Simonas Juzenas1,2, Matthias Hübenthal1,3, Carl Mårten Lindqvist1,4, Robert Kruse5,6, Tim Alexander Steiert1, Frauke Degenhardt1, Dominik Schulte7,8, Susanna Nikolaus9, Sebastian Zeissig10,11, Daniel Bergemalm4, Sven Almer12, Henrik Hjortswang13, Francesca Bresso12, Nina Strüning9, Juozas Kupcinskas14, Andreas Keller15,16, Wolfgang Lieb17, Philip Rosenstiel1, Stefan Schreiber1,9, Mauro D'Amato18,19,20, Jonas Halfvarson21, Georg Hemmrich-Stanisak1, Andre Franke1,22. 1. Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany. 2. Institute of Biotechnology, Life Science Centre, Vilnius University, Vilnius, Lithuania. 3. Department of Dermatology, Quincke Research Center, University Hospital Schleswig-Holstein, Kiel, Germany. 4. School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden. 5. Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden. 6. iRiSC - Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden. 7. Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine I, University Hospital of Schleswig-Holstein , Kiel, Germany. 8. Institute of Diabetes and Clinical Metabolic Research, Kiel University, Kiel, Germany. 9. Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany. 10. Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany. 11. Center for Regenerative Therapies Dresden (CRTD), Technische Universität (TU) Dresden, Dresden, Germany. 12. Department of Medicine, Karolinska Institutet, Solna, and Division of Gastroenterology, Karolinska University Hospital, Stockholm, Sweden. 13. Department of Gastroenterology and Hepatology, Linköping University, Linköping, and Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden. 14. Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania. 15. Chair for Clinical Bioinformatics, Saarland University, Saarbrücken, Germany. 16. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. 17. Institute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany. 18. Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. 19. Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain. 20. Ikerbasque, Basque Foundation for Science, Bilbao, Spain. 21. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden. 22. University Hospital of Schleswig-Holstein (UKSH), Kiel Campus , Kiel, Germany.
Abstract
BACKGROUND AND AIMS: Inflammatory bowel disease [IBD] is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohn's disease [CD] or ulcerative colitis [UC]. These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and, thus, common immune regulatory pathways. METHODS: Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naïve [n = 110] and treatment-exposed [n = 177] IBD patients as well as symptomatic [n = 65] and healthy controls [n = 95]. RESULTS: Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naïve IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, IL1B was identified as the central gene. Levels of co-expression among IL1B and chemosensing receptor [CXCR1/2 and FPR1/2] genes were reduced in the blood of IBD patients when compared with healthy controls. CONCLUSIONS: Immune dysregulation seen in peripheral blood transcriptomes of treatment-naïve IBD patients is mainly driven by neutrophil activation.
BACKGROUND AND AIMS: Inflammatory bowel disease [IBD] is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohn's disease [CD] or ulcerative colitis [UC]. These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and, thus, common immune regulatory pathways. METHODS: Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naïve [n = 110] and treatment-exposed [n = 177] IBD patients as well as symptomatic [n = 65] and healthy controls [n = 95]. RESULTS: Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naïve IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, IL1B was identified as the central gene. Levels of co-expression among IL1B and chemosensing receptor [CXCR1/2 and FPR1/2] genes were reduced in the blood of IBD patients when compared with healthy controls. CONCLUSIONS: Immune dysregulation seen in peripheral blood transcriptomes of treatment-naïve IBD patients is mainly driven by neutrophil activation.
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