W-Health: Tungsten is an Essential Metal for a Healthy Gut Microbiome

W-Health：钨是健康肠道微生物组的必需金属

• 批准号: 10265568
• 负责人: Michael W. Adams
• 金额: $ 43.51万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265568
• 关键词: Alcohols; Aldehydes; Anaerobic Bacteria; Bioinformatics; Cardiovascular system; Chromatography; Collection; Coupling; Cryoelectron Microscopy; Data; Deficiency Diseases; Degenerative polyarthritis; Dependence; Digestion; Electrons; Enzymes; Family; Feces; Food; Gastrointestinal tract structure; Gene Cluster; Gene Expression; Genes; Genome; Goals; Growth; Health; Human; Human Microbiome; Immune; Inductively Coupled Plasma Mass Spectrometry; Kinetics; Laboratories; Metabolic; Metabolism; Metals; Microbe; Modeling; Molecular; Monitor; Nature; Organism; Oxides; Oxidoreductase; Parkinson Disease; Phylogenetic Analysis; Physiological; Physiology; Play; Reaction; Research; Resistance; Role; Schizophrenia; Specificity; Structure; Substrate Specificity; Testing; Tungsten; United States National Institutes of Health; Vent; Work; base; biological systems; cooking; gastrointestinal bacteria; gut microbes; gut microbiome; member; metabolomics; microbiome; microorganism; novel; organic acid; oxidation; reconstruction; reference genome; small molecule

Project Summary/Abstract The NIH Human Microbiome Project (HMP) revolutionized our perspective on human-microbe interactions and provided a tremendous impetus for research in order to obtain a much deeper understanding of how microbes impact human health. The gut microorganisms of the HMP Reference Genomes and the Human Gastrointestinal Bacteria Culture Collection contain 961 species representing 142 genera. Yet, relatively little is known about these microorganisms. Herein we will test the hypothesis that tungsten (W), a metal almost never considered in biological systems, is essential for the health of the human gut microbiome. Our bioinformatics analyses reveal that a large number of these gut microbes contain genes encoding diverse members of the W-containing oxidoreductase (WOR) family of enzymes. Only a very few WOR enzymes have been previously characterized, mainly from exotic thermophilic microbes. The overall goal of the proposed research is to show that other members of the WOR family have essential functions in the gut microbiome. In preliminary studies, we have shown that some gut microbes take up trace amounts of W and their W-containing WORs remove reactive and potentially toxic aldehydes found in the gut, which are generated from cooked foods and microbiome metabolism. Other W-containing WORs are proposed to catalyze other as yet unknown reactions. In the proposed research we will purify ten novel phylogenetically distinct WORs by W-monitored (using ICP-MS) anaerobic chromatography. Their catalytic activities and physiological substrates will be determined by an enzyme-induced metabolomics approach (using LC-MS). In addition, we propose that some of these WORs are electron bifurcating enzymes that simultaneously couple exergonic and endergonic reactions, a recently discovered mechanism of energy conservation in biological systems. Kinetic, spectroscopic (using EPR) and structural (using cryoEM) analyses of this subset of W-enzymes will be used to investigate the nature of the bifurcation reactions. Using genome-based metabolic reconstructions, the physiological functions of the various WORs will be ascertained and we will determine the effects of W on the metabolism of the gut microbes, including on their resistance to gut- and cooking-related aldehydes. Relevance: It is now clear that, in addition to facilitating digestion, the gut microbiome plays roles in a surprisingly extensive range of human conditions, including in Parkinson’s, schizophrenia, osteoarthritis and in cardiovascular and immune-deficiency diseases. The results of the proposed research will provide a completely new perspective on the primary metabolisms of the key microbes in our gastrointestinal tract and the proposed essential role of tungsten, a metal that was thought to be seldom used in biological systems.

项目摘要/摘要 NIH人类微生物组项目（HMP）彻底改变了我们对人类微生物互动的看法 并为研究提供了巨大的动力，以便更深入地了解如何 微生物会影响人类健康。 HMP参考基因组和人类的肠道微生物 胃肠细菌培养物收容含有961种，代表142属。但是，相对 这些微生物知之甚少。在此，我们将检验以下假设：钨（W），一种金属 在生物系统中几乎从未考虑过，对于人类肠道微生物组的健康至关重要。我们的 生物信息学分析表明，许多这些肠道微生物包含编码多样的基因 含W的氧化氧化还原酶（WOR）酶家族的成员。只有极少量的酶 以前已表征，主要来自外来的嗜热微生物。总体目标 拟议的研究表明，Wor家族的其他成员在肠道中具有重要功能 微生物组。在初步研究中，我们表明一些肠道微生物占用痕量的W和 它们的含W剂消除了在肠道中发现的反应性和潜在有毒醛， 由煮熟的食物和微生物组代谢产生。提出了其他含W的恶化 催化其他反应。在拟议的研究中，我们将在纯粹的系统发育上净化十个新颖的系统 W-Monitored（使用ICP-MS）厌氧色谱法会出现明显的恶化。他们的催化活动和 生理底物将通过酶诱导的代谢组学方法（使用LC-MS）确定。 此外，我们建议其中一些恶化是电子分叉的酶 夫妇埃克斯和终极反应，这是一种最近发现的能源保护机制 生物系统。动力学，光谱（使用EPR）和该子集的结构（使用冷冻）分析 W-酶的含量将用于研究分叉反应的性质。使用基于基因组的 代谢重建，各种恶化的物理功能将得到确定，我们将 确定W对肠道微生物的代谢的影响，包括其对肠道和肠道的抗性 与烹饪有关的醛。 相关性：现在很明显，除了促进消化外，肠道微生物组还起着作用 令人惊讶的广泛人类状况，包括帕金森氏症，精神分裂症，骨关节炎和 在心血管和免疫缺陷疾病中。拟议研究的结果将提供 关于我们胃肠道关键微生物的主要代谢的全新观点 钨的拟议基本作用是一种被认为在生物系统中很少使用的金属。