title: Synergy of glucagon-like peptide-2 and epidermal growth factor coadministration on intestinal adaptation in neonatal piglets with short bowel syndrome.
abstract: 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-1·day-1) alone, enteral EGF-cm (80 μg·kg-1·day-1) 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 (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 & NOTEWORTHYGlucagon-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.
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: David W
authors.identifier: http://orcid.org/0000-0002-2397-4110
authors.initials: DW
authors.lastname: Lim
authors.affiliation: Department of Animal Science, South Dakota State University, Brookings, South Dakota.
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Levesque
authors.affiliation: Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Donna F
authors.initials: DF
authors.lastname: Vine
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Muto
authors.affiliation: Department of Animal Science, South Dakota State University, Brookings, South Dakota.
authors.forename: Jacob R
authors.initials: JR
authors.lastname: Koepke
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Nation
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Wizzard
authors.affiliation: Department of Animal and Poultry Science, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Julang
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: David L
authors.initials: DL
authors.lastname: Bigam
authors.affiliation: Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brubaker
authors.affiliation: Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada; justine.turner@albertahealthservices.ca.|Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Justine M
authors.initials: JM
authors.lastname: Turner
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.|Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.|Department of Surgery and Group for the Improvement of Intestinal Function and Treatment, Hospital for Sick Children, Toronto, Ontario, Canada; and.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Wales
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects*; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology* / Q000627:therapeutic use; D053767:Glucagon-Like Peptide 2 / Q000494:pharmacology* / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000187:drug effects; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D012778:Short Bowel Syndrome / Q000188:drug therapy* / Q000473:pathology; D013552:Swine; D016896:Treatment Outcome
chemical_list: D053767:Glucagon-Like Peptide 2; D004815:Epidermal Growth Factor
keywords: growth factors; intestinal failure; intestinal growth; preclinical; trophic peptides