Oleoylethanolamide regulates intestinal stem cell activity and villus size via PPARα signaling pathway

Abstract The size of intestinal villi plays a critical role in determining digestive and absorptive functions, directly affecting nutrient digestibility and feed efficiency. Therefore, elucidating the key mechanisms regulating villus development is of significant importance. This study compares intestinal development in Shaziling pigs and Yorkshire pigs, which exhibit distinct lipid metabolism characteristics, revealing significant enrichment of different fatty acid metabolic pathways and the peroxisome proliferator‐activated receptors (PPAR) signaling pathway. LC‐MS metabolomics analysis further explores the potential correlation between changes in fatty acid metabolism and PPARα expression, identifying glycerophospholipid metabolism and its key metabolite oleoylethanolamide (OEA) as critical factors. Pharmacological interventions and genetic mouse models manipulating PPARα signaling demonstrate that OEA regulates stem cell activity and intestinal villus size via PPARα, with this effect linked to energy metabolism driven by oxidative phosphorylation. Notably, dietary supplementation with OEA or palmitoylethanolamide—another endogenous PPARα ligand increases villus size and nutrient digestibility. These findings indicate that lipid metabolism contributes to the regulation of intestinal villus size and uncover a novel mechanism by which N‐acylethanolamines modulate intestinal morphological development through the PPARα‐oxidative phosphorylation axis. The results provide a theoretical basis for developing novel feed additives based on endogenous lipid signaling molecules.