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BACKGROUND The glucagon-like peptide 2 analogue teduglutide is an effective drug for the treatment of short bowel syndrome patients with intestinal failure (SBS-IF). This intestinotrophic peptide improves intestinal capacity for fluid and nutrient absorption through induction of mucosal growth and reduction of gastrointestinal motility. Clinical trials demonstrated the efficacy of teduglutide in reducing the need for parenteral support (PS). This study describes an SBS-IF patient population receiving teduglutide therapy in a specialized medical care setting. METHOD A retrospective analysis was performed using data of patients experiencing nonmalignant SBS-IF. They were treated with teduglutide in a multidisciplinary SBS-IF program at a single university medical center between June 2016 and June 2020. RESULTS Thirteen patients under teduglutide treatment were included in the final analysis. Mean small bowel length was 82 ± 31 cm, with 77% of patients having their colon in continuity. Over a median follow-up of 107 weeks, all patients (13 of 13, 100%) responded to the therapy with a clinically significant reduction of PS volume. Mean PS reduction increased with therapy duration and ranged from -82.5% at week 24 (n = 13) to -100% in patients (n = 5) who were treated for 144 weeks. Enteral autonomy was achieved in 12 of 13 (92%) patients. Teduglutide therapy improved stool frequency and consistency, changed dietary habits, and reduced disease-associated sleep disruptions. CONCLUSION Integrating SBS-IF patients treated with teduglutide in a proactive and tight-meshed patient care program significantly improves the clinical outcome, leading to an increased proportion of patients reaching enteral autonomy.

Background Previous studies showed that type 2 short bowel syndrome (SBS) rats were accompanied by severe intestinal bacterial dysbiosis. Limited data are available for intestinal fungal dysbiosis. Moreover, no effective therapeutic drugs are available for these microbiota dysbiosis. The aims of our study were to investigate the therapeutic potential of glucagon-like peptide 2 (GLP-2) for these microbiota dysbiosis in type 2 SBS rats. Methods 8-week-old male SD rats which underwent 80% small bowel resection, ileocecum resection, partial colon resection and jejunocolostomy, were treated with saline (SBS group, n = 5) or GLP-2 (GLP2.SBS group, n = 5). The Sham group rats which underwent transection and re-anastomosis were given a saline placebo (Sham group, n = 5). 16S rRNA and ITS sequencing were applied to evaluate the colonic bacterial and fungal composition at 22 days after surgery, respectively. Results The relative abundance of Actinobacteria, Firmicutes and proinflammatory Proteobacteria increased significantly in SBS group rats, while the relative abundance of Bacteroidetes, Verrucomicrobia and Tenericutes decreased remarkably. GLP-2 treatment significantly decreased Proteus and increased Clostridium relative to the saline treated SBS rats. The diversity of intestinal fungi was significantly increased in SBS rats, accompanied with some fungi abnormally increased and some resident fungi (e.g., Penicillium) significantly decreased. GLP-2 treatment significantly decreased Debaryomyces and Meyerozyma, and increased Penicillium. Moreover, GLP-2 partially restored the bacteria-fungi interkingdom interaction network of SBS rats. Conclusion Our study confirms the bacterial and fungal dysbiosis in type 2 SBS rats, and GLP-2 partially ameliorated these microbiota dysbiosis.

Glucagon-like peptide-1 (GLP-1), a product of partial proteolysis of proglucagon, is involved not only in regulation of carbohydrates, but also in water-salt metabolism. The study examined the role of proglucagon derivatives GLP-1, GLP-2, and oxyntomodulin in rat osmoregulation. Of them, only blood plasma GLP-1 increased in response to water load (20 ml/kg). Administration of glucose (1.5 g/kg) elevated GLP-1 and oxyntomodulin but did not change the level of GLP-2. GLP-1 accelerated excretion of excess water during hyperhydration, whereas GLP-2 decreased this parameter. No physiological effects of oxyntomodulin in the kidneys were revealed. Probably, the blood levels of proglucagon derivatives are independently regulated for each peptide. In contrast to GLP-2 and oxyntomodulin, GLP-1 is involved in osmoregulation.

Short bowel syndrome (SBS) is the most common cause of intestinal failure resulting in the need for long-term parenteral nutrition. Treatment for SBS involves the close management of parenteral and...

The intestinal hormone, glucagon-like peptide-2 (GLP-2), enhances the enterocyte chylomicron production. However, GLP-2 is known to require the intestinal-epithelial insulin-like growth factor-1 receptor (IE-IGF-1R) for its other actions to increase intestinal growth and barrier function. The role of the IE-IGF-1R in enterocyte lipid handling was thus tested in the GLP-2 signaling pathway, as well as in response to a Western diet (WD). IE-IGF-1R knockout (KO) and control mice were treated for 11 days with h(GLY2 )GLP-2 or fed a WD for 18 weeks followed by a duodenal fat tolerance test with C14 -labeled triolein. Human Caco-2BBE cells were treated with an IGF-1R antagonist or signaling inhibitors to determine triglyceride-associated protein expression. The IE-IGF-1R was required for GLP-2-induced increases in CD36 and FATP-4 in chow-fed mice, and for expression in vitro; FATP-4 also required PI3K/Akt. Although WD-fed IE-IGF-1R KO mice demonstrated normal CD36 expression, the protein was incorrectly localized 2h post-duodenal fat administration. IE-IGF-1R KO also prevented the WD-induced increase in MTP and decrease in APOC3, increased jejunal mucosal C14 -fat accumulation, and elevated plasma triglyceride and C14 -fat levels. Collectively, these studies elucidate new roles for the IE-IGF-1R in enterocyte lipid handling, under basal conditions and in response to GLP-2 and WD-feeding.

Pigs are increasingly important animals for modeling human pediatric nutrition and gastroenterology and complementing mechanistic studies in rodents. The comparative advantages in size and physiology of the neonatal pig have led to new translational and clinically relevant models of important diseases of the gastrointestinal tract and liver in premature infants. Studies in pigs have established the essential roles of prematurity, microbial colonization, and enteral nutrition in the pathogenesis of necrotizing enterocolitis. Studies in neonatal pigs have demonstrated the intestinal trophic effects of akey gut hormone, glucagon-like peptide 2 (GLP-2), and its role in the intestinal adaptation process and efficacy in the treatment of short bowel syndrome. Further, pigs have been instrumental in elucidating the physiology of parenteral nutrition–associated liver disease and the means by which phytosterols, fibroblast growth factor 19, and a new generation of lipid emulsions may modify disease. The premature pig will continue to be a valuable model in the development of optimal infant diets (donor human milk, colostrum), specific milk bioactives (arginine, growth factors), gut microbiota modifiers (pre-, pro-, and antibiotics), pharmaceutical drugs (GLP-2 analogs, FXR agonists), and novel diagnostic tools (near-infrared spectroscopy) to prevent and treat these pediatric diseases.

