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

Cite this

Bang-Berthelsen, Claus Heiner ; Holm, Thomas L. ; Pyke, Charles ; Simonsen, Lotte ; Sokilde, Rolf ; Pociot, Flemming ; Heller, R. Scott ; Folkersen, Lasse ; Kvist, Peter H. ; Jackerott, Malene ; Fleckner, Jan ; Vilien, Mogens ; Knudsen, Lotte B. ; Heding, Anders ; Frederiksen, Klaus S. / GLP-1 Induces Barrier Protective Expression in Brunner's Glands and Regulates Colonic Inflammation. In: Inflammatory Bowel Diseases. 2016 ; Vol. 22, No. 9. pp. 2078-2097.
@article{f17ab4803fbf4fbe845bb761ad3aed67,
title = "GLP-1 Induces Barrier Protective Expression in Brunner's Glands and Regulates Colonic Inflammation",
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.",
keywords = "IL-33, Brunner's glands, Inflammatory bowel disease, GLP-1, MUC5B",
author = "Bang-Berthelsen, {Claus Heiner} and Holm, {Thomas L.} and Charles Pyke and Lotte Simonsen and Rolf Sokilde and Flemming Pociot and Heller, {R. Scott} and Lasse Folkersen and Kvist, {Peter H.} and Malene Jackerott and Jan Fleckner and Mogens Vilien and Knudsen, {Lotte B.} and Anders Heding and Frederiksen, {Klaus S.}",
year = "2016",
doi = "10.1097/MIB.0000000000000847",
language = "English",
volume = "22",
pages = "2078--2097",
journal = "Inflammatory Bowel Diseases",
issn = "1078-0998",
publisher = "Lippincott Williams & Wilkins",
number = "9",

}

Bang-Berthelsen, CH, Holm, TL, Pyke, C, Simonsen, L, Sokilde, R, Pociot, F, Heller, RS, Folkersen, L, Kvist, PH, Jackerott, M, Fleckner, J, Vilien, M, Knudsen, LB, Heding, A & Frederiksen, KS 2016, 'GLP-1 Induces Barrier Protective Expression in Brunner's Glands and Regulates Colonic Inflammation', Inflammatory Bowel Diseases, vol. 22, no. 9, pp. 2078-2097. https://doi.org/10.1097/MIB.0000000000000847

GLP-1 Induces Barrier Protective Expression in Brunner's Glands and Regulates Colonic Inflammation. / Bang-Berthelsen, Claus Heiner; Holm, Thomas L.; Pyke, Charles; Simonsen, Lotte; Sokilde, Rolf; Pociot, Flemming; Heller, R. Scott; Folkersen, Lasse; Kvist, Peter H.; Jackerott, Malene; Fleckner, Jan; Vilien, Mogens; Knudsen, Lotte B.; Heding, Anders; Frederiksen, Klaus S.

In: Inflammatory Bowel Diseases, Vol. 22, No. 9, 2016, p. 2078-2097.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - GLP-1 Induces Barrier Protective Expression in Brunner's Glands and Regulates Colonic Inflammation

AU - Bang-Berthelsen, Claus Heiner

AU - Holm, Thomas L.

AU - Pyke, Charles

AU - Simonsen, Lotte

AU - Sokilde, Rolf

AU - Pociot, Flemming

AU - Heller, R. Scott

AU - Folkersen, Lasse

AU - Kvist, Peter H.

AU - Jackerott, Malene

AU - Fleckner, Jan

AU - Vilien, Mogens

AU - Knudsen, Lotte B.

AU - Heding, Anders

AU - Frederiksen, Klaus S.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - IL-33

KW - Brunner's glands

KW - Inflammatory bowel disease

KW - GLP-1

KW - MUC5B

U2 - 10.1097/MIB.0000000000000847

DO - 10.1097/MIB.0000000000000847

M3 - Journal article

VL - 22

SP - 2078

EP - 2097

JO - Inflammatory Bowel Diseases

JF - Inflammatory Bowel Diseases

SN - 1078-0998

IS - 9

ER -