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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; Søkilde, Rolf LU ; Pociot, Flemming LU ; Heller, R. Scott; Folkersen, Lasse; Kvist, Peter Helding and Jackerott, Malene, et al. (2016) In Inflammatory Bowel Diseases 22(9). p.97-2078
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... (More)

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.

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type
Contribution to journal
publication status
published
in
Inflammatory Bowel Diseases
volume
22
issue
9
pages
20 pages
publisher
John Wiley & Sons
external identifiers
  • scopus:84983680566
ISSN
1536-4844
DOI
10.1097/MIB.0000000000000847
language
English
LU publication?
no
id
7c0c6e2c-8d1f-498e-a4c7-f23940b7de0a
date added to LUP
2017-09-01 14:27:13
date last changed
2017-11-19 04:42:47
@article{7c0c6e2c-8d1f-498e-a4c7-f23940b7de0a,
  abstract     = {<p>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.</p><p>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.</p><p>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.</p><p>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.</p>},
  author       = {Bang-Berthelsen, Claus Heiner and Holm, Thomas L and Pyke, Charles and Simonsen, Lotte and Søkilde, Rolf and Pociot, Flemming and Heller, R. Scott and Folkersen, Lasse and Kvist, Peter Helding and Jackerott, Malene and Fleckner, Jan and Vilién, Mogens and Knudsen, Lotte B and Heding, Anders and Frederiksen, Klaus S.},
  issn         = {1536-4844},
  language     = {eng},
  number       = {9},
  pages        = {97--2078},
  publisher    = {John Wiley & Sons},
  series       = {Inflammatory Bowel Diseases},
  title        = {GLP-1 Induces Barrier Protective Expression in Brunner's Glands and Regulates Colonic Inflammation},
  url          = {http://dx.doi.org/10.1097/MIB.0000000000000847},
  volume       = {22},
  year         = {2016},
}