glucagon-like-peptide-1 and Colitis

ACE2, a carboxypeptidase that generates Ang-(1-7) from Ang II, is highly expressed in the lung, small intestine and colon. GPBAR1, is a G protein bile acid receptor that promotes the release of the insulinotropic factor glucagon-like peptide (GLP)-1 and attenuates intestinal inflammation.. We investigated the expression of ACE2, GLP-1 and GPBAR1 in two cohorts of Crohn's disease (CD) patients and three mouse models of colitis and Gpbar1. In IBD patients, ACE2 mRNA expression was regulated in a site-specific manner in response to inflammation. While expression of ileal ACE2 mRNA was reduced, the colon expression was induced. Colon expression of ACE2 mRNA in IBD correlated with expression of TNF-α and GPBAR1. A positive correlation occurred between GCG and GPBAR1 in human samples and animal models of colitis. In these models, ACE2 mRNA expression was further upregulated by GPABR1 agonism and reversed by exendin-3, a GLP-1 receptor antagonist. In in vitro studies, liraglutide, a GLP-1 analogue, increased the expression of ACE2 in colon epithelial cells/macrophages co-cultures.. ACE2 mRNA expression in the colon of IBD patients and rodent models of colitis is regulated in a TNF-α- and GLP-1-dependent manner. We have identified a GPBAR1/GLP-1 mechanism as a positive modulator of ACE2.

Topics: Angiotensin-Converting Enzyme 2; Animals; Bile Acids and Salts; Colitis; Crohn Disease; Glucagon-Like Peptide 1; Humans; Inflammation; Mice; Receptors, G-Protein-Coupled; RNA, Messenger; Tumor Necrosis Factor-alpha

The role of the incretin hormone, glucagon-like peptide (GLP-1), in Crohn's disease (CD), is still poorly understood. The aim of this study was to investigate whether colitis is associated with changes in blood glucose levels and the possible involvement of the incretin system as an underlaying factor.. We used a murine model of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). Macroscopic and microscopic score and expression of inflammatory cytokines were measured. The effect of colitis on glucose level was studied by measurement of fasting glucose and GLP-1, dipeptidyl peptidase IV (DPP IV) levels, prohormone convertase 1/3 (PC 1/3) and GLP-1 receptor (GLP-1R) expression in mice. We also measured the level of GLP-1, DPP IV and expression of glucagon (GCG) and PC 1/3 mRNA in serum and colon samples from healthy controls and CD patients.. Fasting glucose levels were increased in animals with colitis compared to controls. GLP-1 was decreased in both serum and colon of mice with colitis in comparison to the control group. DPP IV levels were significantly increased in serum, but not in the colon of mice with colitis as compared to healthy animals. Furthermore, PC 1/3 and GLP-1R expression levels were increased in mice with colitis as compared to controls. In humans, no differences were observed in fasting glucose level between healthy subjects and CD patients. GLP-1 levels were significantly decreased in the serum. Interestingly, GLP-1 level was significantly increased in colon samples of CD patients compared to healthy subjects. No significant differences in DPP IV levels in serum and colon samples were observed between groups.. Changes in the incretin system during colitis seem to contribute to the impaired glucose levels. Differences in incretin levels seem to be modulated by degrading enzyme DPP-IV and PC 1/3. Obtained results suggest that the incretin system may become a novel therapeutic approach in the treatment of CD.

Topics: Adult; Animals; Blood Glucose; Case-Control Studies; Colitis; Crohn Disease; Dipeptidyl Peptidase 4; Disease Models, Animal; Female; Glucagon-Like Peptide 1; Humans; Incretins; Inflammation; Male; Mice; Mice, Inbred C57BL; Middle Aged; Proprotein Convertase 1; Trinitrobenzenesulfonic Acid; Young Adult

There is a close relationship between the gut microbiota and metabolic disorders. In this study, acute administration of the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide to mice increased the cecal levels of caseinolytic protease B, a component of Escherichia coli, and of norepinephrine. Chemical sympathectomy blocked these events. Norepinephrine was found to pass into the intestinal lumen in vitro. c-Fos staining of the intermediolateral nucleus was identified as indirect evidence of sympathetic nervous system activation of the intestinal tract by GLP-1RA. Under normal conditions, the increase in E. coli did not affect the host. However, in mice with colitis, bacterial translocation was observed with attenuation of tight junction gene expression. This is the first study to investigate the unique underlying mechanisms related the effects of GLP-1RA on changes in the gut bacterium.

