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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要人体微生物群是生活在人体内部或表面的微生物的总和，它有助于健康我们之前的工作已经证实，肠道微生物群产生的一氧化氮 (NO) 可以起到促进疾病的作用。通过改变基本宿主，微生物与其宿主之间的物种间交流语言肠道微生物群的改变也被认为是病因学中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 则因过度表达而产生。在 CD 中观察到宿主肠道中的一氧化氮合酶 (NOS)，源自肠道的 NO 的作用微生物群在很大程度上尚未通过翻译后修饰进行研究或考虑。蛋白质通过 S-亚硝基化，NO 与特定半胱氨酸残基的硫醇侧链共价连接，形成 S-亚硝基硫醇 (SNO)，改变蛋白质功能在这里我们将检验通讯的假设。肠道微生物群和哺乳动物宿主之间通过宿主蛋白 S-亚硝基化影响正常小鼠的健康为此，我们首先要描述微生物群衍生的 NO 介导的程度。宿主肠道蛋白（包括已知的 CD 相关蛋白）的 S-亚硝基化，并证明宿主肠道此外，我们将证明肠道微生物群衍生的 NO 受到微生物 NO/SNO 的高度调节。不仅影响邻近的肠道组织，还可能在宿主体内产生深远的系统性影响识别肠道以外的宿主器官，其中内源性蛋白质 S-亚硝基化，从而识别器官在健康小鼠和 CD 小鼠中，功能均受到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 NO 依赖性 SNO 蛋白质组图谱，以比较和识别发现的改变在 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。其 S-亚硝基化显着依赖于肠道微生物群中的 NO，从而能够研究其作用另外，CD 患者中微生物-NO 依赖性 S-亚硝基化特征的改变。使用我们的 CD 小鼠模型，肠道等将有助于 CD 的诊断和治疗。还测试了特定类别的基于氨基喹啉的抑制剂的使用，该抑制剂选择性地针对细菌 NOS——但是不是哺乳动物-NOS——作为 CD 的治疗选择。此外，肠道微生物群-NO-的建立。不同主要器官（肠、肝、心、肺、肾、脑）中依赖的 SNO 蛋白质组图谱将非常有用此外，我们还将在未来研究其对人类疾病的不同小鼠模型的干扰。拟议的工作将确定 NO 从肠道转运到远端器官的机制。首次确定：肠道微生物群来源的 NO 通过 S-对哺乳动物宿主生理机能的影响亚硝基化、生物活性 SNO 从肠道转运至其他器官的机制以及肠道的作用微生物群衍生的 NO/SNO 在正常生理和疾病条件下，特别是 CD。这项工作有望对微生物与宿主之间的通讯方式有新的认识。