glucagon-like-peptide-2 and Colitis--Ulcerative

Patients with short bowel syndrome might have impaired postprandial endogenous glucagon-like peptide-2 (GLP-2) secretion, which is required for optimal intestinal adaptation. We aimed to assess the therapeutic potential of glepaglutide, a novel long-acting GLP-2 analogue, for reducing faecal output and increasing intestinal absorption in patients with short bowel syndrome.. In this single-centre, double-blind, crossover, randomised phase 2 trial, adults (aged ≥18 to ≤90 years) with short bowel syndrome and with a faecal wet weight output of 1500 g/day or more were randomly assigned to receive one of six dose sequences of glepaglutide (10 mg, 1 mg; 10 mg, 0·1 mg; 1 mg, 10 mg; 1 mg, 0·1 mg; 0·1 mg, 10 mg; or 0·1 mg, 1 mg). Patients received daily subcutaneous injections of the first assigned dose of glepaglutide for 3 weeks, followed by a washout period of 4-8 weeks, and then the second dose of glepaglutide for 3 weeks. An unmasked statistician generated the randomisation list, and the trial investigator enrolled patients and assigned them their patient numbers. Trial investigators, patients, and other care providers were masked throughout the trial. The primary endpoint was the absolute change from baseline in faecal wet weight output, measured separately over the two treatment periods. Metabolic balance studies were done before and after each treatment period to assess the primary endpoint. Per-protocol analysis was used to assess the efficacy. Safety analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT02690025, and has completed.. Of the 22 patients screened between Feb 5, 2016, and Jan 25, 2017, 18 patients were randomly assigned and treated with glepaglutide; 16 patients completed the trial. Treatment with 1 mg and 10 mg glepaglutide changed the adjusted mean faecal output by -592 g/day (95% CI -913 to -272; p=0·002) and -833 g/day (-1152 to -515; p=0·0002) from baseline, respectively. No changes were observed with 0·1 mg glepaglutide. Of the 18 patients who were randomly assigned to treatment, common treatment-related adverse events were stoma complications (13 [72%] patients), injection site reactions (11 [61%]), peripheral oedema (ten [56%]), nausea and abdominal pain (eight [44%] each), polyuria and fatigue (six [33%] each), abdominal distention, vomiting, and dizziness (five [28%] each); and cough and decreased appetite (four [22%] each). Related or possibly related serious adverse events were reported in two patients in the 0·1 mg dose group and two patients in the 10 mg dose group. These events included abdominal pain, stoma obstruction, catheter-related sepsis, and infection of unknown origin. No patients died during the trial.. Glepaglutide was well tolerated, and was associated with improved intestinal absorption in patients with short bowel syndrome with 1 mg and 10 mg glepaglutide, but not with 0·1 mg glepaglutide. Larger phase 3 clinical trials of longer durations have been initiated to fully assess the safety and efficacy of glepaglutide.. Zealand Pharma.

Topics: Abdominal Pain; Aged; Anorexia; Colitis, Ulcerative; Crohn Disease; Cross-Over Studies; Double-Blind Method; Edema; Enterostomy; Fatigue; Female; Gastrointestinal Agents; Gastrointestinal Transit; Glucagon-Like Peptide 2; Humans; Injection Site Reaction; Intestinal Absorption; Male; Mesenteric Ischemia; Mesenteric Vascular Occlusion; Middle Aged; Nausea; Short Bowel Syndrome

Ulcerative colitis (UC) is a gastrointestinal disease with complex etiology, and the shortage of the treatment further intensifies the need to discover new therapies based on novel mechanisms and strategies. TGR5 and DPP4 are beneficial to treat UC through multiple mechanisms, notably increasing GLP-2 levels by promoting secretion and inhibiting degradation respectively. However, some unwanted systemic effects caused by systemic exposure hinder development, especially the gallbladder-filling effects. Herein, we firstly reported a series of high-potency gut-restricted TGR5-DPP4 bifunctional molecules by gut-restriction and multitarget strategies to utilize the positive impacts of TGR5 and DPP4 on UC and avoid unwanted systemic effects. In particularly, racemic compound 15, a high-potency TGR5-DPP4 bifunctional molecule, showed favorable intestinal distribution, preferable efficacy in mice colitis model and good gallbladder safety. Therefore, the feasibility of gut-restricted TGR5-DPP4 bifunctional molecule was confirmed for the treatment UC, providing a new insight into the development of anti-UC drugs.

