Open AccessThe inhibition of enterocyte proliferation by lithocholic acid exacerbates necrotizing enterocolitis through downregulating the Wnt/β‐catenin signalling pathway
Author(s) -
Feng Zhoushan,
Jia Chunhong,
Lin Xiaojun,
Hao Hu,
Li Sitao,
Li Fei,
Cui Qiliang,
Chen Yaoyong,
Wu Fan,
Xiao Xin
Publication year - 2022
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/cpr.13228
Subject(s) - lithocholic acid , necrotizing enterocolitis , wnt signaling pathway , apoptosis , cell growth , necroptosis , in vivo , cell cycle , proliferating cell nuclear antigen , biology , cell , programmed cell death , bile acid , cancer research , medicine , signal transduction , endocrinology , biochemistry , microbiology and biotechnology
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.