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

Barry Linnane,Paul Mcnally,Michael Mcdermott,Orla O’Sullivan,Paul D Cotter,Julie Renwick,Fiona Crispie,Calum J Walsh,Aaron M Walsh

doi:10.3390/microorganisms9030492

Abstract

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.

Highlights

Cystic fibrosis (CF) is an autosomal recessive condition with impaired mucociliary clearance and innate airway defences [1]
A total of 336 Bronchoalveolar lavage (BAL) samples were taken from the biobank and, following quality control, 292 (87%) samples provided 16S rRNA gene sequencing reads of sufficient quality to proceed to analysis (Figure S1)
The two exceptions are Staphylococcus and Pseudomonas which are present in significantly greater relative abundance in the cystic fibrosis (CF) lung. These results suggest that infants and young children with CF, that are asymptomatic at the time of sample acquisition, have altered abundance of specific genera to that of aged children without CF

Summary

Introduction

Cystic fibrosis (CF) is an autosomal recessive condition with impaired mucociliary clearance and innate airway defences [1]. Microorganisms 2021, 9, 492 culminating in bronchiectasis are the main drivers of the morbidity and mortality of CF [1]. There is good evidence that these processes start early in life, with asymptomatic infants and pre-school children demonstrating clear associations between the presence of lower airway infection and inflammation and impaired lung function and structural airway changes [1,2]. CF airway infections have been known to be caused by a few well-known bacteria—the ‘usual suspects’. Perturbations in the CF airway microbiome are well described. It is unclear what effect these have on the “infection–inflammation–structural damage”

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Conclusion