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Background: Teduglutide, the first glucagon-like peptide 2 analogue, has been demonstrated to facilitate the absorption of gut nutrient and lessen the need for parenteral assistance in patients with Short Bowel Syndrome (SBS). However, its adverse drug events (AEs) are primarily documented in clinical trials, with a deficit in real-world data. This study evaluates the AEs profile of teduglutide based on Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data. Method: A disproportionality analysis of FAERS data from Quarter 1 (Q1) 2013 to Quarter 3 (Q3) 2023 was conducted to examine the association between teduglutide and adverse events, employing Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) methods. Results: Out of 13,809,302 reports in the FAERS database, 10,114 reports identified teduglutide as the "primary suspect" in AEs identification. During the dosing observation period, the median occurrence of adverse events was 393 days (interquartile range [IQR] 97-996 days). Teduglutide-associated AEs occurred in 27 System Organ Classes (SOC), of which renal and urinary disorders is not mentioned in the specification. Based on the four algorithms, a total of 260 major disproportionality preferred terms (PTs) were filtered out, including previously unreported AEs including weight decreased (n = 805), vascular device infection (n = 683), dehydration (n = 596) and nephrolithiasis (n = 146). Conclusion: Our findings corroborate the AEs listed in the teduglutide prescribing information and additionally unveil new adverse reaction signals such as nephrolithiasis. These discoveries could aid in clinical monitoring and risk identification for teduglutide. [ABSTRACT FROM AUTHOR]

A growing proportion of children with short bowel syndrome (SBS) remain dependent on long-term parenteral nutrition (PN). Teduglutide offers the potential for more children to decrease PN support and achieve enteral autonomy (EA), but at a significant expense. This study aims to assess the incremental costs of teduglutide plus standard of care compared to standard of care alone in weaning PN support per quality-adjusted life year (QALY) gained in children with SBS. This is a cost-utility analysis comparing teduglutide with standard of care alone in children with SBS. A microsimulation model of children with SBS on PN aged 1–17 years was constructed over a time horizon of six years, with a cycle length of one month. The study adopted the healthcare system and societal payer perspectives in Ontario, Canada. The health outcome measure was QALYs, with results expressed in terms of incremental costs and QALYs. Scenario analyses were performed to examine the effects of different time horizons, timing of teduglutide initiation, and modeling cost of teduglutide based on pediatric weight-dosing. Incremental healthcare system costs for teduglutide compared to standard of care were CAD$441,314 (95% CI, 414,006 to 441,314) and incremental QALYs were 1.80 (95% CI, 1.70 to 1.89) resulting in an incremental cost-effectiveness ratio (ICER) of CAD$285,334 (95% CI, 178,209 to 392,459) per QALY gained. Incremental societal costs were CAD$418,504 (95% CI, 409,487 to 427,522) and incremental societal QALYs were 1.91 (95% CI, 1.85 to 1.98) resulting in an ICER of CAD$261,880 (95% CI, 136,887 to 386,874) per QALY gained. Scenario analysis showed that teduglutide was cost-effective when it was started two years after intestinal resection (ICER CAD$48,741, 95% CI, 17,317 to 80,165) and when its monthly cost was adjusted using weight-based dosing, avoiding wastage of the remaining 5 mg dose vial (Teduglutide dominated over SOC as the less costly and most effective strategy). Although teduglutide was not cost-effective in weaning PN support in children with SBS, starting teduglutide once natural intestinal adaptation is reduced and adjusting its monthly cost to reflect cost by volume as dictated by weight-based dosing rendered the intervention cost-effective relative to standard of care. These results indicate the potential for clinicians to re-assess optimal time for initiation of teduglutide after intestinal resection, drug manufacturers to consider the use of multi-dose or paediatric-dose vials, and the opportunity for decision-makers to re-evaluate teduglutide funding. [ABSTRACT FROM AUTHOR]

ABSTRACT: Kraft pulp (KP), an intermediate product obtained when wood chips are converted to paper, contains highly digestible fiber. This study evaluated the effect of KP inclusion in calf starters on growth performance, health, and plasma glucagon-like peptide 2 (GLP-2) concentration in calves. Twenty-five Holstein heifer calves were raised on a high plane of nutrition program using milk replacer containing 29% crude protein and 18% fat until 49 d after birth, and were fed calf starters containing KP at 0 (CON; n = 14) or 12% (KPS; n = 11) on a dry matter basis. All calves were fed the treatment calf starters and timothy hay ad libitum. Blood was collected at 4, 14, 21, 35, 49, 70, and 91 d after birth. Dry matter intake (DMI) of milk replacer and hay was not affected by treatment, whereas calf starter DMI was lower for KPS (0.93 kg/d) than for CON (1.03 kg/d). Higher neutral detergent fiber (NDF) content in KPS (31.7%) than in the CON starter (22.1%) resulted in higher NDF intake for KPS (0.55 kg/d) than for CON (0.47 kg/d). However, the consumption of starch was lower for KPS (0.29 kg/d) than for CON (0.33 kg/d). Despite the lower starter intake for KPS, body weight and average daily gain did not differ between treatments. No significant difference was observed in the plasma concentrations of metabolites, except for β-hydroxybutyrate (BHB); BHB concentration was lower for KPS (216 μmol/L) than for CON (257 μmol/L). The area under the curve for plasma GLP-2 concentration was higher for KPS (54.1 ng/mL × d) than for CON (36.0 ng/mL × d). Additionally, the fecal score postweaning (1.19 and 1.48 for KPS and CON, respectively) and the number of days that calves developed diarrhea throughout the experimental period (2.50 d and 8.10 d for KPS and CON, respectively) were lower for KPS than for CON. These results indicate that feeding KP reduces the severity and frequency of diarrhea without adversely affecting growth performance. This could be attributed to the increased plasma GLP-2 concentration induced by higher NDF intake.

BackgroundCirculating endotoxin (lipopolysaccharide, LPS) increases the gut paracellular permeability. We hypothesized that glucagon-like peptide-2 (GLP-2) acutely reduces LPS-related increased intestinal paracellular permeability by a mechanism unrelated to its intestinotrophic effect.MethodsWe assessed small intestinal paracellular permeability in vivo by measuring the appearance of intraduodenally perfused FITC-dextran 4000 (FD4) into the portal vein (PV) in rats 1-24 h after LPS treatment (5 mg/kg, ip). We also examined the effect of a stable GLP-2 analog teduglutide (TDG) on FD4 permeability.ResultsFD4 movement into the PV was increased 6 h, but not 1 or 3 h after LPS treatment, with increased PV GLP-2 levels and increased mRNA expressions of proinflammatory cytokines and proglucagon in the ileal mucosa. Co-treatment with a GLP-2 receptor antagonist enhanced PV FD4 concentrations. PV FD4 concentrations 24 h after LPS were higher than FD4 concentrations 6 h after LPS, reduced by exogenous GLP-2 treatment given 6 or 12 h after LPS treatment. FD4 uptake measured 6 h after LPS was reduced by TDG 3 or 6 h after LPS treatment. TDG-associated reduced FD4 uptake was reversed by the VPAC1 antagonist PG97-269 or L-NAME, not by EGF or IGF1 receptor inhibitors.ConclusionsSystemic LPS releases endogenous GLP-2, reducing LPS-related increased permeability. The therapeutic window of exogenous GLP-2 administration is at minimum within 6-12 h after LPS treatment. Exogenous GLP-2 treatment is of value in the prevention of increased paracellular permeability associated with endotoxemia.

