Lim David W, Levesque Crystal L, Vine Donna F, Muto Mitsuru, Koepke Jacob R, Nation Patrick N, Wizzard Pamela R, Li Julang, Bigam David L, Brubaker Patricia L, Turner Justine M, Wales Paul W
Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
Department of Animal Science, South Dakota State University, Brookings, South Dakota.
Am J Physiol Gastrointest Liver Physiol. 2017 Apr 1;312(4):G390-G404. doi: 10.1152/ajpgi.00281.2016. Epub 2017 Jan 19.
Glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) treatment enhance intestinal adaptation. To determine whether these growth factors exert synergistic effects on intestinal growth and function, GLP-2 and EGF-containing media (EGF-cm) were administered, alone and in combination, in neonatal piglet models of short bowel syndrome (SBS). Neonatal Landrace-Large White piglets were block randomized to 75% midintestinal [jejunoileal (JI) group] or distal intestinal [jejunocolic (JC) group] resection or sham control, with 7-day infusion of saline (control), intravenous human GLP-2 (11 nmol·kg·day) alone, enteral EGF-cm (80 μg·kg·day) alone, or GLP-2 and EGF-cm in combination. Adaptation was assessed by intestinal length, histopathology, Üssing chamber analysis, and real-time quantitative PCR of intestinal growth factors. Combined EGF-cm and GLP-2 treatment increased intestinal length in all three surgical models ( < 0.01). EGF-cm alone selectively increased bowel weight per length and jejunal villus height in the JI group only. The JC group demonstrated increased intestinal weight and villus height ( < 0.01) when given either GLP-2 alone or in combination with EGF-cm, with no effect of EGF-cm alone. Jejunal permeability of mannitol and polyethylene glycol decreased with combination therapy in both SBS groups ( < 0.05). No difference was observed in fat absorption or body weight gain. IGF-1 mRNA was differentially expressed in JI vs. JC piglets with treatment. Combined treatment with GLP-2 and EGF-cm induced intestinal lengthening and decreased permeability, in addition to the trophic effects of GLP-2 alone. Our findings demonstrate the benefits of novel combination GLP-2 and EGF treatment for neonatal SBS, especially in the JC model representing most human infants with SBS. Glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) are intestinotrophic, with demonstrated benefit in both animal models and human studies of short bowel syndrome (SBS). The current research shows that over and above known trophic effects, the combination of GLP-2 and EGF synergistically lengthens the bowel in neonatal piglet models of SBS. Most notable benefit occurred with resection of the terminal ileum, the common clinical anatomy seen in neonatal SBS and associated with least de novo lengthening postsurgery.
胰高血糖素样肽-2（GLP-2）和表皮生长因子（EGF）治疗可增强肠道适应性。为了确定这些生长因子是否对肠道生长和功能发挥协同作用，在新生仔猪短肠综合征（SBS）模型中单独或联合给予含GLP-2和EGF的培养基（EGF-cm）。将新生长白-大白仔猪随机分为75%中肠切除组[空肠回肠（JI）组]或远段肠切除组[空肠结肠（JC）组]或假手术对照组，分别给予7天的生理盐水输注（对照组）、单独静脉注射人GLP-2（11 nmol·kg·天）、单独肠内给予EGF-cm（80 μg·kg·天）或联合给予GLP-2和EGF-cm。通过肠长度、组织病理学、尤斯灌流小室分析以及肠道生长因子的实时定量PCR来评估适应性。联合给予EGF-cm和GLP-2治疗可增加所有三种手术模型中的肠长度（<0.01）。单独给予EGF-cm仅选择性增加了JI组中每单位长度的肠重量和空肠绒毛高度。单独给予EGF-cm对JC组无影响，而单独给予GLP-2或联合EGF-cm给予时，JC组的肠重量和绒毛高度增加（<0.01）。联合治疗使两个SBS组的空肠对甘露醇和聚乙二醇的通透性均降低（<0.05）。脂肪吸收或体重增加方面未观察到差异。治疗后，JI组与JC组仔猪中IGF-1 mRNA表达存在差异。除了GLP-2单独的营养作用外，联合给予GLP-2和EGF-cm可诱导肠延长并降低通透性。我们的研究结果表明，新型GLP-2和EGF联合治疗对新生SBS有益，尤其是在代表大多数患有SBS的人类婴儿的JC模型中。胰高血糖素样肽-2（GLP-2）和表皮生长因子（EGF）具有肠营养作用，在短肠综合征（SBS）的动物模型和人体研究中均已证明其益处。当前研究表明，除了已知的营养作用外，GLP-2和EGF联合使用可在新生仔猪SBS模型中协同延长肠道。最显著的益处出现在末端回肠切除后，这是新生SBS中常见的临床解剖结构，且术后新生肠管延长最少。
