Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome

2004 ◽  
Vol 286 (6) ◽  
pp. G964-G972 ◽  
Author(s):  
Gary R. Martin ◽  
Laurie E. Wallace ◽  
David L. Sigalet
Keyword(s):  
Short Bowel Syndrome ◽  
Intestinal Permeability ◽  
Therapeutic Potential ◽  
Intestinal Adaptation ◽  
Intestinal Resection ◽  
Sprague Dawley ◽  
Short Bowel ◽  
Intravenous Saline ◽  
Glucagon Like Peptide ◽  
Mucosal Surface Area

Glucagon-like peptide-2 (GLP-2) is an intestinal trophic enteroendocrine peptide that is associated with intestinal adaptation following resection. Herein, we investigate the effects of GLP-2 in a total parenteral nutrition (TPN)-supported model of experimental short bowel syndrome. Juvenile Sprague-Dawley rats underwent a 90% small intestinal resection and jugular catheter insertion. Rats were randomized to three groups: enteral diet and intravenous saline infusion, TPN only, or TPN + 10 μg·kg−1·h−1 GLP-2. Nutritional maintenance was isocaloric and isonitrogenous. After 7 days, intestinal permeability was assessed by quantifying the urinary recovery of gavaged carbohydrate probes. The following day, animals were euthanized, and intestinal tissue was processed for morphological and crypt cell proliferation (CCP) analysis, apoptosis (caspase-3), and expression of SGLT-1 and GLUT-5 transport proteins. TPN plus GLP-2 treatment resulted in increased bowel and body weight, villus height, intestinal mucosal surface area, CCP, and reduced intestinal permeability compared with the TPN alone animals ( P < 0.05). GLP-2 treatment induced increases in serum GLP-2 levels and intestinal SGLT-1 expression ( P < 0.01) compared with either TPN or enteral groups. No differences were seen in the villus apoptotic index between resection groups. Enterally fed resected animals had a significant decrease in crypt apoptotic indexes compared with nontreated animals. This study demonstrates that GLP-2 alone, without enteral feeding, stimulates indexes of intestinal adaptation. Secondly, villus hypertrophy associated with adaptation was predominantly due to an increase in CCP and not to changes in apoptotic rates. Further studies are warranted to establish the mechanisms of action and therapeutic potential of GLP-2.

scholarly journals Exogenous glucagon-like peptide-2 improves outcomes of intestinal adaptation in a distal-intestinal resection neonatal piglet model of short bowel syndrome

2014 ◽  
Vol 76 (4) ◽  
pp. 370-377 ◽  
Author(s):  
Megha Suri ◽  
Justine M. Turner ◽  
David L. Sigalet ◽  
Pamela R. Wizzard ◽  
Patrick N. Nation ◽  
...  
Keyword(s):  
Short Bowel Syndrome ◽  
Intestinal Adaptation ◽  
Intestinal Resection ◽  
Short Bowel ◽  
Neonatal Piglet ◽  
Glucagon Like Peptide

scholarly journals 576 Exogenous Glucagon-Like Peptide 2 Therapy in a Piglet Model of Neonatal Short Bowel Syndrome Promotes Intestinal Adaptation

2014 ◽  
Vol 146 (5) ◽  
pp. S-106
Author(s):  
David W. Lim ◽  
Paul W. Wales ◽  
Donna F. Vine ◽  
Faye Borthwick ◽  
Patrick N. Nation ◽  
...  
Keyword(s):  
Short Bowel Syndrome ◽  
Intestinal Adaptation ◽  
Short Bowel ◽  
Glucagon Like Peptide

scholarly journals Animal models of gastrointestinal and liver diseases. Animal models of infant short bowel syndrome: translational relevance and challenges

2014 ◽  
Vol 307 (12) ◽  
pp. G1147-G1168 ◽  
Author(s):  
Per T. Sangild ◽  
Denise M. Ney ◽  
David L. Sigalet ◽  
Andreas Vegge ◽  
Douglas Burrin
Keyword(s):  
Growth Factor ◽  
Animal Models ◽  
Short Bowel Syndrome ◽  
Genetic Manipulation ◽  
Digestive Enzyme ◽  
Research Question ◽  
Intestinal Adaptation ◽  
Intestinal Resection ◽  
Cellular Mechanisms ◽  
Short Bowel

Intestinal failure (IF), due to short bowel syndrome (SBS), results from surgical resection of a major portion of the intestine, leading to reduced nutrient absorption and need for parenteral nutrition (PN). The incidence is highest in infants and relates to preterm birth, necrotizing enterocolitis, atresia, gastroschisis, volvulus, and aganglionosis. Patient outcomes have improved, but there is a need to develop new therapies for SBS and to understand intestinal adaptation after different diseases, resection types, and nutritional and pharmacological interventions. Animal studies are needed to carefully evaluate the cellular mechanisms, safety, and translational relevance of new procedures. Distal intestinal resection, without a functioning colon, results in the most severe complications and adaptation may depend on the age at resection (preterm, term, young, adult). Clinically relevant therapies have recently been suggested from studies in preterm and term PN-dependent SBS piglets, with or without a functional colon. Studies in rats and mice have specifically addressed the fundamental physiological processes underlying adaptation at the cellular level, such as regulation of mucosal proliferation, apoptosis, transport, and digestive enzyme expression, and easily allow exogenous or genetic manipulation of growth factors and their receptors (e.g., glucagon-like peptide 2, growth hormone, insulin-like growth factor 1, epidermal growth factor, keratinocyte growth factor). The greater size of rats, and especially young pigs, is an advantage for testing surgical procedures and nutritional interventions (e.g., PN, milk diets, long-/short-chain lipids, pre- and probiotics). Conversely, newborn pigs (preterm or term) and weanling rats provide better insights into the developmental aspects of treatment for SBS in infants owing to their immature intestines. The review shows that a balance among practical, economical, experimental, and ethical constraints will determine the choice of SBS model for each clinical or basic research question.