Introduction. Short bowel syndrome (SBS) in children is a rare disease. One of the most common etiological factors for the development of SBS in children is atresia of the small intestine. After surgical correction of the congenital anomaly, the remaining intestine attempts to increase absorption to restore homeostasis, and the process of intestinal adaptation begins. This process of adaptation can be assisted with analogues of endogenous growth factors of the intestine, such as teduglutide. Case outline. This report presents а girl, aged two years and eight months, who had an estimated 20 cm of small intestine after surgical correction of congenital small bowel atresia and clinical signs of SBS. She was repeatedly hospitalized due to frequent need for parenteral correction of fluid, electrolyte, and nutrient imbalances. Stagnation in body weight and slow growth in body height were accompanied by weakened gross motor strength and slowed psychophysical development. After exploit conservative treatment measures, stimulation of intestinal adaptation was initiated with the drug teduglutide. After six months of drug therapy, progress was observed in body parameters, as well as an increase in intelligence quotient and motor abilities. Conclusion. SBS is a challenging entity for every clinician, and its previous therapy has mainly consisted of parenteral substitution of nutrients, fluids, and electrolytes. Surgical treatment carries the risk of loss of the remaining bowel and lifelong immunosuppression. The pharmacological possibilities of promoting intestinal adaptation using drugs such as teduglutide represent a light at the end of the tunnel for patients with SBS.

There are no drugs approved by regulatory agencies for the treatment of nonalcoholic fatty liver disease (NAFLD); incretin combination therapies are being developed for treatment of type 2 diabetes and research has moved to test their usefulness in NAFLD. We reviewed the literature on the effectiveness of dual and triple peptides combining receptor agonists of the glucagon-like peptide 1, the glucose-dependent insulinotropic peptide, and glucagon to treat NAFLD and its associated metabolic diseases, and/or the cardiovascular risk intimately connected with the cluster of the metabolic syndrome. Other combination peptides involved the glucagon-like peptide 2 receptor, the fibroblast growth factor 21, the cholecystokinin receptor 2, and the amylin receptor. Both dual and triple agonists are promising, based on animal, pharmacokinetic and proof-of concept studies, showing effectiveness both in the presence and the absence of diabetes on a few validated surrogate NAFLD biomarkers, but the majority of studies are still in progress. Considering the long natural history of NAFLD, final proof of their efficacy on primary clinical liver outcomes might be also derived from the analysis of large databases of National Healthcare Systems or Insurance companies, when used in diabetes for improving glycemic control, after careful propensity-score matching. [ABSTRACT FROM AUTHOR]

Kraft pulp (KP), an intermediate product obtained when wood chips are converted to paper, contains highly digestible fiber. This study evaluated the effect of KP inclusion in calf starters on growth performance, health, and plasma glucagon-like peptide 2 (GLP-2) concentration in calves. Twenty-five Holstein heifer calves were raised on a high plane of nutrition program using milk replacer containing 29% crude protein and 18% fat until 49 d after birth, and were fed calf starters containing KP at 0 (CON; n = 14) or 12% (KPS; n = 11) on a dry matter basis. All calves were fed the treatment calf starters and timothy hay ad libitum. Blood was collected at 4, 14, 21, 35, 49, 70, and 91 d after birth. Dry matter intake (DMI) of milk replacer and hay was not affected by treatment, whereas calf starter DMI was lower for KPS (0.93 kg/d) than for CON (1.03 kg/d). Higher neutral detergent fiber (NDF) content in KPS (31.7%) than in the CON starter (22.1%) resulted in higher NDF intake for KPS (0.55 kg/d) than for CON (0.47 kg/d). However, the consumption of starch was lower for KPS (0.29 kg/d) than for CON (0.33 kg/d). Despite the lower starter intake for KPS, body weight and average daily gain did not differ between treatments. No significant difference was observed in the plasma concentrations of metabolites, except for β-hydroxybutyrate (BHB); BHB concentration was lower for KPS (216 μmol/L) than for CON (257 μmol/L). The area under the curve for plasma GLP-2 concentration was higher for KPS (54.1 ng/mL × d) than for CON (36.0 ng/mL × d). Additionally, the fecal score postweaning (1.19 and 1.48 for KPS and CON, respectively) and the number of days that calves developed diarrhea throughout the experimental period (2.50 d and 8.10 d for KPS and CON, respectively) were lower for KPS than for CON. These results indicate that feeding KP reduces the severity and frequency of diarrhea without adversely affecting growth performance. This could be attributed to the increased plasma GLP-2 concentration induced by higher NDF intake. [ABSTRACT FROM AUTHOR]

Aims Recent studies have suggested a key role of intestinal microbiota in pathological progress of multiple organs via immune modulation. However, the interactions between heart and gut microbiota remain to be fully elucidated. The aim of the study is to investigate the role of gut microbiota in the post-ischaemia/reperfusion (I/R) inflammatory microenvironment. Methods and results Here, we conducted a case-control study to explore the association of gut bacteria translocation products with inflammation biomarkers and I/R injury severity in ST-elevation myocardial infarction patients. Then, we used a mouse model to determine the effects of myocardial I/R injury on gut microbiota dysbiosis and translocation. Blooming of Proteobacteria was identified as a hallmark of post-I/R dysbiosis, which was associated with gut bacteria translocation. Abrogation of gut bacteria translocation by antibiotic cocktail alleviated myocardial I/R injury via mitigating excessive inflammation and attenuating myeloid cells mobilization, indicating the bidirectional heart–gut–microbiome–immune axis in myocardial I/R injury. Glucagon-like peptide 2 (GLP-2), an endocrine peptide produced by intestinal L-cells, was used in the experimental myocardial I/R model. GLP-2 administration restored gut microbiota disorder and prevented bacteria translocation, eventually attenuated myocardial I/R injury through alleviating systemic inflammation. Conclusion Our work identifies a bidirectional communication along the heart–gut–microbiome–immune axis in myocardial I/R injury and demonstrates gut bacteria translocation as a key regulator in amplifying inflammatory injury. Furthermore, our study sheds new light on the application of GLP-2 as a promising therapy targeting gut bacteria translocation in myocardial I/R injury. [ABSTRACT FROM AUTHOR]

