Lithocholic acid attenuates intestinal mucosal epithelial inflammation and apoptosis associated with bile deficiency through the VDR/IAP axis

Intestinal epithelial barrier dysfunction is a pathological state that can be caused by bile deficiency. Lithocholic acid (LCA) is a component of bile, which participates in the enterohepatic circulation of bile acids and plays important roles in the digestion of food. Our previous researches have found intestinal alkaline phosphatase (IAP), a positive factor maintaining intestinal homeostasis, expression is reduced in bile-deficient mucosa, and LCA maintains intestinal mucosal epithelial tight junctions by activating vitamin D receptor (VDR). However, there is no evidence whether IAP is involved in VDR-mediated intestinal epithelial protection with LCA. In this study, we further investigated the role of LCA in maintaining the intestinal mucosal epithelial barrier. We achieved complete absence of bile in intestine by using C57BL/6J mice model of common bile duct ligation and external bile drainage. Serum and intestinal mucosal tissue were used to assess the effects of LCA on inflammation, apoptosis, intestinal epithelial integrity, and VDR/IAP. In vitro, Lipopolysaccharide (LPS) was used to intervene Caco-2 cells to imitate intestinal epithelial barrier dysfunction as in bile deficiency. Next, the role of the IAP/VDR in the biological efficacy of the LCA was evaluated by immunoblot, qRT-PCR, ELISA, and immunofluorescence. Furthermore, we assessed the effect of VDR on IAP through chromatin immunoprecipitation and dual-luciferase reporter trial. External bile drainage could not alleviate the damage to the intestinal mucosal epithelial barrier caused by biliary obstruction. Supplement of LCA alleviated the impaired intestinal epithelial barrier in mice, and the restoration of VDR/IAP was involved. In vitro, LCA attenuated LPS-induced inflammation and apoptosis through the synergy of VDR and IAP. Mechanistically, LCA facilitated the translocation of activated-VDR into the nucleus to bind to the promoter of the IAP gene. This led to enhanced transcription of IAP and inactivation of the downstream MAPK pathway. Our findings suggest that LCA exerts anti-inflammatory and anti-apoptotic effects via the VDR/IAP/MAPK axis, thereby ameliorating bile deficiency-associated intestinal mucosal epithelial barrier disruption. These findings highlight the important physiological role of LCA in the intestinal environment, indicating its therapeutic potential in LPS detoxification and protection of the intestinal mucosal barrier.