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Title: GLP-2 delays but does not prevent the onset of necrotizing enterocolitis in preterm pigs

item BENIGHT, NANCY - Children'S Nutrition Research Center (CNRC)
item STOLL, BARBARA - Children'S Nutrition Research Center (CNRC)
item OLUTOYE, OLUYINKA - Texas Children'S Hospital
item HOLST, JENS - University Of Copenhagen
item Burrin, Douglas - Doug

Submitted to: Journal of Pediatric Gastroenterology and Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/7/2013
Publication Date: 6/1/2013
Citation: Benight, N.M., Stoll, B., Olutoye, O.O., Holst, J.J., Burrin, D.G. 2013. GLP-2 delays but does not prevent the onset of necrotizing enterocolitis in preterm pigs. Journal of Pediatric Gastroenterology and Nutrition. 56(6):623-630.

Interpretive Summary: Premature infants are at increased risk for an intestinal disease called necrotizing enterocolitis (NEC). A small percentage of infants contract this disease, but it has devastating effects on the health and long-term development. The underlying cause of NEC is not well known, but is thought to be related to reduced flow of blood and oxygen to the lining of the gut that results in diminished growth and development of the intestine in the period after birth. We previously showed that enteral feeding stimulates blood flow and the secretion of a gut growth factor, glucagon-like peptide 2 (GLP-2). These results and other reports showing that GLP-2 has anti-inflammatory actions in the intestine suggest that it might be a therapy to prevent NEC. Thus, we tested whether infusing GLP-2 intravenously immediately after birth could augment intestinal growth and prevent NEC in premature piglets fed infant formula. We found that GLP-2 treatment delayed the onset of NEC but did not prevent the ultimate incidence of disease, such that about 70% of pigs developed NEC. We found that GLP-2 treatment increased intestinal growth as expected, but did not reduce the inflammation that occurs in association with NEC. Our findings suggest that GLP-2 treatment was not effective in the prevention of NEC.

Technical Abstract: Necrotizing enterocolitis (NEC) is a complex disease thought to occur due to an immaturity of 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, GLP-2, would reduce the incidence of NEC when given in combination with TPN in preterm piglets. Preterm, newborn piglets were nourished by TPN and infused continuously with either human GLP-2 (100 micro or control saline for 2 days (n equals 12 per grp). On day 3, TPN was discontinued and pigs were given orogastric formula feeding every 3 hr 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. GLP-2 treatment delayed the onset of NEC but was unable to prevent a high NEC incidence (of or about 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. In conclusion, GLP-2 did not prevent NEC and a proinflammatory response despite some reduction in mucosal injury and increased trophic effect.