Interactions between gut microbial metabolism and host epigenome

肠道微生物代谢与宿主表观基因组之间的相互作用

• 批准号: 9248206
• 负责人: Kimberly Ann Krautkramer
• 金额: $ 3.88万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248206
• 关键词: Acetates; Affect; Algorithm Design; Alpha Cell; Bacteria; Butyrates; Carbohydrates; Carbon; Cell Culture Techniques; Cells; ChIP-seq; Chromatin; Colon Carcinoma; Communities; Complex; Cues; Custom; DNA; Data; Diet; Dietary Component; Dietary Fiber; Distal; Environment; Enzymes; Epidemic; Epigenetic Process; Fermentation; Focus Groups; Follow-Up Studies; Future; Gene Expression; Genetic Materials; Genetic Transcription; Genomics; Germ-Free; Global Change; Glucose Intolerance; Gnotobiotic; Goals; Health protection; Heritability; Histone Acetylation; Histone Deacetylase Inhibitor; Histone H3; Histones; Human; Human body; Immune response; In Situ; Inflammatory Bowel Diseases; Institutes; Intestines; Life Style; Light; Link; Lysine; Mass Spectrum Analysis; Measurable; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolism; Metabolite Interaction; Metagenomics; Methodology; Microbe; Modification; Monitor; Multienzyme Complexes; Mus; N-terminal; Nucleoproteins; Nucleosomes; Nutritional; Nutritional status; Obesity; Organism; Outcome; Outcomes Research; Output; Parents; Pectins; Perception; Phenotype; Plasma; Play; Polysaccharides; Population; Post-Translational Protein Processing; Prevalence; Process; Production; Propionates; Protein Acetylation; Proteins; Proteomics; Regulation; Resistance; Ribosomal RNA; Role; Signal Transduction; Source; Structure; Tail; Techniques; Tissues; Transcriptional Activation; Transcriptional Regulation; Volatile Fatty Acids; Wisconsin; Work; cancer cell; cardiovascular health; combinatorial; dietary starch; environmental adaptation; epigenetic regulation; epigenome; epigenomics; feeding; flexibility; globular protein; gut microbiota; in vivo; in vivo Model; insight; insulin sensitivity; knock-down; member; metabolomics; microbial; microbial community; microbial host; mouse model; nutrition; programs; public health relevance; response; small hairpin RNA; small molecule; transcriptome sequencing; transcriptomics

 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.

 描述(申请人提供)：认为人体是一个单一的、自给自足的有机体的观念正在经历一种范式的转变。随着16S rRNA测序和元基因组学的出现，很明显，人类可能被更好地理解为由宿主细胞和微生物细胞组成的“超有机体”。肠道微生物群在抵抗肥胖、胰岛素敏感性、葡萄糖耐受、心血管健康、预防结肠癌和炎症性肠病方面发挥着关键作用。此外，饮食是肠道微生物群落组成和代谢的主要调节者。未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。这些微生物进化出复杂的机制来分解和代谢这些底物，从而极大地扩大了宿主的代谢范围。肠道细菌产生大量可在宿主血浆中测量到的代谢物，包括短链脂肪酸醋酸酯、丙酸和丁酸盐。众所周知，许多组蛋白修饰酶复合体对小分子代谢物水平非常敏感，并被认为是对环境变化做出反应的“感觉”和整合代谢信号。组蛋白的八聚体构成了真核细胞核小体的核心，核小体是一种核蛋白结构，约147bp的DNA包裹在核小体周围，最终形成高度紧密的染色质。染色质可以以“开放”或“关闭”的状态存在，这取决于组蛋白蛋白上存在的修饰。组蛋白乙酰化通常与“开放”染色质和转录激活有关，而组蛋白H3赖氨酸27三甲基化与“封闭”染色质和转录沉默有关。因此，肠道微生物代谢物是否可能作为 寄主饮食在多种寄主组织中起着染色质水平的调节作用，而不仅仅限于肠道，最终影响寄主的转录编程和整体表型。然而，肠道微生物代谢产物与宿主染色质之间的关系尚不清楚。这项拟议工作的主要目标是在各种宿主组织中建立肠道微生物代谢和宿主表观遗传编程之间的联系。这项工作的第二个目标是利用肠道微生物区系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学变化的影响，并确定肠道微生物代谢物和宿主染色质之间的因果关系。其具体目的是(1)建立肠道微生物区系与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与宿主表观遗传学变化之间的因果关系。在此获得的洞察力将指导后续研究，以确定直接对细菌代谢物做出反应并改变特定染色质基因座的特定染色质复合体。鉴于全球饮食诱导肥胖的流行，这项工作将通过转录程序的表观遗传调节，在宿主营养状况、肠道微生物种群以及最终宿主环境适应之间建立关键联系。