Developing the microbiome-metabolome as a targeted therapy for obesity-associated asthma

开发微生物组-代谢组作为肥胖相关哮喘的靶向治疗

• 批准号: 10725110
• 负责人: Victoria Heinrich
• 金额: $ 5.52万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725110
• 关键词: 16S ribosomal RNA sequencing; Acids; Adrenal Cortex Hormones; Adult; Affect; Aftercare; Age; Airway Resistance; American; Anti-Inflammatory Agents; Antibiotics; Asthma; Attenuated; B-Cell Activation; Bacteria; Blood capillaries; Body mass index; Bronchoalveolar Lavage Fluid; Carbon; Cecum; Cell Count; Childhood; Circulation; Clinical; Clinical Management; Data; Disease; Disease remission; Drug Kinetics; Emergency Care; Enhancers; Extrinsic asthma; Family; Fatty Acids; Frequencies; Gene Expression; Goals; High Fat Diet; Hospitalization; Immune; Inflammation Mediators; Inflammatory; Inflammatory Response; Label; Life; Light; Lung; Mass Spectrum Analysis; Measures; Mediator; Metabolic; Metabolic Pathway; Metabolism; Methods; Morbidity - disease rate; Mus; Nuclear; Obesity; Oleic Acids; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Potato; Production; Quality of life; RNA; Research; Resolution; Risk; Role; Serum; Severities; Signal Pathway; Signal Transduction; Source; Starch; Structure of parenchyma of lung; Symptoms; TNF gene; Techniques; Testing; Translating; United States; Visceral fat; Volatile Fatty Acids; adult obesity; airway hyperresponsiveness; allergic airway disease; asthma exacerbation; asthma inhaler; asthmatic patient; chemokine; clinical phenotype; cytokine; diet-induced obesity; dietary control; experience; gut microbes; gut microbiome; gut microbiota; gut-lung axis; improved; inflammatory modulation; metabolome; metabolomics; metatranscriptomics; microbial; microbial host; microbiome; microbiome composition; microbiota; mortality; mouse model; new therapeutic target; nuclear factor-erythroid 2; obese patients; obese person; obesity treatment; obesity-associated asthma; obesogenic; pulmonary function; response; stable isotope; stool sample; symptom management; systemic inflammatory response; targeted treatment; transcription factor; treatment response

PROJECT SUMMARY/ABSTRACT Obesity worsens asthma severity, and nonatopic asthma that presents late-onset in obese individuals is a distinct asthma phenotype. Obesity-associated asthma poses a challenge to clinical management due to poor therapeutic response to asthma controller medications, resulting in increased frequency of asthma exacerbations and elevated risk of hospitalization. The microbiome-metabolome is a promising target for obesity-associated asthma. Numerous studies support that obesity-associated perturbations to the gut microbiome are mechanistically involved in enhanced airway responsiveness in asthma. Airway hyperresponsiveness is elevated in asthma patients with obesogenic microbiomes. Alterations to host-microbial metabolism in obesity include short-chain fatty acids and other small metabolites involved inflammatory signaling pathways along the gut-lung axis. We have established that nitro-oleic acid, a nitrated fatty acid, targets systemic inflammation in both the host and the gut microbiome. Nitro-oleic acid activates anti-inflammatory (Nrf2) and inhibits proinflammatory (NF- κB) cell signaling pathways in the host while reducing the abundance of unclassified Oscillospiraceae bacterial species associated with detrimental increased small airway resistance in obese asthma. This proposal aims to test the hypothesis that exogenous administration of nitro-oleic acid will modify gut microbiota composition and function to restore microbial-derived metabolites and produce endogenous anti- inflammatory mediators. In Aims 1-2, I will identify contributions from the microbiome, metabolome, and nitro- oleic acid treatment to pulmonary function in a murine model of obesity-associated asthma. Aim 1 will characterize changes to the microbiome, metabolome, and inflammatory gene expression in the lungs following nitro-oleic acid treatment in order to determine how nitro-oleic acid modifies host-microbial anti-inflammatory signaling and metabolism. I have recently adapted a new technique of profiling changes to the microbiome and microbial-derived metabolites with stable isotope probes. Aim 2 will apply this method to track nitro-oleic acid- driven changes to gut microbiota composition and to discern which disease-modifying metabolites are derived from the microbiome. The ultimate goal of this research is to develop targeted therapy options for obesity- associated asthma and reduce patient morbidity and mortality through improved control of airway hyperresponsiveness. The proposal findings will be translated into the clinical setting to leverage the gut microbiome and microbial-derived metabolites to manage symptoms and recover lung function in patients with obesity-associated asthma.

项目总结/摘要 肥胖增加了哮喘的严重程度，肥胖个体迟发的非特应性哮喘是一种独特的哮喘。 哮喘表型由于肥胖相关性哮喘的不良影响，对临床管理提出了挑战 对哮喘控制药物的治疗反应，导致哮喘急性发作频率增加 和住院风险增加。微生物组-代谢组是治疗肥胖相关疾病的一个有前途的靶点。 哮喘许多研究支持，肥胖相关的肠道微生物组的扰动， 机械地参与哮喘气道反应性的增强。气道高反应性升高 哮喘患者体内的致肥微生物。肥胖症中宿主微生物代谢的改变包括 短链脂肪酸和其他小的代谢产物参与炎症信号通路沿着肠-肺 轴线我们已经确定，硝基油酸，一种硝化脂肪酸，靶向全身炎症， 宿主和肠道微生物。硝基油酸激活抗炎（Nrf 2）和抑制促炎（NF-κ B）。 κB）细胞信号传导途径，同时减少未分类的颤螺菌科细菌的丰度。 与肥胖性哮喘中有害的小气道阻力增加相关的物种。这项建议旨在 检验外源性施用硝基油酸将改变肠道微生物群的假设 组合物和功能，以恢复微生物来源的代谢物并产生内源性抗- 炎症介质。在目标1-2中，我将确定微生物组、代谢组和硝基的贡献。 油酸治疗对肥胖相关哮喘小鼠模型肺功能的影响目标1将 表征以下肺部微生物组、代谢组和炎症基因表达的变化 硝基油酸处理，以确定硝基油酸如何改变宿主微生物抗炎 信号传导和新陈代谢。我最近采用了一种新技术来分析微生物组的变化， 微生物衍生的代谢物与稳定同位素探针。目标2将应用该方法追踪硝基油酸- 驱动肠道微生物群组成的变化，并辨别哪些疾病修饰代谢物是由 从微生物组。这项研究的最终目标是开发针对肥胖症的靶向治疗方案- 通过改善气道控制降低患者发病率和死亡率 高反应性该提案的研究结果将被转化为临床环境，以利用肠道 微生物组和微生物衍生的代谢产物，以管理症状和恢复肺功能的患者 肥胖相关性哮喘