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Title: Acute effects of the glucagon-like peptide 2 analogue, teduglutide, on intestinal adaptation in short bowel syndrome

Author
item THYMANN, THOMAS - University Of Copenhagen
item STOLL, BARBARA - Children'S Nutrition Research Center (CNRC)
item MECKLENBURG, LARS - Takeda Pharmaceutical
item Burrin, Douglas - Doug
item VEGGE, ANDREAS - University Of Copenhagen
item QVIST, NIELS - Odense University Hospital
item ERIKSEN, THOMAS - University Of Copenhagen
item JEPPESEN, PALLE - Rigshospitalet - Copenhagen University Hospital
item SANGILD, PER - University Of Copenhagen

Submitted to: Journal of Pediatric Gastroenterology and Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/29/2013
Publication Date: 6/1/2014
Citation: Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D.G., Vegge, A., Qvist, N., Eriksen, T., Jeppesen, P.B., Sangild, P.T. 2014. Acute effects of the glucagon-like peptide 2 analogue, teduglutide, on intestinal adaptation in short bowel syndrome. Journal of Pediatric Gastroenterology and Nutrition. 58(6):694-702.

Interpretive Summary: Premature infants are at increased risk for intestinal diseases that require surgical removal of a major portion of the intestine. After surgery, some of these infants develop a condition called short bowel syndrome (SBS) that limits the ability to digest and absorb nutrition and leads to poor growth and development. A critical feature of the intestine healing and regrowth process after surgery is the production of a growth hormone by the remaining intestine, called glucagon-like peptide 2 (GLP-2). Some infants do not heal properly and develop SBS because they do not produce enough GLP-2. We recently showed in neonatal piglets with SBS that replacing the natural GLP-2 hormone by constant infusion into the blood for 5 days restores the levels of GLP-2 and increases growth of the remaining intestine. A new modified form of the natural GLP-2 protein, called teduglutide, has been developed for human therapy; it lasts longer in the blood once it is injected into the body, thus increasing the potency of the peptide. We designed a study using neonatal piglets as a model of human infants to test whether daily injections of teduglutide at different doses would increase growth and function of the remaining intestine. The results showed that daily teduglutide treatment did increase growth of the intestine, but not functional measures of nutrient absorption. We concluded that use of teduglutide in pediatric SBS patients may require longer treatment periods or more frequent treatment.

Technical 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(-1) / day(-1) (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(-1) / day(-1) 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.