Background: Treatment with glucagon-like peptide-2 (GLP-2) analogs improve intestinal adaptation in patients with short bowel syndrome–associated intestinal failure (SBS-IF) and may reduce parenteral support requirements. Apraglutide is a novel, long-acting GLP-2 analog designed for once-weekly dosing. This trial investigated the safety and efficacy of apraglutide in patients with SBS-IF. Methods: In this placebo-controlled, double-blind, randomized, crossover phase 2 trial, eight adults with SBS-IF were treated with once-weekly 5-mg apraglutide doses and placebo for 4 weeks, followed by once-weekly 10-mg apraglutide doses for 4 weeks, with a washout period of 6–10 weeks between treatments. Safety was the primary end point. Secondary end points included changes from baseline in urine volume output compared with placebo, collected for 48 h before and after each treatment period. Results: Common treatment-related adverse events (AEs) were mild to moderate and included polyuria, decreased stoma output, stoma complications, decreased thirst, and edema. No serious AEs were considered to be related to apraglutide treatment. The safety profile was comparable for the lower and higher doses. Treatment with once-weekly 5- and 10-mg apraglutide doses significantly increased urine volume output by an adjusted mean of 714 ml/day (95% CI, 490–939; P

BACKGROUND Short Bowel Syndrome (SBS) is characterized by debilitating malabsorption requiring parenteral nutrition. The intestinotrophic glucagon-like peptide-2 receptor agonist, h[Gly2]GLP2, is currently used to treat patients with SBS. Recent evidence suggests that GLP-1 receptor agonists such as Exendin-4 (Ex4) may also be beneficial in SBS given their ability to increase intestinal growth and delay gastric emptying (GE). METHODS Intestinal growth, body weight (BW), food intake (FI), GE, gastrointestinal (GI) transit, intestinal permeability, and glucose tolerance were investigated in male and female C57/BL6 mice following vehicle, h[Gly2]GLP2 or Ex4 treatment, alone or in combination at "low", "medium", and "high" doses (0.1, 0.5, 1.0 and 0.01, 0.05, 0.1 μg/g, respectively). RESULTS Only the h[Gly2]GLP2 low/Ex4 high-dose combination increased small intestinal (SI) weight, in an additive manner, compared to vehicle and both mono-agonists (P

Background: Glucagon-like peptide-2 (GLP-2) has protective effects on gastrointestinal functions. Our previous study found that GLP-2 could significantly reduce intestinal permeability and bacterial translocation in total parenteral nutrition (TPN) animal model. However, the effects of GLP-2 on the impairment of the intestinal Paneth cells immune function and gut inflammation during intravenous fluid infusion mainly consisted of nutritional materials is currently scattered.Objective: The current study was aimed to investigate the efficacy of the GLP-2 in alleviating gut inflammation and modulating enteric Paneth cells immune response in parenterally fed mice and its underlying mechanisms.Methods: Thirty-six male ICR mice underwent venous catheterization were divided into 3 groups: Chow, TPN, and TPN+GLP-2 groups. GLP-2 was administered intravenously at 60 μg/day for 5 days. The small intestine tissue and serum samples were collected on the 7th day.Results: Compared with the TPN group, the expression of tight junction proteins occludin and claudin-1 were significantly increased in the TPN+GLP-2 group. In addition, the expression of lysozyme, sPLA2, insulin-like growth factor-1, and epithelial protection and repair genes were improved in the TPN+GLP-2 group. The levels of IL-6 and TNF-α proteins and mRNAs in the ileum tissues were remarkably reduced in the TPN+GLP-2 group, while IL-10 protein and mRNA level were elevated in the TPN+GLP-2 group (all p < 0.05). Moreover, the TPN+GLP-2 group has higher levels of serum endotoxin, D-lactic acid, and MPO than those of the TPN group.Conclusions: GLP-2 alleviated gut inflammation and improved enteric Paneth cells immune responses through intravenous fluid infusion, possibly by improving the functioning of epithelial protection and repair, and reducing mucosal inflammatory responses.

Background: The gut-liver axis and enterohepatic circulation have gained increasing attention lately. Patients with short bowel syndrome (SBS) are, in fact, human knock-out models that may assist in the understanding of bile acid synthesis and regulation. We evaluated effect of glepaglutide (a long-acting glucagon-like peptide-2 analog) on bile acid synthesis (the enterohepatic circulation of bile acids and liver biochemistry in patients with SBS.Method: In a single-center, double-blinded, dose-finding, crossover phase 2 trial, 18 patients with SBS were randomly assigned to 2 of 3 treatment arms (0.1, 1 and 10 mg) with daily subcutaneous injections of glepaglutide for 3 weeks. The washout period between the 2 treatment periods was 4-8 weeks. Measurements were performed at baseline and at the end of each treatment period and included postprandial plasma samples for fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4), total excretion of fecal bile acids, gene expression of farnesoid X receptor (FXR) in intestinal mucosal biopsies, total plasma bile acids, and liver biochemistry.Results: Compared to baseline, the median (interquartile range) postprandial response (area under the curve 0-2h) of FGF19 increased by 150 h × ng/L (41, 195; P = 0.001) and C4 decreased by 82 h × μg/L (-169, -28; P = 0.010) in the 10-mg dose. FXR gene expression did not change in any of the groups. Alkaline phosphatase significantly decreased.Conclusions: Glepaglutide may stimulate the bile acid/FXR/FGF19 axis, leading to increased plasma concentrations of FGF19. Thereby, glepaglutide may ameliorate the accelerated de novo bile acid synthesis and play a role in the prevention and/or treatment of intestinal failure-associated liver disease.

The effects of exercise on nutrient digestion and absorption in the intestinal tract are not well understood. A few studies have reported that exercise training increases the expression of molecules involved in carbohydrate digestion and absorption. Exercise was also shown to increase the blood concentration of glucagon-like peptide-2 (GLP-2), which regulates carbohydrate digestion and absorption in the small intestine. Therefore, we investigated the effects of exercise on the expression of molecules involved in intestinal digestion and absorption, including GLP-2. Six-week-old male mice were divided into a sedentary (SED) and low-intensity exercise (LEx) group. LEx mice were required to run on a treadmill (12.5 m/min, 1 h), whereas SED mice rested. All mice were euthanized 1 h after exercise or rest, and plasma, jejunum, ileum, and colon samples were collected, followed by analysis via IHC, EIA, and immunoblotting. The levels of plasma GLP-2 and the jejunum expression of the GLP-2 receptor, sucrase-isomaltase (SI), and glucose transporter 2 (GLUT2) were higher in LEx mice. Thus, we showed that acute low-intensity exercise affects the expression of molecules involved in intestinal carbohydrate digestion and absorption via GLP-2. Our results suggest that exercise might be beneficial for small intestine function in individuals with intestinal frailty.

BackgroundBerberine is a plant alkaloid that has multiple beneficial effects against intestine inflammation. In our previous study, we have found that berberine also possesses an antidiabetic effect. However, whether berberine is useful in the prevention of type 2 diabetes mellitus (T2DM) through its effect on intestine endocrine function and gut microbiota is unclear.AimTo investigate the effects of berberine in the prevention of T2DM, as well as its effects on intestine GLP-2 secretion and gut microbiota in ZDF rats.MethodsTwenty Zucker Diabetic Fatty (ZDF) rats were fed a high-energy diet until they exhibited impaired glucose tolerance (IGT). The rats were then divided into two groups to receive berberine (100 mg/kg/d; berberine group) or vehicle (IGT group) by gavage for 3 weeks. Five Zucker Lean (ZL) rats were used as controls. Fasting blood glucose (FBG) was measured, an oral glucose tolerance test was performed, and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated. Intestinal expression of TLR-4, NF-κB, TNF-α, mucin, zona occludens-1 (ZO-1) and occludin were assessed (immunohistochemistry). Plasma levels and glutamine-induced intestinal secretion of glucagon-like peptide-1 (GLP-1) and GLP-2 were measured (enzyme-linked immunosorbent assay). The plasma lipopolysaccharide (LPS) level was measured. Fecal DNA extraction, pyrosequencing, and bioinformatics analysis were performed.ResultsAfter 3 weeks of intervention, diabetes developed in all rats in the IGT group, but only 30% of rats in the berberine group. Treatment with berberine was associated with reductions in food intake, FBG level, insulin resistance, and plasma LPS level, as well as increases in fasting plasma GLP-2 level and glutamine-induced intestinal GLP-2 secretion. Berberine could increase the goblet cell number and villi length, and also reverse the suppressed expressions of mucin, occludin, ZO-1 and the upregulated expressions of TLR-4, NF-κB and TNF-α induced in IGT rats (PConclusionBerberine may slow the progression of prediabetes to T2DM in ZDF rats by improving GLP-2 secretion, intestinal permeability, and the structure of the gut microbiota.

