Novel Long‐Acting GLP‐2 Analogue, FE 203799 (Apraglutide), Enhances Adaptation and Linear Intestinal Growth in a Neonatal Piglet Model of Short Bowel Syndrome with Total Resection of the Ileum

Abstract

BackgroundGlucagon‐like peptide‐2 (GLP‐2) is an intestinotrophic factor released from L‐cells in the ileum, a segment commonly resected or atretic in neonatal short bowel syndrome (SBS). In piglets, ileal resection decreases intestinal adaptation and endogenous GLP‐2 production, whereas exogenous replacement promotes adaptation. In this study, we determined the effect of a novel long‐acting GLP‐2 analogue, FE 203799 (FE; apraglutide), upon intestinal growth, adaptation, and function in neonatal SBS piglets without ileum.MethodsNeonatal piglets were randomized to saline (n = 10) vs FE treatment (n = 8). All piglets underwent 75% intestinal resection with jejunocolic anastomosis and were pair‐fed parenteral and enteral nutrition. Saline and FE (5 mg/kg) treatments were administered subcutaneously on days 0 and 4. On day 6, 24‐hour fecal samples were collected for subsequent nutrient analysis. On day 7, small‐intestinal length and weight were measured and tissue collected for analyses.ResultsOn day 7, saline and FE‐treated piglets were healthy and gained equivalent weight (P = 0.12). Compared with saline piglets, FE‐treated piglets had lower fecal fat (P = 0.043) and energy (P = 0.043) losses and exhibited intestinal lengthening (P = 0.001), greater small‐intestinal weight (P = 0.004), longer villus height (P = 0.027), and greater crypt depth (P = 0.054).ConclusionsThe subcutaneous GLP‐2 analogue, FE, enhanced intestinal adaptation in a neonatal model of SBS without ileum. The observed intestinal lengthening with FE treatment was unique compared with our prior experience with native GLP‐2 in this same model and has important clinical implications for treating neonatal SBS. At this developmental stage, growth in the intestine, if augmented, could accelerate weaning from parenteral nutrition.

Comparing the Intestinotrophic Effects of 2 Glucagon‐Like Peptide‐2 Analogues in the Treatment of Short‐Bowel Syndrome in Neonatal Piglets

“…In piglet models, both native GLP‐2 and TED treatments have not shown intestinal lengthening 16,17 . Recently, we studied apraglutide (APRA), a GLP‐2 analogue with an even longer half‐life (t 1/2 ) than TED 18 . APRA was associated with intestinal lengthening in our piglet model of SBS with total ileal resection (jejunocolic [JC] anastomosis), a model wherein consistently we have not seen linear intestinal growth without trophic peptide treatment 17 …”

Site-Specific and Temporal Effects of Apraglutide, a Novel Long-Acting Glucagon-Like Peptide-2 Receptor Agonist, on Intestinal Growth in Mice

“…Indeed, the 13% increase in small intestinal length observed following only 3 weeks of administration of apraglutide is further remarkable given the limited effect of hGly 2 -GLP-2 1-33 reported for this parameter in rodents Hadjiyanni, 2009;Austin, 2015). Apraglutide has also been demonstrated to increase small intestinal length in a neonatal piglet model of short bowel syndrome, leading to the suggestion that the trophic actions of apraglutide may enhance adaptation and weaning from parenteral nutrition in young children with short bowel syndrome (Slim, 2019). Whether enhanced intestinal length will be observed in humans treated with GLP-2R agonists remains to be determined.…”

“…The final version may differ from this version. (Slim, 2019). Furthermore, it remains unclear as to whether teduglutide treatment affects the growth of the colon in humans.…”

“…However, given that many previous pre-clinical studies on the intestinotrophic effects of GLP-2 in the normal murine intestine have been successfully translated to humans, these findings suggest that this novel action of apraglutide may benefit patients through expansion of the residual, healthy tissue. Finally, the half-life of apraglutide is prolonged (t½ = 30 hr) as compared to both native GLP-2 and hGly 2 -GLP-2 1-33 (~6 min and 1-3 hr, respectively), due to both dipeptidylpeptidase IV-resistance and binding to proteins in the circulation (99.8%) (Tavares, 2000;Marier, 2010;Slim, 2019). As a consequence, apraglutide was administered only 3-times per week in the present study, as compared to the current requirement for daily treatment with hGly 2 -GLP-2 1-33 and teduglutide, although it is acknowledged that the dose of apraglutide utilized in the current study on mice is ~3-times greater than that currently being tested for human use (Bolognani, 2019).…”

Novel Strategies to Prevent Total Parenteral Nutrition‐Induced Gut and Liver Inflammation, and Adverse Metabolic Outcomes

“…[ 227 ] This could be used in combination with novel GLP‐2 analogues with low systemic clearance such as apraglutide. [ 228 ] Based on the key role of BA signaling in the gut–liver axis, the use of BAs or analogs such as the hydrophilic ursodeoxycholic acid, as supplements to TPN, could be of potential interest. [ 229 ] Ursodeoxycholic acid is a naturally occurring BA (≈5% of the total human BA pool) and is used in the treatment of primary biliary cirrhosis and cholesteric hepatitis.…”