Topics: Adrenalectomy; Animals; Appetite; Cecum; Colitis; Endopeptidase Clp; Escherichia coli; Escherichia coli Proteins; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heat-Shock Proteins; Liraglutide; Mice, Inbred C57BL; Norepinephrine; Proto-Oncogene Proteins c-fos; Sympathetic Nervous System

High-fat diet (HFD) feeding induces inflammation in various tissues, including the nodose ganglion and hypothalamus, resulting in obesity and metabolic disorders. In this study, we investigated the effect of short-term HFD on aged and young mice. Aged mice easily gained weight during short-term HFD feeding, and required many days to adapt their energy intake. One-day HFD in aged mice induced inflammation in the distal colon, but not in the nodose ganglion or hypothalamus. The anorexic effect of glucagon-like peptide-1 (GLP-1) was attenuated in aged mice. Intraperitoneal administration of GLP-1 did not induce expression of genes that regulate feeding in the hypothalamus of aged mice. mRNA expression of the gene encoding the GLP-1 receptor (Glp1r) in the nodose ganglion was significantly lower in aged mice than in young mice. Our findings suggest that adaptation of energy intake regulation was attenuated in aged mice, causing them to become obese in response to short-term HFD feeding.

Topics: Adaptation, Physiological; Age Factors; Aging; Animals; Colitis; Diet, High-Fat; Disease Models, Animal; Eating; Energy Intake; Energy Metabolism; Feeding Behavior; Gene Expression Regulation; Glucagon-Like Peptide 1; Hypothalamus; Inflammation Mediators; Male; Mice, Inbred C57BL; Nodose Ganglion; Obesity; Time Factors; Weight Gain

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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Calcium Signaling; Cells, Cultured; Colitis; Cytokines; Dextran Sulfate; Enteroendocrine Cells; Glucagon-Like Peptide 1; Humans; Ileum; Interleukin-6; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Middle Aged; Myristic Acids; Proglucagon; Proprotein Convertase 1; Reperfusion Injury; Toll-Like Receptor 4; Young Adult

The gut hormone, glucagon like peptide-1 (GLP-1) exerts anti-inflammatory effects. However, its clinical use is limited by its short half-life. Previously, we have shown that GLP-1 as a nanomedicine (GLP-1 in sterically stabilized phospholipid micelles, GLP-1-SSM) has increased in vivo stability. The current study was aimed at testing the efficacy of this GLP-1 nanomedicine in alleviating colonic inflammation and associated diarrhea in dextran sodium sulfate (DSS) induced mouse colitis model. Our results show that GLP-1-SSM treatment markedly alleviated the colitis phenotype by reducing the expression of pro-inflammatory cytokine IL-1β, increasing goblet cells and preserving intestinal epithelial architecture in colitis model. Further, GLP-1-SSM alleviated diarrhea (as assessed by luminal fluid) by increasing protein expression of intestinal chloride transporter DRA (down regulated in adenoma). Our results indicate that GLP-1 nanomedicine may act as a novel therapeutic tool in alleviating gut inflammation and associated diarrhea in inflammatory bowel disease (IBD).

Topics: Animals; Colitis; Dextran Sulfate; Diarrhea; Disease Models, Animal; Glucagon-Like Peptide 1; Inflammation; Mice; Nanomedicine

We have previously demonstrated that inhibition of dipeptidyl peptidase (DP) activity partially attenuates dextran sulfate sodium (DSS) colitis in mice. The aim of this study was to further investigate the mechanisms of this protection.. Wildtype (WT) and DPIV(-/-) mice consumed 2% DSS in drinking water for 6 days to induce colitis. Mice were treated with saline or the DP inhibitors Ile-Pyrr-(2-CN)*TFA or Ile-Thia. DP mRNA and enzyme levels were measured in the colon. Glucagon-like peptide (GLP)-2 and GLP-1 concentrations were determined by radioimmunoassay, regulatory T-cells (Tregs) by fluorescence activated cell sorting (FACS) on FOXp3+T cells in blood, and neutrophil infiltration assessed by myeloperoxidase (MPO) assay.. DP8 and DP2 mRNA levels were increased (P < 0.05) in WT+saline mice compared to untreated WT mice with colitis. Cytoplasmic DP enzyme activity was increased (P < 0.05) in DPIV(-/-) mice at day 6 of DSS, while DP2 activity was increased (P < 0.05) in WT mice with colitis. GLP-1 (63%) and GLP-2 (50%) concentrations increased in WT+Ile-Pyrr-(2-CN)*TFA mice compared to day-0 controls. MPO activity was lower in WT+Ile-Thia and WT+Ile-Pyrr-(2-CN)*TFA treated mice compared to WT+saline (P < 0.001) at day 6 colitis.. DP expression and activity are differentially regulated during DSS colitis, suggesting a pathophysiological role for these enzymes in human inflammatory bowel disease (IBD). DP inhibitors impaired neutrophil recruitment and maintenance of the Treg population during DSS-colitis, providing further preclinical evidence for the potential therapeutic use of these inhibitors in IBD. Finally, DPIV appears to play a critical role in mediating the protective effect of DP inhibitors.

Topics: Animals; Colitis; Colon; Dextran Sulfate; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Disease Models, Animal; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Peroxidase; T-Lymphocytes, Regulatory