafted with a higher diversity community were protected from severe disease across all strains without suppression ofC. difficilecolonization. These results indicate that when colonization resistance has been breached without overt infection, commensals can attenuate a diversity of virulent strains without inhibiting pathogen colonization, providing insight into determinants of stableC. difficilecarriage.