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  • Clinical Research Article
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Gut–lung microbial dynamics with lumacaftor/ivacaftor in children with cystic fibrosis: a prospective multicenter study

Pediatric Research (2026) Cite this article

Abstract

Background

CFTR modulators such as lumacaftor/ivacaftor (LUM/IVA) may reshape microbiota-mycobiota composition in the lungs and gut. While the gut-lung axis is established in other settings, little is known about its role following modulator therapy, particularly in the 2–11 age group.

Methods

In a prospective national multicentre study, 116 children with cystic fibrosis (2–11 years) starting LUM/IVA were followed for 12 months. Stool and sputum were collected at baseline, 3, 6 and 12 months. Bacterial and fungal communities were profiled by 16S rRNA and ITS2 sequencing; diversity, dysbiosis indices, faecal and sputum calprotectin, and gut–lung microbial networks were analysed.

Results

LUM/IVA was associated with increased bacterial diversity and compositional shifts in gut and lung microbiota, alongside a significant reduction in faecal calprotectin. Airway mycobiota diversity remained stable. Two lung microbiome response profiles emerged: “responders” (greater bacterial diversity gain) and “non-responders” (minimal change). Baseline gut and lung composition predicted these profiles with 81% accuracy in a random-forest model. Inter-organ microbial interactions peaked at 3 months after initiation and then diverged between profiles, indicating distinct gut–lung axis remodelling.

Conclusion

LUM/IVA influences gut-lung microbiota-mycobiota dynamics, with heterogeneous responses between paediatric patients. Identifying factors predictive of response is a key future challenge.

Impact

  • In 116 children aged 2–11, lumacaftor/ivacaftor reshaped gut and lung microbiota and reduced fecal calprotectin over 12 months.

  • First pediatric multicenter study integrating bacterial and fungal profiling of stool and sputum with gut–lung network analyses; identifies two distinct lung microbiome response profiles.

  • Baseline gut and lung composition predicted the response profile with approximately 81% accuracy.

  • Highlights a 3-month interaction peak and baseline profiling as practical markers to guide monitoring and microbiome-informed precision care.

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Fig. 1: Change in lung and gut microbiotas under LUM/IVA therapy.
The alternative text for this image may have been generated using AI.
Fig. 2: Change in faecal calprotectin under LUM/IVA therapy.
The alternative text for this image may have been generated using AI.
Fig. 3: Baseline microbial genera predicting lung microbiota evolution.
The alternative text for this image may have been generated using AI.
Fig. 4: Evolution of the gut-lung interactions under LUM/IVA therapy in “microbiome responders” and “microbiome non-responders”.
The alternative text for this image may have been generated using AI.
Fig. 5: Differential evolution of microbes within the gut-lung interactome between “microbiome responders” and “microbiome non-responders” sub-populations following LUM/IVA therapy.
The alternative text for this image may have been generated using AI.

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Data availability

All sequencing data are available the European Nucleotide Archive (ENA) of European Bioinformatics Institute (EBI) (https://www.ebi.ac.uk/ena/browser/home) under PRJEB82774. Analysis code available on request.

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Acknowledgements

We thank the patients and their families for participating in the study as well as all nurses, physicians, and clinical research coordinators who were involved in the study. We extend our gratitude to the LumIvaBiota study group, comprising Sébastien Imbert and Michael Fayon (Bordeaux University, INSERM U1045); Cécile Bébéar, Julie Macey, Aurore Capelli, Géraldine Robert, and Frédéric Perry (Bordeaux University Hospital); Guillaume Simon, Océane Zaghet and Virginie Saintignan (Bordeaux University Hospital, CIC 1401); Erwan Guichoux, Olivier Lepais, and Zoé Delporte (PGTB, Pierroton); Anne-Sophie Bonnel (Hôpital Necker Enfants malades, AP-HP), Muriel Cornet and Catherine Llerena (Grenoble University Hospital); Geneviève Hery-Arnaud and Stéphanie Gouriou (Brest University Hospital); Michèle Gerardin, Véronique Houdoin, Laurence Le Clainche Viala, Sophie Mayer, and Patricia Mariani (Hôpital Robert Debré, AP-HP); Sophie Ramel (Roscoff Fondation Ildys); Dominique Grenet and Emilie Cardot-Martin (Foch Hospital); Jean-Christophe Dubus, Nathalie Stremler-Le Bel, Mélisande Baravalle-Einaudi, and Stephane Ranque (Marseille University Hospital); Léa Rotidis, Emmanuel Mas, Marie Mittaine, and Sophie Cassaing (Toulouse University Hospital); Nathalie Wizla, Caroline Thumerelle, Dominique Turck, Olivier Le Rouzic, Séverine Loridant, and Anne-Sophie Deleplanque (Lille University Hospital); Philippe Reix, Anne Doleans Jordheim, and Jean Menotti (Hospices Civils de Lyon); Sébastien Kiefer, Aurélie Tatopoulos, Aurore Blonde, and Anne Debourgogne (Nancy University Hospital); Jeanne Languepin, Alexandra Masson-Rouchaud, Magali Dupuy-Grasset, and Marie-Fleur Durieux (Limoges University Hospital); Sylvie Leroy, Sarah Marchal, and Lilia Hasseine (Nice University Hospital); Pierre-Regis Burgel (Hôpital Cochin, AP-HP); Raphael Chiron and Laurence Lachaud (Montpellier University Hospital); and Hélène Morisse-Pradier and Loïc Favennec (Rouen University Hospital).

