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

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 Crohns 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.
Funding Agencies|Swedish Foundation For Strategic Research; Julins Foundation; Bengt Ihre Fellowship; Wilhelm and Martina Lundgren foundation; Magtarmfonden; Svenska Laekarsaellskapet; Calder foundation; Samhaellet i Goeteborg (KVVS) foundation; Sahlgrenska Academy University of Gothenburg [RB13-016]; Medical Faculty at Uppsala University; Apotekare Hedberg foundation; Swedish Research Council [2021-3743]; Swedish state; Swedish government; ALF-agreement; Regional Executive Board, Region Vaestra Goetaland; [2018-02566]; [2019-01052]; [ALFGBG-932651]; [ALFGBG-722331]; [ALFGBG-723921]; [VGFOUREG-940815]