Role of glucagon-like peptide–2 deficiency in neonatal short-bowel syndrome using neonatal piglets

Abstract

Background: Short-bowel syndrome (SBS) is the most common cause of neonatal intestinal failure. Recovery requires intestinal adaptation, dependent on enteral nutrition (EN) and growth factors such as glucagon-like peptide-2 (GLP-2), which is secreted from L cells in the ileum. Neonatal SBS often results in loss of ileum; therefore, we hypothesized that without ileum, endogenous GLP-2 production would be inadequate to promote adaptation. We compared endogenous GLP-2 production and adaptation in neonatal animals with SBS, with and without ileum. Methods: Neonatal piglets (4-6 d) were randomized to 75% mid-intestinal resection, 75% distal-intestinal resection, or sham control without resection. Postoperatively, all piglets commenced parenteral nutrition (PN), tapering as EN was increased to maintain specific growth. results: The resected SBS piglets developed intestinal failure, requiring a longer duration of PN support and experiencing fat malabsorption. The piglets without ileum were not able to wean from PN during the study and did not show adaptation, specifically growth in intestinal length or crypt hyperplasia on histology of the jejunum. Adaptation was observed in the resected SBS piglets with ileum, and these piglets also had an increased plasma GLP-2 level that was not observed in piglets without ileum. conclusion: SBS piglets with ileum undergo adaptation associated with increased endogenous GLP-2 production. SBS piglets without ileum undergo limited adaptation and severe intestinal failure, requiring prolonged PN support. This appears to be related to a deficiency in endogenous GLP-2 production. n eonatal intestinal failure secondary to short-bowel syndrome (SBS) has a particularly poor outcome. It is most common in preterm infants, and necrotizing enterocolitis is the most common cause (1-3). Necrotizing enterocolitis usually results in loss of ileum and right colon and carries a significant mortality (4).After intestinal resection, adaptation of the remnant intestine is essential for survival, compensating for the reduced absorptive surface area, both structurally and functionally (5). This process is regulated by several factors, including the stage of intestinal development, site and length of resection, the underlying disease, nutritional status, and gut-derived hormones and growth factors (6). Among the growth factors, glucagon-like peptide-2 (GLP-2) is considered to have an important role in inducing small-intestinal adaptation after resection. GLP-2 acts specifically at the GLP-2 receptor (GLP-2R), which is expressed throughout the small and large intestines but with greatest concentration in the jejunum (7). GLP-2 is uniquely trophic for the intestine (8). It can stimulate residual small-intestinal adaptation by increasing crypt cell proliferation and inhibiting apoptosis, thereby increasing villus height, crypt depth, mucosal mass, and overall small-intestinal length and weight (9-11). Functionally, GLP-2 increases activities of mucosal enzymes and therefore increases digestion and absorption (...

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

“…However, EGF-cm alone appeared to be selectively beneficial in increasing bowel weight per length and jejunal villus height in the JI group only. This finding may relate to the fact that the JI anatomy retains GLP-2-producing L cells that have been shown to increase their GLP-2 production postresection to mediate intestinal adaptation (21,23). We observed evidence of this intrinsic adaptation in our JI model, with intestinal lengthening and increased intestinal weight and ileal villus height.…”

Interdependency of EGF and GLP-2 Signaling in Attenuating Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

“…In addition, a significant decrease in mucosally derived growth factors has been reported in TPN patients and in animal models of TPN 4, 26, 36, 54, 55. Thus, for patients dependent on TPN, a promising strategy to improve intestinal growth and maintain epithelial barrier function has been with the use of exogenous growth factors 56 .…”

Glucagon‐Like Peptide 2 Improves Cholestasis in Parenteral Nutrition–Associated Liver Disease

“…In light of this, GLP‐2 has been advocated as a potential treatment for patients with short bowel syndrome (SBS), a common cause of intestinal failure 10 . Following the recent approval of Teduglutide, a synthetic analogue of GLP‐2, for the treatment of adult SBS by the U.S. Food and Drug Administration, current research is aimed at studying the role of GLP‐ 2 in pediatric SBS 11 . There is at this time no known effect of GLP‐2 on PNALD.…”