重症哮喘尿代谢型降低独立于口服糖皮质激素治疗的卡尼汀代谢：源自U-BIOPRED研究
2022/07/19
摘要
背景：哮喘是一种异质性疾病，表型定义不明。重症哮喘患者常接受多种治疗，包括口服糖皮质激素（OCS）。治疗可能会改变观察到的代谢型，从而使研究潜在的疾病机制具有挑战性。本研究旨在确定与哮喘严重程度和药物相关的失调代谢过程。
方法：前瞻性收集横断面 U-BIOPRED 队列中健康参与者（n=100）、轻度至中度哮喘患者（n=87）和重度哮喘患者（n=418）的基线期尿液样本；从患有重症哮喘的患者（n=305）中纵向收集12-18 个月尿液样本。代谢组学数据使用高分辨率质谱法获取，并使用单变量和多变量方法进行分析。
结果：本研究共鉴定出 90 种代谢物，其中 40 种在重症哮喘中显著改变（p<0.05，误诊率<0.05），23 种在使用 OCS 时发生显著改变。多变量模型显示，在健康参与者和轻至中度哮喘患者中观察到的代谢型与重度哮喘患者显著不同（p=2.6×10-20），OCS 治疗的哮喘患者与未治疗患者之间存在显著差异（ p=9.5×10-4），纵向代谢型表现出时间稳定性。重症哮喘患者的卡尼汀水平呈现最显著的OCS 非依赖性下降。卡尼汀水平降低与线粒体功能障碍相关，即通过降低脂肪酸代谢的通路富集分数以及痰和支气管刷样本中卡尼汀转运蛋白 SLC22A5 的表达。
结论：本研究为首次描述哮喘中疾病和 OCS 相关代谢差异的大规模研究。本研究所观察到的代谢型与不同疗法的广泛关联表明，仍需基于治疗和代谢物特异性评估潜在的调节作用。卡尼汀代谢变化独立于 OCS 治疗，是一个潜在可操作的治疗靶点，突出了线粒体功能障碍在重症哮喘中的作用。
Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study
Reinke SN, Naz S, Chaleckis R, Gallart-Ayala H, Kolmert J, Kermani NZ, Tiotiu A, Broadhurst DI, Lundqvist A, Olsson H, Ström M, Wheelock ÅM, Gómez C, Ericsson M, Sousa AR, Riley JH, Bates S, Scholfield J, Loza M, Baribaud F, Bakke PS, Caruso M, Chanez P, Fowler SJ, Geiser T, Howarth P, Horváth I, Krug N, Montuschi P, Behndig A, Singer F, Musial J, Shaw DE, Dahlén B, Hu S, Lasky-Su J, Sterk PJ, Chung KF, Djukanovic R, Dahlén SE, Adcock IM, Wheelock CE; U-BIOPRED Study Group
Abstract
BACKGROUND：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.
METHODS：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.
RESULTS：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=2.6×10-20), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10-4), 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 via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings.
CONCLUSIONS：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.
背景：哮喘是一种异质性疾病，表型定义不明。重症哮喘患者常接受多种治疗，包括口服糖皮质激素（OCS）。治疗可能会改变观察到的代谢型，从而使研究潜在的疾病机制具有挑战性。本研究旨在确定与哮喘严重程度和药物相关的失调代谢过程。
方法：前瞻性收集横断面 U-BIOPRED 队列中健康参与者（n=100）、轻度至中度哮喘患者（n=87）和重度哮喘患者（n=418）的基线期尿液样本；从患有重症哮喘的患者（n=305）中纵向收集12-18 个月尿液样本。代谢组学数据使用高分辨率质谱法获取，并使用单变量和多变量方法进行分析。
结果：本研究共鉴定出 90 种代谢物，其中 40 种在重症哮喘中显著改变（p<0.05，误诊率<0.05），23 种在使用 OCS 时发生显著改变。多变量模型显示，在健康参与者和轻至中度哮喘患者中观察到的代谢型与重度哮喘患者显著不同（p=2.6×10-20），OCS 治疗的哮喘患者与未治疗患者之间存在显著差异（ p=9.5×10-4），纵向代谢型表现出时间稳定性。重症哮喘患者的卡尼汀水平呈现最显著的OCS 非依赖性下降。卡尼汀水平降低与线粒体功能障碍相关，即通过降低脂肪酸代谢的通路富集分数以及痰和支气管刷样本中卡尼汀转运蛋白 SLC22A5 的表达。
结论：本研究为首次描述哮喘中疾病和 OCS 相关代谢差异的大规模研究。本研究所观察到的代谢型与不同疗法的广泛关联表明，仍需基于治疗和代谢物特异性评估潜在的调节作用。卡尼汀代谢变化独立于 OCS 治疗，是一个潜在可操作的治疗靶点，突出了线粒体功能障碍在重症哮喘中的作用。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Eur Respir J. 2022 Jun 30;59(6):2101733. doi: 10.1183/13993003.01733-2021.)
(Eur Respir J. 2022 Jun 30;59(6):2101733. doi: 10.1183/13993003.01733-2021.)
Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study
Reinke SN, Naz S, Chaleckis R, Gallart-Ayala H, Kolmert J, Kermani NZ, Tiotiu A, Broadhurst DI, Lundqvist A, Olsson H, Ström M, Wheelock ÅM, Gómez C, Ericsson M, Sousa AR, Riley JH, Bates S, Scholfield J, Loza M, Baribaud F, Bakke PS, Caruso M, Chanez P, Fowler SJ, Geiser T, Howarth P, Horváth I, Krug N, Montuschi P, Behndig A, Singer F, Musial J, Shaw DE, Dahlén B, Hu S, Lasky-Su J, Sterk PJ, Chung KF, Djukanovic R, Dahlén SE, Adcock IM, Wheelock CE; U-BIOPRED Study Group
Abstract
BACKGROUND：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.
METHODS：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.
RESULTS：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=2.6×10-20), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10-4), 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 via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings.
CONCLUSIONS：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.
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