Commensal-pathogen dynamics structure disease outcomes during Clostridioides difficile colonization

Gastrointestinal colonization by Clostridioides difficile is common in healthcare settings and ranges in presentation from asymptomatic carriage to lethal C. difficile infection (CDI). We used a systems biology approach to investigate why patients colonized with C. difficile have a range of clinical outcomes. Microbiota humanization of germ-free mice with fecal samples from toxigenic C. difficile carriers revealed a spectrum of virulence among clinically prevalent clade 1 lineages and identified candidate taxa, including Blautia, as markers of stable colonization. Using gnotobiotic mice engrafted with defined human microbiota, we validated strain-specific CDI severity across clade 1 strains isolated from patients. Mice engrafted with a community broadly representative of colonized patients were protected from severe disease across all strains without suppression of C. difficile colonization. These results underline the capacity of gut community structure to attenuate a diversity of pathogenic strains without inhibiting colonization, providing insight into determinants of stable C. difficile carriage.