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Intestinal Growth in Parenterally-Fed Rats Induced by the Combined Effects of Glucagon-like Peptide 2 and Epidermal Growth Factor

Paul A. Kitchen, MB, PhD, MRCP^*,, Robert A. Goodlad, PhD, DSc, Anthony J. FitzGerald, MSc^,, Nikki Mandir, MSc, Mohammed A. Ghatei, PhD, DSc^¶, Stephen R. Bloom, DSc, FRCP^¶, Jorge Berlanga-Acosta, PhD, Raymond J. Playford, PhD, FRCP, Alastair Forbes, MD, FRCP^* and Julian R.F. Walters, MB, FRCP

From ^* St Mark's Hospital, Imperial College London, Harrow, United Kingdom; the Gastroenterology Section, Department of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom; Histopathology Unit, Cancer Research UK, London, United Kingdom; ^¶ Department of Metabolic Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom; and Centre for Genetic Engineering and Biotechnology, Havana, Cuba

Correspondence: Dr. J.R.F. Walters, Gastroenterology Section, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. Electronic mail may be sent to julian.walters{at}imperial.ac.uk.

Background: Parenteral nutrition and the absence of luminal feeding result in impaired intestinal growth and differentiation of enterocytes. Glucagon-like peptide 2 (GLP-2) and epidermal growth factor (EGF) have each been shown to have trophic effects on the intestine, and thus have the potential to benefit patients fed parenterally, such as those with intestinal failure from short bowel syndrome. We report studies aimed to determine whether there may be synergistic effects of these 2 peptides. Methods: Rats were established on parenteral nutrition (PN) and infused for 6 days with GLP-2 (20 µg/d), EGF (20 µg/d), or GLP-2 + EGF (20 µg/d of each). These groups were compared with untreated PN-fed and orally-fed controls. Tissue was obtained from small intestine and colon to determine growth, proliferation, and representative gene expression. Results: Small intestinal weight was increased by 75%, 43%, and 116% in the GLP-2, EGF, and GLP-2 + EGF groups, respectively, compared with PN controls (all p < .001). Cell proliferation increased with GLP-2, EGF, and GLP-2 + EGF in proximal small intestine by factors of 2.3, 1.7, and 3.4 respectively (p < .001). A synergistic effect on villous and crypt area was observed in the proximal small intestine when GLP-2 and EGF were combined (p < .05). GLP-2 had no effect in the colon, unlike EGF. Further studies showed GLP-2 + EGF significantly increased expression in distal small intestine of transcripts for the bile acid transport protein IBABP (p < .05) and showed a significant correlation between the expression of IBABP and the transcription factor HNF-4. Conclusions: Both GLP-2 and EGF upregulate growth of the small intestine, and this is augmented when GLP-2 and EGF are combined. These findings may lead to improved treatment of patients receiving PN.

Journal of Parenteral and Enteral Nutrition, Vol. 29, No. 4, 248-254 (2005)
DOI: 10.1177/0148607105029004248


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