Exercise affects various organs. However, its effects on nutrient digestion and absorption in the intestinal tract are not well understood. A few studies have reported that exercise training in-creases the expression of carbohydrate digestion and absorption molecules. Exercise was also shown to increase the concentration of blood glucagon like peptide-2(GLP-2), which regulates carbohydrate digestion and absorption in small intestinal epithelium. Therefore, we investigated the effects of exercise on intestinal digestion and absorption molecules and the levels of GLP-2. 6-wk-old of male mice were divided into 2 groups; sedentary (SED) and low-intensity exercise (LEx). LEx mice were required to run on a treadmill (12.5 m/min, 60 min), whereas SED mice rested. All mice were euthanized 1 h after exercise or rest and plasma, jejunum, ileum, and colon were sampled. Samples were analyzed using EIA and immunoblotting. The levels of plasma GLP-2 and the expression of the GLP-2 receptor, sucrase-isomaltase (SI), and glucose transporter (GLUT2) in the jejunum were increased in LEx group. We showed that acute low-intensity exer-cise affects the intestinal carbohydrate digestion and absorption molecules via GLP-2. Our results suggest that exercise might provide new benefits to the small intestine for people with intestinal frailty.

Glucagon-like peptide-2 (GLP-2) is secreted from enteroendocrine L-type cells of the gut and also released from preproglucagonergic (PPG) neurons in the nucleus tractus solitarius (NTS) and adjacent medial reticular nucleus of the brain stem. The neurons in the NTS express GLP-2, and the neurons send extensive projections to the hypothalamus. Recent studies show that the intracerebroventricular administration of GLP-2 significantly suppresses food intake in animals and some evidence suggest that the melanocortin receptor-4 (MC4-R) signaling in the hypothalamus is required for intracerebroventricular GLP-2-mediated inhibition of feeding. There is proopiomelanocortin (POMC) positive neurons expressing MC4-R in the NTS. Suppression of MC4-R expressing neurons in the brain stem inhibits gastric emptying. In this study, we tested the effects of NTS GLP-2R activation and blockade on feeding behavior and evaluated the endogenous melanocortin system's role in the NTS in mediating effects of GLP-2 on feeding behavior in fed and fasted rats. Our results demonstrated that microinjection of GLP-2 into the NTS suppressed food intake in fasted-refeeding rats but did not affect food intake in free-feeding rats, and this inhibition was blocked by pretreatment of either Exendin (9-39) or SHU 9119, suggesting the GLP-2 system in the NTS exerts an inhibitory action on food intake. MC4-R mediates this action in the NTS.

Summary Background and aims The glucagon-like peptide-2 (GLP-2) analogue, teduglutide, allows to reduce the intravenous supplementation (IVS) dependency of patients with short bowel syndrome and intestinal failure (SBS-IF). The rate of candidacy of SBS-IF patients for the treatment is unknown. The candidacy for teduglutide treatment of our patient cohort was investigated by a systematic analysis. Methods The indications, contraindications, special warnings and precautions for use of teduglutide, listed in the drug monographs and in the phase-III trial protocol were adopted to categorize the patients as non-candidates (NC), potential candidates (PC) or straight candidates (SC) for the treatment. All the SBS-IF adult patients who were cured at our centre were assessed according to their clinical status on January 1st, 2020. Results Seventy-nine patients were evaluated: 34.2% were NC due to risk of digestive malignancy, recent history of any other cancer, or listing for intestinal transplantation; 30.4% were PC, because of other premalignant conditions, risk of intestinal obstruction, entero-cutaneous fistulas, or severe co-morbidities; 35.4% were SC. The SC group showed the lowest requirement of IVS: the lowest number of days of infusion per week (p = 0.0054), the lowest amount of energy (p = 0.0110) and volume (p = 0.0136). Conclusions This systematic analysis allowed a pragmatic categorization of the candidacy of patients with SBS-IF for GLP-2 analogue treatment. The SC group appeared to have the highest probability of a successful response to the treatment. A systematic analysis of SBS-IF patient candidate for GLP-2 analogue therapy would allow a homogeneous patient selection and facilitate the worldwide comparison of the results of clinical practice and research.

Background Short bowel syndrome is the leading cause of pediatric intestinal failure, resulting in dependency on long term parenteral nutrition (PN). In order to promote autonomy from PN in neonates, a key outcome may be intestinal growth in length. The purpose of this study was to determine if intestinal lengthening persists following discontinuation of treatment with one of two GLP-2 analogues with different pharmacokinetic profiles. Methods Neonatal short bowel piglets were assigned to: saline control (S), 7-day treatment with teduglutide (0.05mg/kg twice daily) (T), or 7-day treatment with apraglutide (5mg/kg twice weekly) (A). Comparisons were made between day 7 and day 14 endpoints using ANOVA. Data included small intestine length, weight, histology, and qPCR analysis of mucosal transcripts for peptide growth factors and their receptors, nutrient transporters, and tight junction proteins. Results Compared to control, 7 days of GLP-2 analogue treatment induced mucosal adaptation, based on villus hyperplasia (p = 0.003), which was not durable 7 days after treatment cessation (day 14; p = 0.081). Treatment increased intestinal growth in length by day 7 (p = 0.005), which was maintained (by teduglutide) or further increased (by apraglutide) at day 14 (p Conclusion Unlike mucosal adaptation, durable intestinal growth appears to be a lasting outcome of trophic treatment with long acting GLP-2 analogues in a neonatal piglet short bowel model. This has significant clinical implications for neonates given their unique potential for intestinal growth. Intestinal lengthening varies between analogues with different half-lives; however, molecular mechanisms require further elucidation. This article is protected by copyright. All rights reserved.

Intrauterine growth restriction (IUGR) results in abnormal morphology and gastrointestinal function, such as reduced villi height and crypt depth, thinner mucosa and muscle layers, and reduced brush border enzyme activities, delayed gastric emptying, increased stress response. As a gastrointestinal growth factor, the manner by which the porcine glucagon-like peptide-2 (pGLP-2) microsphere administration restored the gastrointestinal function and growth performance of IUGR piglets was investigated. Fourteen newborn Duroc × (Yorkshire × Landrace) IUGR piglets (0.92 ± 0.113 kg) were assigned into the IUGR (negative control group) and pGLP-2 microsphere groups. The piglets in group pGLP-2 were intraperitoneally administered with 100 mg pGLP-2 microspheres on day 1 after birth. From days 15 to 26 of trial, the body weight of the pGLP-2 group was significantly higher than that of the control. IUGR piglets of group pGLP-2 showed a significantly increased pancreas weight, serum insulin content and activity of lipase and amylase. Injection of pGLP-2 microspheres restored the intestinal absorptive capacity by significantly increasing the mRNA expression of the sodium-glucose cotransporter 1 in the jejunum and the peptide transporter 1 in the jejunum. It also restored the redox balance by increasing the catalase mRNA expression and decreasing the heat shock protein 70 mRNA expression. In addition, this improvement was associated with the significant increase in gut diameter, length and weight. Therefore, it was concluded that the injection of pGLP-2 microspheres was a suitable therapeutic strategy for compensatory growth in low birth weight IUGR piglets.

Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although currently used GVHD treatment regimens target the donor immune system, we explored here an approach that aims at protecting and regenerating Paneth cells (PCs) and intestinal stem cells (ISCs). Glucagon-like-peptide-2 (GLP-2) is an enteroendocrine tissue hormone produced by intestinal L cells. We observed that acute GVHD reduced intestinal GLP-2 levels in mice and patients developing GVHD. Treatment with the GLP-2 agonist, teduglutide, reduced de novo acute GVHD and steroid-refractory GVHD, without compromising graft-versus-leukemia (GVL) effects in multiple mouse models. Mechanistically GLP-2 substitution promoted regeneration of PCs and ISCs, which enhanced production of antimicrobial peptides and caused microbiome changes. GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes. Low numbers of L cells in intestinal biopsies and high serum levels of GLP-2 were associated with a higher incidence of nonrelapse mortality in patients undergoing allo-HCT. Our findings indicate that L cells are a target of GVHD and that GLP-2–based treatment of acute GVHD restores intestinal homeostasis via an increase of ISCs and PCs without impairing GVL effects. Teduglutide could become a novel combination partner for immunosuppressive GVHD therapy to be tested in clinical trials.

