Multi-omics–based machine learning model predicts response and guides treatment in Crohn disease: a case study in nutritional therapy

Background: Biomarkers are needed to predict treatment response and guide therapeutic decisions in Crohn disease (CD). We aimed to develop and validate a multi-omics machine learning (ML) model to predict response to nutritional therapy in pediatric CD. Methods: Treatment-naive children with newly diagnosed CD who were initiating exclusive enteral nutrition (EEN) were prospectively enrolled in this study. Metabolomics and lipidomics were measured in the serum and stool, as well as the fecal microbiome. Following feature selection via minimum redundancy maximum relevance, random-forest models were constructed for single- and multi-omics and performances were evaluated. The models were externally validated in an independent prospective cohort of treatment-naive children and young adults with CD treated with EEN. Results: The discovery cohort consisted of 50 children (mean ± SD age 14.3 ± 2.7 years), of whom 34 (68%) responded to EEN. Combining complementary signals from host metabolism, gut microbiota, and lipid profiles from serum and stool in a multi-omics ML model yielded a model for predicting treatment response (training accuracy 94%; 95% CI, 82%-100%). Key predictive features included serum metabolites (2-hydroxyglutaric acid, Cer[d18:0/22:0], and HexCer[d18:1/d26:1]), fecal metabolites (3-methyladipic acid, DG[16:0 20:0], PC aa C42:2), and microbial taxa (family Bifidobacteriaceae and genus CAG-56). The validation cohort consisted of 21 patients of whom 12 (57%) responded to EEN. The multi-omics model performance achieved an area under the receiver operating characteristic curve (AUROC) of 0.81 (95% CI, 0.6-1.0). Clinical and endoscopic features did not improve the predictive ability of the model. Conclusion: As a proof-of-concept, we showed that integrated multi-omics ML models can predict EEN response in pediatric CD patients, supporting their potential use in precision nutrition and personalized care strategies.