Translational Human Pathophysiology: Synergy of glucagon-like peptide-2 and epidermal growth factor coadministration on intestinal adaptation in neonatal piglets with short bowel syndrome

摘要

Lim DW, Levesque CL, Vine DF, Muto M, Koepke JR, Nation PN, Wizzard PR, Li J, Bigam DL, Brubaker PL, Turner JM, Wales PW. Synergy of glucagon-like peptide-2 and epidermal growth factor coadministration on intestinal adaptation in neonatal piglets with short bowel syndrome. Am J Physiol Gastrointest Liver Physiol 312: G390-G404, 2017. First published January 19, 2017; doi: 10.1152/ajpgi.00281.2016.—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% midin-testinal [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~-1·day~-1) alone, enteral EGF-cm (80mug·kg~-1·day~-1) alone, or GLP-2 and EGF-cm in combination. Adaptation was assessed by intestinal length, histopa-thology, Ussing 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 (P < 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 (P < 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 (P < 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. NEW & NOTEWORTHY 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.