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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #342724

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

item WANKHADE, UMESH - Arkansas Children'S Nutrition Research Center (ACNC)
item ZHONG, YING - University Of Arkansas
item KANG, PING - University Of Arkansas
item ALFARO, MARIA - Arkansas Children'S Hospital
item CHINTAPALLI, SREE - Arkansas Children'S Nutrition Research Center (ACNC)
item THAKALI, KESHARI - University Of Arkansas
item SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/29/2017
Publication Date: 4/17/2017
Citation: Wankhade, U.D., Zhong, Y., Kang, P., Alfaro, M., Chintapalli, S.V., Thakali, K.M., Shankar, K. 2017. Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations. PLoS One. 12(4):e0175675. doi:10.1371/journal.pone.0175675.

Interpretive Summary: The last decade has seen a steep rise in obesity and in particular the increasing percentage of overweight pregnant women. Considering the health hazards, social stigma and financial burden it brings on an individual and society, it demands a strong attention of scientific community to investigate and understand the complex phenomenon of obesity and its' complications. Increased weight during the pregnancy bears the potential of affecting the long term health of unborn child. Our study shows that increased weight gain during pregnancy leads to liver disease in the offspring. Mothers pass on genetic information to their babies which programs their response to several diseases later in their lifetime. These findings help us understand the role of mother's obesity in child's short term and long term health.

Technical Abstract: Non-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. Two 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. When 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, Ppargc1ß) 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 a-diversity. Linear regression analysis revealed association between serum ALT levels and Coprococcus, Coriobacteriacae, Helicobacterioceae and Allobaculum. Our findings indicate that maternal HFD detrimentally alters epigenetic and gut microbiome pathways to favor development of fatty liver disease and its progressive sequelae.