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: 10576352
• 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/10576352
• 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; Set protein; Signal Transduction; Signaling Molecule; Sulfhydryl Compounds; Sum; Symptoms; Terminal Ileitis; Testing; Time; Tissues; Ulcerative Colitis; Work; 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 人体微生物组是生活在人体内或人体上的微生物的总和，它有助于健康 和疾病我们以前的工作已经确定，肠道微生物群产生的一氧化氮（NO）作为一种代谢物， 通过改变基本宿主，微生物组与其宿主之间的种间交流语言 功能协调发展的改变的肠道微生物群也被认为是肠梗阻病因学中的重要风险因素。 炎症性肠病，如克罗恩病（CD）。而过量的NO产生的过度表达， 在CD中已经观察到宿主肠道中的一氧化氮合酶（NOS），来自肠道的NO的作用 微生物群尚未被研究或考虑。NO信号在很大程度上是通过后处理修改的 通过S-亚硝基化，NO共价连接到特定半胱氨酸残基的巯基侧链， 形成S-亚硝基硫醇（SNOs），改变蛋白质功能。在这里，我们将测试的假设，通信 肠道微生物群与哺乳动物宿主之间通过宿主蛋白S-亚硝基化作用的相互作用影响正常小鼠的健康， 在小鼠CD模型中。为此，我们将首先描述微生物来源的NO介导的程度， 包括已知CD相关蛋白在内的肠道蛋白的宿主S-亚硝基化，并证明了宿主肠道 蛋白质高度受微生物-NO/SNO调节。此外，我们将证明肠道微生物来源的NO是 不仅限于影响邻近的肠道组织，还可能在宿主体内产生深远的全身性影响， 确定肠道以外的宿主器官，其中内源性蛋白质S-亚硝基化并因此产生器官 在健康小鼠和CD小鼠中，肠道微生物来源的NO影响功能。这将建立一个机构- 基线时特异性肠道微生物NO依赖性SNO-蛋白质组图谱，以比较和鉴定发现的改变 在CD小鼠模型的SNO蛋白质组中。这也将允许鉴定CD中的特定宿主蛋白质 其S-亚硝基化显著依赖于来自肠道微生物群的NO，使得能够研究其作用。 CD患者的特定改变。此外，微生物-NO依赖的S-亚硝基化特征在 肠内外的超声检查有助于CD的诊断和治疗。使用我们的CD鼠标模型，我们将 我还测试了一种特殊的氨基喹啉类抑制剂的使用，这种抑制剂选择性地靶向细菌NOS， 而不是将非典型肺炎作为CD的治疗选择。此外，这种肠道微生物群的建立-NO- 不同主要器官（肠道、肝脏、心脏、肺、肾脏、大脑）中的依赖SNO蛋白质组图谱将非常有用 在未来研究它在人类疾病的不同小鼠模型中的扰动。此外，我们将 确定NO从肠道运输到远端器官的机制。拟议的工作将为 第一次确定：肠道微生物来源的NO通过S- 亚硝基化，生物活性SNO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在正常生理学和疾病条件下，特别是CD。总之，我们的 这项工作使我们对微生物和宿主之间的交流方式有了新的了解。