Acute Effects of the Glucagon‐Like Peptide 2 Analogue, Teduglutide, on Intestinal Adaptation in Short Bowel Syndrome

Abstract

Neonatal short bowel syndrome following massive gut resection is associated with malabsorption of nutrients. The intestinotrophic factor glucagon-like peptide 2 (GLP-2) improves gut function in adult patients with short bowel syndrome, but its effect in pediatric patients remains unknown. Our objective was to test the efficacy of the long-acting synthetic human GLP-2 analogue, teduglutide (ALX-0600), in a neonatal piglet jejunostomy model. Two-day-old pigs were subjected to resection of 50% of the small intestine (distal part), and the remnant intestine was exteriorized on the abdominal wall as a jejunostomy. All pigs were given total parenteral nutrition for 7 days and a single daily injection of the following doses of teduglutide: 0.01 (n = 6), 0.02 (n = 6), 0.1 (n = 5), or 0.2 mg · kg · day (n = 6), and compared with placebo (n = 9). Body weight increment was similar for all 4 teduglutide groups but higher than placebo (P < 0.05). There was a dose-dependent increase in weight per length of the remnant intestine (P < 0.01) and fractional protein synthesis rate in the intestine was increased in the 0.2 mg · kg · day group versus placebo (P < 0.001); however, functional and structural endpoints including activity of digestive enzymes, absorption of enteral nutrients, and immunohistochemistry (Ki67, villin, FABP2, ChgA, and GLP-2R) were not affected by the treatment. Teduglutide induces trophicity on the remnant intestine but has limited acute effects on functional endpoints. Significant effects of teduglutide on gut function may require a longer adaptation period and/or a more frequent administration of the peptide. In perspective, GLP-2 or its analogues may be relevant to improve intestinal adaptation in pediatric patients with short bowel syndrome.

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

“…In parameters such as normalized intestinal weight, mucosal weight, and villus height, there was no difference between combination therapy and GLP-2 alone, but both treatments were superior to saline control and/or EGF-cm alone. This suggests that GLP-2 is the main factor stimulating increases in these parameters, consistent with prior studies demonstrating that GLP-2 administration in rodents and piglets expands the intestinal mucosal epithelium (13,28,30,37,40,42,44). However, EGF-cm alone appeared to be selectively beneficial in increasing bowel weight per length and jejunal villus height in the JI group only.…”

“…Given that remnant anatomy is a significant predictor of pathophysiology and outcome in SBS, we therefore developed two neonatal piglet SBS models, one with midintestinal resection and another with distal intestinal resection (25). GLP-2 or teduglutide administration for 7 or 14 days in neonatal piglet SBS models stimulates structural adaptation, including increases in remnant villus height and crypt depth, but has limited or transient functional effects on digestive enzyme activity or nutrient transport (30,40,42,44).…”

Rapid gut growth but persistent delay in digestive function in the postnatal period of preterm pigs

“…Exogenous GLP-2 administration stimulates intestinal growth and disaccharidase activities in TPN-fed preterm pigs with or without intestinal resection (37,49,51). Preterm piglets normally show increased basal circulating levels of GLP-2, compared with pigs born at term, indicating a role for GLP-2 in the maturational process around birth (38).…”

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

“…Petersen et al (2001) demonstrated that the enzymes sucraseisomaltase and lactase-phloridzin hydrolase were unaffected by GLP-2 in late-gestation foetal and parenterally fed neonatal piglets when GLP-2 (12.5 nmol/kg) was administered twice daily for 6 days. In another study, newborn total parenteral nutrition-fed pigs were subjected to daily single administration of teduglutide for 7 days; as a result, small bowel growth was increased and minimal effect was elicited on digestive enzyme expression or nutrient absorption (Thymann et al, 2014a). However, GLP-2 treatment resulted in adverse outcomes, including decreased tissue maltase and sucrose in both sham and small bowel resection piglets (Pereira-Fantini et al, 2008).…”