GLP-1 Induces Barrier Protective Expression in Brunnerʼs Glands and Regulates Colonic Inflammation

Bang-Berthelsen, Claus Heiner; Holm, Thomas Lindebo; Pyke, Charles; Simonsen, Lotte; Søkilde, Rolf; Pociot, Flemming; Heller, R. Scott; Folkersen, Lasse; Kvist, Peter Helding; Jackerott, Malene; Fleckner, Jan; Vilien, M.; Knudsen, Lotte Bjerre; Heding, Anders; Frederiksen, Klaus Stensgaard

doi:10.1097/mib.0000000000000847

Cited by 65 publications

(57 citation statements)

References 60 publications

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“…This distinct receptor expression corresponds well with GLP-1's inhibitory effects on gastric acid production and gastric emptying [18], [19]. In addition, we confirm Glp1r to be highly expressed in Brunner's glands of the proximal duodenum [36], [57], consistent with a role for GLP-1 in the regulation of intestinal mucin production [38]. Glp1r was also localized to nerve plexuses of the submucosa and muscularis along the full rostro-caudal extension of the intestinal tract [17], [39], [58].…”

Section: Discussionsupporting

confidence: 78%

“…This general assumption focused greater attention on studies of proglucagon-related biology in the distal gut, with limited analysis of the full gastrointestinal tract. The GLP-1R is known to be expressed in several tissues, including brain, gastrointestinal tract, pancreatic islets, kidney, heart, and lung [35], [36], [37], [38]. However, cellular localization of GLP-1R expression is confounded by the lack of validated, specific antibodies [39], [40], [41].…”

Section: Introductionmentioning

confidence: 99%

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The endogenous preproglucagon system is not essential for gut growth homeostasis in mice

Wismann

Barkholt

Secher

et al. 2017

Molecular Metabolism

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ObjectiveThe prevalence of obesity and related co-morbidities is reaching pandemic proportions. Today, the most effective obesity treatments are glucagon-like peptide 1 (GLP-1) analogs and bariatric surgery. Interestingly, both intervention paradigms have been associated with adaptive growth responses in the gut; however, intestinotrophic mechanisms associated with or secondary to medical or surgical obesity therapies are poorly understood. Therefore, the objective of this study was to assess the local basal endogenous and pharmacological intestinotrophic effects of glucagon-like peptides and bariatric surgery in mice.MethodsWe used in situ hybridization to provide a detailed and comparative anatomical map of the local distribution of GLP-1 receptor (Glp1r), GLP-2 receptor (Glp2r), and preproglucagon (Gcg) mRNA expression throughout the mouse gastrointestinal tract. Gut development in GLP-1R-, GLP-2R-, or GCG-deficient mice was compared to their corresponding wild-type controls, and intestinotrophic effects of GLP-1 and GLP-2 analogs were assessed in wild-type mice. Lastly, gut volume was determined in a mouse model of vertical sleeve gastrectomy (VSG).ResultsComparison of Glp1r, Glp2r, and Gcg mRNA expression indicated a widespread, but distinct, distribution of these three transcripts throughout all compartments of the mouse gastrointestinal tract. While mice null for Glp1r or Gcg showed normal intestinal morphology, Glp2r−/− mice exhibited a slight reduction in small intestinal mucosa volume. Pharmacological treatment with GLP-1 and GLP-2 analogs significantly increased gut volume. In contrast, VSG surgery had no effect on intestinal morphology.ConclusionThe present study indicates that the endogenous preproglucagon system, exemplified by the entire GCG gene and the receptors for GLP-1 and GLP-2, does not play a major role in normal gut development in the mouse. Furthermore, elevation in local intestinal and circulating levels of GLP-1 and GLP-2 achieved after VSG has limited impact on intestinal morphometry. Hence, although exogenous treatment with GLP-1 and GLP-2 analogs enhances gut growth, the contributions of endogenously-secreted GLP-1 and GLP-2 to gut growth may be more modest and highly context-dependent.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

The endogenous preproglucagon system is not essential for gut growth homeostasis in mice

