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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要肥胖会加重哮喘的严重程度，而肥胖个体晚发的非特应性哮喘是一种独特的疾病肥胖相关哮喘由于不良的表现对临床管理提出了挑战。对哮喘控制药物的治疗反应，导致哮喘发作频率增加和住院风险增加微生物组代谢组是肥胖相关的一个有希望的目标。大量研究支持肥胖相关的肠道微生物群扰动。机械地参与哮喘气道反应性的增强。在具有致肥微生物组的哮喘患者中，肥胖引起的宿主微生物代谢的改变包括短链脂肪酸和其他小代谢物涉及肠肺炎症信号通路我们已经确定，硝基油酸（一种硝基脂肪酸）可针对全身炎症。硝基油酸激活抗炎剂 (Nrf2) 并抑制促炎剂 (NF-)。 κB) 宿主中的细胞信号传导途径，同时减少未分类的颤旋菌科细菌的丰度与疼痛相关的物种增加了肥胖性哮喘的小气道阻力。检验外源性施用硝基油酸会改变肠道微生物群的假设恢复微生物衍生代谢物并产生内源性抗- 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。表征肺部微生物组、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作用我最近采用了一种分析微生物组变化的新技术，目标 2 将应用这种方法来追踪硝基油酸。驱动肠道微生物群组成的变化并辨别哪些疾病缓解代谢物是源自这项研究的最终目标是开发针对肥胖的靶向治疗方案。通过改善气道控制来减少相关哮喘并降低患者发病率和死亡率该提案的研究结果将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物可控制患者的症状并恢复肺功能肥胖相关哮喘。