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Pregnant patients with short bowel syndrome (SBS) and chronic intestinal failure (CIF) can successfully reach to term their pregnancies while on parenteral nutrition (PN) but with high rates of complications. The combination of rehabilitation surgery, combined with the use of novel treatment with enterohormones, especially semisynthetic glucagon-like peptide 2 (sGLP-2), has increased the chances to achieve intestinal sufficiency. Here, we report the case of a 33-year-old female with SBS/CIF (anatomy type 2), weaned off PN using sGLP-2 for 3.7 years, discontinued when she became pregnant. She was able to carry the pregnancy to term without any additional PN support. Considering that, we queried if the endogenous GLP-2 (eGLP-2) levels in this SBS patient, during the pregnancy and breastfeeding period, could be like those presented in healthy pregnant women and in non-pregnant SBS patients. Also, we inquired if there was any passage or increase in the plasmatic eGLP-2 from the fetus to the mother. Thus, we determined eGLP-2 levels in paired neonatal (cord blood) and maternal plasma samples from the SBS pregnant patient (n = 1), healthy pregnant women (controls, n = 2), and non-pregnant SBS patients (n = 12). The results indicated that the SBS pregnant patient showed higher eGLP-2 levels than non-SBS pregnant patients and healthy pregnant women along all the period studied. Furthermore, we found that the maternal sample had higher eGLP-2 levels than the neonatal sample, suggesting that fetal contribution to maternal eGLP2 levels would be minor. In conclusion, this study not only reports for the first time a case of a patient with SBS that was able to achieve intestinal adaptation after combining the use of autologous reconstructive surgery and sGLP-2, but also enlightens the possibility of carrying out an uneventful pregnancy and lactation without any nutritional support and remaining independent of sGLP-2. [ABSTRACT FROM AUTHOR]

BACKGROUND The gastrointestinal (GI) barrier can be damaged by chemotherapy or radiation therapy, causing fatigue, malnutrition, sepsis, dose-limiting toxicity, and, occasionally, death. Glucagon-like peptide-2 (GLP-2) promotes mucosal epithelium growth and repair in the GI tract. Here, we examined the GI-protective effects of apraglutide, a long-acting peptide GLP-2 analog, in murine models of chemotherapy, and total body irradiation followed by allogeneic transplantation. MATERIAL AND METHODS The impact of apraglutide on cytarabine or melphalan chemotherapy-induced intestinal damage was assessed in BALB/c mice, and the effect on allogeneic transplantation in BALB/cJ and C57BL/6J mice. Outcomes included survival, and changes in body weight, intestinal function and morphology, including colon length and bacterial composition of the intestinal microbiota. RESULTS Adding apraglutide to chemotherapy significantly improved survival rates and reduced weight loss, with no impact on leukocyte counts (and, therefore, no effect on chemotherapy-induced immunosuppression), compared with chemotherapy alone in mice. These benefits were associated with preservation of the morphological integrity of the GI mucosa, attenuation of the negative impact of cytarabine on the intestinal microbiota, and significant improvement in plasma levels of citrulline. In addition, in a model of irradiation followed by allogeneic transplantation, mice in groups receiving apraglutide had improved survival, reduced weight loss, and increased colon length compared with those that did not. CONCLUSIONS Apraglutide protects intestinal function and improves survival in mice following allogeneic transplantation or chemotherapy with cytarabine or melphalan. The potential effect of apraglutide on chemotherapy efficacy and on engraftment following allogeneic transplantation has been investigated in a parallel manuscript.

Patients with short bowel syndrome (SBS) have a risk for cholelithiasis and cholecystitis, particularly those who have received long-term parenteral nutrition (PN). Teduglutide (Revestive), a glucagon-like peptide-2 (GLP-2) analogue, is the first effective therapy approved for treating patients with SBS via self-subcutaneous injection. It also pharmacologically inhibits gallbladder contraction, which may increase the risks for cholelithiasis and cholecystitis. Here, we report a case of cholecystitis occurring after the introduction of a GLP-2 analogue in a patient with SBS and cholelithiasis. A 16-year-old girl, with a residual intestinal anatomy of 5 cm jejunum and left colon, was referred to our hospital for further treatment of SBS. She underwent jejunocolic anastomosis 2 months later. After that, she received PN for 2.5 years. Teduglutide treatment was initiated to reduce PN dependence. Several asymptomatic gallbladder stones were found during a routine ultrasound examination before drug initiation. On day 31 of teduglutide treatment, right subcostal pain with fever occurred, and the patient was diagnosed with acute cholecystitis. GLP-2 analogue treatment was temporarily discontinued. The patient underwent gallbladder drainage followed by cholecystectomy 3 weeks later. Histopathological findings illustrated mucosal hyperplasia of the gallbladder. Her postoperative course was uneventful, and teduglutide was restarted 2 weeks postoperatively. GLP-2 analogues promote gallbladder refilling and epithelial hyperplasia, which may be a risk factor for cholecystitis in patients with cholelithiasis, as observed in our patient. Based on our experience, patients with SBS and established asymptomatic cholelithiasis may be considered for prophylactic cholecystectomy before the administration of GLP-2 analogues., (© 2024 American Society for Parenteral and Enteral Nutrition.)

BackgroundTherapy with nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enteropathy in humans and experimental animals, a cause of considerable morbidity. Unlike foregut NSAID-associated mucosal lesions, most treatments for this condition are of little efficacy. We propose that the endogenously released intestinotrophic hormone glucagon-like peptide-2 (GLP-2) prevents the development of NSAID-induced enteropathy. Since the short-chain fatty acid receptor FFA3 is expressed on enteroendocrine L cells and on enteric nerves in the gastrointestinal tract, we further hypothesized that activation of FFA3 on L cells protects the mucosa from injury via GLP-2 release with enhanced duodenal HCO3- secretion. We thus investigated the effects of synthetic selective FFA3 agonists with consequent GLP-2 release on NSAID-induced enteropathy.MethodsWe measured duodenal HCO3- secretion in isoflurane-anesthetized rats in a duodenal loop perfused with the selective FFA3 agonists MQC or AR420626 (AR) while measuring released GLP-2 in the portal vein (PV). Intestinal injury was produced by indomethacin (IND, 10 mg/kg, sc) with or without MQC (1-10 mg/kg, ig) or AR (0.01-0.1 mg/kg, ig or ip) treatment.ResultsLuminal perfusion with MQC or AR (0.1-10 µM) dose-dependently augmented duodenal HCO3- secretion accompanied by increased GLP-2 concentrations in the PV. The effect of FFA3 agonists was inhibited by co-perfusion of the selective FFA3 antagonist CF3-MQC (30 µM). AR-induced augmented HCO3- secretion was reduced by iv injection of the GLP-2 receptor antagonist GLP-2(3-33) (3 nmol/kg), or by pretreatment with the cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTRinh-172 (1 mg/kg, ip). IND-induced small intestinal ulcers were dose-dependently inhibited by intragastric administration of MQC or AR. GLP-2(3-33) (1 mg/kg, ip) or CF3-MQC (1 mg/kg, ig) reversed AR-associated reduction in IND-induced enteropathy. In contrast, ip injection of AR had no effect on enteropathy.ConclusionThese results suggest that luminal FFA3 activation enhances mucosal defenses and prevents NSAID-induced enteropathy via the GLP-2 pathway. The selective FFA3 agonist may be a potential therapeutic candidate for NSAID-induced enteropathy.