Short bowel syndrome (SBS) is a rare disease that results from extensive resection of the intestine. When the remaining absorption surface of the intestine cannot absorb enough macronutrients, micronutrients, and water, SBS results in intestinal failure (IF). Patients with SBS who suffer from IF require parenteral nutrition for survival, but long-term parenteral nutrition may lead to complications such as catheter sepsis and metabolic diseases. Spontaneous intestinal adaptation occurs weeks to months after resection, resulting in hyperplasia of the remnant gut, modification of gut hormone levels, dysbiosis, and hyperphagia. Oral nutrition and presence of the colon are two major positive drivers for this adaptation. This review aims to summarize the current knowledge of the mechanisms underlying spontaneous intestinal adaptation, particularly in response to modifications of luminal content, including nutrients. In the future, dietary manipulations could be used to treat SBS.

BACKGROUND Teduglutide (TED) is a glucagon-like peptide 2 analogue approved in patients with short bowel syndrome with chronic intestinal failure. Bowel epithelial hyperplasia has been reported after TED treatment. OBJECTIVE The aim of this study was to describe small bowel modifications at imaging in patients with SBS-CIF receiving TED and to assess their predictive value for clinical response. METHODS Monocentric retrospective study including patients with SBS-CIF treated with TED from 2009 to 2018 with available computed tomography (CT) scans at baseline and during follow-up (≥12 mo). Small bowel (SB) wall thickness was measured as the average of 3 measurements on different SB segments. Clinical response to TED was defined as a ≥20% reduction of weekly parenteral support (PS) volume at 12 mo. RESULTS Thirty-one patients [20 male (65%), median age 51 y (IQR: 37-59)] were included. Baseline weekly PS volume was a median 7500 mL (IQR: 3500-15,000). After a median (IQR) follow-up of 16 mo (14-27), 26 of 31 patients (84%) had a clinical response. During follow-up, patients underwent 1 (n = 18/31, 58%), 2 (10/31, 32%), or 3 (3/31 10%) CT scans. Median SB wall thickness was 4.0 mm (IQR: 2.8-4.7) and 8.5 mm (IQR: 6.1-9.8) at baseline and after treatment, respectively [paired P

Glucagon-like peptide-2 (GLP-2), an intestinotrophic hormone, has drawn considerable attention worldwide due to its potential to promote intestinal development. We investigated the effects and mechanisms of GLP-2 against lipopolysaccharide (LPS)-induced intestinal inflammation and injury both in vitro and in vivo. Forty healthy piglets weaned at the age of 28 days with similar body weight (BW) were assigned to four in vivo treatments with ten piglets each: (i) nonchallenged control; (ii) LPS-challenged control; (iii) LPS + low dose GLP-2; and (iv) LPS + high dose GLP-2. Piglets were subcutaneously injected with phosphate-buffered saline supplemented with GLP-2 at doses of 0, 0, 2, and 10 nmol/kg BW per day for seven consecutive days. The piglets were challenged with an intraperitoneal injection with 100 μg/kg LPS on day 14 to induce intestinal damage. After that, the gene and protein expression levels of representative tight junction proteins and myosin light-chain kinase (MLCK)/phosphorylated myosin light chain (pMLC), as well as proinflammatory cytokine levels were determined using quantitative reverse transcription polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay methods. A high dose of GLP-2 pretreatment increased intestinal permeability by downregulating and redistributing tight junction proteins (p

BACKGROUND In treating short-bowel syndrome (SBS), autonomy from parenteral nutrition (PN) relies upon intestinal adaptation, which can be augmented by glucagon-like peptide-2 (GLP-2) analogues. In neonatal piglets with SBS, we compared intestinal adaptation following treatment with 2 GLP-2 analogues: teduglutide (TED) and apraglutide (APRA) METHODS: Following 75% distal small-intestinal resection, piglets were allocated to 4 treatment groups: saline (CON: n = 8), twice weekly APRA (5 mg/kg/dose; n = 8), and TED once daily (TED, 0.05 mg/kg/dose; n = 8) or twice daily (TEDBID, 0.05 mg/kg/dose; n = 7). Pharmacokinetic (PK) studies were undertaken, and on day 7, small-intestinal length and weight were measured and jejunal tissue collected for histology. RESULTS PK profiles were different between the 2 analogues. To achieve a comparable exposure to APRA, TED requires twice daily injection (TEDBID). Compared with CON, APRA and TEDBID increased small-bowel length (cm) (CON: 141, APRA: 166, TED: 153, TEDBID: 165; P = .004), whereas APRA increased small-bowel weight (g) (CON: 26, APRA: 33, TED: 28, TEDBID: 31; P = .007) and villus height (mm) (CON: 0.59, APRA: 0.90, TED: 0.58, TEDBID: 0.74; P < .001). CONCLUSION APRA injected only twice during the 7 consecutive days demonstrated a superior intestinotrophic effect compared with TED injected once daily. Even at more comparable drug exposure, when TED was injected twice a day, APRA showed superior trophic activity at the mucosal level. This is highly relevant for the treatment of pediatric SBS, given the markedly lower dose frequency by subcutaneous injection of APRA.

Background. The enteroendocrine hormone glucagon-like peptide- (GLP-) 2 is a potent trophic factor in the gastrointestinal tract. The GLP-2 receptor (GLP-2R) is expressed in the stroma of the large bowel wall, which is the major therapeutic target area to prevent anastomotic leakage. We investigated the efficacy of the long-acting GLP-2 analogue ZP1849 on colonic anastomotic wound healing. Methods. Eighty-seven male Wistar rats were stratified into four groups and received daily treatment with vehicle or ZP1849 starting one day before (day -1) end-to-end anastomosis was constructed in the left colon on day 0, and on days 0 (resected colon segment), 3, and 5, gene expressions of GLP-2R, Ki67, insulin-like growth factor- (IGF-) 1, type I (COL1A1) and type III (COL3A1) procollagens, cyclooxygenase- (COX-) 1, COX-2, and matrix metalloproteinase- (MMP-) 7 were quantified by RT-qPCR. Breaking strength, myeloperoxidase (MPO), transforming growth factor- (TGF-) β1, and soluble collagen proteins were measured on days 3 and 5. Results. ZP1849 treatment increased Ki67 (P<0.0001) and IGF-1 (P<0.05) mRNA levels in noninjured colon day 0, and postoperatively in the anastomotic wounds compared to vehicle-treated rats. ZP1849-treated rats had increased (P=0.042) anastomotic breaking strength at day 5 compared with vehicle. COL1A1 and COL3A1 mRNA levels (P<0.0001) and soluble collagen proteins (P<0.05) increased from day 3 to day 5 in ZP1849-treated rats, but not in vehicle-treated rats. COX-2 mRNA and MPO protein levels decreased from day 3 to day 5 (P<0.001) in both groups. ZP1849 treatment reduced TGF-β1 protein levels on day 5 (P<0.001) but did not impact MMP-7 transcription. Conclusions. The GLP-2 analogue ZP1849 increased breaking strength, IGF-1 expression, and cell proliferation, which may be beneficial for colonic anastomotic wound healing.

