GLP-1 Induces Barrier Protective Expression in Brunner's Glands and Regulates Colonic Inflammation

Claus Heiner Bang-Berthelsen, Thomas L. Holm, Charles Pyke, Lotte Simonsen, Rolf Sokilde, Flemming Pociot, R. Scott Heller, Lasse Folkersen, Peter H. Kvist, Malene Jackerott, Jan Fleckner, Mogens Vilien, Lotte B. Knudsen, Anders Heding, Klaus S. Frederiksen

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Background: Beneficial roles for glucagon-like peptide 1 (GLP-1)/GLP-1R signaling have recently been described in diseases, where low-grade inflammation is a common phenomenon. We investigated the effects of GLP-1 in Brunner's glands and duodenum with abundant expression of GLP-1 receptors, as well as GLP-1 effect on colonic inflammation.Methods: RNA from Brunner's glands of GLP-1R knockout and wild-type mice were subjected to full transcriptome profiling. Array results were validated by quantitative reverse transcription polymerase chain reaction in wild-type mice and compared with samples from inflammatory bowel disease (IBD) patients and controls. In addition, we performed a detailed investigation of the effects of exogenous liraglutide dosing in a T-cell driven adoptive transfer (AdTr) colitis mouse model.Results: Analyses of the Brunner's gland transcriptomes of GLP-1R knockout and wild-type mice identified 722 differentially expressed genes. Upregulated transcripts after GLP-1 dosing included IL-33, chemokine ligand 20 (CCL20), and mucin 5b. Biopsies from IBD patients and controls, as well as data from the AdTr model, showed deregulated expression of GLP-1R, CCL20, and IL-33 in colon. Circulating levels of GLP-1 were found to be increased in mice with colitis. Finally, the colonic cytokine levels and disease scores of the AdTr model indicated reduced levels of colonic inflammation in liraglutide-dosed animals.Conclusions: We demonstrate that IL-33, GLP-1R, and CCL20 are deregulated in human IBD, and that prophylactic treatment with 0.6 mg/kg liraglutide improves disease in AdTr colitis. In addition, GLP-1 receptor agonists upregulate IL-33, mucin 5b, and CCL20 in murine Brunner's glands. Taken together, our data indicate that GLP-1 receptor agonists affect gut homeostasis in both proximal and distal parts of the gut.
Original languageEnglish
JournalInflammatory Bowel Diseases
Volume22
Issue number9
Pages (from-to)2078-2097
Number of pages20
ISSN1078-0998
DOIs
Publication statusPublished - 2016

Keywords

  • IL-33
  • Brunner's glands
  • Inflammatory bowel disease
  • GLP-1
  • MUC5B

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