尽管吸入皮质类固醇治疗，上呼吸道微生物组仍可作为哮喘恶化的生物标志物
2022/11/22
摘要
背景：哮喘患者吸入糖皮质激素（ICS）的治疗反应受多种因素相互作用的影响。其中，上呼吸道微生物组的作用几乎没有被研究过。我们的目的是评估已使用ICS患者的唾液，咽和鼻微生物组与哮喘急性发作之间的关联。
方法：分析来自哮喘严重程度基因组学和宏基因组学（GEMAS）研究的250例使用ICS的哮喘患者的样本。对照/病例的定义是接受ICS治疗，过去六个月内没有/存在哮喘急性发作。通过测序16S rRNA基因的V3-V4区域来分析细菌微生物群。组间差异通过PERMANOVA评估，回归模型针对潜在的混杂因素进行调整。使用5%的错误发现率（FDR）来校正多重比较。使用基于临床，遗传和微生物组数据的机器学习方法建立ICS治疗的哮喘急性发作的分类模型。
结果：在鼻腔和唾液样本中，病例的细菌多样性（丰富度、香农和信仰指数）低于对照组（0.007≤p≤0.037）。哮喘急性加重占唾液和鼻腔微生物个体间变异的8-9%（0.003≤p≤0.046）。唾液、咽部和鼻部微生物组的三、四、十一个细菌属在各组间差异显著（4.09x10-12≤FDR≤0.047）。通过整合临床，遗传和微生物组数据（AUCtraining: 0.82和AUCvalidation: 0.77）显示出对吸入ICS哮喘患者急性发作风险的良好区分。
结论：对于使用ICS治疗的患者，上呼吸道微生物组的多样性和组成与哮喘急性有关，唾液微生物组仍具有作为哮喘急性发作的生物标志物的潜在应用。
The Upper-Airway Microbiome as a Biomarker of Asthma Exacerbations despite Inhaled Corticosteroid Treatment
Javier Perez-Garcia, Mario González-Carracedo, Antonio Espuela-Ortiz, José M Hernández-Pérez, Ruperto González-Pérez, Olaia Sardón-Prado, Elena Martin-Gonzalez, Elena Mederos-Luis, Paloma Poza-Guedes, Paula Corcuera-Elosegui, Ariel Callero, Inmaculada Sánchez-Machín, Javier Korta-Murua, José A Pérez-Pérez, Jesús Villar, Maria Pino-Yanes, Fabian Lorenzo-Diaz
Abstract
Background：The response to inhaled corticosteroids (ICS) in asthma is affected by the interplay of several factors. Among these, the role of the upper-airway microbiome has been scarcely investigated. We aimed to evaluate the association between the salivary, pharyngeal, and nasal microbiome with asthma exacerbations despite ICS use.
Methods：Samples from 250 asthma patients from the Genomics and Metagenomics of Asthma Severity (GEMAS) study treated with ICS were analyzed. Controls/cases were defined by the absence/presence of asthma exacerbations in the past six months despite being treated with ICS. The bacterial microbiota was profiled by sequencing the V3-V4 region of the 16S rRNA gene. Differences between groups were assessed by PERMANOVA and regression models adjusted for potential confounders. A false discovery rate (FDR) of 5% was used to correct for multiple comparisons. Classification models of asthma exacerbations despite ICS treatment were built with machine learning approaches based on clinical, genetic, and microbiome data.
Results：In nasal and saliva samples, cases had lower bacterial diversity (Richness, Shannon, and Faith indexes) than controls (0.007≤p≤0.037). Asthma exacerbations accounted for 8-9% of the interindividual variation of the salivary and nasal microbiomes (0.003≤p≤0.046). Three, four, and eleven bacterial genera from the salivary, pharyngeal, and nasal microbiomes were differentially abundant between groups (4.09x10-12≤FDR≤0.047). Integrating clinical, genetic, and microbiome data showed good discrimination for the development of asthma exacerbations despite ICS use (AUCtraining:0.82 and AUCvalidation:0.77).
Conclusion：The diversity and composition of the upper-airway microbiome are associated with asthma exacerbations despite ICS treatment. The salivary microbiome has a potential application as a biomarker of asthma exacerbations despite ICS use.
