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

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.

Maternal obesity in pregnancy impacts offspring cardiometabolic health: Systematic review and meta‐analysis of animal studies

“…Birth weight was obtained from N = 63 studies ( N = 6530 offspring), one study was included twice in meta‐analysis since they reported on two separate cohorts . In six studies, data on birth weight was not extractable . There was no difference in birth weight between offspring of mothers with obesity and offspring of mothers with a normal weight, SMD −0.05 [95% CI −0.17; 0.07], I 2 = 74% (figure S1).…”

“…Body weight was measured at age 4 days up to 13 months. We were unable to extract outcome data from four studies . Offspring's body weight was increased following maternal obesity, SMD 0.76 [95% CI 0.60; 0.93], I 2 = 86% (figure S2).…”

“…25 In six studies, data on birth weight was not extractable. [26][27][28][29][30][31] There was no difference in birth weight between offspring of mothers with obesity and offspring of mothers with a normal weight, SMD −0.05 [95% CI −0.17; 0.07], I 2 = 74% (figure S1).…”

Microbiome diurnal rhythmicity and its impact on host physiology and disease risk

“…Through the portal vein that connects the liver to the gastrointestinal tract, the liver is exposed to the influence of the gut microbiome. Perturbations of the gut microbiome, coupled with disturbances in gut barrier function, have been associated with common liver disorders, such as non-alcoholic fatty liver disease [138][139][140], non-alcoholic steatohepatitis [139,[141][142][143][144][145][146][147][148][149][150][151][152], alcoholic liver disease [139,140,142,145,147,148,150,151,[153][154][155][156][157][158][159][160][161][162][163][164], and liver cirrhosis [165][166][167][168][169][170]. Thus, the microbiome serves as a modulator of liver rhythmic functions.…”

Epigenetic Mechanisms Link Maternal Diets and Gut Microbiome to Obesity in the Offspring

“…In a recent mouse study, maternal HFD detrimentally altered gut microbiome profiles in the offspring, which contributed to development of obesity, steatohepatitis and its progressive diseases in the offspring (Paul et al, 2016, 2018; Wankhade et al, 2017). Intriguingly, studies in non-human primates have shown that maternal HFD led to persistently reduced abundance of Campylobacter species in the offspring gut compared to the control diet group even though the primates were weaned and switched to control diet for 6 months ( Table 2 ; Ma et al, 2014).…”