Metformin ameliorates maternal high-fat diet-induced maternal dysbiosis and fetal liver apoptosis

Szu-Wei Huang,Mao-Meng Tiao,You-Lin Tain,Jiunn-Ming Sheen,Ching-Chou Tsai,Hong-Ren Yu,Yu-Che Ou,Kuo-Shu Tang,Li-Tung Huang,I-Chun Lin,Chih-Yao Hou

doi:10.1186/s12944-021-01521-w

Abstract

BackgroundThe deleterious effect of maternal high-fat diet (HFD) on the fetal rat liver may cause later development of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the effect of maternal HFD-induced maternal hepatic steatosis and dysbiosis on the fetal liver and intestines, and the effect of prenatal metformin in a rat model.MethodsSprague–Dawley rats were assigned to three groups (N = 6 in each group). Before mating, the rats were randomly assigned to HFD or normal-chow diet (NCD) group for 7 weeks. After mating, the HFD group rats were continued with high-fat diet during pregnancy and some of the HFD group rats were co-treated with metformin (HFMf) via drinking water during pregnancy. All maternal rats and their fetuses were sacrificed on gestational day 21. The liver and intestinal tissues of both maternal and fetal rats were analyzed. In addition, microbial deoxyribonucleic acid extracted from the maternal fecal samples was analyzed.ResultsHFD resulted in maternal weight gain during pregnancy, intrahepatic lipid accumulation, and change in the serum short-chain fatty acid profile, intestinal tight junctions, and dysbiosis in maternal rats. The effect of HFD on maternal rats was alleviated by prenatal metformin, which also ameliorated inflammation and apoptosis in the fetal liver and intestines.ConclusionsThis study demonstrated the beneficial effects of prenatal metformin on maternal liver steatosis, focusing on the gut-liver axis. In addition, the present study indicates that prenatal metformin could ameliorate maternal HFD-induced inflammation and apoptosis in the fetal liver and intestines. This beneficial effect of in-utero exposure of metformin on fetal liver and intestines has not been reported. This study supports the use of prenatal metformin for pregnant obese women.

Highlights

The deleterious effect of maternal high-fat diet (HFD) on the fetal rat liver may cause later development of non-alcoholic fatty liver disease (NAFLD)
Weights of maternal and fetal rats, and biochemical variables of maternal rats The maternal body weight increased in the HFD group, and treatment of the HFD group with metformin (HFMf treatment) significantly reversed this effect
Western blotting of inflammation and apoptosis analysis of the fetal liver According to our previous studies, excessive fat accumulation in the liver triggers liver cell inflammation and Discussion The results of this study indicate that prenatal metformin could alleviate HFD-induced obesity and liver steatosis in maternal rats and reverse the adverse effect of maternal HFD on the fetal liver and intestine

Summary

Introduction

The deleterious effect of maternal high-fat diet (HFD) on the fetal rat liver may cause later development of non-alcoholic fatty liver disease (NAFLD). Maternal obesity will increase the incidence of gestational diabetes and preeclampsia and the risk of neonatal complications such as large-for-gestational-age and admission to the neonatal intensive care unit [1]. Prenatal metformin has been used in pregnant women with type 2 diabetes or gestational diabetes for a long time to improve maternal-fetal obstetric outcomes, and the incidence of fetal anomalies does not increase under inutero exposure of metformin. A randomized-controlled trial and a meta-analysis suggested that the administration of prenatal metformin to obese pregnant women without diabetes mellitus reduces the risk of preeclampsia, maternal weight gain during pregnancy, and the incidence of admission to the neonatal intensive care unit [6, 7]. The GRoW trial reported no significant improvement in maternalfetal outcomes [8]

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