Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations.
Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations.
复制标题
DOI：
10.1371/journal.pone.0175675
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Shankar K
中科院分区：
文献类型：
--
作者：
Wankhade UD;Zhong Y;Kang P;Alfaro M;Chintapalli SV;Thakali KM;Shankar K
非酒精性脂肪性肝病（NAFLD）是一种与肥胖相关的重要并发症，也是脂肪性肝炎的前兆。然而，妊娠期和早期生活对NAFLD和NASH发展的影响仍然很少被认识。进行了两项独立研究，以检查母体通过暴露于高脂肪饮食（HFD）而导致的营养过剩是否会导致后代对出生后HFD和蛋氨酸胆碱缺乏（MCD）饮食的肝脏反应加剧。将对照饲料和HFD喂养的母鼠的后代断奶至对照组和HFD组，形成四个组。与对照饲料喂养的同窝仔相比，断奶至HFD的HF母鼠的后代体重增加更大;相对肝脏重量增加，并显示肝脏脂肪变性和炎症。类似地，该组通过RNA-seq揭示了显著更大的免疫应答和促纤维化基因表达。同时，用对照或MCD饲料对7-8周龄后代攻毒3周。如经典促纤维化基因的基因表达所示，由于母体HFD，对MCD饲料的反应也加重。超过100万个CpG的定量基因组规模DNA甲基化分析显示，母体HFD的组织发育和代谢（Fgf 21、Ppargc 1 β）以及母体HFD和后代MCD饮食组合的细胞粘附和通讯（VWF、Ephb 2）中的关键基因发生了持续的表观遗传变化。母体HFD还影响后代的肠道微生物组谱，导致α多样性降低。线性回归分析显示血清ALT水平与粪球菌、Coriobacteriums、螺旋杆菌科和Allobaculum相关。我们的研究结果表明，母体HFD在精神上改变了表观遗传和肠道微生物组途径，有利于脂肪肝疾病及其进行性后遗症的发展。
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, 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. Our findings indicate that maternal HFD detrimentally alters epigenetic and gut microbiome pathways to favor development of fatty liver disease and its progressive sequelae.