Lumacaftor/ivacaftor changes the lung microbiome and metabolome in cystic fibrosis patients

Abstract

RationaleTargeted cystic fibrosis (CF) therapy with lumacaftor/ivacaftor partly restores chloride channel function and improves epithelial fluid transport in the airways. Consequently, changes in the microbiome that is adapted to CF lungs may occur.ObjectivesTo investigate the effects of lumacaftor/ivacaftor on respiratory microbial composition and microbial metabolic activity by repeatedly sampling the lower respiratory tract.MethodsThis was a single-center longitudinal observational cohort study in adult CF patients with a homozygous Phe508del mutation. Lung function measurements and microbial cultures of sputum were performed as part of routine care. An oral and nasal wash, and a breath sample were collected before and every 3 months after starting therapy, up to 1 year.ResultsTwenty patients were included in this study. Amplicon 16S RNA and metagenomics sequencing revealed that Pseudomonas aeruginosa was most abundant in sputum and seemed to decrease after 6 months of treatment, although this did not reach statistical significance after correction for multiple testing. Two types of untargeted metabolomics analyses in sputum showed a change in metabolic composition between 3 and 9 months that almost returned to baseline levels after 12 months of treatment. The volatile metabolic composition of breath was significantly different after 3 months and remained different from baseline until 12 months follow up.ConclusionsAfter starting CF transmembrane conductance regulator (CFTR) modulating treatment in CF patients with a homozygous Phe508del mutation, a temporary and moderate change in lung microbiome is observed, which is mainly characterised by a reduction in the relative abundance of Pseudomonas aeruginosa.

CFTR Modulator Therapies: Potential Impact on Airway Infections in Cystic Fibrosis

“…Moreover, a study following up CF patients for 6 years after IVA initiation has demonstrated that the bacterial burden, assessed through cultural methods, remained stable at the pre-treatment levels for all the observation periods [ 75 ]. The addition of CFTR correctors such as LUMA has shown an increase in microbial diversity in the CF airways in some studies [ 76 ] but other studies show a less marked response [ 77 ]. Neerincx et al [ 77 ] showed that in CF patients homozygous for the F508del CFTR mutation, treatment with LUMA/IVA for 6 months induced a temporary and moderate change in the lung microbiome mainly characterised by a reduction in the relative abundance of P. aeruginosa .…”

“…The addition of CFTR correctors such as LUMA has shown an increase in microbial diversity in the CF airways in some studies [ 76 ] but other studies show a less marked response [ 77 ]. Neerincx et al [ 77 ] showed that in CF patients homozygous for the F508del CFTR mutation, treatment with LUMA/IVA for 6 months induced a temporary and moderate change in the lung microbiome mainly characterised by a reduction in the relative abundance of P. aeruginosa . A similar trend was observed in sputum metabolome, in particular for metabolites from the tryptophan–kynurenic acid pathway that seems to be related to the abundance of P. aeruginosa .…”

“…A recent study analysing sputum microbiome and metabolome in a small number of CF patients ( n = 24) before and after ETI therapy showed that this treatment was associated with changes in the airway microbiome and metabolome [ 78 ]. The drug effect was stronger on sputum biochemistry with a decrease in peptides, amino acids and kynurenine metabolism; these findings suggest that ETI therapy and possibly other CFTR modulators [ 77 ] might “reshape microbiome niche space in CF mucus” by decreasing the availability of peptides and amino acids, an effect that could have clinical implications for the treatment of lung infections. However, more long-term studies on larger number of patients are needed to define the effects of ETI treatment and other modulators on airway microbiome as well as to assess whether these treatments will induce an altered steady state of the bacterial and viral community.…”

“…A limited number of studies have assessed the effect of treatment with LUMA/IVA (LUMA/IVA) or TEZA/IVA (TEZA/IVA) on airway microbial communities changes. One of the most recent studies investigated the effects of LUMA/IVA on microbial composition and microbial metabolic activity in adult CF patients homozygous for the F508del mutation, in which repeated sampling of the lower respiratory tract was performed [ 77 ]. The overall results of this study did not show important effects of LUMA/IVA treatment on microbiological composition; in fact, only temporary and moderate changes in the lung microbiome were observed, mainly characterised by a reduction in the relative abundance of P. aeruginosa .…”

Metaproteomics to Decipher CF Host-Microbiota Interactions: Overview, Challenges and Future Perspectives

“…These findings, in combination with volatile metabolite profiles associated with common CF pathogens and the host's immune response to infection, suggest that changes to the volatile metabolome during an exacerbation correlate with changes to the microbiome [49]. Similarly, a study combining metagenomics with two types of untargeted metabolomics analyses applied to sputum samples indicated that the temporary and moderate changes to the lung microbiome observed after initiating the CFTR modulating treatment Ivacaftor/Lumacaftor are mainly characterised by a reduction in the relative abundance of P. aeruginosa [50]. A branch of metabolomics dedicated to lipid analysis [51] (lipidomics) studies the lipids present in a sample, arising from host cells and tissues/lipid substrates [52].…”