Conserved Fetal Epigenomic and Metagenomic Signatures in a Primate Model of Maternal Obesity

鉴于越来越多的证据表明，许多（如果不是绝大多数）慢性非传染性疾病， 疾病起源于胎儿生活，了解影响胎儿代谢的子宫内因素， 发展是我们时代最重要的公共卫生问题之一。在最初的拨款期间，我们 产生并发表了大量的数据，这些数据（与其他工作一起）共同表明，胎儿 代谢和发育基因表达途径的（重新）编程通过以下途径的稳定修饰发生： 不仅表观基因组，而且宏基因组（例如，微生物群落遗传库）。在当前 更新，我们提出了一系列的实验，将大大推进这些发现。 为什么要在我们的非人类灵长类动物模型中研究微生物组？利用我们的非人类灵长类动物模型， 我们是第一个证明高脂肪饮食，而不是肥胖本身， 微生物生态失调几年来，我们已经开发并采用宏基因组学来表征 早期人类发育微生物组，并观察其社区成员及其 由于多种因素的作用。然而，考虑到人类队列固有的混杂性， 目前还不清楚母体饮食对早期后代微生物组的相对影响，以及这是否 由宿主表观基因组修饰驱动。此外，这如何导致终身代谢疾病尚不清楚。 根据我们公布的和初步的数据，从最初的赠款期，我们的中心假设是， 在母体妊娠期和哺乳期高脂饮食暴露条件下， 下丘脑表观基因组和正在建立的微生物组经历一系列高度预测性的修饰。 这些修饰导致后代代谢组的有意义的功能改变， 转录组，导致代谢紊乱以及行为改变。虽然这些 后代的改变不容易通过断奶后改善饮食来改变， 在怀孕前控制饮食对她的后代很大程度上是恢复性的。为了证明这个假设， 我们将在灵长类动物群体中实现四个基本目标。完成这些目标的最终结果将是 首先建立胎儿和青少年肠道和口腔微生物组的保守改变， 光谱代谢组学，以确定稳定和持久的代谢（宿主和细菌）足迹， 母亲高脂肪饮食暴露。通过整合我们现有的表观基因组学数据与衍生的宏基因组学 数据，我们将能够预测这些微生物组和代谢组的变化如何反过来影响胎儿和 后代代谢结果和表型性状。在花了十多年时间建立和 分子表征目前的NHP模型，我们是唯一的准备，现在进行复杂的整合 我们在科学上严谨、可行、合理和可能的研究中得出的独特数据集 长期意义和高转化影响。

Given the growing body of evidence that many (if not the vast majority) of chronic, non-communicable disease have their origins in fetal life, understanding the in utero factors that impact fetal metabolism and development are among the most important public health issues of our time. During the initial grant period, we generated and published considerable data which (together with others work) collectively suggest that fetal (re)programming of metabolic and developmental gene expression pathways occur via stable modification of not only the epigenome, but the metagenome (e.g., the microbial community genetic repertoire). In the current renewal, we propose a series of experiments that will considerably advance these findings. Why study the microbiome in our non-human primate model? Employing our non-human primate model, we were the first to demonstrate that a high fat diet, and not obesity per se, drives both maternal and offspring microbial dysbiosis. For several years we have developed and employed metagenomics to characterize the early human developmental microbiome, and observed variation in its community membership and their function by virtue of multiple factors. However, given the inherent confounding of human cohorts, it remains unknown what the relative impact of maternal diet is on the early offspring microbiome, and whether this is driven by host epigenomic modifications. Moreover, how this leads to lifelong metabolic disease is unknown. Based on our published and preliminary data from the initial grant period, our central hypothesis is that under conditions of maternal high fat diet exposure in gestation and lactation, the offspring hepatic and hypothalamic epigenome and the establishing microbiome undergo a series of highly predictive modifications. These modifications result in meaningful functional alterations to the offspring metabolome as well as transcriptome, resulting in both metabolic disturbances as well as behavioral modifications. While these offspring modifications are not readily modifiable with an improved diet post-weaning, reversion of the dams onto control diet just prior to pregnancy is largely restorative to her offspring. In order to prove this hypothesis, we will execute four essential aims in our primate cohort. The net result of the completion of these aims will be to first establish the conserved alterations to the fetal and juvenile gut and oral microbiome, alongside full spectral metabolomics, to identify the stable and lasting metabolic (both host and bacterial) footprint of maternal high fat diet exposure. By integrating our existing epigenomics data with the derived metagenomics data, we will be able predict how these microbiome and metabolome variations in turn influence fetal and offspring metabolic outcomes and phenotypic traits. After having spent over a decade establishing and molecular characterizing the current NHP model, we are uniquely poised to now undertake complex integration of our derived unique data sets in studies which are scientifically rigorous, feasible, justifiable, and of likely long-term significance and high translational impact.