Glucagon-like peptide (GLP)-1 is involved in glucose homeostasis via its role in stimulating insulin secretion, whereas GLP-2 increases mucosal growth of the small intestine. To our knowledge, the effect of delayed colostrum feeding on plasma GLP-1 and GLP-2 in neonatal calves has not been evaluated. To investigate the effect of delayed colostrum feeding on plasma concentrations of GLP-1 and GLP-2 in newborn calves, we randomly assigned 27 Holstein bull calves to 1 of 3 treatment groups: those fed colostrum within 1 h after birth (control), 6 h after birth (6H), and 12 h after birth (12H; n = 9 for each treatment). Blood samples were obtained before the colostrum feeding and every 3 h after each colostrum feeding for a 36-h period, and plasma concentrations of GLP-1, GLP-2, insulin, and glucose were measured. Plasma GLP-1 concentration at 12 h after colostrum feeding was lower in 12H than in control calves. In addition, plasma insulin concentration was lower in the 6H and 12H calves than in the controls. Plasma glucose and GLP-2 concentrations were, however, not affected by treatment. These results indicate that delayed colostrum feeding can decrease plasma GLP-1 and insulin concentrations without affecting glucose or GLP-2 concentration.

This study investigates the relationship between the enteric hormone glucagon-like peptide 2 (GLP-2) production, sensitivity, and intestinal adaptation in infants following resection or repair of gastroschisis.With IRB approval (UCalgary #10656), consent was obtained from families of infants undergoing surgery for prospective monitoring of nutritional status, GLP-2 levels, and where possible, tissue sampling.Infants who adapted and weaned from parenteral nutrition (PN) had increased GLP-2 (86±32) n=24 vs. controls: 45±20 n=10 and vs. patients on prolonged PN: 42±6 pM, n=10). This was maintained to one year: weaned patients: 72±49 vs. non-weaned: 35±15 pM (p0.05). Infants with gastroschisis (n=33) had decreased GLP-2 levels until enteral function was achieved and then became elevated: (21±15 with first feeding vs. 102±60 at full feeds and 60±19 pM at one year). There were no changes in the density or distribution of GLP-2 producing L-cells related to gestational age, nor in the expression of the GLP-2 receptor.GLP-2 levels correlate with intestinal adaptation in infants, and with recovery of intestinal function in gastroschisis. GLP-2 productive capacity (L-cell expression) and GLP-2 receptor expression do not vary with maturity. The findings support a role for GLP-2 in regulating intestinal function. Further study is suggested.

Parenteral nutrition (PN) is associated with increased infectious risks due to impaired intestinal immunity. Although glucagon-like peptide-2 (GLP-2) enhances the gut barrier function, it is uncertain whether it improves mucosal immunologic barrier function. We hypothesized that injecting the PN mouse model with GLP-2 improved innate and acquired immunity, and prevented bacterial translocation. Forty-eight hours after venous cannulation, male Institute of Cancer Research mice were randomly divided into 3 groups based on their diet: chow with saline (n = 10), PN (n = 9), or PN + GLP-2 (30 μg bid per mouse, n = 10) provided for 5 days. Compared with chow, PN reduced interleukin (IL)-4 and IL-13 levels (P < .05, respectively), whereas, compared with PN alone, GLP-2 injection increased IL-4 and IL-13 levels (P < .05, respectively). Compared with chow, PN considerably suppressed, whereas GLP-2 improved, secretory phospholipase A2 and cryptdin-4 expression. PN, compared with chow, considerably decreased lysozyme and polymeric immunoglobulin receptor levels, whereas, compared with PN, GLP-2 significantly increased these protein levels (P < .01, respectively). In tissue and luminal samples, compared with chow, PN reduced secretory immunoglobulin A levels (P < .05), whereas, compared with PN alone, GLP-2 increased secretory immunoglobulin A levels (P < .05). Functionally, more bacterial translocation was observed in the PN group compared with the chow group (P < .001), and GLP-2 injection decreased bacterial translocation to chow levels (P < .05). In summary, GLP-2 treatment may improve intestinal innate and acquired immunity, and prevent bacterial translocation in mice on total parenteral nutrition.

Dietary β-glucans are soluble fibers with potentially health-promoting effects. Gut peptides are important signals in the regulation of energy and glucose homeostasis. This article reviews the effects of different enriched β-glucan food consumption on immune responses, inflammation, gut hormone and cancer. Gut hormones are influenced by enriched β-glucan food consumption and levels of such peptide as YY, ghrelin, glucagon-like peptide 1 and 2 in humans influence serum glucose concentration as well as innate and adaptive immunity. Cancer cell development is also regulated by obesity and glucose dishomeostasy that are influenced by β-glucan food consumption that in turn regulated gut hormones.

Inadequate feed consumption reduces intestinal barrier function in both ruminants and monogastrics. Objectives were to characterize how progressive feed restriction (FR) affects inflammation, metabolism, and intestinal morphology, and to investigate if glucagon-like peptide 2 (GLP2) administration influences the aforementioned responses. Twenty-eight Holstein cows (157 ± 9 d in milk) were enrolled in 2 experimental periods. Period 1 [5 d of ad libitum (AL) feed intake] served as baseline for period 2 (5 d), during which cows received 1 of 6 treatments: (1) 100% of AL feed intake (AL100; n = 3), (2) 80% of AL feed intake (n = 5), (3) 60% of AL feed intake (n = 5), (4) 40% of AL feed intake (AL40; n = 5), (5) 40% of AL feed intake + GLP2 administration (AL40G; 75 µg/kg of BW s.c. 2×/d; n = 5), or (6) 20% of AL feed intake (n = 5). As the magnitude of FR increased, body weight and milk yield decreased linearly. Blood urea nitrogen and insulin decreased, whereas nonesterified fatty acids and liver triglyceride content increased linearly with progressive FR. Circulating endotoxin, lipopolysaccharide binding protein, haptoglobin, serum amyloid A, and lymphocytes increased or tended to increase linearly with advancing FR. Circulating haptoglobin decreased (76%) and serum amyloid A tended to decrease (57%) in AL40G relative to AL40 cows. Cows in AL100, AL40, and AL40G treatments were euthanized to evaluate intestinal histology. Jejunum villus width, crypt depth, and goblet cell area, as well as ileum villus height, crypt depth, and goblet cell area, were reduced (36, 14, 52, 22, 28, and 25%, respectively) in AL40 cows compared with AL100 controls. Ileum cellular proliferation tended to be decreased (14%) in AL40 versus AL100 cows. Relative to AL40, AL40G cows had improved jejunum and ileum morphology, including increased villus height (46 and 51%), villus height to crypt depth ratio (38 and 35%), mucosal surface area (30 and 27%), cellular proliferation (43 and 36%), and goblet cell area (59 and 41%). Colon goblet cell area was also increased (48%) in AL40G relative to AL40 cows. In summary, progressive FR increased circulating markers of inflammation, which we speculate is due to increased intestinal permeability as demonstrated by changes in intestinal architecture. Furthermore, GLP2 improved intestinal morphology and ameliorated circulating markers of inflammation. Consequently, FR is a viable model to study consequences of intestinal barrier dysfunction and administering GLP2 appears to be an effective mitigation strategy to improve gut health.

Diabetes is a metabolic condition. The composition of the gut microbiota is altered in diabetes with reduced levels of short chain fatty acids (SCFA) producers, notably butyrate. Butyrate is associated with a number of beneficial effects including promoting the integrity of the gastrointestinal barrier. Diabetes may lead to an increase in the permeability of the gut barrier, which is thought to contribute to systemic inflammation and worsen the microvascular complications of diabetes. Prebiotics, non-digestible carbohydrates, are fermented by the colonic microbiota leading to the production of a range of metabolites including SCFAs. Thus, prebiotics represent a dietary approach to increase levels of microbially produced SCFAs and improve intestinal permeability in diabetes. Whether prebiotics can lead to a reduction in the risk of developing diabetes complications in individuals with type 2 diabetes needs to be explored.

