Developing the microbiome-metabolome as a targeted therapy for 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 哮喘表型。由于肥胖相关哮喘的治疗效果不佳，给临床管理带来了挑战。 对哮喘控制药物的治疗反应，导致哮喘发作频率增加 以及住院风险增加。微生物组-代谢组是肥胖相关疾病的一个有前景的靶点 哮喘。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。气道高反应性升高 具有致胖微生物组的哮喘患者。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代谢物涉及肠肺炎症信号通路 轴。我们已经确定硝基油酸（一种硝化脂肪酸）针对全身炎症 宿主和肠道微生物组。硝基油酸激活抗炎剂 (Nrf2) 并抑制促炎剂 (NF- κB) 宿主细胞信号通路，同时减少未分类的颤螺科细菌的丰度 与肥胖性哮喘中小气道阻力增加相关的物种。该提案旨在 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- 炎症介质。在目标 1-2 中，我将确定微生物组、代谢组和硝基组的贡献。 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 描述肺部微生物组、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 信号传导和代谢。我最近采用了一种分析微生物组变化的新技术， 具有稳定同位素探针的微生物衍生代谢物。目标2将应用该方法来追踪硝基油酸- 驱动肠道微生物群组成的变化，并辨别衍生出哪些缓解疾病的代谢物 来自微生物组。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 过度反应。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。

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.