The inhibition of enterocyte proliferation by lithocholic acid exacerbates necrotizing enterocolitis through downregulating the Wnt/β‐catenin signalling pathway

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 throughdownregulating the Wnt/β-catenin pathway. | INTRODUCTIONNecrotizing enterocolitis (NEC) is a catastrophic disease that predominantly occurs in preterm infants. Approximately 7% of infants with a birth weight between 500 and 1500 g develop NEC, with an overall mortality rate of 10%-50%. 1,2 According to our previous retrospective analysis from 2008 to 2017 in Guangdong province, the incidence of NEC in very preterm infants was 10.1%. 3 This disease can be mild to severe with clinical symptoms including abdominal distension, pneumatosis intestinalis, bowel Zhoushan Feng, Chunhong Jia and Xiaojun Li contributed to this work equally.

Necroptosis of macrophage is a key pathological feature in biliary atresia via GDCA/S1PR2/ZBP1/p-MLKL axis

“…Fox example, deoxycholic acid (DCA, 200 μM and beyond) exhibits a dose-dependent inhibitory effect to cell proliferation [ 61 ]. Similarly, lithocholic acid significantly inhibits cell proliferation in a dose-dependent manner (60–180 μM) [ 62 ]. Treatment with 10–100 μM chenodeoxycholic acid and DCA also lead to concentration-dependent deleterious effects on cell viability under starvation [ 63 ].…”

Succinate aggravates intestinal injury in mice with necrotizing enterocolitis

“…It has been widely reported in previous studies that changes in the intestinal flora are closely related to the development of NEC (He et al, 2021;Liu et al, 2022a;Samara et al, 2022). In exploring the pathological mechanism whereby the gut flora affects NEC, some investigators have proven that gut microbiota-derived metabolites, including short-chain fatty acids, DL-lactate, tauroursodeoxycholic acid, and other related metabolites, play important messenger roles in NEC progression or can contribute to its prediction (Li et al, 2019a;Feng et al, 2022;Huang et al, 2022). Then, we analyzed the relationship between gut luminal succinate and intestinal flora in samples from human neonates and mouse pups.…”

Lactobacillus johnsonii Attenuates Liver Steatosis and Bile Acid Dysregulation in Parenteral Nutrition-Fed Rats

“…For liver tissues, approximately 50 mg of lyophilized, homogenized tissue was weighed and grounded with methanol to precipitate protein. After vortexing and centrifuging at 4 • C, the supernatant was mixed with water and filtered before being analyzed [16]. A total of 38 bile acids were quantified in both liver and serum.…”