Role of Fatty Acid Oxidation in Crohn's Disease and Ulcerative Colitis: Metabolomics Analysis and Experimental Evidence.

The metabolic determinants that distinguish Crohn's disease (CD) from ulcerative colitis (UC) and their roles in driving immune dysregulation remain elusive. We aimed to identify systemic metabolic signatures of inflammatory bowel disease (IBD) and elucidate the mechanistic link between metabolite availability and regulatory T cell (Treg) homeostasis. We performed untargeted LC-MS-based metabolomics on plasma from patients with CD (n = 17), UC (n = 13), and healthy controls (n = 15). Pathway enrichment and topology analysis were used to identify perturbed biological processes. The functional role of identified metabolites was validated using primary murine naive CD4+ T cell differentiation assays, Seahorse XF metabolic flux analysis, and siRNA-mediated knockdown. The therapeutic relevance was assessed in a DSS-induced murine model of colitis. Metabolomic profiling identified 175 significant differential metabolites, revealing a profound systemic depletion of fatty acids and a specific deficit in the fatty acid oxidation (FAO) pathway in CD patients. Palmitic acid and butyrate emerged as robust diagnostic biomarkers (AUC = 0.877-0.975). In vitro, butyrate dose-dependently promoted iTreg differentiation by increasing the oxygen consumption rate and maximal respiratory capacity. This effect was dependent on carnitine palmitoyltransferase 1A (CPT1A), as pharmacological or genetic inhibition of CPT1A-mediated FAO abolished butyrate's pro-differentiation capacity. In vivo, the ability of butyrate to attenuate colitis and promote colonic iTreg accumulation was significantly reversed by the CPT1 inhibitor etomoxir. CPT1A-mediated fatty acid oxidation is a critical metabolic pivot through which butyrate signals to maintain immune tolerance. The systemic loss of FAO intermediates in CD patients directly contributes to impaired iTreg development, identifying the butyrate-CPT1A axis as a potential target for precision metabolic intervention.