Integrated Multi-Omics Reveals Complementary Luminal and Mucosal Host–Microbiome Interactions Associated with Disease Activity and Phenotype in Paediatric Inflammatory Bowel Disease

Inflammatory bowel diseases (IBD) arise from complex interactions among the immune system, intestinal microbiota, and host metabolism. However, how different intestinal compartments contribute to disease activity and phenotype in paediatric IBD remains incompletely understood. Children with Crohn’s disease (CD) and ulcerative colitis (UC) were stratified according to disease phenotype and inflammatory activity to distinguish disease-associated signatures from dynamic inflammatory processes. We performed an integrated multi-omics analysis combining luminal and mucosal bacterial and fungal metataxonomy, faecal metabolomics, and microbial- and host-derived biomarkers, including IgA, lysozyme, bile acids, and urinary indican. Luminal bacterial communities largely preserved their ecological structure, while disease activity was associated with coordinated taxonomic, metabolic, and interactional remodelling. These changes were accompanied by alterations in microbial metabolites and host biomarkers consistent with altered fermentation, proteolytic metabolism, and immune–metabolic coupling. In contrast, phenotype-associated ecological differences were more evident in the mucosal compartment, particularly within the fungal community, whereas mucosal bacterial changes were more limited. Together, these findings suggest that luminal and mucosal host–microbiome interactions provide complementary information on inflammatory activity and disease phenotype in paediatric IBD, highlighting the value of integrated multi-omic approaches to investigate compartment-specific host–microbiome interactions in paediatric IBD.