Gut Microbe-Derived Nitric Oxide As A Signal To Host: Role In Normal Physiology And In Disease

肠道微生物衍生的一氧化氮作为宿主信号：在正常生理和疾病中的作用

• 批准号: 10357961
• 负责人: JONATHAN S. STAMLER
• 金额: $ 35.42万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10357961
• 关键词: Address; Affect; Aminoquinolines; Atlases; Bacteria; Biological Models; Biological Process; Blood; Blood Circulation; Brain; Caenorhabditis elegans; Communication; Crohn' s disease; Cysteine; Diagnosis; Disease; Disease Progression; Distant; Drug Targeting; Etiology; Foundations; Frequencies; Functional disorder; Future; Gastrointestinal Diseases; Gastrointestinal tract structure; Glutathione; Goals; Health; Heart; Hemoglobin; Human; Human Microbiome; Human body; Inflammatory Bowel Diseases; Investigation; Kidney; Knock-in Mouse; Knock-out; Language; Liver; Lung; Mammals; Mediating; Microbe; Modeling; Mus; Nematoda; Nitric Oxide; Nitric Oxide Synthase; Organ; Organism; Pathology; Pathway interactions; Patients; Persons; Physiological; Physiology; Plasma; Play; Post-Translational Protein Processing; Probiotics; Production; Protein S; Proteins; Proteome; Publishing; Recurrent disease; Regulation; Risk Factors; Role; S-Nitrosothiols; SKIL gene; Set protein; Side; Signal Transduction; Signaling Molecule; Sulfhydryl Compounds; Sum; Symptoms; Terminal Ileitis; Testing; Time; Tissues; Ulcerative Colitis; Work; base; dysbiosis; gut bacteria; gut microbes; gut microbiota; host microbiota; human disease; human model; inhibitor; interspecies communication; intestinal homeostasis; microbial; microbiome; microbiota; mouse model; new therapeutic target; novel; overexpression; protein function; success; treatment strategy

PROJECT SUMMARY The human microbiome is the sum of microbes that live in or on the human body, and it contributes to both health and disease. Our previous work has established that nitric oxide (NO) generated by gut microbiota acts as a language of inter-species communication between the microbiome and its host by changing fundamental host functions. Altered gut microbiota has also been implicated as an important risk factor in the etiology of inflammatory bowel diseases such as Crohn’s disease (CD). While excess NO generated by overexpression of nitric oxide synthase (NOS) in the host gut has been observed in CD, the role of the NO derived from gut microbiota has not been investigated or considered. NO signals in large part by post-translationally modifying proteins via S-nitrosylation, the covalent attachment of NO to the thiol side-chain of specific cysteine residues to form S-nitrosothiols (SNOs), altering protein function. Here we will test the hypothesis that communication between gut microbiota and mammalian host via host protein S-nitrosylation impacts health in normal mice and in a mouse model of CD. To do this, we will first characterize the extent to which microbiota-derived NO mediates host S-nitrosylation of gut proteins including known CD-associated proteins, and demonstrate that host gut proteins are highly regulated by microbiotal-NO/SNO. Further, we will show that gut microbiota-derived NO is not limited to affecting just adjacent gut tissue but may have far-reaching systemic effects within the host, by identifying host organs beyond the gut where endogenous protein S-nitrosylation and consequently organ functions are impacted by gut microbiota-derived NO, in both healthy and CD mice. This will establish an organ- specific, gut microbial NO-dependent SNO-proteome atlas at baseline, to compare and identify alterations found in the SNO-proteome in the CD mouse model. This will also allow identification of specific host proteins in CD whose S-nitrosylation depends significantly on NO derived from gut microbiota, enabling investigation of the role of specific alterations in patients with CD. Additionally, the microbial-NO dependent S-nitrosylation signature in gut and beyond will be helpful towards the diagnosis and treatment of CD. Using our CD mouse model, we will also test the use of a specific class of aminoquinoline-based inhibitors that selectively target bacterial-NOSbut not mammalian-NOSsas a treatment option of CD. Furthermore, the establishment of this gut microbiota-NO- dependent SNO-proteome atlas in different major organs (gut, liver, heart, lung, kidney, brain) will be very useful in studying its perturbations across different mice models of human disease in the future. In addition, we will identify the mechanism(s) by which NO is transported from the gut to distant organs. The proposed work will, for the first time, determine: the effect of gut microbiota-derived NO on mammalian host physiology via S- nitrosylation, the mechanism of transport of bioactive SNOs from the gut to other organs, and the role of gut microbiota-derived NO/SNO in normal physiology and in disease conditions, particularly CD. Altogether, our work promises new understanding of means of communication between microbes and host.

项目摘要 人类微生物组是居住在人体或人体上的微生物的总和，这两者都有助于健康 和疾病。我们以前的工作已经确定，肠道菌群产生的一氧化氮（NO）充当 通过改变基本主机，微生物组与主机之间的种间交流语言 功能。改变的肠道微生物群也被认为是病因的重要危险因素 炎症性肠道疾病，例如克罗恩病（CD）。虽然超过过度表达产生 在CD中观察到了宿主肠道中的一氧化氮合酶（NOS），NO源自肠的作用 尚未研究或考虑微生物群。在翻译后修改中，没有很大的信号 通过S-亚硝基化蛋白质，NO与特异性半胱氨酸残基的硫醇侧链的共价附着 形成S-硝基硫醇（SNOS），改变蛋白质功能。在这里，我们将测试沟通的假设 通过宿主蛋白S-亚硝基化在肠道菌群和哺乳动物宿主之间影响正常小鼠的健康和 在CD的鼠标模型中。为此，我们将首先描述微生物群衍生的无媒体的程度 肠道蛋白的宿主S-亚硝基化，包括已知的CD相关蛋白，并证明宿主肠道 蛋白质由微生物-NO/SNO高度调节。此外，我们将证明肠道微生物群的否是 不限于仅影响相邻的肠道组织，但可能在宿主内部具有深远的系统影响 识别肠道以外的宿主器官，其中内源性蛋白S-亚硝基化并因此 在健康和CD小鼠中，功能受肠道微生物群衍生的NO的影响。这将建立一个器官 基线时特定的，肠道微生物无依赖性的SNO蛋白质组合体，以比较和识别发现的变化 在CD鼠标模型中的SNO-蛋白酶中。这也将允许识别CD中的特定宿主蛋白 其S-硝基化显着取决于肠道菌群的NO，从而研究了该角色 CD患者的特定改变。此外，微生物-NO依赖性S-硝基化特征 肠道及以后将有助于CD的诊断和治疗。使用我们的CD鼠标模型，我们将 还可以测试特定类别的基于氨基喹啉的抑制剂，这些抑制剂有选择地靶向细菌 - 核糖 不是哺乳动物 - 纳斯 - gas CD的治疗选择。此外，建立了这种肠道微生物群 不同主要器官（肠道，肝脏，心脏，肺，肾脏，大脑）中的依赖性SNO-蛋白质体非常有用 在未来研究其在不同小鼠模型中的扰动。此外，我们将 确定将NO从肠道传输到远处器官的机制。拟议的工作将是 第一次确定：肠道微生物群的NO对哺乳动物宿主生理的影响通过S- 硝基化，生物活性SNOS从肠道到其他器官的运输机制，肠道的作用 在正常生理学和疾病状况，尤其是CD中，微生物群衍生的NO/SNO。总共，我们的 工作承诺对微生物和主机之间的沟通方式的新理解。