Dietary modulation of gut microbiome and host gene expression across human evolution and the emergence of modern human disease

有证据表明，与农业和工业化相一致的生活方式的改变， 影响了人类现代文明中所谓疾病的出现（例如代谢紊乱， 心血管疾病等）。这些疾病在当代工业化人口中的发病率是 据信与我们的基因组缺乏适应快速的饮食和生活方式变化有关， 发生在人类进化过程中。然而，这种疾病进化模型的有效性和解决方案 是有限的。此外，尽管人类进化的饮食和遗传标记已经研究过， 缺乏对微生物组（我们的第二个基因组）如何与营养和宿主相互作用的理解， 基因轴赋予现代人类增加的疾病风险。我们小组的初步数据显示， 饮食变化显著调节了野生灵长类动物的肠道微生物组和代谢组， 进化上的亲戚此外，我们还确定了仅在人群中发现的肠道微生物组标志物， 代表旧石器时代的生活方式（狩猎采集者），并将其与传统的农业主义者区分开来， 工业化人口。因此，考虑到1）饮食在人类进化中的潜在作用，2） 肠道微生物组对哺乳动物营养和免疫状况的影响，以及3）肠道微生物组的存在 微生物组模式排除狩猎采集者，我们假设代谢疾病的出现， 现代人的饮食，肠道微生物组和人类之间的相互作用显着介导 基因组的进化。这些问题尚未探讨。因此，在本提案的目标1中，我们将使用多- OMIC方法（宿主结肠组织的肠道代谢组学、宏基因组学和转录组学） 代谢和遗传标记，出现和/或丢失时，人类从狩猎采集过渡到 农业和工业化生活方式，以及受代谢疾病表型影响的人类。在目标2中， 我们将使用整合的元OMIC和网络理论方法来预测代谢疾病表型， 从狩猎采集者到向农业转型的人口，再到面临风险的现代人口。本系统级 这项研究将扩大我们对外在（环境/营养）和内在因素的理解 （遗传/代谢）影响现代人类疾病的演变。此外，进化方法 提出的将揭示潜在的新的饮食和微生物为基础的翻译策略，以减轻 当代人群中代谢性疾病的发病率。

Evidence suggests that lifestyle changes, concordant with the adoption of agriculture and industrialization, have impacted the emergence of the so-called diseases of modern civilization in humans (e.g. metabolic disorders, cardiovascular disease etc.). The incidence of these diseases in contemporary, industrialized populations is believed to be associated with a lack of adaptation of our genomes to the rapid dietary and lifestyle changes that occurred across human evolution. However the usefulness and resolution of this evolutionary model of disease are limited. Moreover, although the dietary and genetic markers of human evolution have been studied, we still lack understanding on how the microbiome, our second genome, has interacted with nutritional and host- genomic axes to confer increased disease risk in modern humans. Preliminary data by our group show that dietary shifts significantly modulate the gut microbiome and metabolome of wild primates, our closest evolutionary relatives. Additionally, we have identified gut microbiome markers only found in populations representing Paleolithic lifestyles (hunter-gatherers) and distinguishing them from traditional agriculturalists and industrialized populations. Thus, given 1) the potential role of diet in human evolution, 2) the critical impact of the gut microbiome on the nutritional and immune landscape of mammals, and 3) the existence of gut microbiome patterns exclusive of hunter-gatherers, we hypothesize that the emergence of metabolic disease in modern humans was significantly mediated by interactions between diet, the gut microbiome and the human genome across evolution. These issues are still unexplored. Thus, in Aim 1 of this proposal we will use a multi- OMIC approach (gut metabolomics, metagenomics and transcriptomics of the host colonic tissue) to identify metabolic and genetic markers that emerged and/or were lost when humans transitioned from hunter-gatherer to agricultural and industrialized lifestyles, and in humans affected by metabolic disease phenotypes. In Aim 2, we will use integrated meta-OMICs and network theory approaches to predict metabolic disease phenotypes, from hunter-gatherers to, populations in transition to agriculture to modern populations at risk. This system-level study will broaden our understanding of the extrinsic (environmental/nutritional) and intrinsic factors (genetic/metabolic) impacting the evolution of modern human disease. Additionally, the evolutionary approach proposed will shed light on potentially novel diet and microbe-based translational strategies to mitigate the incidence of metabolic disease in contemporary human populations.