Abstract
Ulcerative colitis (UC) is associated with epithelial metabolic derangements which exacerbate gut inflammation. Here, we develop colon organoid (colonoid) lines from pediatric patients with endoscopically active UC, inactive UC, and those without intestinal inflammation to interrogate functional metabolic differences in the colon epithelia. We demonstrate that active UC colonoids exhibit hypermetabolic features and cellular stress, specifically during differentiation. Hypermetabolism in active UC colonoids is driven, in part, by increased proton leak, and excess lipid accumulation. Active UC colonoids exhibit heightened activation of the master lipid regulator PPAR-α and its transcriptional pathways. Pharmacological PPAR-α inhibition limits lipid accumulation, induces a metabolic shift towards glucose utilization, suppresses hypermetabolism, and reduces chemokine secretion and cellular stress markers. Collectively, our findings identify lipid-related metabolic dysfunction as a key pathologic feature of the pediatric UC epithelium and highlight the potential of patient-derived colonoids as a preclinical model for evaluating epithelial-targeted therapies addressing this dysfunction.