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: 10184663
• 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/10184663
• 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; 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/antagonist; 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.

项目总结 人体微生物群是生活在人体内或体内的微生物的总和，它对两者的健康都有贡献。 和疾病。我们以前的工作已经证实，肠道微生物区系产生的一氧化氮(NO)作为一种 通过改变基本寄主，微生物与其寄主之间的种间交流语言 功能。肠道微生物区系的改变也被认为是糖尿病的一个重要危险因素。 炎症性肠病，如克罗恩病(CD)。而过量的NO是由过量表达的 一氧化氮合酶(NOS)在宿主肠道中的作用已被观察到，其作用来源于肠道中的NO 微生物区系尚未被调查或考虑。在很大程度上是由于翻译后修改而没有信号 蛋白质通过S-亚硝化，NO共价连接到特定半胱氨酸残基的硫醇侧链上 形成S亚硝硫醇(SNOS)，改变蛋白质功能。在这里，我们将检验一种假设，即交流 肠道微生物区系和哺乳动物宿主之间通过宿主蛋白S-亚硝化影响正常小鼠和 在CD的小鼠模型中。要做到这一点，我们将首先表征微生物区系衍生的NO在多大程度上发挥中介作用 宿主S-包括已知CD相关蛋白在内的肠道蛋白的亚硝化，并证明宿主肠道 蛋白质受微生物-NO/SNO的高度调控。此外，我们将证明肠道微生物区系衍生的NO是 不仅限于影响邻近的肠道组织，而且可能在宿主内产生深远的全身影响，通过 确定肠道以外的宿主器官中内源蛋白S-亚硝化的地方以及随后的器官 肠道微生物区系衍生的NO对健康和CD小鼠的功能都有影响。这将建立一个器官- 基线时特定的肠道微生物NO依赖的SNO蛋白质组图谱，以比较和识别发现的变化 在CD小鼠模型中的SNO-蛋白质组。这也将允许识别CD中的特定宿主蛋白 其S亚硝化反应明显依赖于肠道微生物区系中的NO，使研究其作用成为可能 CD患者的特异性改变。此外，微生物-NO依赖的S-亚硝化签名 肠外有助于CD的诊断和治疗。使用我们的CD鼠标模型，我们将 还要测试一类特定类型的氨基喹啉类抑制剂的使用，这种抑制剂选择性地针对细菌-一氧化氮合酶，但 非哺乳动物-NOSS作为CD的治疗选择。此外，肠道微生物区系的建立-没有- 不同主要器官(肠、肝、心、肺、肾、脑)的依赖SNO蛋白质组图谱将非常有用 在未来研究它在不同的人类疾病小鼠模型中的扰动。此外，我们还将 确定NO从肠道运输到远处器官的机制(S)。拟议的工作将用于 首次通过S测定：肠道微生物源性NO对哺乳动物宿主生理的影响-- 亚硝化作用、生物活性亚硝酸基从肠道到其他器官的运输机制，以及肠道的作用 微生物来源的NO/SNO在正常生理和疾病条件下，特别是CD。总之，我们的 这项工作承诺对微生物和宿主之间的交流方式有新的理解。