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
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
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DOI：
10.1002/jpen.1500
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发表时间：
2019-09-01
影响因子：
3.4
通讯作者：
Turner, Justine M.
中科院分区：
文献类型：
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作者：
Slim, George M.;Lansing, Marihan;Turner, Justine M.
背景胰高血糖素样肽-2 (GLP-2) 是一种由回肠 L 细胞释放的肠营养因子，回肠是新生儿短肠综合征 (SBS) 中常见切除或闭锁的部分。在仔猪中，回肠切除会降低肠道适应和内源性 GLP-2 的产生，而外源性替代则促进适应。在这项研究中，我们确定了一种新型长效 GLP-2 类似物 FE 203799（FE；阿普拉鲁肽）对无回肠的新生 SBS 仔猪的肠道生长、适应和功能的影响。方法 将新生仔猪随机分为生理盐水治疗组 (n = 10) 和 FE 治疗组 (n = 8)。所有仔猪均接受75%肠切除和空肠结肠吻合术，并进行肠外和肠内营养配对喂养。第 0 天和第 4 天皮下注射盐水和 FE (5 mg/kg) 治疗。第 6 天，收集 24 小时粪便样本用于后续营养分析。第 7 天，测量小肠长度和重量并收集组织进行分析。结果第 7 天，经盐水和 FE 处理的仔猪健康且体重增加（P = 0.12）。与盐水仔猪相比，FE处理仔猪的粪便脂肪（P = 0.043）和能量（P = 0.043）损失较低，并表现出肠道延长（P = 0.001）、更大的小肠重量（P = 0.004）、更长的绒毛高度（P = 0.027）和更大的隐窝深度（P = 0.054）。结论 皮下注射 GLP-2 类似物 FE 可增强无回肠 SBS 新生儿模型的肠道适应。与我们之前在同一模型中使用天然 GLP-2 的经验相比，FE 治疗观察到的肠道延长是独特的，并且对于治疗新生儿 SBS 具有重要的临床意义。在这个发育阶段，肠道的生长如果得到增强，可以加速肠外营养的断奶。
Background Glucagon-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. Methods Neonatal 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. Results On 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). Conclusions The 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.