Sustained glucagon-like peptide-2 infusion is required for intestinal adaptation, and cessation reverses increased cellularity in rats with intestinal failure

Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent, proglucagon-derived hormone that is a proposed treatment for human short bowel syndrome (SBS). The objective was to determine how the timing, duration, and cessation of GLP-2 administration affect intestinal adaptation and enterocyte kinetics in a rat model of human SBS that results in intestinal failure requiring total parenteral nutrition (TPN). Rats underwent 60% jejunoileal resection plus cecectomy and jugular vein cannulation and were maintained exclusively with TPN for 18 days in these treatments: TPN control (no GLP-2); sustained GLP-2 (1–18 days); early GLP-2 (1–7 days, killed at 7 or 18 days); and delayed GLP-2 (12–18 days). Body weight gain was similar across groups, and plasma bioactive GLP-2 was significantly increased with coinfusion of GLP-2 (100 μg·kg−1·day−1) with TPN. GLP-2-treated rats showed significant increases in duodenum and jejunum mucosal dry mass, protein, DNA, and sucrase activity compared with TPN control. The increased jejunum cellularity reflected significantly decreased apoptosis and increased crypt mitosis and crypt fission due to GLP-2. When GLP-2 infusion stopped at 7 days, these effects were reversed at 18 days. Sustained GLP-2 infusion significantly increased duodenum length and decreased 18-day mortality to 0% from 37.5% deaths in TPN control ( P = 0.08). Colon proglucagon expression quantified by real-time RT-qPCR was increased in TPN controls and attenuated by GLP-2 infusion; jejunal expression of the GLP-2 receptor did not differ among groups. In summary, early, sustained GLP-2 infusion reduces mortality, induces crypt fission, and is required for intestinal adaptation, whereas cessation of GLP-2 reverses gains in mucosal cellularity in a rat model of intestinal failure.

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Synergistic effect of supplemental enteral nutrients and exogenous glucagon-like peptide 2 on intestinal adaptation in a rat model of short bowel syndrome

American Journal of Clinical Nutrition ◽

10.1093/ajcn/84.5.1142 ◽

2006 ◽

Vol 84 (5) ◽

pp. 1142-1150 ◽

Cited By ~ 37

Author(s):

Xiaowen Liu ◽

David W Nelson ◽

Jens J Holst ◽

Denise M Ney

Keyword(s):

Synergistic Effect ◽

Short Bowel Syndrome ◽

Rat Model ◽

Intestinal Adaptation ◽

Short Bowel ◽

Glucagon Like Peptide ◽

Enteral Nutrients

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Sa1958 Exogenous Glucagon-Like Peptide-2 in Combination With Enteral Nutrients Containing Whey Protein Permits Intestinal Adaptation and Complete Independence From Parenteral Nutrition in a Rat Model of Human Short Bowel Syndrome

Gastroenterology ◽

10.1016/s0016-5085(12)61392-4 ◽

2012 ◽

Vol 142 (5) ◽

pp. S-368

Author(s):

Adam S. Brinkman ◽

Sangita G. Murali ◽

Patrick Solverson ◽

Jens J. Holst ◽

Denise M. Ney

Keyword(s):

Parenteral Nutrition ◽

Whey Protein ◽

Short Bowel Syndrome ◽

Rat Model ◽

Intestinal Adaptation ◽

Short Bowel ◽

Complete Independence ◽

Glucagon Like Peptide ◽

Enteral Nutrients

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Intestinal adaptation in short bowel syndrome. What is new?

Nutrición Hospitalaria ◽

10.20960/nh.1952 ◽

2018 ◽

Author(s):

L Billiauws ◽

M Thomas

Keyword(s):

Growth Factor ◽

Short Bowel Syndrome ◽

Dietary Intervention ◽

Intestinal Adaptation ◽

Intestinal Failure ◽

Short Bowel ◽

Energy Recuperation ◽

Glucagon Like Peptide ◽

First Cause

Short bowel syndrome is the first cause of intestinal failure, which requires intravenous supplementation (hydro-electrolytic and/or caloric). Physiological intestinal adaptation occurs 1 to 2 years after resection. This adaptation includes hyperphagia, changes in microbiota, morphological intestinal changes (including hyperplasia), hormonal adaptation... The colon plays a major role and permits hydro-electrolytic and energy recuperation. It is possible to enhance the physiologic adaptation by optimizing the dietary intervention, restoring the continuity and by giving a growth factor treatments such as GLP-2 analog(Glucagon-Like Peptide-2).

