Interdependency of EGF and GLP-2 Signaling in Attenuating Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

Yongjia Feng, Farok R. Demehri, Weidong Xiao, Yu Hwai Tsai, Jennifer C. Jones, Constance D. Brindley, David W. Threadgill, Jens J. Holst, Bolette Hartmann, Terrence A. Barrett, Daniel H. Teitelbaum, Peter J. Dempsey

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Background & Aims Total parenteral nutrition (TPN), a crucial treatment for patients who cannot receive enteral nutrition, is associated with mucosal atrophy, barrier dysfunction, and infectious complications. Glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) improve intestinal epithelial cell (IEC) responses and attenuate mucosal atrophy in several TPN models. However, it remains unclear whether these 2 factors use distinct or overlapping signaling pathways to improve IEC responses. We investigated the interaction of GLP-2 and EGF signaling in a mouse TPN model and in patients deprived of enteral nutrition. Methods Adult C57BL/6J, IEC-Egfrknock out (KO) and IEC-pik3r1KO mice receiving TPN or enteral nutrition were treated with EGF or GLP-2 alone or in combination with reciprocal receptor inhibitors, GLP-2(3-33) or gefitinib. Jejunum was collected and mucosal atrophy and IEC responses were assessed by histologic, gene, and protein expression analyses. In patients undergoing planned looped ileostomies, fed and unfed ileum was analyzed. Results Enteral nutrient deprivation reduced endogenous EGF and GLP-2 signaling in mice and human beings. In the mouse TPN model, exogenous EGF or GLP-2 attenuated mucosal atrophy and restored IEC proliferation. The beneficial effects of EGF and GLP-2 were decreased upon Gefitinib treatment and in TPN-treated IEC-EgfrKO mice, showing epidermal growth factor–receptor dependency for these IEC responses. By contrast, in TPN-treated IEC-pi3kr1KO mice, the beneficial actions of EGF were lost, although GLP-2 still attenuated mucosal atrophy. Conclusions Upon enteral nutrient deprivation, exogenous GLP-2 and EGF show strong interdependency for improving IEC responses. Understanding the differential requirements for phosphatidylinositol 3-kinase/phosphoAKT (Ser473) signaling may help improve future therapies to prevent mucosal atrophy.

Original languageEnglish
Pages (from-to)447-468
Number of pages22
JournalCMGH
Volume3
Issue number3
DOIs
StatePublished - May 2017

Bibliographical note

Publisher Copyright:
© 2017 The Authors

Keywords

  • EGF
  • EGFR
  • GLP-2
  • Mucosal Atrophy
  • PI3K
  • Total Parenteral Nutrition

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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