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Impact of the CFTR-potentiator ivacaftor on airway microbiota in cystic fibrosis patients carrying a G551D mutation.

Bernarde C, Keravec M, Mounier J, Gouriou S, Rault G, Férec C, Barbier G, Héry-Arnaud G - PLoS ONE (2015)

Bottom Line: There was no significant difference in total bacterial load before and after treatment.Comparison of global community composition found no significant changes in microbiota.Two OTUs, however, showed contrasting dynamics: after initiation of ivacaftor, the relative abundance of the anaerobe Porphyromonas 1 increased (p<0.01) and that of Streptococcus 1 (S. mitis group) decreased (p<0.05), possibly in relation to the anti-Gram-positive properties of ivacaftor.

View Article: PubMed Central - PubMed

Affiliation: EA 3882-Laboratoire Universitaire de Biodiversité et Ecologie Microbienne, Université de Brest, Brest, France.

ABSTRACT

Background: Airway microbiota composition has been clearly correlated with many pulmonary diseases, and notably with cystic fibrosis (CF), an autosomal genetic disorder caused by mutation in the CF transmembrane conductance regulator (CFTR). Recently, a new molecule, ivacaftor, has been shown to re-establish the functionality of the G551D-mutated CFTR, allowing significant improvement in lung function.

Objective and methods: The purpose of this study was to follow the evolution of the airway microbiota in CF patients treated with ivacaftor, using quantitative PCR and pyrosequencing of 16S rRNA amplicons, in order to identify quantitative and qualitative changes in bacterial communities. Three G551D children were followed up longitudinally over a mean period of more than one year covering several months before and after initiation of ivacaftor treatment.

Results: 129 operational taxonomy units (OTUs), representing 64 genera, were identified. There was no significant difference in total bacterial load before and after treatment. Comparison of global community composition found no significant changes in microbiota. Two OTUs, however, showed contrasting dynamics: after initiation of ivacaftor, the relative abundance of the anaerobe Porphyromonas 1 increased (p<0.01) and that of Streptococcus 1 (S. mitis group) decreased (p<0.05), possibly in relation to the anti-Gram-positive properties of ivacaftor. The anaerobe Prevotella 2 correlated positively with the pulmonary function test FEV-1 (r=0.73, p<0.05). The study confirmed the presumed positive role of anaerobes in lung function.

Conclusion: Several airway microbiota components, notably anaerobes (obligate or facultative anaerobes), could be valuable biomarkers of lung function improvement under ivacaftor, and could shed light on the pathophysiology of lung disease in CF patients.

No MeSH data available.


Related in: MedlinePlus

Principal coordinates analysis (PCoA) of CF sputum samples according to ivacaftor treatment and microbial community composition and abundance.A) PCoA of microbial community structures using weighted and normalized UniFrac phylogenetic distances. A clustering of 6 of the 8 BT samples (before ivacaftor treatment; red squares) was observed. Conversely, AT samples (after ivacaftor treatment; blue circles) appeared scattered on the graph. PC1 and PC2 represented 75.2% of the variability. B) PCoA of microbial community structures using Bray Curtis non-phylogenetic distances. Seven of the 8 BT samples (red squares) were clustered. PC1 and PC2 represented 55.3% of the variability.
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pone.0124124.g004: Principal coordinates analysis (PCoA) of CF sputum samples according to ivacaftor treatment and microbial community composition and abundance.A) PCoA of microbial community structures using weighted and normalized UniFrac phylogenetic distances. A clustering of 6 of the 8 BT samples (before ivacaftor treatment; red squares) was observed. Conversely, AT samples (after ivacaftor treatment; blue circles) appeared scattered on the graph. PC1 and PC2 represented 75.2% of the variability. B) PCoA of microbial community structures using Bray Curtis non-phylogenetic distances. Seven of the 8 BT samples (red squares) were clustered. PC1 and PC2 represented 55.3% of the variability.

Mentions: PCoA based on UniFrac and Bray Curtis distance metrics revealed groupings of respectively 6 and 7 out of the 8 BT samples (Fig 4A and 4B). Conversely, the AT samples did not cluster, suggesting broader dissimilarity in microbial community composition and relative abundance after ivacaftor treatment. These two observations, taken together with a tendency for greater diversity in AT samples (S4 Fig), suggest that ivacaftor may disrupt the CF microbiota, even if no significant differences were observed on the Colin White test (S2 Table). This tendency corroborates the hypothesis made by Rowe et al., who suggested increased microbial diversity resulting from ivacaftor administration [14]. As for other clinical situations in CF [11,25,32], increased biodiversity may be supposed to be associated with improved respiratory function, as well as other clinical endpoints in phase-3 studies of ivacaftor [15,16].


