Interactions between gut microbial metabolism and host epigenome

 描述（由申请人提供）：人体作为一个单一的，自足的有机体的看法正在经历一个范式转变。随着16S rRNA测序和宏基因组学的出现，很明显，人类可能更好地理解为由宿主和微生物细胞组成的“超有机体”。肠道微生物种群在抵抗肥胖、胰岛素敏感性、葡萄糖耐受不良、心血管健康、保护结肠癌和炎症性肠病中发挥关键作用。此外，饮食是肠道微生物群落组成和代谢的主要调节剂。不被宿主吸收的膳食淀粉和纤维是肠道细菌碳和能量的主要来源。这些微生物已经进化出复杂的机制来分解和代谢这些底物，从而极大地扩展了宿主的代谢库。肠道细菌产生许多在宿主血浆中可测量的代谢物，包括短链脂肪酸乙酸酯、丙酸酯和丁酸酯。已知许多组蛋白修饰酶复合物对小分子代谢物水平非常敏感，并且被认为响应于环境变化而“感知”和整合代谢信号。组蛋白的八聚体形成真核核小体的核心，核小体是一种核蛋白结构，约147 bp的DNA包裹在其周围，最终形成高度致密的染色质。染色质可以以“开放”或“封闭”状态存在，这取决于组蛋白上存在的修饰。组蛋白乙酰化通常与“开放”染色质和转录激活相关，而组蛋白H3赖氨酸27三甲基化与“封闭”染色质和转录沉默相关。因此，肠道微生物代谢物是否可能作为 宿主饮食，在多种宿主组织中的染色质水平上发挥调节作用，而不仅仅限于肠道，最终影响宿主转录编程和整体表型。然而，肠道微生物代谢产物和宿主染色质之间的关系仍然未知。拟议工作的主要目标是建立肠道微生物代谢和宿主表观遗传编程在各种宿主组织之间的联系。这项工作的第二个目标是利用肠道微生物群的营养敏感性来阐明det对这些微生物代谢物介导的表观遗传变化的影响，并确定肠道微生物代谢物和宿主染色质之间的因果关系。具体目标是（1）建立肠道微生物群和宿主表观基因组之间的联系，（2）确定饮食和微生物群落组成对宿主表观基因组的影响，以及（3）确定肠道微生物代谢产物和宿主表观遗传变化之间的因果关系。这里获得的见解将指导后续研究，以确定直接响应细菌代谢产物和改变特定染色质位点的特定染色质复合物。鉴于全球饮食诱导的肥胖症流行，这项工作将通过转录程序的表观遗传调控在宿主营养状况、肠道微生物种群和最终宿主环境适应之间建立关键联系。

 DESCRIPTION (provided by applicant): The perception of the human body as a single, self-contained organism is undergoing a paradigm shift. With the advent of 16S rRNA sequencing and metagenomics, it has become clear that humans are perhaps better understood as a "supraorganism" comprised of both host and microbial cells. Gut microbial populations play key roles in resistance to obesity, insulin sensitivity, glucose intolerance, cardiovascular health, an protection from colon cancer and inflammatory bowel disorders. Additionally, diet is a major modulator of gut microbial community composition and metabolism. Dietary starches and fibers that are not absorbed by the host are a major source of carbon and energy for gut bacteria. These microbes have evolved complex mechanisms to break down and metabolize such substrates, thereby vastly expanding the metabolic repertoire of the host. Gut bacteria produce a number of metabolites that are measureable in host plasma, including the short-chain fatty acids acetate, propionate, and butyrate. Many histone modifying enzyme complexes are known to be exquisitely sensitive to small-molecule metabolite levels and are thought to "sense" and integrate metabolic signals in response to changes in environment. An octamer of histone proteins forms the core of the eukaryotic nucleosome, a nucleoprotein structure around which ~147bp of DNA wraps to ultimately form highly compacted chromatin. Chromatin can exist in either an "open" or "closed" state, depending on the modifications present on histone proteins. Histone acetylation is generally associated with "open" chromatin and transcriptional activation, whereas Histone H3 lysine 27 trimethylation is associated with "closed" chromatin and transcriptional silencing. Therefore, is it likely that gut microbial metabolites, as a function of host diet, play a regulatory role at the level of chromatin in a variety of host tissues, not limitd solely to the gut, ultimately affecting host transcriptional programming and overall phenotype. However, the relationship between gut microbial metabolites and host chromatin remains unknown. The primary goal of the proposed work is to establish a link between gut microbial metabolism and host epigenetic programming in a variety of host tissues. A secondary goal of this work is to harness the nutritional sensitivity of gut microbiota to elucidate the effects of det on these microbial metabolite-mediated epigenetic changes, and to determine causal relationships between gut microbial metabolites and host chromatin. The specific aims are to (1) establish a link between gut microbiota and the host epigenome, (2) determine the effects of diet and microbial community composition on the host epigenome, and (3) determine causal relationships between gut microbial metabolites and host epigenetic changes. The insight gained here will guide follow-up studies to identify specific chromatin complexes that directly respond to bacterial metabolites and alter specific chromatin loci. In light of the global diet-induced obesity epidemic, this work will make key connections between host nutritional status, gut microbial populations, and ultimately host environmental adaptation via epigenetic regulation of transcriptional programs.