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

项目摘要/摘要 肥胖会加重哮喘的严重程度，而在肥胖者中表现为晚发的非特应性哮喘是一种截然不同的 哮喘表型。肥胖相关哮喘对临床管理构成挑战 对哮喘控制药物的治疗反应，导致哮喘加重的频率增加 和更高的住院风险。微生物组-代谢组是肥胖相关的一个有前途的靶点 哮喘。大量研究支持肥胖对肠道微生物群的干扰是 从机制上参与了哮喘患者的呼吸道反应增强。呼吸道高反应性升高 在患有肥胖微生物的哮喘患者中。肥胖患者宿主微生物代谢的改变包括 短链脂肪酸和其他小的代谢物参与肠道-肺的炎症信号通路。 轴心。我们已经确定硝基油酸是一种硝化脂肪酸，它针对的是全身炎症 寄主和肠道微生物群。硝基油酸激活抗炎(NRF2)并抑制促炎(NF- κB)寄主中的细胞信号通路，同时降低未分类的环状螺旋菌科细菌的丰度 与肥胖哮喘中有害的小气道阻力增加有关的物种。这项建议旨在 验证外源给药硝基油酸会改变肠道微生物区系的假设 修复微生物来源的代谢物和产生内源性抗肿瘤药物的组成和功能 炎症介质。在目标1-2中，我将确定微生物组、代谢组和硝基- 油酸治疗对肥胖相关性哮喘小鼠肺功能的影响。目标1将 描述下列肺部微生物组、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修饰宿主微生物的抗炎作用 信号和新陈代谢。我最近采用了一种新的技术来分析微生物组的变化，并 微生物衍生的代谢物，具有稳定的同位素探针。目标2将应用这种方法来跟踪硝基油酸- 推动肠道微生物区系组成的变化，并辨别哪些疾病修饰代谢物是衍生出来的 从微生物组中。这项研究的最终目标是为肥胖症开发有针对性的治疗方案。 通过改善对呼吸道的控制，降低相关哮喘的发病率和死亡率 高反应性。建议的结果将被转化为临床环境，以利用肠道 微生物群和微生物衍生代谢物对慢性阻塞性肺疾病患者症状和肺功能恢复的影响 肥胖相关的哮喘。

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.