Ret heterozygous mice have enhanced intestinal adaptation after massive small bowel resection

Meredith C. Hitch, Jennifer A. Leinicke, Derek Wakeman, Jun Guo, Chris R. Erwin, Kathryn J. Rowland, Ellen C. Merrick, Robert O. Heuckeroth, Brad W. Warner

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Intestinal adaptation is an important compensatory response to massive small bowel resection (SBR) and occurs because of a proliferative stimulus to crypt enterocytes by poorly understood mechanisms. Recent studies suggest the enteric nervous system (ENS) influences enterocyte proliferation. We, therefore, sought to determine whether ENS dysfunction alters resection-induced adaptation responses. Ret+/- mice with abnormal ENS function and wild-type (WT) littermates underwent sham surgery or 50% SBR. After 7 days, ileal morphology, enterocyte proliferation, apoptosis, and selected signaling proteins were characterized. Crypt depth and villus height were equivalent at baseline in WT and Ret+/- mice. In contrast after SBR, Ret+/- mice had longer villi (Ret+/- 426.7 ± 46.0 μm vs. WT 306.5 ± 7.7 μm, P < 0.001) and deeper crypts (Ret+/- 119 ± 3.4 μm vs. WT 82.4 ± 3.1 μm, P < 0.001) than WT. Crypt enterocyte proliferation was higher in Ret+/- (48.8 ± 1.3%) than WT (39.9 ± 2.1%; P < 0.001) after resection, but apoptosis rates were similar. Remnant bowel of Ret+/- mice also had higher levels of glucagon-like peptide 2 (6.2-fold, P = 0.005) and amphiregulin (4.6-fold, P < 0.001) mRNA after SBR, but serum glucagon-like peptide 2 protein levels were equal in WT and Ret+/- mice, and there was no evidence of increased c-Fos nuclear localization in submucosal neurons. Western blot confirmed higher crypt epidermal growth factor receptor (EGFR) protein levels (1.44-fold; P < 0.001) and more phosphorylated EGFR (2-fold; P = 0.003) in Ret+/- than WT mice after SBR. These data suggest that Ret heterozygosity enhances intestinal adaptation after massive SBR, likely via enhanced EGFR signaling. Reducing Ret activity or altering ENS function may provide a novel strategy to enhance adaptation attenuating morbidity in patients with short bowel syndrome.

Original languageEnglish (US)
Pages (from-to)G1143-G1150
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume302
Issue number10
DOIs
StatePublished - May 15 2012

Fingerprint

Enteric Nervous System
Enterocytes
Glucagon-Like Peptide 2
Epidermal Growth Factor Receptor
Apoptosis
Short Bowel Syndrome
Proteins
Western Blotting
Morbidity
Neurons
Messenger RNA
Serum

Keywords

  • Enteric nervous system
  • Epidermal growth factor receptor
  • Short bowel syndrome

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

Ret heterozygous mice have enhanced intestinal adaptation after massive small bowel resection. / Hitch, Meredith C.; Leinicke, Jennifer A.; Wakeman, Derek; Guo, Jun; Erwin, Chris R.; Rowland, Kathryn J.; Merrick, Ellen C.; Heuckeroth, Robert O.; Warner, Brad W.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 302, No. 10, 15.05.2012, p. G1143-G1150.

Research output: Contribution to journalArticle

Hitch, Meredith C. ; Leinicke, Jennifer A. ; Wakeman, Derek ; Guo, Jun ; Erwin, Chris R. ; Rowland, Kathryn J. ; Merrick, Ellen C. ; Heuckeroth, Robert O. ; Warner, Brad W. / Ret heterozygous mice have enhanced intestinal adaptation after massive small bowel resection. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2012 ; Vol. 302, No. 10. pp. G1143-G1150.
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AU - Merrick, Ellen C.

AU - Heuckeroth, Robert O.

AU - Warner, Brad W.

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