Abstract 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.

Background and ObjectivesShort-bowel syndrome (SBS) results from the loss of a significant portion of the small intestine leading to a state of malabsorption. After an intestinal loss, there is a process of adaptation involving the Glucagon-Like Peptide-2 (GLP-2), an enteroendocrine peptide also involved in nutrient absorption. Teduglutide is a recombinant analog of GLP-2 approved in 2016 to treat selected SBS pediatric patients who are dependent on parenteral support. The present systematic review aims to evaluate the efficacy of Teduglutide in pediatric patients with SBS in reducing the need for parenteral nutrition (PN).Materials and MethodsWe performed a literature search on MEDLINE and Embase to include articles up to November 2021. We included articles that involved using Teduglutide in the SBS pediatric population to define its efficacy in reducing the need for PN. The key words used were GLP-2, teduglutide, child.ResultsFourteen studies completely fulfilled the inclusion criteria. Two hundred 23 patients were treated with Teduglutide, and the median duration of treatment was 45 weeks (IQR: 36–52.5 weeks). One-hundred and fifty-two patients were treated with 0.05 mg/Kg/d of subcutaneous Teduglutide, 38 received 0.025 mg/Kg/d and 8 received either 0.125 mg/Kg/d or 0.20 mg/Kg/d. A total of 36 patients achieved enteral autonomy (EA) after a median of 24 weeks of treatment (IQR: 24–48 weeks) and 149 patients showed a reduction in PN needs in terms of volume, calories, or hours per day. Eleven studies reported complications: gastrointestinal were the most common, with 89 cases reported in treated patients and 11 in non-treated patients.ConclusionTeduglutide appears safe and effective in reducing PN requirements and improving EA in the pediatric population. However, more studies are needed to understand its efficacy in the long term and after discontinuation and possible complications.Systematic Review Registration[https://www.crd.york.ac.uk/prospero/], identifier [CRD42022301593].

Purpose of reviewTo summarize and illuminate the recent findings regarding gastroduodenal mucosal defense mechanisms and the specific biomolecules involved in regulating this process, such as glucagon-like peptides (GLPs).Recent findingsThere has been a growing interest in luminal nutrient chemosensing and its physiological effects throughout the digestive system. From the ingestion of food in the oral cavity to the processing and absorption of nutrients in the intestines, nutrient chemosensing receptors signal the production and release of numerous bioactive peptides from enteroendocrine cells, such as the proglucagon-derived peptides. There has been a major emphasis on two proglucagon-derived peptides, namely GLP-1 and GLP-2, due to their apparent beneficial effect on gut structure, function, and on metabolic processes. As an incretin, GLP-1 not only enhances the effect and release of insulin on pancreatic βcells but also has been implicated in having trophic effects on the intestinal epithelium. In addition, GLP-2, the other major proglucagon-derived peptide, has potent intestinotrophic effects, such as increasing the rate of mucosal stem cell proliferation, mucosal blood flow, and fluid absorption, as well as augmenting the rate of duodenal bicarbonate secretion to improve gastric mucosal health and longevity.SummaryUnderstanding the mechanisms underlying nutrient chemosensing and how it relates to GLP release can further elucidate how the gut functions in response to cellular changes and disturbances. Furthermore, a more in-depth comprehension of GLP release and its tissue-specific effects will help improve the utility of GLP-1 and GLP-2 receptor agonists in clinical settings. This, in turn, should help patients suffering from intestinal failure, malabsorption, and mucosal injury.

Glucagon-like peptide 2 (GLP2) is a proglucagon-derived peptide produced by intestinal enteroendocrine L-cells. The main biological actions of GLP2 in mammals are related to regulating energy absorption and maintaining the morphology, integrity of intestinal mucosa. However, the in vivo function of fish GLP2 in intestinal barrier and immune defense is essentially unknown. With an aim to elucidate the antimicrobial mechanism of GLP2 in fish, we in this study examined the function of GLP2 from hybrid crucian carp. Hybrid crucian carp GLP2 (WR-GLP2) possesses the conserved glucagon like hormones 2 domain. WR-GLP2 is mainly expressed in the intestine and is significantly upregulated after Aeromonas hydrophila infection. AB-PAS staining analysis showed WR-GLP2 significantly increased the number of goblet cells in intestine. WR-GLP2 induced significant inductions in the expression of the antimicrobial molecules (MUC2 , Lyzl-1 , Hepcidin-1 and LEAP-2) and tight junctions (ZO-1 , Occludin and Claudin-4). In addition, WR-GLP2 significantly alleviated the intestinal apoptosis, thereby enhancing host's resistance against Aeromonas hydrophila infection. Together these results indicate that WR-GLP2 is involved in intestinal mucosal barrier and immune defense against pathogen infection. • mRNA expression of WR-GLP2 in intestine was significantly induced by bacterial challenge. • WR-GLP2 protects the intestinal mucosal barrier. • WR-GLP2 inhibits the bacterial colonization in fish tissues. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Teduglutide, the first glucagon-like peptide 2 analogue, has been demonstrated to facilitate the absorption of gut nutrient and lessen the need for parenteral assistance in patients with Short Bowel Syndrome (SBS). However, its adverse drug events (AEs) are primarily documented in clinical trials, with a deficit in real-world data. This study evaluates the AEs profile of teduglutide based on Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data., Method: A disproportionality analysis of FAERS data from Quarter 1 (Q1) 2013 to Quarter 3 (Q3) 2023 was conducted to examine the association between teduglutide and adverse events, employing Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) methods., Results: Out of 13,809,302 reports in the FAERS database, 10,114 reports identified teduglutide as the "primary suspect" in AEs identification. During the dosing observation period, the median occurrence of adverse events was 393 days (interquartile range [IQR] 97-996 days). Teduglutide-associated AEs occurred in 27 System Organ Classes (SOC), of which renal and urinary disorders is not mentioned in the specification. Based on the four algorithms, a total of 260 major disproportionality preferred terms (PTs) were filtered out, including previously unreported AEs including weight decreased (n = 805), vascular device infection (n = 683), dehydration (n = 596) and nephrolithiasis (n = 146)., Conclusion: Our findings corroborate the AEs listed in the teduglutide prescribing information and additionally unveil new adverse reaction signals such as nephrolithiasis. These discoveries could aid in clinical monitoring and risk identification for teduglutide., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Chen, Han, Li, Chen and Yang.)

