Fecal microbiota changes in people with cystic fibrosis after 6 months of elexacaftor/tezacaftor/ivacaftor: Findings from the promise study

Jennifer T Duong; Hillary S Hayden; Adrian J Verster; Christopher E Pope; Carson Miller; Kelsi Penewit; Stephen J Salipante; Steven M Rowe; George M Solomon; David Nichols; Andrea Kelly; Sarah Jane Schwarzenberg; Steven D Freedman; Lucas R Hoffman

doi:10.1016/j.jcf.2025.05.006

Fecal microbiota changes in people with cystic fibrosis after 6 months of elexacaftor/tezacaftor/ivacaftor: Findings from the promise study

J Cyst Fibros. 2025 Jun 6:S1569-1993(25)01487-0. doi: 10.1016/j.jcf.2025.05.006. Online ahead of print.

Authors

Affiliations

¹ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of California San Francisco School of Medicine, San Francisco, CA, USA. Electronic address: Jennifer.duong@ucsf.edu.
² Department of Microbiology, University of Washington School of Medicine, Seattle, WA, USA.
³ Pythia Informatics, Ottawa, Canada.
⁴ Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA.
⁵ Department of Medicine and the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA and CF Foundation, Bethesda, MD, USA.
⁶ CF Foundation, Bethesda, MD, USA and University of Washington School of Medicine, Seattle, WA, USA.
⁷ Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁸ Department of Pediatrics, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA.
⁹ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Microbiology and Department of Pediatrics, Division of Pulmonary and Sleep Medicine, University of Washington School of Medicine, Seattle, WA, USA.

PMID: 40483244
DOI: 10.1016/j.jcf.2025.05.006

Abstract

Background: People with cystic fibrosis (PwCF) often have fecal dysbioses relative to those without CF, characterized by increased pro-inflammatory microbiota and gastrointestinal (GI) inflammation as measured by fecal calprotectin, suggesting that inflammation contributes to CF GI disease. The multicenter observational PROMISE study (NCT04038047) found that calprotectin decreased in PwCF treated with elexacaftor/tezacaftor/ivacaftor (ETI). To better understand the dynamics between fecal dysbiosis and GI inflammation, we characterized the microbiomes of fecal samples from PROMISE and the relationships with calprotectin before, 1-month post, and 6-months post ETI.

Methods: Fecal microbiota from participants ≥12 y/o were determined by shotgun metagenomic sequencing with random forest modeling and multivariate linear regression analysis to define relationships between microbiota, calprotectin, and deltaF508 genotype before and after ETI.

Results: We analyzed 345 samples from 124 participants. At baseline, we observed community-level differences in the fecal microbiota among participants with abnormal compared to normal calprotectin. With ETI, the relative abundances of 7 bacterial species - Escherichia coli, Staphylococcus aureus, Clostridium scindens, Enterocloster clostridioformis, Clostridium butyricum, Anaeroglobus geminatus, and Ruminococcus gnavus - decreased significantly, correlating with calprotectin decrease. We detected community-level differences in the fecal microbiota based on CFTR genotype and a distinct pattern of microbiota change in F508del homozygous compared to heterozygous participants after ETI.

Conclusions: We identified 7 species for which fecal abundances decreased with ETI and correlated with calprotectin decrease, supporting a close relationship between fecal microbiota and inflammation in PwCF. Future work will define these relationships with metabolites and GI symptoms during long-term ETI therapy.

Keywords: Dysbiosis; Elexacaftor/tezacaftor/ivacaftor; Fecal calprotectin; Fecal microbiome.