Vitamin D 3 Metabolite-Enhanced Hepatic VDR-FXR Binding Attenuates Bile Acid Dysregulation-Induced Diarrhea in Weaned Piglets

Hepatic bile acid (BA) dysregulation contributes to diarrhea in weaned piglets. Although farnesoid X receptor (FXR) is a key therapeutic target, its agonist chenodeoxycholic acid (CDCA) may exacerbate intestinal injury, underscoring the need for safer FXR-targeting strategies. In this study, BA metabolomics identified ileal accumulation of 7-ketoLCA in naturally diarrheic piglets. Mouse oral gavage confirmed the pathogenicity of 7-ketoLCA. Using AlphaFold3 and Co-IP assays, we uncover a novel interaction between FXR and vitamin D receptor (VDR) in porcine liver and TNF-α-stimulated hepatocytes. Dietary vitamin D₃ metabolites alleviate diarrhea, reduce ileal 7-ketoLCA, and enhance intestinal barrier integrity in diarrheic piglets. These effects occur through enhanced VDR-FXR binding, which potentiates FXR transactivity. This interaction downregulates BA synthesis genes CYP7A1/CYP8B1 while upregulating export transporters BSEP/MRP2, ultimately restoring BA homeostasis and attenuating inflammatory injury. These findings reveal a VDR-FXR-mediated regulatory mechanism and support vitamin D₃ metabolites as a safe nutritional intervention for piglet diarrhea.