Funding

This work was funded by research grants from VERTEX (Lumivabiota study referenced as IIS-2016-105028) and Vaincre la Mucoviscidose (VLM) association (EMILII project under VLM reference: RC20200502658); both playing no role in the data collection and analysis, or in the decision to submit the article.

Author information

Author notes

  1. These authors contributed equally: Florian Lussac-Sorton, Jayanth Kumar Narayana.

  2. These authors jointly supervised this work: Laurence Delhaes, Raphael Enaud.

Authors and Affiliations

  1. University of Bordeaux, INSERM U1045, Centre de Recherche Cardio-thoracique de Bordeaux, Bordeaux, France

    Florian Lussac-Sorton, Elena Charpentier, Fabien Beaufils, Patrick Berger, Laurence Delhaes & Raphael Enaud

  2. Bordeaux University Hospital, University of Bordeaux, FHU ACRONIM, Bordeaux, France

    Florian Lussac-Sorton, Elena Charpentier, Fabien Beaufils, Patrick Berger, Laurence Delhaes & Raphael Enaud

  3. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

    Jayanth Kumar Narayana & Sanjay H. Chotirmall

  4. Lille University Hospital, CRCM Pédiatrique, Lille, France

    Nathalie Wizla

  5. Nancy University Hospital, CRCM Pédiatrique, Vandeouvre les Nancy, France

    Aurélie Tatopoulos

  6. CHU Timone-Enfants, CRCM Pédiatrique, Marseille, France

    Mélissa Baravalle

  7. Toulouse University Hospital, CRCM Pédiatrique, Toulouse, France

    Léa Rotidis

  8. Hôpital Robert-Debré APHP, CRCM Pédiatrique, Paris, France

    Véronique Houdoin

  9. Grenoble University Hospital, CRCM Pédiatrique, Grenoble, France

    Catherine Llerena

  10. Lyon University Hospital, CRCM Pédiatrique, Lyon, France

    Philippe Reix

  11. Centre de Référence Maladies Rares Mucoviscidose et Maladies Apparentées, Hôpital Necker Enfants malades, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Paris Centre, Paris, France

    Isabelle Sermet

  12. Limoges University Hospital, CRCM Mixte, Limoges, France

    Jeanne Languepin

  13. Bordeaux University Hospital, Service de Parasitologie-Mycologie, Bordeaux, France

    Maxime Lefranc & Laurence Delhaes

  14. PGTB, University of Bordeaux, INRAE, Cestas, France

    Préscillia Alves Gomes & Laurence Delhaes

  15. Bordeaux University Hospital, CRCM Pédiatrique, CIC 1401, INSERM-U, Bordeaux, France

    Stéphanie Bui & Raphael Enaud

  16. Department of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore, Singapore

    Sanjay H. Chotirmall

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  1. Florian Lussac-Sorton
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Contributions

R.E., L.D. designed and granted the study. F.L.S., N.W., A.T., M.B., L.R., V.H., C.L., P.R., I.S., J.L., S.B., F.B., L.D., R.E. contributed to data collection. R.E., F.L.S., E.C., L.D., PAG. designed and performed NGS experiments. R.E., F.L.S., E.C., M.L., J.K.N., P.B., S.H.C., L.D. contributed to data management and analysis. R.E., F.L.S., M.L., J.K.N., S.H.C., L.D. performed the statistical analysis. R.E., F.L.S., and L.D. wrote the first draft of the manuscript that was revised and approved for important intellectual content by all authors. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Raphael Enaud.

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Competing interests

Raphaël Enaud reports support for the present manuscript from Association Vaincre la Mucoviscidose. Outside the submitted work, he has received personal fees from Biocodex and Menarini, as well as non-financial support from Pfizer, MSD, Nutricia, Nestlé, AbbVie, Mayoly Spindler, Gilead Sciences, Hospira, and Aptalis Pharma. Laurence Delhaes reports support for the present work from Vertex Pharmaceuticals (Lumivabiota study, IIS-2016-105028), and additional grants from ANR (“Inf-HOLOBIONT”) and Pfizer (“IA-holobiont”). Isabelle Sermet-Gaudelus reports grants from Vertex Therapeutics and Tavanta, outside the submitted work. She has been the principal investigator of clinical trials sponsored by Corbus Pharmaceuticals, PTC Therapeutics, and Vertex Pharmaceuticals. She also participated in a scientific advisory board at Vertex Therapeutics. Philippe Reix declares honorary grants and lecture payments from Vertex Pharmaceuticals. Jeanne Languepin and Stéphanie Bui received personal fees for presentations from Viatris and Vertex Pharmaceuticals. Patrick Berger declares an unrestricted grant from AstraZeneca, consulting and speaking fees from AstraZeneca, Sanofi, Chiesi, and GSK, as well as patent ownership and stock holdings in Tesla, NIO, and ALSET. Sanjay H. Chotirmall reports receiving grants from various Singapore national agencies and consulting fees, lecture fees, and advisory board participation from CSL Behring, Boehringer Ingelheim, Pneumagen, Sanofi, AstraZeneca, Chiesi Farmaceutici, and others. All other authors declare no competing interests.

Informed consent

Written informed consent was obtained from participants’ parents or legal guardians prior to inclusion, in accordance with French regulations in force at the time of the study; assent was sought from children when appropriate. The study used residual care samples and was registered at ClinicalTrials.gov (NCT03565692).

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Lussac-Sorton, F., Narayana, J.K., Wizla, N. et al. Gut–lung microbial dynamics with lumacaftor/ivacaftor in children with cystic fibrosis: a prospective multicenter study. Pediatr Res (2026). https://doi.org/10.1038/s41390-026-04774-2

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