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

Luiza Moraes Holst; Jonas Halfvarson; Marie Carlson; Charlotte Hedin; Robert Kruse; Carl Mårten Lindqvist; Daniel Bergemalm; Sven Almér; Francesca Bresso; Maria Ling Lundström; Dirk Repsilber; Mauro D'Amato; Åsa Keita; Henrik Hjortswang; Johan Söderholm; Johanna Sundin; Hans Törnblom; Magnus Simrén; Hans Strid; Maria K Magnusson; Lena Öhman

doi:10.2147/CEG.S368040

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

Clin Exp Gastroenterol. 2022 Jul 27:15:129-144. doi: 10.2147/CEG.S368040. eCollection 2022.

Authors

Luiza Moraes Holst¹, Jonas Halfvarson², Marie Carlson³, Charlotte Hedin⁴, Robert Kruse⁵, Carl Mårten Lindqvist⁶, Daniel Bergemalm², Sven Almér⁴, Francesca Bresso⁷, Maria Ling Lundström³, Dirk Repsilber⁶, Mauro D'Amato^{8

9

10}, Åsa Keita¹¹, Henrik Hjortswang¹², Johan Söderholm¹¹, Johanna Sundin¹³, Hans Törnblom¹⁴, Magnus Simrén^{14

15}, Hans Strid¹⁶, Maria K Magnusson¹, Lena Öhman¹

Affiliations

¹ Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
² Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
³ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
⁴ Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
⁵ Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
⁶ School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
⁷ Karolinska University Hospital, Gastroenterology Unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden.
⁸ Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
⁹ IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
¹⁰ Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain.
¹¹ Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
¹² Department of Clinical and Experimental Science, Linköping University, Linköping, Sweden.
¹³ Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, Gothenburg, Sweden.
¹⁴ Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁵ Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁶ Department of Internal Medicine, Södra Älvsborg Hospital, Borås, Sweden.

Abstract

Background: 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: gene expression; homeostasis; host response; inflammatory bowel diseases; mucosal transcriptome.

Grants and funding

This study was funded by the Swedish Foundation For Strategic Research (grant no RB13-016 to J.H., L.Ö., J.Sö. and M.A.), the Julins Foundation (J.Su. and C.H.), Bengt Ihre Fellowship (to J.Su. and C.H.), Wilhelm and Martina Lundgren foundation (grant no. 2021-3743 to M.K.M.), the Mag-tarmfonden (J.Su. and C.H.), Svenska Läkarsällskapet (C.H.), the Calder foundation (C.H.), Gastrofonden (C.H.), Professor Nanna Svartx Fund (C.H.), Kungliga Vetenskaps- och Vitterhets-Samhället i Göteborg (KVVS) foundation (J.Su.), Sahlgrenska Academy University of Gothenburg (J.Su. and L.Ö.), the Medical Faculty at Uppsala University (M.C.), the Apotekare Hedberg foundation (M.K.M.), the Swedish Research Council (grant no. 2018-02566 to M.S. and 2019-01052 to L.Ö.), grants from the Swedish state under the agreement between the Swedish government and the county councils; the ALF-agreement (grant nos. ALFGBG-932651 to H.S., ALFGBG-722331 M.S. and ALFGBG-723921 to L.Ö.) and the Regional Executive Board, Region Västra Götaland (grant no. VGFOUREG-940815 to H.S.).