C. difficile may be overdiagnosed in adults and is a prevalent commensal in infants

Clostridioides difficile infection (CDI) is an urgent threat in nosocomial infections, yet its associated microbiome remains poorly characterised. Among 534 metagenomes from 10 public CDI study populations we detected C. difficile in only 30% of samples, yet other toxigenic species with CDI-like symptomatology were prevalent, indicating possible CDI overdiagnosis. Tracking C. difficile across 42,900 metagenomes from 253 public studies, we found that prevalence, abundance and biotic context were age-dependent. C. difficile is a rare taxon associated with reduced diversity in healthy adults, but common and associated with increased diversity in infants. We identified a group of species co-occurring with C. difficile exclusively in healthy infants, enriched in obligate anaerobes and in species typical of the healthy adult gut microbiome. Overall, C. difficile in healthy infants is associated with multiple indicators of healthy gut microbiome maturation, suggesting that C. difficile is an important commensal in infants and that its asymptomatic carriage in adults depends on microbial context. ### Competing Interest Statement The authors have declared no competing interest.