Pediatric chronic intestinal failure (PIF) is a rare and heterogeneous condition characterized by the inability of the patient's intestine to adequately absorb the required fluids and/or nutrients for growth and homeostasis. As a result, patients will become dependent on home parenteral nutrition (HPN). A MEDLINE search was performed in May 2024 with keywords "intestinal failure", "parenteral nutrition" and "pediatric". Different underlying conditions which may result in PIF include short bowel syndrome, intestinal neuromuscular motility disorders and congenital enteropathies. Most common complications associated with HPN are catheter-related bloodstream infections, catheter-related thrombosis, intestinal failure-associated liver disease, small intestinal bacterial overgrowth, metabolic bone disease and renal impairment. Treatment for children with PIF has markedly improved with a great reduction in morbidity and mortality. Centralization of care in specialist centers and international collaboration between centers is paramount to further improve care for this vulnerable patient group. A recently promising medical therapy has become available for children with short bowel syndrome which includes glucagon-like peptide 2, a naturally occurring hormone which is known to delay gastric emptying and induce epithelial proliferation. Despite advances in curative and supportive treatment, further research is necessary to improve nutritional, pharmacological and surgical care and prevention of complications associated with parenteral nutrition use.

Background: Chronic intestinal failure (CIF) is a heterogeneous disease that affects pediatric and adult populations worldwide and requires complex multidisciplinary management. In recent years, many advances in intravenous supplementation support, surgical techniques, pharmacological management, and intestinal transplants have been published. Based on these advances, international societies have published multiple recommendations and guidelines for the management of these patients. The purpose of this paper is to show the differences that currently exist between the recommendations (ideal life) and the experiences published by different programs around the world., Methods: A review of the literature in PubMed from 1980 to 2024 was carried out using the following terms: intestinal failure, CIF, home parenteral nutrition, short bowel syndrome, chronic intestinal pseudo-obstruction, intestinal transplant, enterohormones, and glucagon-like peptide-2., Conclusions: There is a difference between what is recommended in the guidelines and consensus and what is applied in real life. Most of the world's countries are not able to offer all of the steps needed to treat this pathology. The development of cooperative networks between countries is necessary to ensure access to comprehensive treatment for most patients on all continents, but especially in low-income countries.

Competing Interests: Declaration of competing interest The authors declare no competing interests.

Background: Glucagon-like peptide 2 (GLP-2) is a highly conserved enteroendocrine hormone that seems to be a regulator promoting intestinal adaptation. This study aimed to summarize the evidence on the efficacy and safety of exogenous GLP-2 in patients with short bowel syndrome (SBS)., Methods: A database search was performed on PubMed, Web of Science Core Collection, Scopus, Ovid, and the Cochrane Central Register of Controlled Trials in November 2022. Clinical trials on the effect of GLP-2 on patients with SBS were included. The Cochrane Risk of Bias 2 and Risk Of Bias In Non-randomized Studies - of Interventions tools for quality assessment of randomized and nonrandomized trials were used. The extracted data were analyzed qualitatively and quantitatively using a network meta-analysis model., Results: This study included 23 clinical trials with 843 patients. The patients' ages ranged from 4.0 to 62.4 years. The treatment doses were 0.1, 0.05, and 0.025 mg/kg/day for teduglutide; 5 and 10 mg/week for apraglutide, and 0.1, 1, and 10 mg/day for glepaglutide. The treatment duration ranged from 1 to 32 weeks. Regarding citrulline level, 0.1 mg/kg/day of teduglutide had the highest mean difference (MD; 14.77; 95% CI, 10.20-19.33), followed by 0.05 mg/kg/day (13.04; 95% CI, 9.79-16.2) and 0.025 mg/kg/day (7.84; 95% CI, 2.42-13.26) of teduglutide. In addition, the effect estimate showed significant differences between all teduglutide dose groups and the control group. Different doses of glepaglutide were analyzed to assess the effect on alkaline phosphatase (ALP) levels, in which 0.1 mg/day of glepaglutide showed a significantly higher MD (20.71; 95% CI, 2.62-38.80) than 1 mg/day (the reference) and 10 mg/day (8.45; 95% CI, -10.72 to 27.62) of glepaglutide. However, 0.1 vs 10 mg of glepaglutide has an MD of -14.57 (95% CI, -437.24 to 148.11) for the indirect estimate, whereas 10 mg of glepaglutide has an MD of 8.45 (95% CI, -10.72 to 27.62) for the network estimate. Regarding safety outcomes, there was no significant difference among all teduglutide and apraglutide dose groups compared with the control group. Catheter-related bloodstream infection was the most common adverse event reported with the use of apraglutide, teduglutide, and glepaglutide., Conclusion: Despite the small number of patients in the included studies and variable follow-up duration, GLP-2 seems to be safe and effective in patients with SBS. GLP-2 showed a positive effect on increasing plasma citrulline level and decreasing ALP level., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Background and aimLuminal nutrients stimulate enteroendocrine L cells to release gut hormones, including intestinotrophic glucagon-like peptide-2 (GLP-2). Because L cells express the bile acid receptor TGR5 and dipeptidyl peptidase-IV (DPPIV) rapidly degrades GLPs, we hypothesized that luminal TGR5 activation may attenuate intestinal injury via GLP-2 release, which is enhanced by DPPIV inhibition.MethodsIntestinal injury was induced in mice by administration of dextran sulfate sodium (DSS) in drinking water (free access to water containing 5% DSS for 7 days). The selective TGR5 agonist betulinic acid (BTA) and the DPPIV inhibitor sitagliptin phosphate monohydrate (STG) were administered orally for 7 days. Male C57BL/6 mice (6-7 weeks old) were divided into five groups: normal control group, disease control group, BTA low group (drinking water containing 15 mg/L BTA), BTA high group (50 mg/L BTA), and BTA high + STG (3 mg/kg, i.g.) group.ResultsThe selective TGR5 agonist BTA dose-dependently suppressed disease activity index and mRNA expression of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the colon. Nevertheless, STG administration had little additive effect on BTA-induced protection. Fibroblast activation protein mRNA expression, but not expression of other DPP family members, was increased in the colon of DSS-treated mice with increased mucosal DPPIV. Co-administration of the selective GLP-2 antagonist GLP-2 (3-33) reversed the effect of BTA.ConclusionThe selective TGR5 agonist BTA ameliorated DSS-induced colitis in mice via the GLP-2 pathway with no effect of DPPIV inhibition, suggesting that other DPP enzymatic activity is involved in GLP-2 degradation.

