Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations.

Umesh D Wankhade,Keshari M Thakali,Ping Kang,Ying Zhong,Kartik Shankar,Maria Alfaro,Sree V Chintapalli,Nick Ashton

doi:10.1371/journal.pone.0175675

Abstract

ObjectiveNon-alcoholic fatty liver disease (NAFLD) is an important co-morbidity associated with obesity and a precursor to steatohepatitis. However, the contributions of gestational and early life influences on development of NAFLD and NASH remain poorly appreciated.MethodsTwo independent studies were performed to examine whether maternal over-nutrition via exposure to high fat diet (HFD) leads to exacerbated hepatic responses to post-natal HFD and methionine choline deficient (MCD) diets in the offspring. Offspring of both control diet- and HFD-fed dams were weaned onto control and HFD, creating four groups.ResultsWhen compared to their control diet-fed littermates, offspring of HF-dams weaned onto HFD gained greater body weight; had increased relative liver weight and showed hepatic steatosis and inflammation. Similarly, this group revealed significantly greater immune response and pro-fibrogenic gene expression via RNA-seq. In parallel, 7–8 week old offspring were challenged with either control or MCD diets for 3 weeks. Responses to MCD diets were also exacerbated due to maternal HFD as seen by gene expression of classical pro-fibrogenic genes. Quantitative genome-scale DNA methylation analysis of over 1 million CpGs showed persistent epigenetic changes in key genes in tissue development and metabolism (Fgf21, Ppargc1β) with maternal HFD and in cell adhesion and communication (VWF, Ephb2) in the combination of maternal HFD and offspring MCD diets. Maternal HFD also influenced gut microbiome profiles in offspring leading to a decrease in α-diversity. Linear regression analysis revealed association between serum ALT levels and Coprococcus, Coriobacteriacae, Helicobacterioceae and Allobaculum.ConclusionOur findings indicate that maternal HFD detrimentally alters epigenetic and gut microbiome pathways to favor development of fatty liver disease and its progressive sequelae.

Highlights

The steep rise in obesity over the last quarter century has been mirrored by an increasingly troubling trend of obesity during pregnancy
When compared to their control diet-fed littermates, offspring of HF-dams weaned onto high fat diet (HFD) gained greater body weight; had increased relative liver weight and showed hepatic steatosis and inflammation
Our findings indicate that maternal HFD detrimentally alters epigenetic and gut microbiome pathways to favor development of fatty liver disease and its progressive sequelae

Summary

Introduction

The steep rise in obesity over the last quarter century has been mirrored by an increasingly troubling trend of obesity during pregnancy. Over 60% of all pregnancies in the United States are in women who are either overweight or obese at conception [1] This is significant since maternal obesity confers several detrimental risk factors to the offspring, including the increased predisposition to obesity and metabolic dysfunction in adulthood [2]. Infants of obese mothers show greater intrahepatic lipid levels as assessed by MRI imaging soon after birth [12]. Despite these important studies, whether maternal diet and obesity alter development of other pathological features associated with fatty liver disease remains to be clarified. Specific mechanisms through which gestational and early-life exposure to maternal obesity predispose offspring to liver disease remain unanswered

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Conclusion