Impact of extended Elexacaftor/Tezacaftor/Ivacaftor therapy on the gut microbiome in cystic fibrosis

Marsh, Ryan; Santos, Claudio Dos; Yule, Alexander; Dellschaft, Neele S; Hoad, Caroline L; Ng, Christabella; Major, Giles; Smyth, Alan R; Rivett, Damian; van der Gast, Christopher

Abstract

Background
There is a paucity of knowledge on the longer-term effects of CF transmembrane conductance regulator (CFTR) modulator therapies upon the gut microbiome and associated outcomes. In a pilot study, we investigated longitudinal Elexacaftor/Tezacaftor/Ivacaftor (ETI) therapy on the gut microbiota, metabolomic functioning, and clinical outcomes in people with CF (pwCF).

Study design
Faecal samples from 20 pwCF were acquired before and then following 3, 6, and 17+ months of ETI therapy. Samples were subjected to microbiota sequencing and targeted metabolomics to profile and quantify short-chain fatty acid composition. Ten healthy matched controls were included for comparison. Clinical data, including markers of intestinal function were integrated to investigate relationships.

Results
Extended ETI therapy increased core microbiota diversity and composition, which translated to gradual shifts in whole microbiota composition towards that observed in healthy controls. Despite becoming more similar over time, CF microbiota and functional metabolite compositions remained significantly different to healthy controls. Antibiotic treatment for pulmonary infection significantly explained a relatively large degree of variation within the whole microbiota and rarer satellite taxa. Clinical outcomes were not significantly different following ETI.

Conclusions
Whilst differences persisted, a positive trajectory towards the microbiota observed in healthy controls was found. We posit that progression was predominately impeded by pulmonary antibiotics administration. We recommend future studies use integrated omics approaches within a combination of long-term longitudinal patient studies and model experimental systems. This will deepen our understanding of the impacts of CFTR modulator therapy and respiratory antibiotic interventions upon the gut microbiome and gastrointestinal pathophysiology in CF.

Citation

Marsh, R., Santos, C. D., Yule, A., Dellschaft, N. S., Hoad, C. L., Ng, C., Major, G., Smyth, A. R., Rivett, D., & van der Gast, C. (2024). Impact of extended Elexacaftor/Tezacaftor/Ivacaftor therapy on the gut microbiome in cystic fibrosis. Journal of Cystic Fibrosis, 23(5), 967-976. https://doi.org/10.1016/j.jcf.2024.05.002

• Journal Article Type: Article
• Acceptance Date: May 4, 2024
• Online Publication Date: May 14, 2024
• Publication Date: 2024-09
• Deposit Date: Jul 23, 2024
• Publicly Available Date: Jul 24, 2024
• Journal: Journal of Cystic Fibrosis
• Print ISSN: 1569-1993
• Electronic ISSN: 1873-5010
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 23
• Issue: 5
• Pages: 967-976
• DOI: https://doi.org/10.1016/j.jcf.2024.05.002
• Public URL: https://nottingham-repository.worktribe.com/output/34874755
• Publisher URL: https://www.cysticfibrosisjournal.com/article/S1569-1993(24)00064-X/fulltext