Background Environmental enteric dysfunction (EED) is associated with chronic gut inflammation affecting nutrient absorption and development of children, primarily in low- and middle-income countries. Several studies have shown that rice bran (RB) supplementation provides nutrients and modulates gut inflammation, which may reduce risk for undernutrition. Objective The aim was to evaluate the effect of daily RB dietary supplementation for 6 mo on serum biomarkers in weaning infants and associated changes in serum and stool metabolites. Methods A 6-mo randomized-controlled dietary intervention was conducted in a cohort of weaning 6-mo-old infants in León, Nicaragua. Anthropometric indices were obtained at 6, 8, and 12 mo. Serum and stool ionomics and metabolomics were completed at the end of the 6-mo intervention using inductively coupled plasma MS and ultra-high performance LC–tandem MS. The ɑ1-acid glycoprotein, C-reactive protein, and glucagon-like peptide 2 (GLP-2) serum EED biomarkers were measured by ELISA. Results Twenty-four infants in the control group and 23 in the RB group successfully completed the 6-mo dietary intervention with 90% dietary compliance. RB participants had higher concentrations of GLP-2 as compared with control participants at 12 mo [median (IQR): 743.53 (380.54) pg/mL vs. 592.50 (223.59) pg/mL; P  = 0.04]. Metabolite profiles showed significant fold differences of 39 serum metabolites and 44 stool metabolites from infants consuming RB compared with control, and with significant metabolic pathway enrichment scores of 4.7 for the tryptophan metabolic pathway, 5.7 for polyamine metabolism, and 5.7 for the fatty acid/acylcholine metabolic pathway in the RB group. No differences were detected in serum and stool trace elements or heavy metals following daily RB intake for 6 mo. Conclusions RB consumption influences a suite of metabolites associated with growth promotion and development, while also supporting nutrient absorption as measured by changes in serum GLP-2 in Nicaraguan infants. This clinical trial was registered at  https://clinicaltrials.gov as NCT02615886. [ABSTRACT FROM AUTHOR]

Background: Short‐bowel syndrome is the leading cause of pediatric intestinal failure, resulting in dependency on long‐term parenteral nutrition (PN). To promote enteral autonomy 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 1 of 2 GLP‐2 analogues with different pharmacokinetic profiles. Methods: Neonatal short‐bowel piglets were assigned to saline control (S), 7‐day treatment with teduglutide (T) (0.05 mg/kg twice daily), or 7‐day treatment with apraglutide (A) (5 mg/kg twice weekly). Comparisons were made between day 7 and day 14 endpoints using analysis of variance. Data included small‐intestine length, weight, histology, and quantitative polymerase chain reaction analysis of mucosal transcripts for peptide growth factors and their receptors, nutrient transporters, and tight‐junction proteins. Results: Compared with control, 7 days of GLP‐2 analogue treatment induced mucosal adaptation based on villus hyperplasia (P =.003), which was not durable 7 days after treatment cessation (day 14; P =.081). Treatment increased intestinal growth in length by day 7 (P =.005), which was maintained (by T) or further increased (by A) at day 14 (P <.001). No significant differences in mucosal transcripts were detected. Conclusion: Unlike mucosal adaptation, intestinal growth appears to be a lasting outcome of treatment with long‐acting GLP‐2 analogues in a neonatal piglet short‐bowel model. This has significant clinical implications for neonates, given their potential for intestinal growth. Intestinal lengthening varies between analogues with different half‐lives; however, molecular mechanisms require further elucidation. [ABSTRACT FROM AUTHOR]

Backgrounds and aimsWe studied the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) as a possible therapy for non-steroidal anti-inflammatory drug (NSAID)-induced intestinal ulcers. Luminal nutrients release endogenous GLP-2 from enteroendocrine L cells. Since GLP-2 is degraded by dipeptidyl peptidase IV (DPPIV), we hypothesized that DPPIV inhibition combined with luminal administration of nutrients potentiates the effects of endogenous GLP-2 on intestinal injury.MethodsIntestinal injury was induced by indomethacin (10 mg/kg, sc) in fed rats. The long-acting DPPIV inhibitor K579 was given intragastrically (ig) or intraperitoneally (ip) before or after indomethacin treatment. L-Alanine (L-Ala) and inosine 5'-monophosphate (IMP) were co-administered ig after the treatment.ResultsIndomethacin treatment induced intestinal ulcers that gradually healed after treatment. Pretreatment with ig or ip K579 given at 1 mg/kg reduced total ulcer length, whereas K579 at 3 mg/kg had no effect. Exogenous GLP-2 also reduced intestinal ulcers. The preventive effect of K579 was dose-dependently inhibited by a GLP-2 receptor antagonist. Daily treatment with K579 (1 mg/kg), GLP-2, or L-Ala + IMP after indomethacin treatment reduced total ulcer length. Co-administration (ig) of K579 and L-Ala + IMP further accelerated intestinal ulcer healing.ConclusionDPPIV inhibition and exogenous GLP-2 prevented the formation and promoted the healing of indomethacin-induced intestinal ulcers, although high-dose DPPIV inhibition reversed the preventive effect. Umami receptor agonists also enhanced the healing effects of the DPPIV inhibitor. The combination of DPPIV inhibition and luminal nutrient-induced GLP-2 release may be a useful therapeutic tool for the treatment of NSAIDs-induced intestinal ulcers.

AimTo investigate the short-term effect of ileal interposition (IT) surgery on gut morphology and enteroendocrine cell numbers in the pre-diabetic UC Davis type 2 diabetes mellitus (UCD-T2DM) rat.Study designTwo-month old male UCD-T2DM rats underwent either sham (n=5) or IT (n=5) surgery. Intestines were collected 1.5months after surgery. The jejunum, ileum and colon regions were processed for histochemical and immunohistochemical labeling and stereological analyses of changes in gut morphometry and number of enteroendocrine cells.ResultsStereological analysis showed that intestinal volume, luminal surface area and the number of all chromogranin A-positive enteroendocrine cells were markedly increased in the IT rats compared with sham-operated animals. Subanalyses of the glucagon-like peptide 2, cholecystokinin, serotonin cells and the neurotensin immunoreactive sub-pool of enteroendocrine cells in the IT region revealed an increase in numbers across phenotypes. However, the density of the different cell types varied.ConclusionIT surgery in the UCD-T2DM rat leads to rapid alterations in gut morphometry and an increase in the number of enteroendocrine cells. This effect may potentially explain why IT surgery delays the onset of type 2 diabetes in the UCD-T2DM rat.

