Dynamics of airway microbiota at pulmonary exacerbation in cystic fibrosis

囊性纤维化肺部恶化时气道微生物群的动态

• 批准号: 9906260
• 负责人: JOHN J LIPUMA
• 金额: $ 38.59万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-03 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906260
• 关键词: Acute; Age; Antibiotic Therapy; Area; Biochemical Pathway; Caregivers; Caring; Cause of Death; Cessation of life; Clinical; Clinical Data; Collection; Communities; Complex; Cystic Fibrosis; Cystic Fibrosis sputum; DNA analysis; DNA sequencing; Data; Drops; Etiology; Event; Functional disorder; Goals; Health Care Costs; Inflammation; Inflammatory; Lung; Lung Inflammation; Lung diseases; Measures; Metadata; Microbe; Microbiology; Modeling; Patients; Pattern; Persons; Phenotype; Pilot Projects; Play; Predictive Value; Pseudomonas; Pulmonary Cystic Fibrosis; Quality of life; Recovery; Recovery of Function; Reporting; Resolution; Respiratory Failure; Respiratory Signs and Symptoms; Respiratory physiology; Role; Sampling; Severities; Signs and Symptoms; Specimen; Sputum; Statistical Models; Structure; Symptoms; Systems Biology; Testing; Time; Toxic effect; airway inflammation; antimicrobial; bacterial community; chronic infection; cohort; cost; cystic fibrosis patients; density; host-microbe interactions; inflammatory marker; interest; loss of function; mathematical model; metabolome; metabolomics; microbial; microbial community; microbial host; microbiome; microbiome research; next generation; novel strategies; pathogen; personalized medicine; predictive modeling; prevent; prospective; respiratory; respiratory microbiome; respiratory microbiota; response; targeted treatment

Project Summary There is an increasing recognition that the airways of persons with cystic fibrosis (CF) typically harbor complex polymicrobial communities that include numerous bacterial species. It is unknown, however, how changes in these communities relate to the progression of lung disease. More specifically, how changes in the structure and/or activity of airway bacterial communities are associated with the intermittent pulmonary exacerbations (PExs) that characterize CF has not been systematically investigated. The lack of respiratory specimens and granular clinical data from periods of time preceding PExs has been a critical barrier to progress in this area. The scientific premise for this project is that a better understanding of airway microbial community dynamics with respect to PExs will provide new opportunities to better care to persons with CF. The overarching hypothesis is that changes in the structure and/or activity of these communities drive the pathophysiology of PExs. In the short term, this study will identify targets of immediate translational clinical interest. In the longer term, this project will elucidate the mechanisms governing microbial community and host changes associated with PExs. The specific aims of this project are to (i) characterize microbial community and host inflammatory changes that occur with PEx, (ii) develop predictive models of PEX resolution, and (iii) develop dynamic models that predict microbe-microbe and host-microbe interactions during PEx. The feasibility of this project is supported by a pilot project in which we prospectively collected daily sputum samples from a cohort of CF patients during the course of up to two years. The prospective collection of daily samples and clinical metadata proposed in the current project incorporates several improvements that will yield more robust results. Next- generation DNA sequencing and analysis of bacterial metabolites will be used to characterize the structure and activity of the bacterial communities in samples obtained around the time of pulmonary exacerbations. Microbial community changes that correlate with exacerbation onset, severity and recovery will be identified. Modeling of these changes will describe the microbial-microbial and host-microbial interactions associated with transitions in clinical state throughout the PEx cycle. This information will form the basis of follow on studies to better understand the pathophysiologic mechanisms of PEx in CF.