Wismann

Barkholt

Secher

et al. 2017

Molecular Metabolism

View full text Add to dashboard Cite

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“…The physiological relevance of GLP-1 secretion in the control of basal gut barrier homeostasis remains obscure. Nevertheless, liraglutide, a GLP-1 analog, improved gut permeability in rats (Nozu et al, 2017) and induced barrier protective effect by improving Brunner's gland function (Bang-Berthelsen et al, 2016). In addition, GLP-1R agonists promoted intestinal growth (Kissow et al, 2012;Simonsen et al, 2007) through fibroblast growth factor 7 (Koehler et al, 2015), and exogenous GLP-1 protects the gut against oxidative damage (Deniz et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Enteroendocrine L Cells Sense LPS after Gut Barrier Injury to Enhance GLP-1 Secretion

et al. 2017

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Glucagon-like peptide 1 (GLP-1) is a hormone released from enteroendocrine L cells. Although first described as a glucoregulatory incretin hormone, GLP-1 also suppresses inflammation and promotes mucosal integrity. Here, we demonstrate that plasma GLP-1 levels are rapidly increased by lipopolysaccharide (LPS) administration in mice via a Toll-like receptor 4 (TLR4)-dependent mechanism. Experimental manipulation of gut barrier integrity after dextran sodium sulfate treatment, or via ischemia/reperfusion experiments in mice, triggered a rapid rise in circulating GLP-1. This phenomenon was detected prior to measurable changes in inflammatory status and plasma cytokine and LPS levels. In human subjects, LPS administration also induced GLP-1 secretion. Furthermore, GLP-1 levels were rapidly increased following the induction of ischemia in the human intestine. These findings expand traditional concepts of enteroendocrine L cell biology to encompass the sensing of inflammatory stimuli and compromised mucosal integrity, linking glucagon-like peptide secretion to gut inflammation.

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“…is correlated with elevated GLP‐1 levels in patients after gastric bypass surgery and dietary intervention for obesity . Active GLP‐1 likely plays a broad role in supporting gut homoeostasis as prophylactic administration of liraglutide has been shown to be protective in a T cell‐driven adoptive transfer colitis mouse model . Our study suggests that GLP‐1 agonism, maintenance of gut homoeostasis and Akkermansia species occurrence are inter‐related factors for T2DM aetiology.…”

Section: Discussionmentioning

confidence: 99%

Gut microbiome differences between metformin‐ and liraglutide‐treated T2DM subjects

Wang

Saha

Horn

et al. 2017

Endocrino Diabet & Metabol

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Introduction Metformin and glucagon‐like peptide‐1 ( GLP ‐1) agonists are widely used for treating type two diabetes mellitus (T2 DM ). While recent studies suggest these drugs might modify the gastrointestinal tract ( GIT ) microbiome, further confirmation is required from human clinical trials. Materials and methods Here, we compare, in patients with T2 DM , the effects of metformin (n = 18 subjects) and liraglutide (n = 19), a GLP ‐1 agonist, on their GIT microbiomes over a 42 day period (n = 74 samples) using 16S ribosomal RNA ( rRNA ) sequencing. Results We found that these drugs had markedly different effects on the microbiome composition. At both baseline and Day 42, subjects taking metformin had a significant increase (Baseline adj. P = .038, Day 42 adj. P = .041) in the relative abundance of the bacterial genus Sutterella , whereas liraglutide dosing is associated with a significant increase (Baseline adj. P = .048, Day 42 adj. P = .003) in the genus Akkermansia , a GIT bacteria positively associated with gut barrier homoeostasis. Bacteroides and Akkermansia relative abundances were also significantly associated with duration of subject diabetes (adj P < .05). Specifically, there was a significantly higher abundance of Akkermansia in subjects with short and medium durations than those with long duration of diabetes. Discussion To our knowledge, this is the first report of GLP ‐1 agonist‐associated changes in the human microbiome and its differentiating effects to metformin. Our study suggests that modulation of the GIT microbiome is a potentially important component in the mechanism of action of these drugs.

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GLP-1 Induces Barrier Protective Expression in Brunnerʼs Glands and Regulates Colonic Inflammation

Cited by 65 publications

References 60 publications

The endogenous preproglucagon system is not essential for gut growth homeostasis in mice

The endogenous preproglucagon system is not essential for gut growth homeostasis in mice

Enteroendocrine L Cells Sense LPS after Gut Barrier Injury to Enhance GLP-1 Secretion

Gut microbiome differences between metformin‐ and liraglutide‐treated T2DM subjects

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