Bovine colostrum contains growth factors, cytokines, hormones, and enzymes, which have important roles in stimulating gastrointestinal development of neonatal calves. In the present study, we measured the concentration of glucagon-like peptide 2 (GLP-2), one of the gut-derived peptides secreted from intestinal L-cells, in colostrum and transition milk of Japanese black cattle. All colostrum samples were collected within 24 h after calving (d 0) and transition milk was collected at 24, 48 and 72 h relative to the time at colostrum sampling (d 1, d 2 and d 3, respectively). Concentrations of GLP-2 in colostrum were 5.53 ± 1.07 ng/mL on average (range = 0.94–9.60 ng/mL) and decreased from d 0 to 3 (P < 0.01). Furthermore, concentrations of GLP-2 in colostrum and transition milk were quadratically decreased with the elapsed time from parturition until colostrum sampling (R2 = 0.48, P < 0.01). Our results show for the first time that GLP-2 is present in bovine colostrum and transition milk and that concentrations decreased with elapsed time from parturition.

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. [ABSTRACT FROM AUTHOR]

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 <.05), for example, zona occluden‐1 (ZO‐1) and occludin. GLP‐2 decreased the transcription of proinflammatory cytokines genes including interleukin‐1β (IL‐1β), IL‐6, IL‐8, and tumor necrosis factor‐α in small intestines (p <.05). GLP‐2 prevented the LPS‐induced increase in the expression of MLCK dose‐dependently and the increase in pMLC levels in the duodenum, jejunum, and ileum. To assess further the protective effect of GLP‐2 on LPS‐induced intestinal barrier injury after weaning and its possible mechanism, an in vitro intestinal epithelial barrier model was established with IPEC‐J2 monolayers and treated with 100 μg/ml LPS with or without 1 × 10−8 mol/L GLP‐2 pretreatment. The in vitro analysis included control, LPS, and GLP‐2 + LPS treatments. GLP‐2 treatment alleviated the destructive effect of LPS on barrier permeability by restoring the expression and ultrastructure of ZO‐1 and occludin (p <.05). In addition, GLP‐2 reversed the LPS‐induced MLCK hyperexpression and pMLC hyperphosphorylation (p <.05). Taken together, our findings revealed a mechanism by which GLP‐2 alleviated LPS‐challenged intestinal barrier injury and inflammation in weaned piglets and IPEC‐J2 cells via the MLCK/pMLC signaling pathway. [ABSTRACT FROM AUTHOR]

Consumption of high-grain diets by cattle can result in large quantities of starch that flow to the small intestine for potential enzymatic digestion. However, small intestinal starch digestion is potentially limited because of insufficient activity of pancreatic and/or small intestinal carbohydrases. Studies suggest regulation of carbohydrase activity is complex in cattle and perhaps uncoordinated in response to luminal carbohydrate flow. The objective of this experiment was to use postruminal casein infusion and exogenous glucagon-like peptide 2 (GLP-2) administration, known stimulators of pancreatic and small intestinal function, to evaluate their effects on pancreatic and small intestinal carbohydrase activities. Twenty-four Holstein steers [250 ± 23 kg body weight (BW)] were used in a randomized complete block design with a 2 × 2 factorial arrangement of treatments. Steers were fed an alfalfa cube-based diet to limit dietary starch intake. Steers received a continuous abomasal infusion of 4 g/kg of BW of raw corn starch combined with either 0 or 1.33 g/kg of BW of casein for 7 d. Steers received subcutaneous injections in two portions daily of excipient (0.5% bovine serum albumin) or 100 μg/kg of BW GLP-2. This resulted in four treatments: control, casein, GLP-2, and casein + GLP-2. At the end of the 7-d treatment period, steers were slaughtered for pancreatic and small intestinal tissue collection. Data were analyzed using the GLM procedure of SAS. Postruminal casein infusion increased (P = 0.03) pancreatic mass by 12.6%, total pancreatic a-amylase activity by 50%, and postruminal starch disappearance from 96.7% to 99.3%. Exogenous GLP-2 increased (P < 0.01) total small intestinal mass and small intestinal mucosal mass by 1.2 kg and 896 g, respectively. Relative to control, GLP-2 and casein + GLP-2 treatments increased (P = 0.04) total small intestinal a-glucosidase activity (sum of maltase, isomaltase, glucoamylase) by 83.5%. Total small intestinal maltase, isomaltase, and glucoamylase activity was 90%, 100%, and 66.7% greater for GLP-2 and casein + GLP-2 steers compared with control. The use of postruminal casein infusion and exogenous GLP-2 administration resulted in four distinct carbohydrase activity phenotypes. Relative to control, casein increased pancreatic a-amylase activity, GLP-2 increased small intestinal a-glucosidase activity, and the combination of casein and GLP-2 increased both pancreatic a-amylase activity and small intestinal a-glucosidase activity. This approach provides a novel in vivo animal model to selectively increase endogenous carbohydrase activity to overcome complications of coordinating carbohydrase activity with luminal nutrient flows. This model could be useful to understand physiological mechanisms that might improve small intestinal starch assimilation and efficiency of cattle consuming high-grain diets. [ABSTRACT FROM AUTHOR]

GoalsThe aim of this report is to delineate the clinical, pathologic, and enteroendocrine (EE) features of prohormone convertase 1/3 (PC1/3) deficiency in children.BackgroundProhormone convertases play a pivotal role in the activation of biologically inactive hormones. Congenital defects in the EE axis, such as PC1/3 deficiency, have been rarely reported and their pathophysiological mechanisms are largely unknown.StudyEE function and pathology was evaluated in 4 males (1, 2, 7, and 10 y old) from 2 families with PC1/3 deficiency at a university children's hospital. Clinical course, pathology analysis including immunohistochemistry for PC1/3, PC2, and glucagon-like peptide 1 (GLP-1) and electron microscopy, as well as EE function tests (GLP-1, GLP-2, oral glucose tolerance test) were performed.ResultsAll (n=4) suffered from congenital severe diarrhea associated with malabsorption. The diarrhea improved during the first year of life and hyperphagia with excessive weight gain (BMI>97th percentile) became the predominant phenotype at an older age. Analysis of the enteroendocrine axis revealed high proinsulin levels (57 to 1116 pmol/L) in all patients, low serum GLP-2 levels, and impaired insulin and GLP-1 secretion after an oral glucose tolerance test at a young age, with improvement in 1 older child tested. Electron microscopy showed normal ultrastructure of enterocytes and EE cells. Immunohistochemistry revealed normal expression of chromogranin A, a marker of EE cells but markedly reduced immunostaining for PC1/3 and PC2 in all patients.ConclusionsPC1/3 deficiency is associated with an age dependent, variable clinical phenotype caused by severe abnormalities in intestinal and EE functions. Serum level of proinsulin can be used as an effective screening tool.