Aim: Glukagon-like-peptide-1 (GLP-1) and -2 (GLP-2), produced by intestinal L-cells, are key hormones regulating intestinal transit, secretion, absorption, and mucosal growth. We evaluated nai ve fasting serum GLP-1 and GLP-2 levels in pediatric intestinal failure (IF). Methods: Fifty-five IF patients with median age 4.2 (IQR 1.3-12) years and 47 matched healthy controls underwent measurement of fasting serum GLP-1 and GLP-2. Results: Serum GLP-2 [19.9 (13.8-27.9) vs 11.6 (7.0-18.6) ng/mL, P

AIM To investigate whether glucagon-like peptide-2 (GLP-2) influences the neurally-induced responses in gastric strips from mice, since no data are available. METHODS For functional experiments, gastric fundal strips were mounted in organ baths containing Krebs-Henseleit solution. Mechanical responses were recorded via force-displacement transducers, which were coupled to a polygraph for continuous recording of isometric tension. Electrical field stimulation (EFS) was applied via two platinum wire rings through which the preparation was threaded. The effects of GLP-2 (2 and 20 nmol/L) were evaluated on the neurally-induced contractile and relaxant responses elicited by EFS. Neuronal nitric oxide synthase (nNOS) enzyme was evaluated by immunohistochemistry. RESULTS In the functional experiments, electrical field stimulation (EFS, 4-16 Hz) induced tetrodotoxin (TTX)-sensitive contractile responses, which were reduced in amplitude by GLP-2 (P < 0.05). In the presence of the nitric oxide (NO) synthesis inhibitor L-NNA, GLP-2 no longer influenced the neurally-evoked contractile responses (P > 0.05). The direct smooth muscle response to methacholine was not influenced by GLP-2 (P > 0.05). In the presence of guanethidine and carbachol, the addition of GLP-2 to the bath medium evoked TTX-sensitive relaxant responses that were unaffected by L-NNA (P > 0.05). EFS induced a fast NO-mediated relaxation, whose amplitude was enhanced in the presence of the hormone (P < 0.05). Immunohistochemical experiments showed a significant increase (P < 0.05) in nNOS immunoreactivity in the nerve structures after GLP-2 exposure. CONCLUSION The results demonstrate that in gastric fundal strips, GLP-2 influences the amplitude of neurally-induced responses through the modulation of the nitrergic neurotransmission and increases nNOS expression.

Gut resection is followed by wide changes in the gastrointestinal tract. The goal is to increase nutrient, water and mineral absorption in the remnant intestine. These changes are going on for several months. They affect gut mucosa structure, intestine peristaltic activity and enterocytes function. The crucial role is ileum preserving. Ileum has higher adaptation ability comparing to jejunum and inhibits peristaltic function of proximal parts of GIT. A lot of factors involved in intestinal adaptation were identified, hormones, growth factors, regulating peptides, intracellular signalizing cascades, cytokines and tissue factors. The most important seems to be GLP2 (glucagon like peptide 2) which has positive trophic influence on gut mucosa. Early enteral nutrition after gut resection enhances its adaptation. Recombinant analogueGLP2 teduglutide was introduced to be used in the short bowel syndrome treatment. It inhibits stomach evacuation and hypersecretion, increases intestine perfusion and enhances intestinal adaptation. Its long-term application accelerates the parenteral nutrition weaning.Key words: enteral nutrition - enterocytes - GLP2 - gut resection - intestinal adaptation.

Multidrug resistance-associated protein 2 (Mrp2, ABCC2) and P-glycoprotein (P-gp, ABCB1) constitute essential components of the intestinal biochemical barrier that prevent incorporation of food contaminants, drugs or toxic metabolites into the blood stream. Endotoxemia induced in rats by administration of bacterial lipopolysaccharide (LPS) results in elevated intestinal permeability and toxicity of xenobiotics in part associated with down-regulation of expression and activity of Mrp2 and P-gp. We evaluated the protective effect of glucagon-like peptide 2 (GLP-2), a peptide hormone with enterotrophic properties, on Mrp2 and P-gp alterations induced by single i.p. injection of LPS (5 mg/kg b.wt.) to rats. Two different protocols of GLP-2 administration, namely prevention and reversion, were examined. The prevention protocol consisted of 7s.c. injections of GLP-2 (125 μg/kg b.wt.) administered every 12 h, starting 60 h before LPS administration. The reversion protocol consisted of 2 doses of GLP-2, starting 3 h after LPS injection. Intestinal samples were collected 24 h after LPS administration and expression (protein and mRNA) and activity of Mrp2 were evaluated in proximal jejunum whereas those of P-gp were studied in ileum. GLP-2 completely neutralized down-regulation of expression of Mrp2 and P-gp and loss of their respective activities induced by LPS under prevention protocol. GLP-2 was also able to prevent internalization of both transporters from the apical membrane of the enterocyte to intracellular compartments, as detected by confocal microscopy. LPS induced an increase in IL-1β and oxidized glutathione tissue levels, which were also counterbalanced by GLP-2 administration. In contrast, the reversion protocol failed to attenuate Mrp2 and P-gp down-regulation induced by LPS. We conclude that GLP-2 can prevent down-regulation of intestinal expression and activity of Mrp2 and P-gp in endotoxemic rats and that IL-1β and oxidative stress constitute potential targets of GLP-2 protective effects. Fil: Arana, Maite Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Tocchetti, Guillermo Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Zecchinati, Felipe. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Londero, Ana Sofia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Dominguez, Camila Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Perdomo, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina Fil: Rigalli, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina. University of Heidelberg; Alemania Fil: Villanueva, Silvina Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Mottino, Aldo Domingo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina

Recent studies have confirmed that locally released proglucagon derived gene products, other than glucagon, have a major influence on pancreatic endocrine function. We assessed the impact of glucagon-like peptide-2 (GLP-2) on beta-cell secretory function, proliferation and apoptosis, as well as glucose tolerance, feeding behaviour and islet adaptions to chemically-induced insulin deficiency and resistance. The GLP-2 receptor was evidenced on cultured rodent and human beta-cells, rodent alpha-cells and isolated mouse islets. GLP-2 had no effect on insulin secretion from beta-cells, or isolated mouse islets. In vivo, GLP-2 administration significantly (P < 0.05 to P < 0.01) decreased food intake in mice. Conversely, GLP-2 had no discernible effects on glucose disposal or insulin secretion. As expected, streptozotocin treatment decreased and hydrocortisone increased beta-cell mass in mice. GLP-2 was visualised in mouse islets and intestinal L-cells. Islet GLP-2 co-localisation with glucagon was significantly decreased (P < 0.01) by both streptozotocin and hydrocortisone. In contrast, both interventions increased (P < 0.05) co-localisation of GLP-2 with somatostatin. Interestingly, GLP-2 positive cells were reduced (P < 0.05) in the intestines of streptozotocin, but not hydrocortisone, treated mice. Further in vitro investigations revealed that GLP-2 protected rodent and human 1.1B4 beta-cells against streptozotocin induced DNA damage. Furthermore, GLP-2 augmented (P < 0.05) BRIN BD11 beta-cell proliferation, but was less efficacious in 1.1B4 cells. These data highlight the involvement of GLP-2 receptor signalling in the adaptations to pancreatic islet cell stress.

