Multi-omic host-microbe biomarkers predict future relapse in treatment-naive children with ulcerative colitis
Objective: Pediatric ulcerative colitis (UC) has an increasing global incidence and is often more severe than in adults. Current first-line treatments are effective in only half of the patients. We aimed to identify relapse-predictive multi-omic biomarkers in the other half, to enable earlier introduction of immunosuppressants.Design: Intestinal biopsies (ileum, ascending/descending colon, rectum) were collected at baseline during endoscopy of 56 pediatric patients, of which half experienced relapse within 6 months after initial treatment (5-ASA and corticosteroids). To predict this subset, we combined mucosal quantitative microbial profiling (qPCR-normalised 16S rRNA V3-V4 amplicons) with host epigenomics (MethylationEPIC arrays), transcriptomics (RNASeq) and genotypes (ImmunoArray), using machine learning (XgBoost). In vitro (epithelial cell-lines co-culture) and in vivo (IL10KO mice) experiments were carried out on differentiating bacteria.Results: Baseline bacterial diversity was lower in the future relapse group, which had fewer butyrate producers (Faecalibacterium and Roseburia) but more oral-associated genera (Veilonella and Fusobacterium). Veilonella parvula induced proinflammatory cytokines in epithelial cells and increased murine mKC and colon weight. Mucosal microbiota composition had the strongest association with future relapse in treatment-naive pediatric UC, followed by host epigenome and transcriptome. Weak, albeit significant, relapse-predictive signals in separated omics data were outperformed (AUC=0.77) by combining microbiome and epigenome features.Conclusions: We demonstrated that combinatory machine learning of host-microbe data, especially the microbiome and epigenome, offers promising prognostic potential in pediatric UC. Our translational findings further compounded that pro-inflammatory colonizers from the upper gastrointestinal tract can exploit the reduced bacterial diversity in the colon of relapsing children.