背景：哮喘患者吸入糖皮质激素（ICS）的治疗反应受多种因素相互作用的影响。其中，上呼吸道微生物组的作用几乎没有被研究过。我们的目的是评估已使用ICS患者的唾液，咽和鼻微生物组与哮喘急性发作之间的关联。
方法：分析来自哮喘严重程度基因组学和宏基因组学（GEMAS）研究的250例使用ICS的哮喘患者的样本。对照/病例的定义是接受ICS治疗，过去六个月内没有/存在哮喘急性发作。通过测序16S rRNA基因的V3-V4区域来分析细菌微生物群。组间差异通过PERMANOVA评估，回归模型针对潜在的混杂因素进行调整。使用5%的错误发现率（FDR）来校正多重比较。使用基于临床，遗传和微生物组数据的机器学习方法建立ICS治疗的哮喘急性发作的分类模型。
结果：在鼻腔和唾液样本中，病例的细菌多样性（丰富度、香农和信仰指数）低于对照组（0.007≤p≤0.037）。哮喘急性加重占唾液和鼻腔微生物个体间变异的8-9%（0.003≤p≤0.046）。唾液、咽部和鼻部微生物组的三、四、十一个细菌属在各组间差异显著（4.09x10-12≤FDR≤0.047）。通过整合临床，遗传和微生物组数据（AUCtraining: 0.82和AUCvalidation: 0.77）显示出对吸入ICS哮喘患者急性发作风险的良好区分。
结论：对于使用ICS治疗的患者，上呼吸道微生物组的多样性和组成与哮喘急性有关，唾液微生物组仍具有作为哮喘急性发作的生物标志物的潜在应用。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2022 Nov 4;S0091-6749(22)01475-0. doi: 10.1016/j.jaci.2022.09.041.)
(J Allergy Clin Immunol. 2022 Nov 4;S0091-6749(22)01475-0. doi: 10.1016/j.jaci.2022.09.041.)
The Upper-Airway Microbiome as a Biomarker of Asthma Exacerbations despite Inhaled Corticosteroid Treatment
Javier Perez-Garcia, Mario González-Carracedo, Antonio Espuela-Ortiz, José M Hernández-Pérez, Ruperto González-Pérez, Olaia Sardón-Prado, Elena Martin-Gonzalez, Elena Mederos-Luis, Paloma Poza-Guedes, Paula Corcuera-Elosegui, Ariel Callero, Inmaculada Sánchez-Machín, Javier Korta-Murua, José A Pérez-Pérez, Jesús Villar, Maria Pino-Yanes, Fabian Lorenzo-Diaz
Abstract
Background：The response to inhaled corticosteroids (ICS) in asthma is affected by the interplay of several factors. Among these, the role of the upper-airway microbiome has been scarcely investigated. We aimed to evaluate the association between the salivary, pharyngeal, and nasal microbiome with asthma exacerbations despite ICS use.
Methods：Samples from 250 asthma patients from the Genomics and Metagenomics of Asthma Severity (GEMAS) study treated with ICS were analyzed. Controls/cases were defined by the absence/presence of asthma exacerbations in the past six months despite being treated with ICS. The bacterial microbiota was profiled by sequencing the V3-V4 region of the 16S rRNA gene. Differences between groups were assessed by PERMANOVA and regression models adjusted for potential confounders. A false discovery rate (FDR) of 5% was used to correct for multiple comparisons. Classification models of asthma exacerbations despite ICS treatment were built with machine learning approaches based on clinical, genetic, and microbiome data.
Results：In nasal and saliva samples, cases had lower bacterial diversity (Richness, Shannon, and Faith indexes) than controls (0.007≤p≤0.037). Asthma exacerbations accounted for 8-9% of the interindividual variation of the salivary and nasal microbiomes (0.003≤p≤0.046). Three, four, and eleven bacterial genera from the salivary, pharyngeal, and nasal microbiomes were differentially abundant between groups (4.09x10-12≤FDR≤0.047). Integrating clinical, genetic, and microbiome data showed good discrimination for the development of asthma exacerbations despite ICS use (AUCtraining:0.82 and AUCvalidation:0.77).
Conclusion：The diversity and composition of the upper-airway microbiome are associated with asthma exacerbations despite ICS treatment. The salivary microbiome has a potential application as a biomarker of asthma exacerbations despite ICS use.
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