scholarly journals Increased Intestinal Permeability in Patients With Short Bowel Syndrome is not Affected by Parenteral Nutrition

2019 ◽  
pp. 817-825 ◽  
Author(s):  
A. CINKAJZLOVÁ ◽  
Z. LACINOVÁ ◽  
J. KLOUČKOVÁ ◽  
P. KAVÁLKOVÁ ◽  
H. KRATOCHVÍLOVÁ ◽  
...  
Keyword(s):  
Parenteral Nutrition ◽  
Short Bowel Syndrome ◽  
Intestinal Permeability ◽  
Fatty Acid Binding Protein ◽  
Binding Protein ◽  
Control Group ◽  
Fatty Acid Binding ◽  
Short Bowel ◽  
Glucagon Like Peptide ◽  
Circulating Levels

The aim of our study was to assess the presence and degree of intestinal leakage in subjects suffering from short bowel syndrome (SBS) and its modification by parenteral nutrition. To this end we assessed circulating levels of selected makers of intestinal permeability including zonulin, fatty acid binding protein 2 (FABP-2), citrulline and glucagon-like peptide 2 (GLP-2). We also measured lipopolysaccharide binding protein (LBP) as a marker of circulating levels of lipopolysaccharide acting through the CD14 molecule. Eleven SBS and 10 age- and BMI-matched control subjects were included into the study. The effect of parenteral nutrition was assessed after 14 days, 6 and 12 months from its initiation, respectively. At baseline, SBS patients had increased gut permeability as measured by zonulin (47.24±2.14 vs. 39.48±1.20 ng/ml, p=0.006) and LBP (30.32±13.25 vs. 9.77±0.71 µg/ml, p<0.001) compared to healthy controls. Furthermore, SBS subjects had reduced FABP-2, unchanged citrulline and increased sCD14 and GLP-2 relative to control group. Throughout the whole study period the administered parenteral nutrition had no significant effect on any of the studied parameters. Taken together, our data show that patients with short bowel syndrome have increased intestinal permeability that is not affected by parenteral nutrition.

scholarly journals Therapeutic Potential of an Intestinotrophic Hormone, Glucagon-Like Peptide 2, for Treatment of Type 2 Short Bowel Syndrome Rats with Intestinal Bacterial and Fungal Dysbiosis

2021 ◽  
Author(s):  
Xiuting Hu ◽  
Wei Cheng ◽  
Shengxian Fan ◽  
Yuhua Huang ◽  
Xi Chen ◽  
...  
Keyword(s):  
Short Bowel Syndrome ◽  
Relative Abundance ◽  
Sham Group ◽  
Therapeutic Potential ◽  
Interaction Network ◽  
Small Bowel Resection ◽  
Its Sequencing ◽  
Short Bowel ◽  
Glucagon Like Peptide

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.

scholarly journals Synergy of glucagon-like peptide-2 and epidermal growth factor coadministration on intestinal adaptation in neonatal piglets with short bowel syndrome

2017 ◽  
Vol 312 (4) ◽  
pp. G390-G404 ◽  
Author(s):  
David W. Lim ◽  
Crystal L. Levesque ◽  
Donna F. Vine ◽  
Mitsuru Muto ◽  
Jacob R. Koepke ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Short Bowel Syndrome ◽  
Intestinal Adaptation ◽  
Villus Height ◽  
Short Bowel ◽  
Intestinal Length ◽  
Epidermal Growth ◽  
Glucagon Like Peptide

Glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) treatment enhance intestinal adaptation. To determine whether these growth factors exert synergistic effects on intestinal growth and function, GLP-2 and EGF-containing media (EGF-cm) were administered, alone and in combination, in neonatal piglet models of short bowel syndrome (SBS). Neonatal Landrace-Large White piglets were block randomized to 75% midintestinal [jejunoileal (JI) group] or distal intestinal [jejunocolic (JC) group] resection or sham control, with 7-day infusion of saline (control), intravenous human GLP-2 (11 nmol·kg−1·day−1) alone, enteral EGF-cm (80 μg·kg−1·day−1) alone, or GLP-2 and EGF-cm in combination. Adaptation was assessed by intestinal length, histopathology, Üssing chamber analysis, and real-time quantitative PCR of intestinal growth factors. Combined EGF-cm and GLP-2 treatment increased intestinal length in all three surgical models ( P < 0.01). EGF-cm alone selectively increased bowel weight per length and jejunal villus height in the JI group only. The JC group demonstrated increased intestinal weight and villus height ( P < 0.01) when given either GLP-2 alone or in combination with EGF-cm, with no effect of EGF-cm alone. Jejunal permeability of mannitol and polyethylene glycol decreased with combination therapy in both SBS groups ( P < 0.05). No difference was observed in fat absorption or body weight gain. IGF-1 mRNA was differentially expressed in JI vs. JC piglets with treatment. Combined treatment with GLP-2 and EGF-cm induced intestinal lengthening and decreased permeability, in addition to the trophic effects of GLP-2 alone. Our findings demonstrate the benefits of novel combination GLP-2 and EGF treatment for neonatal SBS, especially in the JC model representing most human infants with SBS. NEW & NOTEWORTHY Glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) are intestinotrophic, with demonstrated benefit in both animal models and human studies of short bowel syndrome (SBS). The current research shows that over and above known trophic effects, the combination of GLP-2 and EGF synergistically lengthens the bowel in neonatal piglet models of SBS. Most notable benefit occurred with resection of the terminal ileum, the common clinical anatomy seen in neonatal SBS and associated with least de novo lengthening postsurgery.

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