Multi-omic analysis of Clostridioides difficile infection and response to therapy in pediatric inflammatory bowel disease

Clostridioides difficile infection (CDI) is often severe in vulnerable populations such as children with inflammatory bowel disease (IBD). Here we used a multi-omic approach to analyze determinants of disease vulnerability and severity in pediatric subjects with IBD+CDI and IBD alone, and also subjects with malignancy+CDI and healthy controls. We compared C. difficile genotype assessed from 27 high-quality genome sequences; gut microbiome structure interrogated by longitudinal metagenomic analysis; and the joint host/microbial metabolome interrogated by longitudinal mass spectrometry. The metabolomic data showed the most consistent association with IBD+CDI severity. Molecules enriched in IBD+CDI included polyamines, taurine, primary bile acids, and human DNA. Candidate mechanisms accounting for differences include altered metabolism by the dysbiotic microbiota, induction of inflammation, and host tissue breakdown. Following antibiotic therapy, a reduction in human DNA and other host-derived compounds reported successful short-term therapy, but a lack of long-term normalization of the metabolome and microbiome documented ongoing vulnerability.