Impact of the CFTR-potentiator ivacaftor on airway microbiota in cystic fibrosis patients carrying a G551D mutation.

Bernarde C, Keravec M, Mounier J, Gouriou S, Rault G, Férec C, Barbier G, Héry-Arnaud G - PLoS ONE (2015)

Principal coordinates analysis (PCoA) of CF sputum samples according to ivacaftor treatment and microbial community composition and abundance.A) PCoA of microbial community structures using weighted and normalized UniFrac phylogenetic distances. A clustering of 6 of the 8 BT samples (before ivacaftor treatment; red squares) was observed. Conversely, AT samples (after ivacaftor treatment; blue circles) appeared scattered on the graph. PC1 and PC2 represented 75.2% of the variability. B) PCoA of microbial community structures using Bray Curtis non-phylogenetic distances. Seven of the 8 BT samples (red squares) were clustered. PC1 and PC2 represented 55.3% of the variability.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390299&req=5

pone.0124124.g004: Principal coordinates analysis (PCoA) of CF sputum samples according to ivacaftor treatment and microbial community composition and abundance.A) PCoA of microbial community structures using weighted and normalized UniFrac phylogenetic distances. A clustering of 6 of the 8 BT samples (before ivacaftor treatment; red squares) was observed. Conversely, AT samples (after ivacaftor treatment; blue circles) appeared scattered on the graph. PC1 and PC2 represented 75.2% of the variability. B) PCoA of microbial community structures using Bray Curtis non-phylogenetic distances. Seven of the 8 BT samples (red squares) were clustered. PC1 and PC2 represented 55.3% of the variability.
Mentions: PCoA based on UniFrac and Bray Curtis distance metrics revealed groupings of respectively 6 and 7 out of the 8 BT samples (Fig 4A and 4B). Conversely, the AT samples did not cluster, suggesting broader dissimilarity in microbial community composition and relative abundance after ivacaftor treatment. These two observations, taken together with a tendency for greater diversity in AT samples (S4 Fig), suggest that ivacaftor may disrupt the CF microbiota, even if no significant differences were observed on the Colin White test (S2 Table). This tendency corroborates the hypothesis made by Rowe et al., who suggested increased microbial diversity resulting from ivacaftor administration [14]. As for other clinical situations in CF [11,25,32], increased biodiversity may be supposed to be associated with improved respiratory function, as well as other clinical endpoints in phase-3 studies of ivacaftor [15,16].

Bottom Line: There was no significant difference in total bacterial load before and after treatment.Comparison of global community composition found no significant changes in microbiota.Two OTUs, however, showed contrasting dynamics: after initiation of ivacaftor, the relative abundance of the anaerobe Porphyromonas 1 increased (p<0.01) and that of Streptococcus 1 (S. mitis group) decreased (p<0.05), possibly in relation to the anti-Gram-positive properties of ivacaftor.

View Article: PubMed Central - PubMed

Affiliation: EA 3882-Laboratoire Universitaire de Biodiversité et Ecologie Microbienne, Université de Brest, Brest, France.

ABSTRACT

Background: Airway microbiota composition has been clearly correlated with many pulmonary diseases, and notably with cystic fibrosis (CF), an autosomal genetic disorder caused by mutation in the CF transmembrane conductance regulator (CFTR). Recently, a new molecule, ivacaftor, has been shown to re-establish the functionality of the G551D-mutated CFTR, allowing significant improvement in lung function.

Objective and methods: The purpose of this study was to follow the evolution of the airway microbiota in CF patients treated with ivacaftor, using quantitative PCR and pyrosequencing of 16S rRNA amplicons, in order to identify quantitative and qualitative changes in bacterial communities. Three G551D children were followed up longitudinally over a mean period of more than one year covering several months before and after initiation of ivacaftor treatment.

Results: 129 operational taxonomy units (OTUs), representing 64 genera, were identified. There was no significant difference in total bacterial load before and after treatment. Comparison of global community composition found no significant changes in microbiota. Two OTUs, however, showed contrasting dynamics: after initiation of ivacaftor, the relative abundance of the anaerobe Porphyromonas 1 increased (p<0.01) and that of Streptococcus 1 (S. mitis group) decreased (p<0.05), possibly in relation to the anti-Gram-positive properties of ivacaftor. The anaerobe Prevotella 2 correlated positively with the pulmonary function test FEV-1 (r=0.73, p<0.05). The study confirmed the presumed positive role of anaerobes in lung function.

Conclusion: Several airway microbiota components, notably anaerobes (obligate or facultative anaerobes), could be valuable biomarkers of lung function improvement under ivacaftor, and could shed light on the pathophysiology of lung disease in CF patients.

No MeSH data available.


Related in: MedlinePlus