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Synergistic effect of supplemental enteral nutrients (SEN) and glucagon‐like peptide‐2 (GLP‐2) in intestinal adaptation in a rat model of human short bowel syndrome (SBS)

The FASEB Journal ◽

10.1096/fasebj.20.4.a548-c ◽

2006 ◽

Vol 20 (4) ◽

Author(s):

Xiaowen Liu ◽

David W. Nelson ◽

Jens J. Holst ◽

Denise M. Ney

Keyword(s):

Synergistic Effect ◽

Short Bowel Syndrome ◽

Rat Model ◽

Intestinal Adaptation ◽

Short Bowel ◽

Glucagon Like Peptide ◽

Enteral Nutrients

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Effect of subcutaneous insulin on intestinal adaptation in a rat model of short bowel syndrome

Pediatric Surgery International ◽

10.1007/s00383-004-1308-2 ◽

2004 ◽

Vol 21 (3) ◽

pp. 132-137 ◽

Cited By ~ 10

Author(s):

Igor Sukhotnik ◽

Jorge Mogilner ◽

Raanan Shamir ◽

Naim Shehadeh ◽

Jacob Bejar ◽

...

Keyword(s):

Short Bowel Syndrome ◽

Rat Model ◽

Intestinal Adaptation ◽

Subcutaneous Insulin ◽

Short Bowel

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Early but not late administration of glucagon-like peptide-2 following ileo-cecal resection augments putative intestinal stem cell expansion

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90588.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. G643-G650 ◽

Cited By ~ 49

Author(s):

Aaron P. Garrison ◽

Christopher M. Dekaney ◽

Douglas C. von Allmen ◽

P. Kay Lund ◽

Susan J. Henning ◽

...

Keyword(s):

Side Population ◽

Intestinal Failure ◽

Serum Levels ◽

Optimal Timing ◽

Side Population Cells ◽

Stem Cell Expansion ◽

Crypt Fission ◽

Igf I ◽

Glucagon Like Peptide ◽

Mucosal Mass

Expansion of intestinal progenitors and putative stem cells (pISC) occurs early and transiently following ileo-cecal resection (ICR). The mechanism controlling this process is not defined. We hypothesized that glucagon-like peptide-2 (GLP-2) would augment jejunal pISC expansion only when administered to mice immediately after ICR. Since recent reports demonstrated increases in intestinal insulin-like growth factor (IGF)-I following GLP-2 administration, we further hypothesized that increased intestinal IGF-I expression would correlate with pISC expansion following ICR. To assess this, GLP-2 or vehicle was administered to mice either immediately after resection (early) or before tissue harvest 6 wk following ICR (late). Histological analysis quantified proliferation and intestinal morphometrics. Serum levels of GLP-2 were measured by ELISA and jejunal IGF-I mRNA by qRT-PCR. Expansion of jejunal pISC was assessed by fluorescent-activated cell sorting of side population cells, immunohistochemistry for phosphorylated β-catenin at serine 552 (a pISC marker), percent of crypt fission, and total numbers of crypts per jejunal circumference. We found that early but not late GLP-2 treatment after ICR significantly augmented pISC expansion. Increases in jejunal IGF-I mRNA correlated temporally with early pISC expansion and effects of GLP-2. Early GLP-2 increased crypt fission and accelerated adaptive increases in crypt number and intestinal caliber. GLP-2 increased proliferation and intestinal morphometrics in all groups. This study shows that, in mice, GLP-2 promotes jejunal pISC expansion only in the period immediately following ICR. This is associated with increased IGF-I and accelerated adaptive increases in mucosal mass. These data provide clinical rationale relevant to the optimal timing of GLP-2 in patients with intestinal failure.

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Short bowel syndrome in infancy: recent advances and practical management

Frontline Gastroenterology ◽

10.1136/flgastro-2020-101457 ◽

2020 ◽

pp. flgastro-2020-101457

Author(s):

Elena Cernat ◽

Chloe Corlett ◽

Natalia Iglesias ◽

Nkem Onyeador ◽

Julie Steele ◽

...

Keyword(s):

Parenteral Nutrition ◽

Short Bowel Syndrome ◽

Intestinal Adaptation ◽

Intestinal Failure ◽

Rare Condition ◽

Oral Feeding ◽

Short Bowel ◽

Intestinal Continuity ◽

Gastrointestinal Reconstruction ◽

Lipid Reduction

Short bowel syndrome (SBS) is a rare condition characterised by extensive loss of intestinal mass secondary to congenital or acquired disease. The outcomes are determined by dependency on parenteral nutrition (PN), its possible complications and factors that influence intestinal adaptation. In order to achieve the best results, patients should be managed by a specialised multidisciplinary team with the aims of promoting growth and development, stimulating intestinal adaptation and preventing possible complications. This involves timely surgical management aimed at rescuing maximum bowel length and eventually re-establishing intestinal continuity where appropriate. A combination of enteral and parenteral nutrition needs to be targeted towards maintaining a balance between fulfilling the nutritional and metabolic needs of the child while preventing or at least minimising potential complications. Enteral nutrition and establishment of oral feeding play a fundamental role in stimulating bowel adaptation and promoting enteral autonomy. Other measures to promote enteral autonomy include the chyme recycling in patients where bowel is not in continuity, autologous gastrointestinal reconstruction and pharmacological treatments, including promising new therapies like teduglutide. Strategies such as lipid reduction, changing the type of lipid emulsion and cycling PN are associated with a reduction in the rates of intestinal failure–associated liver disease. Even though vast improvements have been made in the surgical and medical management of SBS, there is still lack of consensus in many aspects and collaboration is essential.

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