Topics: Animals; Colitis; Colitis, Ulcerative; Dipeptidyl Peptidase 4; Disease Models, Animal; Gallbladder; Glucagon-Like Peptide 2; Mice; Mice, Inbred C57BL; Receptors, G-Protein-Coupled

The global incidence of ulcerative colitis (UC) continues to increase while it's clinical cure rate remains low. Intestinal mucosal ulcers have segmental distribution and variable severity. Intestinal bacteria are closely related to intestinal immunity and metabolism; however, the relationship between intestinal microbiome profile and the occurrence of UC, as well as the contribution of glucose metabolism, are not well understood. This was investigated in the present study using mucosal biopsies from patients with UC and healthy control subjects. We performed high throughput 16S rRNA gene sequencing to estimate microbiota composition and abundance as well as their association with clinical indices such as lesion severity. The results showed that the diversity and abundance of intestinal microbiota were significantly lower in patients with UC than in healthy subjects; however, these were unrelated to ulcer severity. Serum glucagon-like peptide 2 (GLP-2) level was associated with reduced microbiota diversity and abundance in UC. These results indicate that colonization by specific microbiota is not the main determinant of pathologic status in UC. Additionally, therapeutic strategies that increase GLP-2 levels in intestinal mucosa may be effective in the treatment of UC.

Topics: Adult; Aged; Colitis, Ulcerative; Female; Gastrointestinal Microbiome; Glucagon-Like Peptide 2; Glucose; High-Throughput Nucleotide Sequencing; Humans; Intestinal Mucosa; Male; Middle Aged

Polyethylene glycosylated (PEGylated) porcine glucagon-like peptide-2 (pGLP-2) considerably increases half-life and stability compared with the native pGLP-2, but the effective dose for intestinal damage is still unclear. This study aims to evaluate the available dose of polyethylene glycosylated porcine glucagon-like peptide-2 (PEG-pGLP-2), a modified, long-acting form of pGLP-2 in an experimental rat model of ulcerative colitis.. Thirty-five male rats were randomly assigned into five groups: control, dextran sodium sulphate (DSS), DSS + PEG-pGLP-2(L), DSS + PEG-pGLP-2(M) and DSS + PEG-pGLP-2(H). Rats in control group received only water; other rats were fed with 5% (w/v) DSS and intraperitoneally administered with 12.5, 25 and 100 nmol/kg PEG-pGLP-2 daily for 6 days.. Compared with the control treatment, DSS treatment significantly (p < 0.05) decreased body weight change, colonic length, duodenal villus height and expression of zonula occludens-1, whereas significantly (p < 0.05) increased colonic damage score and expression of claudin-1, interleukin (IL)-1, IL-7, IL-10, interferon-γ and tumour necrosis factor (TNF)-α in colon. However, the three doses of PEG-pGLP-2 all reduced these effects; these treatments significantly (p < 0.05) increased body weight change and duodenal villus height, whereas significantly (p < 0.05) decreased colonic damage score and expression of IL-1, IL-7 and TNF-α in colon. Specifically, low-dose (12.5 nmol/kg/d) PEG-pGLP-2 was effective.. These results indicated that PEG-pGLP-2 is a novel and potentially effective therapy for intestinal healing in a relatively low dose.

Topics: Animals; Body Weight; Claudin-1; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Duodenum; Glucagon-Like Peptide 2; Intestinal Mucosa; Male; Polyethylene Glycols; Rats; Zonula Occludens-1 Protein

Glucagon-like peptide-2 (GLP-2) is an intestinal hormone that promotes intestinal growth, but the rapid degradation by dipeptidyl peptidase-IV limits its applications. PLGA microsphere is a well-developed drug delivery system, while seldom been studied as a solution for prolonging in vivo effects of GLP-2. In this study, we encapsulated porcine GLP-2 (pGLP-2) into microspheres and investigated its therapeutic effects in dextran sulfate sodium (DSS)-treated mice. pGLP-2 microspheres showed 20.36% in initial burst and constant release for at least 9 d. In the DSS-treated mice, a single injection of GLP-2 microspheres significantly increased the body weight, colonic length, small intestinal weight and mRNA expression of Occludin, decreased the colonic damage score, mRNA expression of IL-6, IL-10, TNF-α and IFN-γ. In conclusion, pGLP-2 microspheres were resistant to degradation and decreased the severity of DSS-induced ulcerative colitis which suggested that GLP-2-loaded microspheres could be a proper candidate for the treatment of ulcerative colitis.

