Dataset Information

Changes in Microbiome Dominance Are Associated With Declining Lung Function and Fluctuating Inflammation in People With Cystic Fibrosis.

ABSTRACT: Airway inflammation and microbiome dysbiosis are hallmarks of cystic fibrosis (CF) lung disease. However, longitudinal studies are needed to decipher which factors contribute to the long-term evolution of these key features of CF. We therefore evaluated the relationship between fluctuation in microbiome and inflammatory parameters in a longitudinal study including a short- (1-year) and a long-term (3+ years) period. We collected 118 sputum samples from 26 CF adult patients and analyzed them by 16S rRNA gene sequencing. We measured the levels of inflammatory cytokines, neutrophil elastase, and anti-proteinases; lung function (FEV1% predicted); and BMI. The longitudinal evolution was analyzed based on (i) the rates of changes; (ii) the intra-patient stability of the variables; and (iii) the dependency of the rates of changes on the baseline values. We observed that the diversity of the microbiome was highly variable over a 1-year period, while the inflammatory markers showed a slower evolution, with significant changes only observed in the 3+ year cohort. Further, the degree of fluctuation of the biomass and the dominance of the microbiome were associated with changes in inflammatory markers, especially IL-1β and IL-8. This longitudinal study demonstrates for the first time that the long-term establishment and periodical variation of the abundance of a dominant pathogen is associated with a more severe increase in inflammation. This result indicates that a single time point or 1-year study might fail to reveal the correlation between microbial evolution and clinical degradation in cystic fibrosis.

SUBMITTER: Frey DL

PROVIDER: S-EPMC9136159 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Changes in Microbiome Dominance Are Associated With Declining Lung Function and Fluctuating Inflammation in People With Cystic Fibrosis.

Frey Dario L DL Bridson Calum C Dittrich Susanne S Graeber Simon Y SY Stahl Mirjam M Wege Sabine S Herth Felix F Sommerburg Olaf O Schultz Carsten C Dalpke Alexander A Mall Marcus A MA Boutin Sébastien S

Frontiers in microbiology 20220513

Airway inflammation and microbiome dysbiosis are hallmarks of cystic fibrosis (CF) lung disease. However, longitudinal studies are needed to decipher which factors contribute to the long-term evolution of these key features of CF. We therefore evaluated the relationship between fluctuation in microbiome and inflammatory parameters in a longitudinal study including a short- (1-year) and a long-term (3+ years) period. We collected 118 sputum samples from 26 CF adult patients a ...[more]

PMID: 35633718

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Project description:Rationale: Modulation of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein improves clinical outcomes in patients with CF and specific CFTR genetic mutations. It remains unclear how improving CFTR function modifies existing airway infection and inflammation.Objectives: To compare sputum microbiome and markers of inflammation before and after 6 months of ivacaftor treatment.Methods: The study included 31 people with CF, ages 10 years and older, with at least one G551D CFTR allele and an forced expiratory volume in 1 second (FEV1) of 40% predicted or greater who were enrolled in the GOAL (G551D Observational) study. Sputum samples were collected either by induction (n = 14) or by spontaneous expectoration (n = 17) before and 6 months after initiation of ivacaftor. Changes in bacterial community indices by sequencing of 16S rRNA amplicons, total and specific bacterial load, and a panel of proteases, antiproteases, and inflammatory cytokines were determined.Results: The cohort that spontaneously expectorated sputum had a lower FEV1, a higher proportion with Pseudomonas aeruginosa infection, and higher concentrations of sputum inflammatory markers compared with the cohort that provided sputum by induction. Although the overall cohort experienced significant improvements in FEV1 and reductions in sweat chloride, no significant changes in bacterial diversity, specific bacterial pathogens, or markers of inflammation were observed in these subjects. Neither total bacterial load nor presence of Pseudomonas changed significantly between paired samples with ivacaftor treatment. Younger patients experienced more shifts in their microbial communities than older patients.Conclusions: In this multicenter cohort, 6 months of ivacaftor treatment were not associated with significant changes in airway microbial communities or measures of inflammation. These data suggest that concomitant antimicrobial and antiinflammatory treatments will still be needed to manage airway disease in patients with CF treated with highly effective CFTR modulator therapy, especially in older patients with more advanced disease.

Project description:In cystic fibrosis, dynamic and complex communities of microbial pathogens and commensals can colonize the lung. Cultured isolates from lung sputum reveal high inter- and intraindividual variability in pathogen strains, sequence variants, and phenotypes; disease progression likely depends on the precise combination of infecting lineages. Routine clinical protocols, however, provide a limited overview of the colonizer populations. Therefore, a more comprehensive and precise identification and characterization of infecting lineages could assist in making corresponding decisions on treatment. Here, we describe longitudinal tracking for four cystic fibrosis patients who exhibited extreme clinical phenotypes and, thus, were selected from a pilot cohort of 11 patients with repeated sampling for more than a year. Following metagenomics sequencing of lung sputum, we find that the taxonomic identity of individual colonizer lineages can be easily established. Crucially, even superficially clonal pathogens can be subdivided into multiple sublineages at the sequence level. By tracking individual allelic differences over time, an assembly-free clustering approach allows us to reconstruct multiple lineage-specific genomes with clear structural differences. Our study showcases a culture-independent shotgun metagenomics approach for longitudinal tracking of sublineage pathogen dynamics, opening up the possibility of using such methods to assist in monitoring disease progression through providing high-resolution routine characterization of the cystic fibrosis lung microbiome.IMPORTANCE Cystic fibrosis patients frequently suffer from recurring respiratory infections caused by colonizing pathogenic and commensal bacteria. Although modern therapies can sometimes alleviate respiratory symptoms by ameliorating residual function of the protein responsible for the disorder, management of chronic respiratory infections remains an issue. Here, we propose a minimally invasive and culture-independent method to monitor microbial lung content in patients with cystic fibrosis at minimal additional effort on the patient's part. Through repeated sampling and metagenomics sequencing of our selected cystic fibrosis patients, we successfully classify infecting bacterial lineages and deconvolute multiple lineage variants of the same species within a given patient. This study explores the application of modern computational methods for deconvoluting lineages in the cystic fibrosis lung microbiome, an environment known to be inhabited by a heterogeneous pathogen population that complicates management of the disorder.

Dataset Information

Changes in Microbiome Dominance Are Associated With Declining Lung Function and Fluctuating Inflammation in People With Cystic Fibrosis.

Publications

Changes in Microbiome Dominance Are Associated With Declining Lung Function and Fluctuating Inflammation in People With Cystic Fibrosis.

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