Inflammatory bowel disease and metabolic reprogramming: From pathological mechanisms to targeted interventions

Abstract Inflammatory bowel disease (IBD) comprises Crohn's disease (CD) and ulcerative colitis and arises from the convergence of genetic susceptibility, environmental exposures, immune dysregulation, and gut microbiome perturbations. Metabolic reprogramming has emerged as a central feature of IBD pathogenesis. Immune and epithelial cells in IBD show coordinated disturbances in glycolysis, fatty‐acid metabolism, and oxidative phosphorylation, which shape macrophage and T‐cell polarization and weaken epithelial barrier integrity. Microbiota‐derived metabolites, including short‐chain fatty acids (SCFAs), bile acids, and tryptophan derivatives, act as key immunometabolic signals, with SCFAs promoting regulatory programs and barrier repair, whereas disordered bile‐acid pools and dysregulated receptor signaling can drive inflammation and disrupt the barrier. These insights motivate metabolic interventions that complement immunotherapy, including modulation of the microbiota, supplementation or engineered delivery of specific metabolites, and targeting of metabolic pathways (AMPK, mTOR) and receptors (FXR, TGR5, AhR). Early clinical studies indicate potential benefit in selected patient subsets, although effect sizes are variable, and translation remains limited by disease heterogeneity, context‐dependent metabolite effects, suboptimal delivery to inflamed segments, and the absence of predictive biomarkers. This review synthesizes recent advances in IBD immunometabolism, integrates evidence across cells, pathways, and microbial metabolites, and outlines actionable opportunities for development, including patient stratification, target‐engagement readouts, and rigorously designed trials with endpoints such as mucosal healing, corticosteroid‐free remission, and relapse reduction.