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

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

doi:10.1097/mib.0000000000000847

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

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

Institut for Klinisk Medicin

29 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Inflammatory Bowel Diseases
Vol/bind	22
Udgave nummer	9
Sider (fra-til)	2078-97
Antal sider	20
ISSN	1078-0998
DOI	https://doi.org/10.1097/mib.0000000000000847
Status	Udgivet - 10 aug. 2016

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Bang-Berthelsen, C. H., Holm, T. L., Pyke, C., Simonsen, L., Søkilde, R., Pociot, F., Heller, R. S., Folkersen, L., Kvist, P. H., Jackerott, M., Fleckner, J., Vilien, M., Knudsen, L. B., Heding, A., & Frederiksen, K. S. (2016). GLP-1 Induces Barrier Protective Expression in Brunner's Glands and Regulates Colonic Inflammation. Inflammatory Bowel Diseases, 22(9), 2078-97. https://doi.org/10.1097/mib.0000000000000847

Bang-Berthelsen, CH, Holm, TL, Pyke, C, Simonsen, L, Søkilde, 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, bind 22, nr. 9, s. 2078-97. https://doi.org/10.1097/mib.0000000000000847

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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 = "Journal Article",

author = "Bang-Berthelsen, {Claus H} and Holm, {Thomas L} and Charles Pyke and Lotte Simonsen and Rolf S{\o}kilde 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",

month = aug,

day = "10",

doi = "10.1097/mib.0000000000000847",

language = "English",

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

AU - Bang-Berthelsen, Claus H

AU - Holm, Thomas L

AU - Pyke, Charles

AU - Simonsen, Lotte

AU - Søkilde, 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 - 2016/8/10

Y1 - 2016/8/10

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 - Journal Article

U2 - 10.1097/mib.0000000000000847

DO - 10.1097/mib.0000000000000847

M3 - Journal article

C2 - 27542128

SN - 1078-0998

VL - 22

SP - 2078

EP - 2097

JO - Inflammatory Bowel Diseases

JF - Inflammatory Bowel Diseases

IS - 9

ER -

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

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