Sputum Microbial Markers of Type 2-Low Asthma

摘要 哮喘是一种异质性疾病，吸入性皮质类固醇（ICS）是治疗哮喘的基石。 按照现行的指导方针治疗。然而，高达45%的患者对ICS治疗无反应， 更有效地对抗由2型免疫反应驱动的气道炎症。此外，约50%的 哮喘成人没有表现出明显的2型气道炎症的证据。因此，患者 “2型-低”哮喘包括一个很大的亚组，其疾病病因学知之甚少， 有限的治疗选择。此外，在2型低血糖患者中， 是不确定的，甚至可能是有害的。最近的支气管镜检查研究表明，2型低 哮喘，即使在ICS初治患者中，也与气道微生物组的显著改变相关 （“气道生态失调”），并且气道生态失调的模式与哮喘控制的差异有关。这些 这些发现很大程度上依赖于使用支气管镜检查的侵入性研究。相反，诱导的分析 痰允许纵向研究更多的患者，因此， 可以更好地理解气道生态失调、气道免疫应答模式和哮喘控制。在 此外，哮喘表型或结果的基于真菌的微生物生物标志物将允许 识别特定患者以进行针对微生物组的定制干预。在目标1中， 进行横断面分析，以识别差异富集的诱导痰菌群 在2型-低个体中，根据ICS使用分层，其哮喘得到或未得到良好控制。在目标2中，a 每组中的哮喘受试者亚组将被随访12个月，跨越季节变化 在哮喘控制中，气道微生物组组成和ICS治疗是重要的考虑因素。 我们将进行宏基因组测序研究，以全面了解所有微生物群 目前，他们贡献的功能，以及气道微生物组之间的关系，同时 2型低血糖患者的气道免疫应答模式和临床结局。我们希望能找出 2型哮喘的新的基于真菌的微生物生物标志物-低哮喘和该人群的哮喘结局 这将为这个重要的亚组带来新的治疗途径。

ABSTRACT Asthma is a heterogeneous disease for which inhaled corticosteroids (ICS) are a cornerstone of treatment by current guidelines. However, up to 45% of patients do not respond to ICS therapy, which is more effective against airway inflammation driven by type 2 immune responses. Moreover, ~50% of asthmatic adults do not demonstrate evidence of significant type 2 airway inflammation. Thus, patients with “Type 2-low” asthma comprise a large subgroup with poorly understood disease etiologies and limited treatment options. Moreover, the consequences of chronic ICS treatment in Type 2-low patients are uncertain and potentially even harmful. Recent bronchoscopy studies have revealed that Type 2-low asthma, even in ICS-naïve patients, is associated with significant alterations in the airway microbiome (“airway dysbiosis”), and patterns of airway dysbiosis are linked to differences in asthma control. These findings have largely relied on invasive studies using bronchoscopy. In contrast, analysis of induced sputum allows for larger numbers of patients to be studied longitudinally, so that relationships between airway dysbiosis, airway immune response patterns, and asthma control can be better understood. In addition, a sputum-based microbial biomarker(s) of asthma phenotype or outcome would allow for identification of particular patients for tailored interventions targeting the microbiome. In Aim 1 we will conduct cross-sectional analyses to identify induced sputum microbiota that are differentially enriched among Type 2-low individuals, stratified by ICS use, whose asthma is or is not well controlled. In Aim 2, a subset of asthmatic subjects in each group will be followed for 12 months, spanning seasonal variations in asthma control, airway microbiome composition, and ICS treatments that are important to consider. We will perform metagenomic sequencing studies to gain comprehensive insights into all microbiota present, the functions they contribute, and relationships between the airway microbiome, concurrent airway immune response patterns and clinical outcomes in Type 2-low patients. We expect to identify novel sputum-based microbial biomarkers of Type 2-low asthma and asthma outcomes in this population that will lead to new therapeutic avenues for this important subgroup.