A Volatile and Dynamic Longitudinal Microbiome Is Associated With Less Reduction in Lung Function in Adolescents With Cystic Fibrosis

Progressive impairment in lung function caused by chronic polymicrobial airway infection remains the major cause of death in patients with cystic fibrosis (CF). Cross-sectional studies suggest an association between lung function decline and specific lung microbiome ecotypes. However, longitudinal studies on the stability of the airway microbiome are missing for adolescents with CF constituting the age group showing the highest rate of decline in lung function. In this study, we analyzed longitudinal lung function data and sputum samples collected over a period of 3 to 5 years from 12 adolescents with CF. The sputum microbiome was analyzed using 16S rRNA gene sequencing. Our results indicate that the individual course of the lung microbiome is associated with longitudinal lung function. In our cohort, patients with a dynamic, diverse microbiome showed a slower decline of lung function measured by FEV1% predicted, whereas a more stable and less diverse lung microbiome was related to worse outcomes. Specifically, a higher abundance of the phyla Bacteroidetes and Firmicutes was linked to a better clinical outcome, while Proteobacteria were correlated with a decline in FEV1% predicted. Our study indicates that the stability and diversity of the lung microbiome and the abundance of Bacteroidetes and Firmicutes are associated with the lung function decline and are one of the contributing factors to the disease severity.

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Correction: Pyrosequencing Unveils Cystic Fibrosis Lung Microbiome Differences Associated with a Severe Lung Function Decline

PLoS ONE ◽

10.1371/journal.pone.0160726 ◽

2016 ◽

Vol 11 (8) ◽

pp. e0160726 ◽

Cited By ~ 1

Author(s):

Giovanni Bacci ◽

Patrizia Paganin ◽

Loredana Lopez ◽

Chiara Vanni ◽

Claudia Dalmastri ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Cystic Fibrosis Lung ◽

Lung Function Decline ◽

Lung Microbiome ◽

Severe Lung

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Refinement of metabolite detection in cystic fibrosis sputum reveals heme negatively correlates with lung function

10.1101/475525 ◽

2018 ◽

Author(s):

Nathaniel R. Glasser ◽

Ryan C. Hunter ◽

Theodore G. Liou ◽

Dianne K. Newman ◽

Keyword(s):

Mass Spectrometry ◽

Cystic Fibrosis ◽

Lung Function ◽

High Performance ◽

16S Rrna Gene Sequencing ◽

Initial Study ◽

Rrna Gene ◽

Sequencing Data ◽

Unknown Compound ◽

Mountain West

SummaryPseudomonas aeruginosalung infections are a leading cause of morbidity and mortality in cystic fibrosis (CF) patients (1, 2). Our laboratory has studied a class of small molecules produced byP. aeruginosaknown as phenazines, including pyocyanin and its biogenic precursor phenazine-1-carboxylic acid (PCA). As phenazines are known virulence factors (3), we and others have explored the possibility of using phenazine concentrations as a marker for disease progression (4–6). Previously, we reported that sputum concentrations of pyocyanin and PCA negatively correlate with lung function in cystic fibrosis patients (6). Our study used high performance liquid chromatography (HPLC) to quantify phenazines by UV–vis absorbance after extraction from lung sputum. Since our initial study, methods for metabolite analysis have advanced considerably, aided in large part by usage of mass spectrometry (LC-MS) and tandem mass spectrometry (LC-MS/MS). Because a more recent study employing LC-MS/MS revealed a surprising decoupling ofP. aeruginosametabolites in sputum and the detection ofP. aeruginosathrough culturing or microbiome profiles (4), we decided to check whether we could reproduce our previous findings by analyzing sputum samples from a different patient cohort with a new LC-MS instrument in our laboratory. Our new samples were provided by the Mountain West CF Consortium Sputum Biomarker study (7). In the course of performing our new analyses, comparison of our old HPLC data to our new LC-MS data led us to realize that the peak previously assigned to PCA instead originates from heme, and the peak assigned to pyocyanin originates from an as-yet unknown compound. This correction only affects the measurements of phenazines in sputum, and we are confident in the phenazine measurements from isolated cultures and the 16S rRNA gene sequencing data from that study (6). Here we outline the basis for our correction and present additional data showing that heme concentration negatively correlates with lung function in cystic fibrosis patients.

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Pyrosequencing Unveils Cystic Fibrosis Lung Microbiome Differences Associated with a Severe Lung Function Decline

PLoS ONE ◽

10.1371/journal.pone.0156807 ◽

2016 ◽

Vol 11 (6) ◽

pp. e0156807 ◽

Cited By ~ 18

Author(s):

Giovanni Bacci ◽

Patrizia Paganin ◽

Loredana Lopez ◽

Chiara Vanni ◽

Claudia Dalmastri ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Cystic Fibrosis Lung ◽

Lung Function Decline ◽

Lung Microbiome ◽

Severe Lung

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Aspergillus and progression of lung disease in children with cystic fibrosis

Thorax ◽

10.1136/thoraxjnl-2018-211550 ◽

2018 ◽

Vol 74 (2) ◽

pp. 125-131 ◽

Cited By ~ 15

Author(s):

