Clinical and Experimental Gastroenterology (Jul 2022)

Downregulated Mucosal Autophagy, Alpha Kinase-1 and IL-17 Signaling Pathways in Active and Quiescent Ulcerative Colitis

  • Moraes Holst L,
  • Halfvarson J,
  • Carlson M,
  • Hedin C,
  • Kruse R,
  • Lindqvist CM,
  • Bergemalm D,
  • Almér S,
  • Bresso F,
  • Ling Lundström M,
  • Repsilber D,
  • D'Amato M,
  • Keita Å,
  • Hjortswang H,
  • Söderholm J,
  • Sundin J,
  • Törnblom H,
  • Simrén M,
  • Strid H,
  • Magnusson MK,
  • Öhman L

Journal volume & issue
Vol. Volume 15
pp. 129 – 144

Abstract

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Luiza Moraes Holst,1 Jonas Halfvarson,2 Marie Carlson,3 Charlotte Hedin,4 Robert Kruse,5 Carl Mårten Lindqvist,6 Daniel Bergemalm,2 Sven Almér,4 Francesca Bresso,7 Maria Ling Lundström,3 Dirk Repsilber,6 Mauro D’Amato,8– 10 Åsa Keita,11 Henrik Hjortswang,12 Johan Söderholm,11 Johanna Sundin,13 Hans Törnblom,14 Magnus Simrén,14,15 Hans Strid,16 Maria K Magnusson,1 Lena Öhman1 1Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 2Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 3Department of Medical Sciences, Uppsala University, Uppsala, Sweden; 4Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden; 5Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 6School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 7Karolinska University Hospital, Gastroenterology Unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden; 8Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; 9IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; 10Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain; 11Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; 12Department of Clinical and Experimental Science, Linköping University, Linköping, Sweden; 13Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, Gothenburg, Sweden; 14Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 15Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 16Department of Internal Medicine, Södra Älvsborg Hospital, Borås, SwedenCorrespondence: Lena Öhman, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, Tel +46703616499, Email [email protected]: Improved mucosal immune profiling in active and quiescent colonic inflammatory bowel disease (IBD) is needed to develop therapeutic options for treating and preventing flares. This study therefore aimed to provide a comprehensive mucosal characterization with emphasis on immunological host response of patients with active ulcerative colitis (UC active), UC during remission (UC remission) and active colonic Crohn’s disease (CD active).Methods: Colonic biopsies from 47 study subjects were collected for gene expression and pathway analyses using the NanoString host-response panel, including 776 genes and 56 immune-related pathways.Results: The majority of mucosal gene expression and signaling pathway scores were increased in active IBD (n=27) compared to healthy subjects (n=10). However, both active IBD and UC remission (n=10) demonstrated decreased gene expression and signaling pathway scores related to autophagy, alpha kinase-1 and IL-17 signaling pathways compared to healthy subjects. Further, UC remission was characterized by decreased scores of several signaling pathways linked to homeostasis along with increased mononuclear cell migration pathway score as compared to healthy subjects. No major differences in the colonic mucosal gene expression between CD active (n=7) and UC (n=20) active were observed.Conclusion: This study indicates that autophagy, alpha kinase-1 and IL-17 signaling pathways are persistently downregulated in UC irrespective of disease activity. Further, UC patients in remission present a unique mucosal environment, potentially preventing patients from reaching and sustaining true homeostasis. These findings may enable better comprehension of the remitting and relapsing pattern of colonic IBD and guide future treatment and prevention of flares.Keywords: inflammatory bowel diseases, gene expression, mucosal transcriptome, homeostasis, host response

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