Metabolic, Inflammatory, and Microbial Factors Shaping Organ Health in CF
(2026) In Lund University, Faculty of Medicine Doctoral Dissertation Series- Abstract
- Background: Cystic fibrosis (CF) is a multisystem genetic disease characterized by chronic airway infection and progressive lung function decline. With increasing life expectancy, extrapulmonary comorbidities such as cystic fibrosis–related diabetes (CFRD) and hepatobiliary involvement have become important contributors to disease burden in people with CF (pwCF).
Aim: The overall aim of this thesis was to investigate the role of CFRD and dysglycaemia in CF lung disease, focusing on airway inflammation, proteomic and microbiome signatures, and longitudinal lung function, and to evaluate the impact of CFTR modulator therapy on hepatobiliary involvement in children with CF.
Methods: Paper I and II were observational studies... (More) - Background: Cystic fibrosis (CF) is a multisystem genetic disease characterized by chronic airway infection and progressive lung function decline. With increasing life expectancy, extrapulmonary comorbidities such as cystic fibrosis–related diabetes (CFRD) and hepatobiliary involvement have become important contributors to disease burden in people with CF (pwCF).
Aim: The overall aim of this thesis was to investigate the role of CFRD and dysglycaemia in CF lung disease, focusing on airway inflammation, proteomic and microbiome signatures, and longitudinal lung function, and to evaluate the impact of CFTR modulator therapy on hepatobiliary involvement in children with CF.
Methods: Paper I and II were observational studies focusing on airway inflammation (Meso Scale Discovery assays and chromogenic assays), sputum proteomics (tandem mass spectrometry) and airway microbiome analysis (16S rRNA amplification and sequencing). Paper III was a retrospective study using data from the Swedish CF Registry, investigating lung function trajectories at baseline and over a three year follow up in people with CF across different glycaemic statuses. Paper IV retrospectively evaluated the effect of CFTR modulator therapy, elexacaftor/tezacaftor/ivacaftor (ETI), on liver stiffness in children with CF, assessed by two dimensional shear wave liver elastography.
Results: In Paper I pwCF with CFRD had lower lung function and higher levels of airway inflammation, including increased neutrophil elastase, IL 8, and IL 1β, compared with pwCF without CFRD. Proteomic analyses identified CFRD specific protein profiles related to neutrophil degranulation and carbohydrate metabolism. Paper II showed that pwCF with CFRD had increased airway inflammation and reduced microbial diversity. Paper III, demonstrated that CFRD was associated with lower baseline lung function but not with accelerated lung function decline over three years, while impaired glucose tolerance was not associated with inferior pulmonary outcomes.
Paper IV showed that treatment with ETI was associated with reduced liver stiffness and improved pulmonary outcomes, including in children with already established hepatobiliary involvement.
Conclusion: This thesis demonstrates that CFRD represents a distinct metabolic phenotype in CF, associated with specific inflammatory, proteomic, and microbial airway signatures and reduced lung function. The findings highlight the importance of contextualizing metabolic and microbial biomarkers within lung disease severity and support a precision medicine approach integrating metabolic profiling. Furthermore, CFTR modulation can improve hepatobiliary involvement in pwCF.
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Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/ba68c823-8409-42aa-a89e-f0adc8b74526
- author
- Diemer, Stefanie LU
- supervisor
-
- Lisa Påhlman LU
- Erik Eklund LU
- Christine Rönne Hansen LU
- Jonas Erjefält LU
- opponent
-
- Head of department Bakkeheim, Egil, Oslo University Hospital, Norway
- organization
- publishing date
- 2026
- type
- Thesis
- publication status
- published
- subject
- keywords
- cystic fibrosis, cystic fibrosis-related diabetes, airway inflammation, airway microbiome, proteomics, cystic fibrosis-related hepatobiliary involvement, ETI, liver stiffness, elastography
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2026:125
- pages
- 117 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Belfragesalen, BMC D15, Klinikgatan 32 i Lund
- defense date
- 2026-10-16 09:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-923-5
- language
- English
- LU publication?
- yes
- id
- ba68c823-8409-42aa-a89e-f0adc8b74526
- date added to LUP
- 2026-09-07 21:31:03
- date last changed
- 2026-09-16 07:34:29
@phdthesis{ba68c823-8409-42aa-a89e-f0adc8b74526,
abstract = {{Background: Cystic fibrosis (CF) is a multisystem genetic disease characterized by chronic airway infection and progressive lung function decline. With increasing life expectancy, extrapulmonary comorbidities such as cystic fibrosis–related diabetes (CFRD) and hepatobiliary involvement have become important contributors to disease burden in people with CF (pwCF). <br/><br/>Aim: The overall aim of this thesis was to investigate the role of CFRD and dysglycaemia in CF lung disease, focusing on airway inflammation, proteomic and microbiome signatures, and longitudinal lung function, and to evaluate the impact of CFTR modulator therapy on hepatobiliary involvement in children with CF.<br/><br/>Methods: Paper I and II were observational studies focusing on airway inflammation (Meso Scale Discovery assays and chromogenic assays), sputum proteomics (tandem mass spectrometry) and airway microbiome analysis (16S rRNA amplification and sequencing). Paper III was a retrospective study using data from the Swedish CF Registry, investigating lung function trajectories at baseline and over a three year follow up in people with CF across different glycaemic statuses. Paper IV retrospectively evaluated the effect of CFTR modulator therapy, elexacaftor/tezacaftor/ivacaftor (ETI), on liver stiffness in children with CF, assessed by two dimensional shear wave liver elastography.<br/><br/>Results: In Paper I pwCF with CFRD had lower lung function and higher levels of airway inflammation, including increased neutrophil elastase, IL 8, and IL 1β, compared with pwCF without CFRD. Proteomic analyses identified CFRD specific protein profiles related to neutrophil degranulation and carbohydrate metabolism. Paper II showed that pwCF with CFRD had increased airway inflammation and reduced microbial diversity. Paper III, demonstrated that CFRD was associated with lower baseline lung function but not with accelerated lung function decline over three years, while impaired glucose tolerance was not associated with inferior pulmonary outcomes.<br/>Paper IV showed that treatment with ETI was associated with reduced liver stiffness and improved pulmonary outcomes, including in children with already established hepatobiliary involvement.<br/><br/>Conclusion: This thesis demonstrates that CFRD represents a distinct metabolic phenotype in CF, associated with specific inflammatory, proteomic, and microbial airway signatures and reduced lung function. The findings highlight the importance of contextualizing metabolic and microbial biomarkers within lung disease severity and support a precision medicine approach integrating metabolic profiling. Furthermore, CFTR modulation can improve hepatobiliary involvement in pwCF.<br/>}},
author = {{Diemer, Stefanie}},
isbn = {{978-91-8021-923-5}},
issn = {{1652-8220}},
keywords = {{cystic fibrosis, cystic fibrosis-related diabetes, airway inflammation, airway microbiome, proteomics, cystic fibrosis-related hepatobiliary involvement, ETI, liver stiffness, elastography}},
language = {{eng}},
number = {{2026:125}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Metabolic, Inflammatory, and Microbial Factors Shaping Organ Health in CF}},
url = {{https://lup.lub.lu.se/search/files/260217325/Avhandling_Stefanie_Diemer_LUCRIS.pdf}},
year = {{2026}},
}