The glucagon‐like peptide‐2 (GLP‐2) analogue teduglutide is a medical treatment option for patients with short‐bowel syndrome–associated chronic intestinal failure. Because studies in mice have shown that GLP‐2 analogues may promote the growth of colonic neoplasms, surveillance colonoscopies before and during teduglutide therapy were recommended. The occurrence of small‐intestinal neoplasms has not been reported so far, except for a recent report about de novo development of hamartomatous duodenal polyps. We report a case of de novo development of small‐intestinal premalignant adenomatous polyps in both bulbar duodenum and distal jejunum in a patient treated with teduglutide for 41 months. Therefore, additional endoscopic surveillance of the upper gastrointestinal tract may be advised during teduglutide therapy for early detection and removal of potential small‐bowel adenomas. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Teduglutide use in pediatric patients with short bowel syndrome can aid in the achievement of enteral autonomy, but with a price of >$400,000 per y. Objective The current study evaluated the cost-effectiveness of using teduglutide in conjunction with offering intestinal transplantation in US pediatric patients with short bowel syndrome. Design A Markov model was used to evaluate the costs (in US dollars) and effectiveness [in quality-adjusted life years (QALYs)] of using teduglutide compared with offering intestinal transplantation. Parameters were estimated from published data where available. The primary effect modeled was the probability of weaning from parenteral nutrition while on teduglutide. Sensitivity analyses were performed on all model parameters. Results Compared with offering only intestinal transplantation, adding teduglutide cost |${\$}$| 124,353/QALY gained. Reducing the cost of the medication by 16% allowed the cost to reach the typical benchmark of |${\$}$| 100,000/QALY gained. Probabilistic sensitivity analysis favored transplantation without offering teduglutide in 68% of iterations at a |${\$}$| 100,000/QALY threshold. Never using teduglutide created an opportunity cost of over |${\$}$| 100,000 per patient. Conclusions At its current price, teduglutide does not provide a cost-effective addition to transplantation in the treatment of pediatric short bowel syndrome. Further work should look to identify cost-reducing strategies, including alternative dosing regimens. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide 2 (GLP2) is a proglucagon-derived peptide that is involved in the regulation of energy absorption and exerts beneficial effects on glucose metabolism. However, the exact mechanisms underlying the GLP2 during osteogenic differentiation has not been illustrated. Herein, we indicated that GLP2 was demonstrated to result in positive action during the osteogenic differentiation of human osteosarcoma cells. Our findings demonstrate that GLP2 inhibis the growth of osteosarcoma cells in vivo and in vitro. Mechanistic investigations reveal GLP2 inhibits the expression and activity of nuclear factor κB (NF-κB), triggering the decrease of c-Myc, PKM2, and CyclinD1 in osteosarcoma cells. In particular, rescued NF-κB abrogates the functions of GLP2 in osteosarcoma cells. Strikingly, GLP2 overexpression significantly increased the expression of osteogenesis-associated genes (e.g., Ocn and PICP) dependent on c-Fos-BMP signaling, which promotes directed differentiation from osteosarcoma cells to osteoblasts with higher alkaline phosphatase activity. Taken together, our results suggested that GLP2 could be a valuable drug to promote directed differentiation from osteosarcoma cells to osteoblasts, which may provide potential therapeutic targets for the treatment of osteosarcoma.

This study investigated how providing hay mixed with calf starter to dairy calves affected their solid feed intake, feed sorting, growth, and plasma metabolite and hormone concentrations. Forty Holstein heifer calves were fed a texturized calf starter (23.4% crude protein, 32.3% starch on a dry matter basis) and chopped Klein grass hay as separate components (CONT) or the same starter and hay mixed at a 90:10 ratio on an as-fed basis (MIX) ad libitum from the date transported to the research farm (4–7 d of life) to 90 d of life. Calves were provided milk replacer (28% crude protein, 15% fat) at up to 557 g/d before the study, 737 g/d from d 14 to 20, 1,105 g/d from d 21 to 41, 737 g/d from d 42 to 48, and 557 g/d from d 49 to 55 on a dry matter basis. calves were fully weaned on d 56. Feed sorting for the MIX calves was evaluated using the Penn State Particle Separator; the sorting index was calculated as the actual intake as a percentage of predicted intake, with values >100% indicating sorting for and values <100% indicating sorting against. Treatment did not affect solid feed intake, growth performance, or plasma metabolite or hormone concentration during the preweaning or weaning periods. However, calves in the MIX treatment had less neutral detergent fiber intake as a percentage of solid feed intake than CONT calves in the preweaning (23.3 vs. 37.0%) and weaning (23.5 vs. 25.8%) periods, although MIX calves sorted (107.2%) for long particles, which were primarily hay, during weaning. During the postweaning period, MIX calves had greater neutral detergent fiber intake as a percentage of solid feed intake compared with CONT calves (23.4 vs. 22.7%), although they sorted against long particles (84.4%), and decreased solid feed dry matter intake compared with CONT calves (3,292 vs. 3,536 g/d) and average daily gain (1.20 vs. 1.31 kg/d). Weaned calves in the MIX treatment also had lower plasma concentration of glucagon-like peptide 2 compared with CONT (0.46 vs. 0.77 ng/mg) but had higher plasma concentrations of ghrelin (0.05 vs. 0.03 ng/mg). These results suggest that feeding a mixture of texturized calf starter and chopped hay at the 90:10 ratio to postweaned calves may decrease solid feed intake and growth. [ABSTRACT FROM AUTHOR]

Background Adults with short bowel syndrome have a high mortality and significant morbidity due to unsuccessful attempts at rehabilitation that necessitate chronic use of parenteral nutrition (PN). Teduglutide is a novel therapy that promotes intestinal adaptation to improve rehabilitation but with a price >$400,000/y. Objective The current study evaluated the cost-effectiveness of using teduglutide in US adult patients with short bowel syndrome. Methods A Markov model evaluated the costs (in US dollars) and effectiveness (in quality-adjusted life years, or QALYs) of treatment compared with no teduglutide use, with a presumed starting age of 40 y. Parameters were obtained from published data or estimation. The primary effect modeled was the increased likelihood of reduced PN days per week when using teduglutide, leading to greater quality of life and lower PN costs. Sensitivity analyses were performed on all model parameters. Results In the base scenario, teduglutide cost $949,910/QALY gained. In 1-way sensitivity analyses, only reducing teduglutide cost decreased the cost/QALY gained to below the typical threshold of $100,000/QALY gained. Specifically, teduglutide cost would need to be reduced by >65% for it to reach the threshold value. Probabilistic sensitivity analysis favored no teduglutide use in 80% of iterations at a $100,000/QALY threshold. However, teduglutide therapy was cost-saving in 13% of model iterations. Conclusions Teduglutide does not meet a traditional cost-effectiveness threshold as treatment for PN reduction in adult patients with short bowel syndrome compared with standard intestinal rehabilitation. Subpopulations that demonstrate maximum benefit could be cost-saving, and complete nonuse could lead to financial loss. Teduglutide becomes economically reasonable only if its cost is substantially reduced. [ABSTRACT FROM AUTHOR]