Impact of Elexacaftor/Tezacaftor/Ivacaftor Therapy on the Cystic Fibrosis Airway Microbial Metagenome
ABSTRACT The introduction of mutation-specific combination therapy with the cystic fibrosis transmembrane conductance regulator (CFTR) modulators elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has substantially improved lung function and quality of life of people with cystic fibrosis (CF). Collectin...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2022-10-01
|
| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.01454-22 |
| _version_ | 1811329711935062016 |
|---|---|
| author | Sophia T. Pallenberg Marie-Madlen Pust Ilona Rosenboom Gesine Hansen Lutz Wiehlmann Anna-Maria Dittrich Burkhard Tümmler |
| author_facet | Sophia T. Pallenberg Marie-Madlen Pust Ilona Rosenboom Gesine Hansen Lutz Wiehlmann Anna-Maria Dittrich Burkhard Tümmler |
| author_sort | Sophia T. Pallenberg |
| collection | DOAJ |
| description | ABSTRACT The introduction of mutation-specific combination therapy with the cystic fibrosis transmembrane conductance regulator (CFTR) modulators elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has substantially improved lung function and quality of life of people with cystic fibrosis (CF). Collecting deep cough swabs and induced sputum, this postapproval study examined the effect of 14- and 50-week treatment with ELX/TEZ/IVA on the airway microbial metagenome of pancreatic- insufficient CF patients aged 12 years and older. Compared to pretreatment, the total bacterial load decreased, the individual species were more evenly distributed in the community, and the individual microbial metagenomes became more similar in their composition. However, the microbial network remained vulnerable to fragmentation. The initial shift of the CF metagenome was attributable to the ELX/TEZ/IVA-mediated gain of CFTR activity followed by a diversification driven by a group of commensals at the 1-year time point that are typical for healthy airways. IMPORTANCE Shotgun metagenome sequencing of respiratory secretions with spike-in controls for normalization demonstrated that 1 year of high-efficient CFTR modulation with elexacaftor/tezacaftor/ivacaftor extensively reduced the bacterial load. Longer observation periods will be necessary to resolve whether the partial reversion of the basic defect that is achieved with ELX/TEZ/IVA is sufficient in the long run to render the CF lungs robust against the recolonization with common opportunistic pathogens. |
| first_indexed | 2024-04-13T15:48:43Z |
| format | Article |
| id | doaj.art-8c031c8c72cc46bebc9e4f8b4a080e41 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-04-13T15:48:43Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-8c031c8c72cc46bebc9e4f8b4a080e412022-12-22T02:40:54ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972022-10-0110510.1128/spectrum.01454-22Impact of Elexacaftor/Tezacaftor/Ivacaftor Therapy on the Cystic Fibrosis Airway Microbial MetagenomeSophia T. Pallenberg0Marie-Madlen Pust1Ilona Rosenboom2Gesine Hansen3Lutz Wiehlmann4Anna-Maria Dittrich5Burkhard Tümmler6Department for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, GermanyDepartment for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, GermanyDepartment for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, GermanyDepartment for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, GermanyResearch Core Unit Genomics, Hannover Medical School, Hannover, GermanyDepartment for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, GermanyDepartment for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, GermanyABSTRACT The introduction of mutation-specific combination therapy with the cystic fibrosis transmembrane conductance regulator (CFTR) modulators elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has substantially improved lung function and quality of life of people with cystic fibrosis (CF). Collecting deep cough swabs and induced sputum, this postapproval study examined the effect of 14- and 50-week treatment with ELX/TEZ/IVA on the airway microbial metagenome of pancreatic- insufficient CF patients aged 12 years and older. Compared to pretreatment, the total bacterial load decreased, the individual species were more evenly distributed in the community, and the individual microbial metagenomes became more similar in their composition. However, the microbial network remained vulnerable to fragmentation. The initial shift of the CF metagenome was attributable to the ELX/TEZ/IVA-mediated gain of CFTR activity followed by a diversification driven by a group of commensals at the 1-year time point that are typical for healthy airways. IMPORTANCE Shotgun metagenome sequencing of respiratory secretions with spike-in controls for normalization demonstrated that 1 year of high-efficient CFTR modulation with elexacaftor/tezacaftor/ivacaftor extensively reduced the bacterial load. Longer observation periods will be necessary to resolve whether the partial reversion of the basic defect that is achieved with ELX/TEZ/IVA is sufficient in the long run to render the CF lungs robust against the recolonization with common opportunistic pathogens.https://journals.asm.org/doi/10.1128/spectrum.01454-22CFTR modulationELX/TEZ/IVAairway metagenomecystic fibrosismetagenomicswhole-genome sequencing |
| spellingShingle | Sophia T. Pallenberg Marie-Madlen Pust Ilona Rosenboom Gesine Hansen Lutz Wiehlmann Anna-Maria Dittrich Burkhard Tümmler Impact of Elexacaftor/Tezacaftor/Ivacaftor Therapy on the Cystic Fibrosis Airway Microbial Metagenome Microbiology Spectrum CFTR modulation ELX/TEZ/IVA airway metagenome cystic fibrosis metagenomics whole-genome sequencing |
| title | Impact of Elexacaftor/Tezacaftor/Ivacaftor Therapy on the Cystic Fibrosis Airway Microbial Metagenome |
| title_full | Impact of Elexacaftor/Tezacaftor/Ivacaftor Therapy on the Cystic Fibrosis Airway Microbial Metagenome |
| title_fullStr | Impact of Elexacaftor/Tezacaftor/Ivacaftor Therapy on the Cystic Fibrosis Airway Microbial Metagenome |
| title_full_unstemmed | Impact of Elexacaftor/Tezacaftor/Ivacaftor Therapy on the Cystic Fibrosis Airway Microbial Metagenome |
| title_short | Impact of Elexacaftor/Tezacaftor/Ivacaftor Therapy on the Cystic Fibrosis Airway Microbial Metagenome |
| title_sort | impact of elexacaftor tezacaftor ivacaftor therapy on the cystic fibrosis airway microbial metagenome |
| topic | CFTR modulation ELX/TEZ/IVA airway metagenome cystic fibrosis metagenomics whole-genome sequencing |
| url | https://journals.asm.org/doi/10.1128/spectrum.01454-22 |
| work_keys_str_mv | AT sophiatpallenberg impactofelexacaftortezacaftorivacaftortherapyonthecysticfibrosisairwaymicrobialmetagenome AT mariemadlenpust impactofelexacaftortezacaftorivacaftortherapyonthecysticfibrosisairwaymicrobialmetagenome AT ilonarosenboom impactofelexacaftortezacaftorivacaftortherapyonthecysticfibrosisairwaymicrobialmetagenome AT gesinehansen impactofelexacaftortezacaftorivacaftortherapyonthecysticfibrosisairwaymicrobialmetagenome AT lutzwiehlmann impactofelexacaftortezacaftorivacaftortherapyonthecysticfibrosisairwaymicrobialmetagenome AT annamariadittrich impactofelexacaftortezacaftorivacaftortherapyonthecysticfibrosisairwaymicrobialmetagenome AT burkhardtummler impactofelexacaftortezacaftorivacaftortherapyonthecysticfibrosisairwaymicrobialmetagenome |