Integrated Metabolomics and Genome-Scale Metabolic Modeling Reveal Metabolic Rewiring in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation resulting from complex interactions among host genetics, immune dysregulation, environmental factors, and the gut microbiota. Although microbial dysbiosis has been consistently associated with IBD, the metabolic mechanisms linking microbial activity to host immune responses remain poorly understood. This study presents an integrative systems biology framework combining multiomics data and genome scale metabolic modeling (GEM) to investigate host-microbiome metabolic interactions underlying IBD pathogenesis.

Fecal and peripheral blood samples will be collected from patients with IBD, healthy controls, and dextran sulfate sodium (DSS) induced murine colitis models. Community level GEMs of the gut microbiota will be constructed. Plasma metabolomic profiling will quantify short chain fatty acids, bile acids, amino acid derivatives, and other microbiota derived metabolites. Peripheral blood mononuclear cell transcriptomes will be analyzed and in parallel, publicly available colonic epithelial and fibroblast transcriptomic datasets (GSE277964) will be integrated to generate cell type specific GEMs representing Crohn's disease, ulcerative colitis, and healthy tissues. Predicted microbial metabolite fluxes will subsequently be incorporated into host metabolic models to simulate metabolic cross talk between the gut microbiota and host cells.

This study establishes a comprehensive computational framework for integrating metagenomics, metabolomics, transcriptomics, and GEMs to investigate host-microbiome interactions in IBD. Beyond characterizing disease associated metabolic alterations, this approach provides a platform for mechanistic hypothesis generation and precision nutrition or microbiome-targeted therapeutic strategies. The resulting systems level models will offer a valuable resource for future translational studies and personalized metabolic interventions in inflammatory bowel disease.