Thymann Thomas, Stoll Barbara, Mecklenburg Lars, Burrin Douglas G, Vegge Andreas, Qvist Niels, Eriksen Thomas, Jeppesen Palle B, Sangild Per T
*Department of Nutrition, Exercise, and Sports, University of Copenhagen, Frederiksberg C, Denmark †Childrens Nutrition Research Center, Baylor College of Medicine, Houston, TX ‡Takeda GmbH, Konstanz, Germany §Department of Surgery, Gastroenterology, Pediatrics and Endocrinology, Odense University Hospital, Odense C ||Department of Small Animal Clinical Sciences, University of Copenhagen, Frederiksberg C ¶Department of Gastroenterology, Rigshospitalet, Copenhagen, Denmark.
J Pediatr Gastroenterol Nutr. 2014 Jun;58(6):694-702. doi: 10.1097/MPG.0000000000000295.
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.
大量肠道切除术后的新生儿短肠综合征与营养物质吸收不良有关。肠营养因子胰高血糖素样肽2（GLP-2）可改善成年短肠综合征患者的肠道功能，但其在儿科患者中的作用尚不清楚。我们的目的是在新生仔猪空肠造口模型中测试长效合成人GLP-2类似物替度鲁肽（ALX-0600）的疗效。对2日龄仔猪进行50%小肠（远端部分）切除术，将残余肠段作为空肠造口外置在腹壁上。所有仔猪接受7天的全胃肠外营养，并每日单次注射以下剂量的替度鲁肽：0.01（n = 6）、0.02（n = 6）、0.1（n = 5）或0.2 mg·kg·天（n = 6），并与安慰剂组（n = 9）进行比较。所有4个替度鲁肽组的体重增加相似，但高于安慰剂组（P < 0.05）。残余肠段单位长度的重量呈剂量依赖性增加（P < 0.01），0.2 mg·kg·天组肠道的蛋白质合成率分数相对于安慰剂组增加（P < 0.001）；然而，包括消化酶活性、肠内营养物质吸收以及免疫组织化学（Ki67、绒毛蛋白、FABP2、ChgA和GLP-2R）在内的功能和结构终点未受治疗影响。替度鲁肽可诱导残余肠段的营养作用，但对功能终点的急性影响有限。替度鲁肽对肠道功能的显著影响可能需要更长的适应期和/或更频繁地给药该肽。从长远来看，GLP-2或其类似物可能与改善儿科短肠综合征患者的肠道适应性有关。