Topics: Animals; Cell Proliferation; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Drug Delivery Systems; Glucagon-Like Peptide 2; Immune System; Interferon-gamma; Interleukin-1; Interleukin-6; Male; Mice; Mice, Inbred BALB C; Microspheres; Occludin; Real-Time Polymerase Chain Reaction; Swine; Tumor Necrosis Factor-alpha

Glucagon-like peptide-2 (GLP-2) is an important regulator of nutritional absorptive capacity with anti-inflammatory actions. We hypothesized that GLP-2 reduces intestinal mucosal inflammation by activation of vasoactive intestinal polypeptide (VIP) neurons of the submucosal plexus. Ileitis or colitis was induced in rats by injection of trinitrobenzene sulfonic acid (TNBS), or colitis was induced by administration of dextran sodium sulfate (DSS) in drinking water. Subsets of animals received (1-33)-GLP-2 (50 mug/kg sc bid) either immediately or 2 days after the establishment of inflammation and were followed for 3-5 days. The involvement of VIP neurons was assessed by concomitant administration of GLP-2 and the VIP antagonist [Lys(1)-Pro(2,5)-Arg(3,4)-Tyr(6)]VIP and by immunohistochemical labeling of GLP-2-activated neurons. In all models, GLP-2 treatment, whether given immediately or delayed until inflammation was established, resulted in significant improvements in animal weights, mucosal inflammation indices (myeloperoxidase levels, histological mucosal scores), and reduced levels of inflammatory cytokines (IFN-gamma, TNF-alpha, IL-1beta) and inducible nitric oxide synthase, with increased levels of IL-10 in TNBS ileitis and DSS colitis. Reduced rates of crypt cell proliferation and of apoptosis within crypts in inflamed tissues were also noted with GLP-2 treatment. These effects were abolished with coadministration of GLP-2 and the VIP antagonist. GLP-2 was shown to activate neurons and to increase the number of cells expressing VIP in the submucosal plexus of the ileum. These findings suggest that GLP-2 acts as an anti-inflammatory agent through activation of enteric VIP neurons, independent of proliferative effects. They support further studies to examine the role of neural signaling in the regulation of intestinal inflammation.

Topics: Animals; Anti-Inflammatory Agents; Colitis, Ulcerative; Dextran Sulfate; Disease Models, Animal; Enteric Nervous System; Glucagon-Like Peptide 2; Ileitis; Male; Neurotensin; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Trinitrobenzenesulfonic Acid; Vasoactive Intestinal Peptide

Glucagon-like peptide-2 (GLP-2) and peptide YY (PYY) are produced in endocrine L-cells of the intestine and secreted in response to food intake. GLP-2 has a trophic effect on the intestinal epithelium, whereas PYY has pro-absorptive effects. It can be speculated that, in inflammatory bowel disease (IBD), the production and secretion of GLP-2 and PYY could be affected as a part of a regulatory mechanism. Therefore, tissue levels and meal-stimulated secretion of GLP-2 and PYY were studied in IBD patients and compared to controls.. Outpatients with IBD and control patients were included. Mucosal biopsies were taken from the ileum and colon and the content of GLP-2 and PYY was measured. After colonoscopy the patients took a mixed meal and plasma was collected for 90 min for plasma measurements of GLP-2 and PYY.. Tissue levels of GLP-2 in control patients were highest in the terminal ileum (407+/-82 pmol/g tissue, n=10), whereas PYY was highest in the rectum (919+/-249 pmol/g tissue, n=10). In IBD patients with acute inflammation, the content of GLP-2 was similar to controls, whereas PYY was decreased to 72.1+/-17.7% (P=0.03, n=13) of control values. Neither the fasting plasma levels nor the meal responses of GLP-2 and PYY differed between controls and IBD patients.. The similar responses of GLP-2 and PYY in patients and controls do not support the suggestion that L-cell secretion is altered in IBD. The decreased tissue PYY concentrations may contribute to the diarrhoea of some of these patients.

