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.

项目摘要/摘要肥胖症恶化了哮喘的严重程度和肥胖个体迟到的非原子哮喘是一个明显的哮喘表型。肥胖相关的哮喘由于较差而对临床管理面临挑战对哮喘控制器药物的治疗反应，导致哮喘恶化的频率增加并增加了住院的风险。微生物组 - 代谢组是与肥胖相关的承诺目标哮喘。众多的研究支持肥胖相关扰动与肠道微生物组的扰动是机械上的哮喘中气道反应性增强。气道高反应升高在哮喘患者中，肥胖的微生物组。肥胖中宿主微生物代谢的改变包括短链脂肪酸和其他小型代谢物涉及沿肠肺的炎症信号通路轴。我们已经确定硝基酸是一种硝化脂肪酸，靶向两者的全身注入宿主和肠道微生物组。硝基酸会激活抗炎（NRF2）并抑制促炎（NF- κB）宿主中的细胞信号传导途径，同时还原未分类的示意道细菌的抽象与有害的物种相关的物种增加了肥胖哮喘的小气道耐药性。该建议旨在测试假说，外源给予硝基酸会改变肠道菌群恢复微生物衍生的代谢物并产生内源性抗 - 的组成和功能炎症介体。在AIMS 1-2中，我将确定微生物组，代谢组和硝基的贡献在肥胖相关哮喘的鼠模型中，油酸处理肺功能。目标1意志表征微生物组，代谢组和炎症基因表达的变化硝基酸处理以确定硝基酸如何修饰宿主 - 微生物抗炎信号传导和代谢。我最近改编了一种新技术，以对微生物组进行更改和具有稳定同位素问题的微生物衍生代谢产物。 AIM 2将应用这种方法跟踪硝基酸 - 对肠道菌群组成的驱动变化，并辨别出哪些疾病改良代谢物来自微生物组。这项研究的最终目的是为肥胖开发目标治疗方案 - 通过改善气道的控制，相关哮喘并降低患者的发病率和死亡率反应性过高。提案发现将转化为临床环境，以利用肠道微生物组和微生物衍生的代谢产物，以管理符号并在患者中恢复肺功能肥胖相关哮喘。