Glepaglutide, a novel glucagon-like peptide-2 agonist, has anti-inflammatory and mucosal regenerative effects in an experimental model of inflammatory bowel disease in rats.

BACKGROUND: Glucagon-like peptide-2 (GLP-2) enhances intestinal repair and attenuates inflammation in preclinical inflammatory bowel disease (IBD) models, making GLP-2 analogues attractive candidates for IBD therapy. Glepaglutide is a long-acting GLP-2 receptor agonist in clinical development for treatment of short bowel syndrome. Here, we investigated if glepaglutide is therapeutically beneficial in rats with small intestinal inflammation. METHODS: Small intestinal inflammation was induced with indomethacin in naive Wistar rats, followed by glepaglutide administration at different disease stages. Glepaglutide was administered in co-treatment and post-treatment regimens. Small intestinal length and concentrations of inflammatory markers α-1-acid glycoprotein and myeloperoxidase were used to assess anti-inflammatory effects. Small intestinal mass was evaluated to determine intestinotrophic effects. RESULTS: Glepaglutide co- and post-treatment significantly reduced severity of small intestinal inflammation, evidenced by reversed small intestinal shortening and decreased α-1-acid glycoprotein and/or myeloperoxidase concentration(s). Co- and post-treatment with glepaglutide also significantly increased small intestinal mass, indicating intestinal regenerative effects. Similar effects were observed in naive rats after glepaglutide treatment. CONCLUSION: Glepaglutide has anti-inflammatory and intestinotrophic effects without the need for pre-treatment in a rat model of small intestinal inflammation. Thus, glepaglutide is of potential clinical interest for patients with IBD.

Early weaning stimulates intestinal brush border enzyme activities in piglets, mainly at the posttranscriptional level.

BACKGROUND: Weaning-associated anorexia is the main factor responsible for structural alterations of the small intestine. However, whether weaning and the postweaning feed intake level affect disaccharidase and peptidase gene expression remains to be elucidated. METHODS: Adaptation of the small intestine to early weaning at 7 days of age and the effects of postweaning feed intake were investigated on 56 pigs in two trials. Structural parameters and gene expression and activities of intestinal lactase, maltase, sucrase, aminopeptidases A and N, and dipeptidyl peptidase IV were determined along the small intestine. RESULTS: Within 3 days, weaning induced increases in maltase, sucrase, and peptidase specific activities (P < 0.05) and a decrease in lactase activity and villous height (P < 0.05). Only for maltase activity were the weaning-induced changes closely correlated with corresponding mRNA levels. In weaned piglets, aminopeptidase N activity was consistently stimulated and dipeptidyl peptidase IV depressed by high level of feed intake but without effects on the corresponding mRNA levels. Furthermore, the longitudinal distribution of enzyme activities along the small intestine showed poor correlation with the corresponding mRNA levels. CONCLUSION: Early weaning in pigs is associated with a remarkable capacity of the small intestine to rapidly increase the activity of key brush border enzymes. This adaptation, largely independent on feed intake for intestinal enzyme mRNAs and disaccharidase activities, occurred at the posttranscriptional rather than at the transcriptional level of enzyme biosynthesis (except for maltase). The length of the postweaning anorexia period did not affect the subsequent intestinal capacity for villous elongation but may postpone maturation of peptidase activities.

Preterm birth makes the immature intestine sensitive to feeding-induced intestinal atrophy.

Preterm birth and formula feeding predispose to small intestinal dysfunction, which may lead to necrotizing enterocolitis (NEC). In piglets, we tested whether the physiological and environmental transitions occurring at birth affect the response of the immature intestine to enteral feeding. Pig fetuses (106 days gestation, term = 115 days) were prepared with esophageal feeding tubes and fed either sow's colostrum (n = 8) or infant formula (n = 7) in utero. After 24 h of oral feeding, the pig fetuses were delivered by cesarean section and their gastrointestinal morphology and function were compared with those of preterm newborn (NB) littermates that were not fed (n = 8) or fed colostrum (n = 7) or formula (n = 13) for 24 h after birth. Before birth, both colostrum and formula feeding resulted in marked increases in intestinal mass, brush-border enzyme activities, and plasma glucagon-like peptide 2 concentrations, to levels similar to those in NB colostrum-fed piglets. In contrast, NB formula-fed piglets showed reduced intestinal growth, decreased brush-border enzyme activities, and intestinal lesions, reflecting NEC. NB formula-fed pigs also showed impaired enterocyte endocytotic function and decreased antioxidative capacity, whereas brush-border enzyme mRNA levels were unaltered, relative to NB colostrum-fed pigs. Our results indicate that the feeding-induced growth and enzyme maturation of the immature intestine are not birth dependent. However, with a suboptimal diet (milk formula), factors related to preterm birth (e.g., microbial colonization and metabolic and endocrine changes) make the immature intestine sensitive to atrophy and development of NEC.