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: 10121180
• 负责人: Michael W. Adams
• 金额: $ 49.88万
• 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/10121180
• 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.

项目概要/摘要 NIH 人类微生物组计划 (HMP) 彻底改变了我们对人类与微生物相互作用的看法 并为研究提供了巨大的推动力，以便更深入地了解如何 微生物影响人类健康。 HMP 参考基因组和人类肠道微生物 胃肠道细菌培养物保藏中心包含 142 属 961 种。然而，相对 人们对这些微生物知之甚少。在这里，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被考虑过，这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，大量肠道微生物含有编码多种基因的基因。 含 W 氧化还原酶 (WOR) 家族的成员。只有极少数的 WOR 酶 之前已对其进行了表征，主要来自外来嗜热微生物。该项目的总体目标是 拟议的研究旨在表明 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，我们已经表明一些肠道微生物会吸收微量的 W 和 它们的含 WOR 可以去除肠道中发现的反应性和潜在有毒的醛，这些醛是 由熟食和微生物代谢产生。建议其他含W WOR 催化其他尚未可知的反应。在拟议的研究中，我们将从系统发育上纯化十种新的 通过 W 监测（使用 ICP-MS）厌氧色谱法得出不同的 WOR。它们的催化活性和 生理底物将通过酶诱导的代谢组学方法（使用 LC-MS）测定。 此外，我们提出其中一些 WOR 是电子分叉酶，同时 耦合放能和吸能反应，这是最近发现的能量守恒机制 生物系统。该子集的动力学、光谱（使用 EPR）和结构（使用冷冻电镜）分析 W-酶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 WOR 的生理功能将被确定，我们将 确定 W 对肠道微生物代谢的影响，包括对肠道微生物的抵抗力 与烹饪相关的醛类。 相关性：现在很清楚，除了促进消化之外，肠道微生物组还在以下方面发挥着重要作用： 令人惊讶的是，人类疾病范围广泛，包括帕金森病、精神分裂症、骨关节炎和 心血管和免疫缺陷疾病。拟议研究的结果将提供 对我们胃肠道中关键微生物的初级代谢的全新视角 钨的重要作用被认为是一种很少在生物系统中使用的金属。