The inhibition of enterocyte proliferation by lithocholic acid exacerbates necrotizing enterocolitis through downregulating the Wnt/β‐catenin signalling pathway
Zhoushan Feng, Chunhong Jia, Xiaojun Lin, Hao Hu, Sitao Li, Fei Li, Qiliang Cui, Yaoyong Chen, Fan Wu, Xin Xiao
Abstract
OBJECTIVES: Necrotizing enterocolitis (NEC) is a catastrophic gastrointestinal emergency in preterm infants, whose exact aetiology remains unknown. The role of lithocholic acid (LCA), a key component of secondary bile acids (BAs), in NEC is unclear. METHODS: Clinical data were collected to analyse the changes of BAs in NEC patients. In vitro studies, the cell proliferation and cell death were assessed. In vivo experiments, the newborn rats were administered with low or high dose of LCA and further induced NEC. RESULTS: Clinically, compared with control group, total BAs in the NEC patients were significantly higher when NEC occurred. In vitro, LCA treatment significantly inhibited the cell proliferation through arresting cell cycle at G1/S phase without inducing apoptosis or necroptosis. Mechanistically, the Wnt/β-catenin pathway was involved. In vivo, LCA inhibited intestinal cell proliferation leading to disruption of intestinal barrier, and thereby increased the severity of NEC. Specifically, LCA supplementation caused higher levels of FITC-labelled dextran in serum, reduced PCNA expression and inhibited the activity of Wnt/β-catenin pathway in enterocytes. The LC-MS/MS test found that LCA was significantly higher in intestinal tissue of NEC group, and more obviously in the NEC-L and NEC-H group compared with the DM group. CONCLUSION: LCA exacerbates NEC by inhibiting intestinal cell proliferation through downregulating the Wnt/β-catenin pathway.