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

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

doi:10.1016/j.jcf.2024.05.002

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

J Cyst Fibros. 2024 May 14:S1569-1993(24)00064-X. doi: 10.1016/j.jcf.2024.05.002. Online ahead of print.

Authors

Affiliations

¹ Department of Applied Sciences, Northumbria University, Newcastle, UK.
² Department of Natural Sciences, Manchester Metropolitan University, UK.
³ School of Medicine, University of Nottingham, UK; NIHR Nottingham Biomedical Research Centre, UK.
⁴ Sir Peter Mansfield Imaging Centre, University of Nottingham, UK.
⁵ School of Medicine, University of Nottingham, UK; Nestlé Institute of Health Sciences, Société des Produits Nestlé, Lausanne, Switzerland.
⁶ School of Medicine, University of Nottingham, UK; NIHR Nottingham Biomedical Research Centre, UK; School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, UK.
⁷ Department of Applied Sciences, Northumbria University, Newcastle, UK; Department of Respiratory Medicine, Northern Care Alliance NHS Foundation Trust, Salford, UK. Electronic address: chris.vandergast@northumbria.ac.uk.

PMID: 38749891
DOI: 10.1016/j.jcf.2024.05.002

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.

Keywords: CFTR modulator therapy; Dysbiosis; Gut microbiome; Kaftrio; Pulmonary antibiotics; Trikafta.