This paper aimed to evaluate the influence of modified biliopancreatic diversion (BPD) on the levels of GLP-1 and GLP-2 and correlate them with satiety regulation. This is a pilot prospective cohort study that evaluated six mildly obese individuals with type 2 diabetes mellitus, which underwent modified BPD and were followed-up for 12 months. Levels of GLP-1 and GLP-2 after a standard meal tolerance test were determined and correlated with satiety scores obtained by means of a visual analogue scale (VAS). There were significant changes in BMI (33 ± 2.2 versus 26.3 ± 2.2 kg/m2; p

The relationship between type 2 diabetes mellitus and intestinal neoplasia has been shown epidemiologically. A high-fat diet (HFD) is also known to promote insulin resistance, which is a risk factor for intestinal neoplasia. Dipeptidyl peptidase-4 (DPP-4) inhibitors are used in the clinic for the treatment of type 2 diabetes and also to prolong the effects of glucagon-like peptide-1 (GLP-1). However, since the intestinotrophic hormone GLP-2 and chemokines, such as CXCL5 and stromal cell-derived factor-1 (SDF-1), are also substrates of DPP-4, DPP-4 inhibitors may increase the risk of intestinal carcinogenesis. In this study, we evaluated the impact of a DPP-4 inhibitor on intestinal tumorigenesis in ApcMin/+ mice fed a HFD. Six-week-old male ApcMin/+ mice were randomized to either a normal diet (10 kcal% fat) group, a HFD (60 kcal% fat) group, or a HFD group treated with sitagliptin (STG). The mice were euthanized nine weeks after the start of treatment. Daily treatment with STG did not increase number of intestinal tumors in the HFD group; however, this increase was not statistically significant. The mucosal concentration of total GLP-2 was significantly increased in the HFD group. The chemokine protein array showed elevated plasma concentrations of CXCL5 and SDF-1 in the HFD group. The administration of STG significantly suppressed the levels of plasma CXCL5 and SDF-1 in mice fed a HFD. Since CXCL5 expression is increased in patients with type 2 diabetes, and GLP-2, CXCL5 and SDF-1 are associated with tumor progression, DPP-4 inhibition may have potential as an agent for decreasing the risk of cancer in obese or diabetic patients.

Background This study aimed to ascertain if prospective determinations of specific gut hormones and growth factors could predict bowel adaptation in children with short bowel syndrome (SBS). Methods We studied parenteral nutrition (PN) independency as the short-term result and discontinuation of enteral nutrition (EN) as the long-term result from a retrospective chart review of 7 patients with SBS, who were managed in the absence of growth retardation. The correlation between increased numbers of enteral feedings or enteral nutrients and fasting levels of serum gastrin, glucagon-like peptide 2 (GLP-2), citrulline, and diamine oxidase (DAO) activity was analyzed. Five patients were weaned from PN, and 2 from EN. Results Fasting serum gastrin levels were significantly higher and the serum GLP-2 levels were lower in the PN-dependent patients than in the patients weaned from EN. The upper limit of fasting serum gastrin for PN independence and for EN independence was 300 and 200 pg/mL, respectively. The lower limit of fasting serum citrulline for PN independence was 15 μmol/L. However, the relationship between the serum citrulline and DAO levels and the course of bowel adaptation were poor. Conclusions Serum citrulline levels are predictors of PN independence in children with SBS. Fasting serum gastrin and GLP-2 levels are indicators for monitoring the adaptation of the residual intestine. However, this is a small study and further larger prospective trials are required to confirm these results. This article is protected by copyright. All rights reserved.

The European Society for Clinical Nutrition has published recommendations on the 'definition and classification of intestinal failure (IF)'. Two criteria must be present: a 'decreased absorption of macronutrients and/or water and electrolytes due to a loss of gut function' and the 'need for parenteral support'. Home parenteral support (HPS) is the primary treatment for chronic IF but is associated with complications. Areas covered: The principal cause of chronic IF is short bowel syndrome (SBS). The aim of treatment is to maximize intestinal absorption and reduce or eliminate the need for HPS to achieve the best possible quality of life. Teduglutide, an analog of glucagon-like peptide 2, improves intestinal rehabilitation by promoting mucosal growth, reducing intestinal loss and promoting intestinal absorption. This article provides an overview and opinion on teduglutide for SBS. Expert opinion: Teduglutide may provide a new treatment strategy for SBS patients with chronic IF. When prescribed, patients should be informed of the benefits and risks of the drug and must be closely monitored in an expert center. Furthermore, as this treatment is costly, cost-effectiveness analysis as well as the risk-benefit ratio needs to be better evaluated.

Objective Glucagon-like peptides (GLPs) are secreted from enteroendocrine cells in response to nutrients and bile acids and control metabolism via actions on structurally-related yet distinct G protein coupled receptors. GLP-1 regulates gut motility, appetite, islet function, and glucose homeostasis, whereas GLP-2 enhances intestinal nutrient absorption. GLP-1R agonists are used to treat diabetes and obesity, and a GLP-2R agonist is approved to treat short bowel syndrome. Unexpectedly, reports of gallbladder disease have been associated with the use of both GLP-1R and GLP-2R agonists and after bariatric surgery, although the mechanisms remain unknown. Methods We investigated whether GLP-1 or GLP-2 acutely controls gallbladder (GB) volume and whether GLP-2 regulates GB muscle activity in mice. The expression of Tgr5, Glp2r, and Glp1r was assessed in mouse GB, and the effects of GLP-2 on hepatic bile acid (BA) flow, intestinal and liver BA uptake, and GB gene expression were determined. GLP-2 regulation of GB volume was assessed in wildtype, Glp2r−/− and Tgr5−/− mice. The effect of GLP-2 on GB smooth muscle (GBSM) calcium transients was characterized ex vivo. Results Acute administration of the GLP-1R agonist exendin-4 lowered glucose but had no effect on GB volume in mice. In contrast, GLP-2 rapidly enhanced GB filling in a dose-dependent manner, actions maintained in the presence of cholecystokinin, and mediated through the canonical GLP-2R. GLP-2 also rapidly induced immediate early gene expression in GB, consistent with detection of the endogenous Glp2r in GB RNA. The ability of GLP-2 to increase GB volume was not abrogated by systemic administration of hexamethonium, propranolol, a vasoactive peptide receptor antagonist or N-Nitroarginine methyl ester, and was maintained in Tgr5−/− mice. In contrast, lithocholic acid, a Tgr5 agonist, increased GB filling in Glp2r−/− but not in Tgr5−/− mice. GLP-2 had no effect on ileal uptake or hepatic clearance of taurocholic acid or on hepatic bile flow, yet reduced the frequency of spontaneous calcium transients in murine GBSM ex vivo, in a tetrodotoxin-sensitive manner. Conclusions Our data extend endocrine concepts of regulation of GB filling beyond FXR-FGF15/19 and the direct effects of BA via Tgr5, to encompass a novel BA-Tgr5-L cell GLP-2 axis providing nutrient-mediated feedback from BA to terminate meal-related GB contraction. These findings have implications for conditions characterized by elevated circulating levels of GLP-2 such as after bariatric surgery and the development and use of agents that promote Tgr5 activation, L cell secretion, or GLP-2R agonism for the treatment of metabolic disease., Highlights • GLP-2 promotes gallbladder filling in mice. • The actions of GLP-2 on the gallbladder are absent in Glp2r−/− mice. • GLP-2 promotes gallbladder filling independent of Tgr5. • The Glp2r is expressed in the murine and human gallbladder. • GLP-2R-stimulated calcium flux in the gallbladder is blocked by tetrodotoxin.