Topics: Colitis, Ulcerative; Colon; Crohn Disease; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Ileum; Inflammatory Bowel Diseases; Intestinal Mucosa; Peptide YY; Peptides; Postprandial Period; Radioimmunoassay

The intestinal hormone glucagon-like peptide-2 (GLP-2) enhances bowel growth and reduces the severity of colonic injury in dextran sulfate sodium (DSS)-induced colitis in mice. In humans, ulcerative colitis is normally treated with aminosalicylates (ASAs) and corticosteroids (CSs) to reduce inflammation. However, whether the intestinotropic effects of GLP-2 are altered when combined with ASAs and/or CSs has not previously been explored. Thus, each agent [vehicle, ASA (sulfasalazine), CS (methylprednisolone), and ASA + CS] was administered alone or with GLP-2 to normal mice or mice with 3.5% DSS in the drinking water, for 10 consecutive days. GLP-2 treatment of DSS-mice increased survival and small intestinal weight (p < 0.05), and decreased body weight loss and colonic damage (p < 0.05). Furthermore, GLP-2 increased the number of proliferating cells in the colonic crypts of DSS-mice (p < 0.05). Administration of ASA, CS, or ASA + CS alone did not affect growth of the intestine in DSS-mice. However, administration of GLP-2 in combination with ASA was permissive for the beneficial effects of GLP-2 on survival and colonic damage, whereas CS treatment prevented these effects of GLP-2. Concomitant administration of GLP-2 with ASA + CS resulted in intermediate effects. No differences between colonic myeloperoxidase activity or IkappaB levels (an inhibitor of the nuclear factor-kappaB pro-inflammatory pathway) were found for any of these therapeutic agents. When taken together, the ability of GLP-2 to protect colonic mucosal architecture in DSS-colitis, and its effectiveness when given in combination with ASA, but not with CS, suggests a novel approach for the treatment of patients with colitis.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Animals; Colitis, Ulcerative; Colon; Disease Models, Animal; Drug Therapy, Combination; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Intestine, Small; Mice; Peptide Fragments; Peptides

Glucagon-like peptide-2 (GLP-2) is a recently characterized intestine-derived peptide that exerts trophic activity in the small and large intestine. Whether circulating levels of GLP-2 are perturbed in the setting of human inflammatory bowel disease (IBD) remains unknown. The circulating levels of bioactive GLP-2-(1-33) compared with its degradation product GLP-2-(3-33) were assessed using a combination of RIA and HPLC in normal and immunocompromised control human subjects and patients hospitalized for IBD. The activity of the enzyme dipeptidyl peptidase IV (DP IV), a key determinant of GLP-2-(1-33) degradation was also assessed in the plasma of normal controls and subjects with IBD. The circulating levels of bioactive GLP-2-(1-33) were increased in patients with either ulcerative colitis (UC) or Crohn's Disease (CD; to 229 +/- 65 and 317 +/- 89%, P < 0.05, of normal, respectively). Furthermore, the proportion of total immunoreactivity represented by intact GLP-2-(1-33), compared with GLP-2-(3-33), was increased from 43 +/- 3% in normal healthy controls to 61 +/- 6% (P < 0.01) and 59 +/- 2% (P < 0.01) in patients with UC and CD, respectively. The relative activity of plasma DP IV was significantly reduced in subjects with IBD compared with normal subjects (1.4 +/- 0.3 vs. 5.0 +/- 1.1 mU/ml, respectively; P < 0.05). These results suggest that patients with active IBD may undergo an adaptive response to intestinal injury by increasing the circulating levels of bioactive GLP-2-(1-33), facilitating enhanced repair of the intestinal mucosal epithelium in vivo.

Topics: Adaptation, Physiological; Adult; Colitis, Ulcerative; Colon; Crohn Disease; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Intestinal Mucosa; Intestine, Small; Male; Middle Aged; Peptides; Radioimmunoassay; Short Bowel Syndrome