GLP‐2 Delays but Does Not Prevent the Onset of Necrotizing Enterocolitis in Preterm Pigs

Abstract

Objectives Necrotizing enterocolitis (NEC) is complex disease thought to occur as a result of an immaturity of the gastrointestinal tract of preterm infants. Intestinal dysfunction induced by total parental nutrition (TPN) may increase the risk for NEC upon introduction of enteral feeding. We hypothesized that the intestinal trophic and anti-inflammatory actions previously ascribed to the gut hormone, glucagon-like peptide-2 (GLP-2), would reduce the incidence of NEC when given in combination with TPN in preterm piglets. Methods Preterm, newborn piglets were nourished by TPN and infused continuously with either human GLP-2 (100 μg · kg−1 · day−1) or control saline for 2 days (n = 12/group). On day 3, TPN was discontinued and pigs were given orogastric formula feeding every 3 hours, and continued GLP-2 or control treatment until the onset of clinical signs of NEC for an additional 96 hours and tissue was collected for molecular and histological endpoints. Results GLP-2 treatment delayed the onset of NEC but was unable to prevent a high NEC incidence (~70%) and severity that occurred in both groups. GLP-2–treated pigs had less histological injury and increased proximal intestinal weight and mucosal villus height, but not crypt depth or Ki-67–positive cells. Inflammatory markers of intestinal myeloperoxidase were unchanged and serum amyloid A levels were higher in GLP-2–treated pigs. Conclusions GLP-2 did not prevent NEC and a proinflammatory response despite some reduction in mucosal injury and increased trophic effect.

PEGylated porcine glucagon-like peptide-2 improved the intestinal digestive function and prevented inflammation of weaning piglets challenged with LPS

“…However, GLP-2 (3-33) decreased the crypt Ki67-positive cells in the small intestines of dietinduced obesity models; GLP-2 also increased the per cent of caspase-3-positive cells possibly by reducing endogenous GLP-2 (Baldassano et al, 2013). Ki-67 was considered as a marker of proliferating cells, but we found no significant difference in cell proliferation in the ileum; this result was similar to that of Benight et al (2013). One possible explanation was that the rate of proliferation was maximally stimulated by enteral feeding and limited any effect of GLP-2.…”

Prematurity reduces citrulline-arginine-nitric oxide production and precedes the onset of necrotizing enterocolitis in piglets

“…Gross scoring was based on the presence of inflammation, Means within a row with different superscripted letter differ (P Ͻ 0.05); *n ϭ 27 PT pigs, n ϭ 9 NT pigs, and n ϭ 11 FT pigs; †n ϭ 7 PT pigs, n ϭ 5 NT pigs, and n ϭ 5 FT pigs; ‡n ϭ 19 PT pigs, n ϭ 9 NT pigs, and n ϭ 11 FT pigs; §Villus height data analyzed by Kruskal-Wallis test and Dunn's multiple comparison test. necrosis, and pneumatosis intestinalis (4,19). Gross NEC score was used to stratify animals as fulminant NEC (positive NEC score throughout the bowel), colonic NEC (NEC lesions localized to the distal bowel), and NEC resistant (for piglets without lesions).…”

“…Gross NEC score was used to stratify animals as fulminant NEC (positive NEC score throughout the bowel), colonic NEC (NEC lesions localized to the distal bowel), and NEC resistant (for piglets without lesions). Histological NEC score was performed on hematoxylin-eosin-stained sections of proximal jejunum, distal ileum, and colon (4,8). Sections were assigned a histological NEC severity score (0 -4) based on the degree of epithelial and/or mucosal damage; a tissue score of Ն3 indicated necrosis and/or pneumatosis.…”

Invited Review: The preterm pig as a model in pediatric gastroenterology

“…During TPN, in the absence of any enteral food, administration of the gut tropic hormone, glucagon-like peptide 2 ( GLP-2 ), markedly improves gut growth and adaptation in preterm and term pigs, with and without SBS (Burrin et al, 2000; Petersen et al, 2001, 2002; Sangild et al, 2007; Vegge et al, 2013). Somewhat surprisingly, GLP-2 failed to prevent NEC in preterm pigs (Sangild et al, 2006; Benight et al, 2013). Apparently, this promising novel drug candidate only acts under certain physiological conditions, and studies in pigs may help to define therapeutic potential of GLP-2 for infants dependent on PN.…”