Objective Glucagon-like peptide-2 (GLP-2) is co-secreted with GLP-1 from gut endocrine cells, and both peptides act as growth factors to expand the surface area of the mucosal epithelium. Notably, GLP-2 also enhances glucose and lipid transport in enterocytes; however, its actions on control of amino acid (AA) transport remain unclear. Here we examined the mechanisms linking gain and loss of GLP-2 receptor (GLP-2R) signaling to control of intestinal amino acid absorption in mice. Methods Absorption, transport, and clearance of essential AAs, specifically lysine, were measured in vivo by Liquid Chromatography triple quadrupole Mass Spectrometry (LC-MS/MS) and ex vivo with Ussing chambers using intestinal preparations from Glp2r+/+ and Glp2r−/− mice. Immunoblotting determined jejunal levels of protein components of signaling pathways (PI3K-AKT, and mTORC1-pS6-p4E-BP1) following administration of GLP-2, protein gavage, and rapamycin to fasted Glp2r+/+ and Glp2r−/− mice. Expression of AA transporters from full thickness jejunum and 4F2hc from brush border membrane vesicles (BBMVs) was measured by real-time PCR and immunoblotting, respectively. Results Acute administration of GLP-2 increased basal AA absorption in vivo and augmented basal lysine transport ex vivo. GLP-2-stimulated lysine transport was attenuated by co-incubation with wortmannin, rapamycin, or tetrodotoxin ex vivo. Phosphorylation of mTORC1 effector proteins S6 and 4E-BP1 was significantly increased in wild-type mice in response to GLP-2 alone, or when co-administered with protein gavage, and abolished following oral gavage of rapamycin. In contrast, activation of GLP-1R signaling did not enhance S6 phosphorylation. Disruption of GLP-2 action in Glp2r−/− mice reduced lysine transport ex vivo and attenuated the phosphorylation of S6 and 4E-BP1 in response to oral protein. Moreover, the expression of cationic AA transporter slc7a9 in response to refeeding, and the abundance of 4F2hc in BBMVs following protein gavage, was significantly attenuated in Glp2r−/− mice. Conclusions These findings reveal an important role for GLP-2R signaling in the physiological and pharmacological control of enteral amino acid sensing and assimilation, defining an enteroendocrine cell-enterocyte axis for optimal energy absorption., Graphical abstract, Highlights • GLP-2 promotes intestinal amino acid absorption in vivo. • Intestinal amino acid absorption is reduced in Glp2r−/− mice. • GLP-2 stimulates amino acid transport independently of blood flow. • GLP-2, but not GLP-1, activates the mTORC1 signaling pathway. • Amino acid transport by GLP-2 requires the enteric nervous system and mTORC1.

Diarrhea episodes in dairy calves involve profound alterations in the mechanism controlling gut barrier function that ultimately compromise intestinal permeability to macromolecules, including pathogenic bacteria. Intestinal dysfunction models suggest that a key element of intestinal adaptation during the neonatal phase is the nutrient-induced secretion of glucagon-like peptide (GLP)-2 and associated effects on mucosal cell proliferation, barrier function, and inflammatory response. Bioactive molecules found in Olea europaea have been shown to induce the release of regulatory peptides from model enteroendocrine cells. The ability to enhance GLP-2 secretion via the feeding of putative GLP-2 secretagogues is untested in newborn calves. The objectives of this study were to determine whether feeding a bioactive extract from Olea europaea (OBE) mixed in the milk replacer (1) can stimulate GLP-2 secretion beyond the response elicited by enteral nutrients and, thereby, (2) improve intestinal permeability and animal growth as well as (3) reduce the incidence of diarrhea in preweaning dairy calves. Holstein heifer calves (n = 60) were purchased, transported to the research facility, and blocked by body weight and total serum protein and assigned to 1 of 3 treatments. Treatments were control (CON), standard milk replacer (MR) and ad libitum starter; CON plus OBE added into MR at 30 mg/kg of body weight (OBE30); and CON plus OBE added into MR at 60 mg/kg of body weight (OBE60). The concentration of GLP-2 was measured at the end of wk 2. Intestinal permeability was measured at the onset of the study and the end of wk 2 and 6, with lactulose and d-mannitol as markers. Treatments did not affect calf growth and starter intake. Compared with CON, administration of OBE60 increased the nutrient-induced response in GLP-2 by about 1 fold and reduced MR intake during the second week of study. Throughout the study, however, all calves had compromised intestinal permeability and a high incidence of diarrhea. The GLP-2 response elicited by OBE60 did not improve intestinal permeability (lactulose-to-d-mannitol ratio) and incidence of diarrhea over the course of the preweaning period. The response in GLP-2 secretion to the administration of OBE reported herein warrants further research efforts to investigate the possibility of improving intestinal integrity through GLP-2 secretion in newborn calves.

Biliopancreatic diversion (BPD) is a predominantly malabsorptive procedure. Glucagon-like peptide 2 (GLP-2) plays predominantly trophic effects on the gut. A significant increase in GLP-2 after BPD in rats was previously observed, but there are no studies investigating the effect of BPD in GLP-2 levels in humans. The aim of this study is to evaluate the influence of BPD on the release of GLP-2. This is a prospective cohort study that evaluated diabetic individuals with class I obesity which underwent BPD (Scopinaro operation) and were followed up for 12 months. Of 12 individuals, four did not comply with the proposed follow-up and were excluded from the analysis. GLP-2 levels were determined by means of an enzyme-linked immunosorbent assay (ELISA), and we collected serial lab samples through a standard meal tolerance test (MTT) in the immediate preoperative period and 12 months after surgery. During standard MTT, we observed significant increases of GLP-2 levels from 15 to 60 min (respectively, at 15 min, 5.7 ± 3.4 versus 12.4 ± 4.3, p = 0.029; 30 min, 6 ± 3.5 versus 14.6 ± 3.9; p = 0.004; 45 min, 5.6 ± 4.1 versus 12.6 ± 5.2, p = 0.013; 60 min, 5.8 ± 2.9 versus 10.6 ± 5.6, p = 0.022); then it began to gradually decrease to levels close to the basal. Our findings have confirmed that there is a significant increase in GLP-2 levels after BPD in humans. GLP-2 plays a number of roles which may be adaptive, compensatory, and beneficial in the context of BPD. The clinical implications of this finding remain to be completely understood.

The intracerebroventicular (i.c.v.) administration of glucagon-like peptide-2 (GLP-2) to rodents was shown to have antidepressant-like effects in imipramine-resistant depression-model mice. In order to utilize GLP-2 as a clinical treatment tool for depression, we herein focused on the intranasal delivery that is non-invasive approach, because the i.c.v. administration is invasive and impractical. In the present study, we prepared a GLP-2 derivative containing cell penetrating peptides (CPPs) and a penetration accelerating sequence (PAS) (PAS-CPPs-GLP-2) for the intranasal (i.n.) administration. PAS-CPPs-GLP-2 (i.n.) exhibited antidepressant-like effects in the forced-swim test (FST) and tail suspension test (TST) in naïve mice as well as adrenocorticotropic hormone (ACTH) treated-mice. However, PAS-CPPs-GLP-2 (i.v.) and the GLP-2 derivative containing CPPs without a PAS (CPPs-GLP-2) (i.n.) did not affect the immobility time in the mouse FST. Moreover, fluorescein isothiocyanate (FITC)-labeled PAS-CPPs-GLP-2 (i.n.), but not FITC-labeled CPPs-GLP-2 (i.n.) was distributed through the mouse brain after the FST session. These results suggest that PAS-CPPs-GLP-2 is effective for i.n. delivery to the brain, and may be useful in the clinical treatment of major depression.

Introduction Glucagon-like peptide-2 (GLP-2) is a known intestinal growth factor that enhances mucosal mass and function in residual small intestine after massive small bowel resection (MSBR). Luminal omega-3 (OM-3) has been shown to have some growth factor properties. It is possible that their mechanisms of action differ. Thus, we hypothesized that administering these two substances together may have a synergistic effect. Methods A total of 60 adult female Sprague–Dawley rats underwent 80% MSBR and divided as follows (n = 15/group): Saline (Control) + regular feeds; GLP-2 + regular feeds; Saline + OM-3 enriched feeds; and GLP-2 + OM-3 enriched feeds. Five animals per group were sacrificed at 7, 14, and 28 days. Small intestine mucosa was harvested. DNA and protein content were measured (mucosal mass markers) at all three time points. Galactose and Glycine absorption were measured (functional capacity markers) at 28 days. Statistical analysis was done by ANOVA with post hoc Tukey's HSD test. Results At all three time points, DNA was increased in all treatment groups compared to control (P