Sabariah Noor Harun ◽

Claire E Wainwright ◽

Keith Grimwood ◽

Stefanie Hennig

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Bronchoalveolar Lavage ◽

Lung Disease ◽

Lung Function Decline ◽

Air Trapping ◽

Cross Sectional ◽

Progression Model ◽

Non Linear ◽

The Impact

BackgroundThe impact of Aspergillus on lung disease in young children with cystic fibrosis is uncertain.AimsTo determine if positive respiratory cultures of Aspergillus species are associated with: (1) increased structural lung injury at age 5 years; (2) accelerated lung function decline between ages 5 years and 14 years and (3) to identify explanatory variables.MethodsA cross-sectional analysis of association between Aspergillus positive bronchoalveolar lavage (BAL) cultures and chest high-resolution CT (HRCT) scan findings at age 5 years in subjects from the Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study was performed. A non-linear mixed-effects disease progression model was developed using FEV1% predicted measurements at age 5 years from the ACFBAL study and at ages 6–14 years for these subjects from the Australian Cystic Fibrosis Data Registry.ResultsPositive Aspergillus BAL cultures at age 5 years were significantly associated with increased HRCT scores for air trapping (OR 5.53, 95% CI 2.35 to 10.82). However, positive Aspergillus cultures were not associated with either FEV1% predicted at age 5 years or FEV1% predicted by age following adjustment for body mass index z-score and hospitalisation secondary to pulmonary exacerbations. Lung function demonstrated a non-linear decline in this population.ConclusionIn children with cystic fibrosis, positive Aspergillus BAL cultures at age 5 years were associated contemporaneously with air trapping but not bronchiectasis. However, no association was observed between positive Aspergillus BAL cultures on FEV1% predicted at age 5 years or with lung function decline between ages 5 years and 14 years.

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Azithromycin and the microbiota of cystic fibrosis sputum

BMC Microbiology ◽

10.1186/s12866-021-02159-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Nicole Acosta ◽

Christina S. Thornton ◽

Michael G. Surette ◽

Ranjani Somayaji ◽

Laura Rossi ◽

...

Keyword(s):

Cystic Fibrosis ◽

Community Structure ◽

Microbial Community ◽

Lung Function ◽

Rrna Gene ◽

Lung Function Decline ◽

Disease Pathogenesis ◽

Cystic Fibrosis Sputum ◽

Clustering Effect ◽

The 16S Rrna Gene

Abstract Background Azithromycin is commonly prescribed drug for individuals with cystic fibrosis (CF), with demonstrated benefits in reducing lung function decline, exacerbation occurrence and improving nutrition. As azithromycin has antimicrobial activity against components of the uncultured microbiome and increasingly the CF microbiome is implicated in disease pathogenesis – we postulated azithromycin may act through its manipulation. Herein we sought to determine if the CF microbiome changed following azithromycin use and if clinical benefit observed during azithromycin use associated with baseline community structure. Results Drawing from a prospectively collected biobank we identified patients with sputum samples prior to, during and after initiating azithromycin and determined the composition of the CF microbial community by sequencing the V3-V4 region of the 16S rRNA gene. We categorized patients as responders if their rate of lung function decline improved after azithromycin initiation. Thirty-eight adults comprised our cohort, nine who had not utilized azithromycin in at least 3 years, and 29 who were completely naïve. We did not observe a major impact in the microbial community structure of CF sputum in the 2 years following azithromycin usage in either alpha or beta-diversity metrics. Seventeen patients (45%) were classified as Responders – demonstrating reduced lung function decline after azithromycin. Responders who were naïve to azithromycin had a modest clustering effect distinguishing them from those who were non-Responders, and had communities enriched with several organisms including Stenotrophomonas, but not Pseudomonas. Conclusions Azithromycin treatment did not associate with subsequent large changes in the CF microbiome structure. However, we found that baseline community structure associated with subsequent azithromycin response in CF adults.

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The Lung Microbiome in Young Children with Cystic Fibrosis: A Prospective Cohort Study

Microorganisms ◽

10.3390/microorganisms9030492 ◽

2021 ◽

Vol 9 (3) ◽

pp. 492

Author(s):

Barry Linnane ◽

Aaron M. Walsh ◽

Calum J. Walsh ◽

Fiona Crispie ◽

Orla O’Sullivan ◽

...

Keyword(s):

Cystic Fibrosis ◽

Demographic Data ◽

Alpha Diversity ◽

16S Rrna Gene Sequencing ◽

Illumina Miseq ◽

Lower Airway ◽

Rrna Gene ◽

Lung Microbiome ◽

Microbiome Diversity ◽

R Project

The cystic fibrosis (CF) lung harbours a diverse microbiome and reduced diversity in the CF lung has been associated with advancing age, increased inflammation and poorer lung function. Data suggest that the window for intervention is early in CF, yet there is a paucity of studies on the lung microbiome in children with CF. The objective of this study was to thoroughly characterise the lower airway microbiome in pre-school children with CF. Bronchoalveolar lavage (BAL) samples were collected annually from children attending the three clinical centres. Clinical and demographic data were collated on all subjects alongside BAL inflammatory markers. 16S rRNA gene sequencing was performed on the Illumina MiSeq platform. Bioinformatics and data analysis were performed using Qiime and R project software. Data on 292 sequenced BALs from 101 children with CF and 51 without CF show the CF lung microbiome, while broadly similar to that in non-CF children, is distinct. Alpha diversity between the two cohorts was indistinguishable at this early age. The CF diagnosis explained only 1.1% of the variation between the cohort microbiomes. However, several key genera were significantly differentially abundant between the groups. While the non-CF lung microbiome diversity increased with age, diversity reduced in CF with age. Pseudomonas and Staphylococcus were more abundant with age, while genera such as Streptococcus, Porphyromonas and Veillonella were less abundant with age. There was a negative correlation between alpha diversity and interleukin-8 and neutrophil elastase in the CF population. Neither current flucloxacillin or azithromycin prophylaxis, nor previous oral or IV antibiotic exposure, was correlated with microbiome diversity. Consecutive annual BAL samples over 5 years from a subgroup of children demonstrated diverse patterns of development in the first years of life.

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