Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
Centre for Integrative Metabolomics and Computational Biology, School of Science, Edith Cowan University, Perth, Australia.
Eur Respir J. 2022 Jun 30;59(6). doi: 10.1183/13993003.01733-2021. Print 2022 Jun.
Asthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication.
Baseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort; 12-18-month longitudinal samples were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods.
A total of 90 metabolites were identified, with 40 significantly altered (p<0.05, false discovery rate <0.05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and patients with mild-to-moderate asthma differed significantly from those in patients with severe asthma (p=2.6×10), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings.
This is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.
哮喘是一种异质性疾病，表型定义不明确。重度哮喘患者常接受多种治疗，包括口服皮质类固醇（OCS）。治疗可能会改变观察到的代谢表型，从而难以研究潜在的疾病机制。在这里，我们旨在确定与哮喘严重程度和药物治疗相关的失调代谢过程。
前瞻性地从健康参与者（n=100）、轻度至中度哮喘患者（n=87）和重度哮喘患者（n=418）的 U-BIOPRED 队列中收集基线尿液；从重度哮喘患者（n=305）中收集 12-18 个月的纵向样本。使用高分辨率质谱法获取代谢组学数据，并使用单变量和多变量方法进行分析。
共鉴定出 90 种代谢物，其中 40 种在重度哮喘中发生显著改变（p<0.05，假发现率<0.05），23 种与 OCS 使用有关。多变量模型显示，健康参与者和轻度至中度哮喘患者的观察代谢表型与重度哮喘患者的代谢表型有显著差异（p=2.6×10），OCS 治疗的哮喘患者与未治疗的患者有显著差异（p=9.5×10），并且纵向代谢表型表现出时间稳定性。肉碱水平在重度哮喘中表现出最强的 OCS 独立下降。肉碱水平降低与线粒体功能障碍有关，脂肪酸代谢途径的富集分数降低，以及在痰液和支气管刷取物中肉碱转运蛋白 SLC22A5 的表达降低有关。
这是第一项描述哮喘中疾病和 OCS 相关代谢差异的大规模研究。观察到的代谢表型与不同治疗方法的广泛关联表明，需要基于治疗和代谢物特异性来评估潜在的调节作用。改变的肉碱代谢是一个潜在的可治疗的靶点，它与 OCS 治疗无关，突出了线粒体功能障碍在重度哮喘中的作用。