项目摘要 人们越来越认识到囊性纤维症(CF)患者的呼吸道通常含有复合体 多种微生物群落，包括许多细菌物种。然而，目前尚不清楚 这些群落与肺部疾病的进展有关。更具体地说，结构如何变化 和/或呼吸道细菌群落的活性与间歇性肺加重有关 (Pexs)的特征还没有被系统地研究过。呼吸道样本的缺乏和 来自PExs之前一段时间的细粒度临床数据一直是这一领域取得进展的关键障碍。 这个项目的科学前提是更好地了解呼吸道微生物群落动力学 在PExs方面，将提供新的机会，更好地照顾患有CF的人。最重要的是 假说是这些群落的结构和/或活动的变化推动了 PExs。在短期内，这项研究将确定立即转化为临床感兴趣的靶点。在更长的时间里 学期中，本项目将阐明控制微生物群落和相关宿主变化的机制 带着PExs。该项目的具体目标是(I)描述微生物群落和宿主炎症 PEX发生的变化，(Ii)开发PEX分辨率的预测模型，以及(Iii)开发动态 预测PEX期间微生物-微生物和宿主-微生物相互作用的模型。这个项目的可行性是 由一个试点项目支持，在该试点项目中，我们前瞻性地收集了一组CF患者的每日痰样本 患者在长达两年的疗程中接受治疗。每日样本和临床元数据的前瞻性收集 目前项目中提出的一些改进措施将产生更有力的成果。下一步- 将使用代DNA测序和细菌代谢物分析来表征结构和 在肺部恶化前后采集的样本中细菌群落的活性。 将确定与恶化开始、严重程度和恢复相关的微生物群落变化。 对这些变化的建模将描述与以下相关的微生物-微生物和宿主-微生物相互作用 在整个PEX周期中临床状态的转变。这些信息将构成后续研究的基础 更好地了解PEX在CF中的病理生理机制。

项目成果

Liquid Chromatography Mass Spectrometry Detection of Antibiotic Agents in Sputum from Persons with Cystic Fibrosis.

液相色谱质谱法检测囊性纤维化患者痰液中的抗生素。

• DOI: 10.1128/aac.00927-20
• 发表时间: 2021
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Gallagher,Tara;Riedel,Stefan;Kapcia,Joseph;Caverly,LindsayJ;Carmody,Lisa;Kalikin,LindaM;Lu,Junnan;Phan,Joann;Gargus,Matthew;Kagawa,Miki;Leemans,SimonW;Rothman,JasonA;Grun,Felix;LiPuma,JohnJ;Whiteson,KatrineL
• 通讯作者: Whiteson,KatrineL

Airway bacterial community composition in persons with advanced cystic fibrosis lung disease.

晚期囊性纤维化肺病患者的气道细菌群落组成。

• DOI: 10.1016/j.jcf.2023.01.001
• 发表时间: 2023
• 期刊: Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
• 作者: Thornton,ChristinaS;Carmody,LisaA;Kalikin,LindaM;Opron,Kristopher;Caverly,LindsayJ;LiPuma,JohnJ
• 通讯作者: LiPuma,JohnJ

Changes in airway bacterial communities occur soon after initiation of antibiotic treatment of pulmonary exacerbations in cystic fibrosis.

• DOI: 10.1016/j.jcf.2022.05.011
• 发表时间: 2022-09
• 期刊: JOURNAL OF CYSTIC FIBROSIS
• 影响因子: 5.2
• 作者: Carmody, Lisa A.;Kalikin, Linda M.;VanDevanter, Donald R.;Li, Gen;Opron, Kristopher;Simon, Richard H.;Caverly, Lindsay J.;LiPuma, John J.
• 通讯作者: LiPuma, John J.

Capturing Actively Produced Microbial Volatile Organic Compounds from Human-Associated Samples with Vacuum-Assisted Sorbent Extraction.

通过真空辅助吸附剂萃取从人类相关样品中捕获活跃产生的微生物挥发性有机化合物。

• DOI: 10.3791/62547
• 发表时间: 2022
• 期刊: Journal of visualized experiments : JoVE
• 作者: Phan,Joann;Kapcia3rd,Joseph;Rodriguez,CynthiaI;Vogel,VictoriaL;Cardin,DanielB;Dunham,SageJB;Whiteson,Katrine
• 通讯作者: Whiteson,Katrine