Sputum Metabolomic Profiling Reveals Metabolic Pathways and Signatures Associated With Inflammatory Phenotypes in Patients With Asthma.
Sputum Metabolomic Profiling Reveals Metabolic Pathways and Signatures Associated With Inflammatory Phenotypes in Patients With Asthma.
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痰代谢组学分析揭示与哮喘患者炎症表型相关的代谢途径和特征
DOI：
10.4168/aair.2022.14.4.393
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发表时间：
2022-07
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代谢和炎症之间的分子联系，驱动不同的炎症表型哮喘知之甚少。我们的目的是确定不同炎症性哮喘表型的代谢特征和潜在的分子途径。在发现组（n = 119）中，应用非靶向超高效液相色谱-质谱（UHPLC-MS），使用正交偏最小二乘判别分析（OPLS-DA）和途径拓扑富集分析来表征具有不同炎症表型的哮喘患者的诱导痰代谢谱。在验证集中（n = 114），选择差异代谢产物进行靶向定量。分析哮喘患者靶向代谢产物与临床指标的相关性。建立Logistic和负二项回归模型，以评估代谢产物与重度哮喘急性发作之间的相关性。在发现集中鉴定了77种差异代谢物。通路拓扑分析发现，组氨酸代谢、甘油磷脂代谢、烟酸和烟酰胺代谢、亚油酸代谢以及苯丙氨酸、酪氨酸和色氨酸的生物合成参与了不同哮喘表型的发病机制。在验证集中，24种靶向定量代谢物在哮喘炎症表型之间显著表达。最后，腺苷5′-单磷酸（调整的相对风险[adj RR] = 1.000; 95%置信区间[CI] = 1.000-1.000; P = 0.050），尿囊素（adj RR = 1.000; 95% CI = 1.000-1.000; P = 0.043）和烟酰胺（adj RR = 1.001; 95% CI = 1.000-1.002; P = 0.021）被证明可预测重度哮喘急性发作率。不同的炎症性哮喘表型在诱导痰中具有特定的代谢谱。潜在的代谢特征可以识别不同炎性哮喘表型的治疗靶点。
The molecular links between metabolism and inflammation that drive different inflammatory phenotypes in asthma are poorly understood. We aimed to identify the metabolic signatures and underlying molecular pathways of different inflammatory asthma phenotypes. In the discovery set (n = 119), untargeted ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was applied to characterize the induced sputum metabolic profiles of asthmatic patients with different inflammatory phenotypes using orthogonal partial least-squares discriminant analysis (OPLS-DA), and pathway topology enrichment analysis. In the validation set (n = 114), differential metabolites were selected to perform targeted quantification. Correlations between targeted metabolites and clinical indices in asthmatic patients were analyzed. Logistic and negative binomial regression models were established to assess the association between metabolites and severe asthma exacerbations. Seventy-seven differential metabolites were identified in the discovery set. Pathway topology analysis uncovered that histidine metabolism, glycerophospholipid metabolism, nicotinate and nicotinamide metabolism, linoleic acid metabolism as well as phenylalanine, tyrosine and tryptophan biosynthesis were involved in the pathogenesis of different asthma phenotypes. In the validation set, 24 targeted quantification metabolites were significantly expressed between asthma inflammatory phenotypes. Finally, adenosine 5′-monophosphate (adjusted relative risk [adj RR] = 1.000; 95% confidence interval [CI] = 1.000–1.000; P = 0.050), allantoin (adj RR = 1.000; 95% CI = 1.000–1.000; P = 0.043) and nicotinamide (adj RR = 1.001; 95% CI = 1.000–1.002; P = 0.021) were demonstrated to predict severe asthma exacerbation rates. Different inflammatory asthma phenotypes have specific metabolic profiles in induced sputum. The potential metabolic signatures may identify therapeutic targets in different inflammatory asthma phenotypes.