Changes in the Cystic Fibrosis Airway Microbiome in Response to CFTR Modulator Therapy

Yi, Buqing; Dalpke, Alexander H.; Boutin, Sébastien

doi:10.3389/fcimb.2021.548613

Cited by 38 publications

(32 citation statements)

References 59 publications

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“…[162]. In addition to the direct influence of CFTR functionality on parameters such as salinity [163], the composition of the oropharyngeal bacterial community is also related to the CFTR genotype [164], with possible downstream effects on antibiotic activity. Furthermore, the prescription of CFTR modulators fully depends on the CFTR genotype of patients, and CFTR modulators have been shown to interfere with antibiotic activity.…”

Section: Mediators Of the Immune Responsementioning

confidence: 99%

The cystic fibrosis lung microenvironment alters antibiotic activity: causes and effects

et al. 2021

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Chronic airway colonisation by Pseudomonas aeruginosa, a hallmark of cystic fibrosis (CF) lung disease, is associated with increased morbidity and mortality and despite aggressive antibiotic treatment, P. aeruginosa is able to persist in CF airways. In vitro antibiotic susceptibility assays are poor predictors of antibiotic efficacy to treat respiratory tract infections in the CF patient population and the selection of the antibiotic(s) is often made on an empirical base. In the current review, we discuss the factors that are responsible for the discrepancies between antibiotic activity in vitro and clinical efficacy in vivo. We describe how the CF lung microenvironment, shaped by host factors (such as iron, mucus, immune mediators and oxygen availability) and the microbiota, influences antibiotic activity and varies widely between patients. A better understanding of the CF microenvironment and population diversity may thus help improve in vitro antibiotic susceptibility testing and clinical decision making, in turn increasing the success rate of antibiotic treatment.

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Section: Mediators Of the Immune Responsementioning

confidence: 99%

The cystic fibrosis lung microenvironment alters antibiotic activity: causes and effects

et al. 2021

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“…In addition to this, while the study assesses the role cough swabs might have in patients treated with CFTR modulators the data was collected from patients in a pre-modulator era. While, the number of studies investigating the impact of highly effective modulators on the airway microbiome is limited, the majority indicate that CFTR modulators may alter the airway microbiome, restoring a degree of eubiosis [ 38 ]. According to the adapted island model [ 35 ] such changes could theoretically protect the microbiota from bacterial overgrowth.…”

Section: Discussionmentioning

confidence: 99%

Comparison of microbial composition of cough swabs and sputum for pathogen detection in patients with cystic fibrosis

Fenn¹,

Abdel‐Aziz

Brinkman

et al. 2022

Journal of Cystic Fibrosis

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Background: With the continued advancement of CFTR modulator therapies there is likely to be a burgeoning population of adult cystic fibrosis (CF) patients unable to expectorate sputum. Consequently, the detection and surveillance of pulmonary colonisation, previously reliant on sputum culture, needs reexamining. We hypothesised that cough swabs analysed with culture-independent analysis of the 16S gene could serve as a surrogate for colonisation of the lower airways. Methods: Cough swabs and sputum samples were prospectively collected from consecutive adults and children with CF across two sites at regular outpatient appointments. Conventional culture analysis and next generation sequencing were used to compare paired same day samples. Results: Twenty-two adults and 8 paediatric patients provided 75 paired cough swabs and sputum samples. Alpha diversity measures showed increased bacterial richness in sputum, while evenness and Simpson's diveristy index were higher in cough swabs. Within each sampling technique, microbial composition showed greater similarity when considering intra-patient variation. Poor concordance was observed between culture independent cough swabs and culture dependent/independent sputum analysis for specific pathogens, with cough swabs unable to accurately identify commonly associated CF pathogens (AUROCC range: 0.51 to 0.64). Conclusion: Culture independent analysis of cough swabs provides an inaccurate diagnosis of lower respiratory tract colonisation and should not be used as a diagnostic test in patients with CF.

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“…Highly effective CFTR modulator drugs have significantly improved outcomes in pwCF; however, in a few recent studies, they have been shown to have either no effect or a modest effect on the number of P. aeruginosa in the CF lungs (10, 67). Thus, new approaches are needed to reduce the bacterial load in the lungs of chronically colonized pwCF.…”

Section: Discussionmentioning

confidence: 99%

“…Highly effective CFTR modulator drugs have significantly improved outcomes in pwCF; however, in a few recent studies, they have been shown to have either no effect or a modest effect on the P. aeruginosa burden in the CF lungs (Davies and Martin, 2018;Yi et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Tobramycin-induced secretion of P. aeruginosa 5′ tRNA-fMet halves suppresses lung inflammation via AGO2 gene silencing

Koeppen

Ashare

et al. 2021

Preprint

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Although inhaled tobramycin increases lung function in people with cystic fibrosis (pwCF), the density of P. aeruginosa in the lungs is only modestly reduced; hence, the mechanism whereby tobramycin improves lung function remains unclear. Previously, we demonstrated that P. aeruginosa secretes outer membrane vesicles (OMVs) that fuse with bronchial epithelial cells (HBECs), delivering small RNAs (sRNAs) that suppress the host immune response. Thus, we hypothesized that tobramycin modifies the sRNA content of OMVs leading to reduced inflammation and neutrophil-mediated lung damage. We found that tobramycin increased the amount of two 5′ tRNA-fMet halves in OMVs (Tobi-OMVs) and that Tobi-OMVs elicited less IL-8 secretion by CF-HBECs than control OMVs (ctrl-OMVs). A specific 5′ tRNA-fMet halves inhibitor reduced the ability of Tobi-OMVs to suppress IL-8 secretion. Tobi-OMVs were also less effective in stimulating KC secretion and neutrophil recruitment in mouse lungs compared to ctrl-OMVs. Tobramycin also reduced IL-8 and neutrophil abundance in bronchoalveolar lavage fluid obtained from pwCF. The 5′ tRNA-fMet halves reduced IL-8 secretion by an AGO2-mediated post-transcriptional regulatory mechanism. The clinical benefit of tobramycin is partly due to an increase in the secretion of 5′ tRNA-fMet halves in OMVs, leading to the attenuation of IL-8 and neutrophil-mediated CF lung damage.

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Changes in the Cystic Fibrosis Airway Microbiome in Response to CFTR Modulator Therapy

Cited by 38 publications

References 59 publications

The cystic fibrosis lung microenvironment alters antibiotic activity: causes and effects

The cystic fibrosis lung microenvironment alters antibiotic activity: causes and effects

Comparison of microbial composition of cough swabs and sputum for pathogen detection in patients with cystic fibrosis

Tobramycin-induced secretion of P. aeruginosa 5′ tRNA-fMet halves suppresses lung inflammation via AGO2 gene silencing

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