Acute stress disrupts intestinal homeostasis via GDNF-RET

  • Cell Prolif. 2020 Oct;53(10):e12889. doi: 10.1111/cpr.12889.
Lin Lin  1  2 ,  Bingcheng Feng  1  2 ,  Ruchen Zhou  1  2 ,  Yi Liu  1  3 ,  Lixiang Li  1  2 ,  Kairuo Wang  1  2 ,  Yanbo Yu  1  2 ,  Chao Liu  1  2 ,  Xin Long  1  2 ,  Xiang Gu  1  2 ,  Bing Li  1  2 ,  Xiaojie Wang  4 ,  Xiaoyun Yang  1  2 ,  Yingzi Cong  5 ,  Xiuli Zuo  1  2 ,  Yanqing Li  1  2
Affiliations
  • 1. Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 2. Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 3. Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China.
  • 4. Department of dermatology, Peking University People's Hospital, Beijing, China.
  • 5. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
PMID: 32808420 DOI: 10.1111/cpr.12889
Abstract

Objectives: Enterochromaffin (EC) cells have been associated with functional gastrointestinal disorders such as IBS. Recently, we found that glial cell-derived neurotrophic factor (GDNF)-rearranged during transfection (RET) localized in EC cells in human colonic epithelia. Here, we examine the role of GDNF-RET in the pathophysiology of diarrhoea-predominant irritable bowel syndrome (IBS-D).

Materials and methods: GDNF was assessed by ELISA and immunohistochemistry in biopsies from IBS-D patients and healthy controls. Stress was induced by using a wrap-restraint stress (WRS) procedure to serve as an acute stress-induced IBS model. The function of GDNF-RET axis to intestinal stem cell (ISC) homeostasis, and EC cell numbers were assessed in vivo and in vitro.

Results: GDNF-RET was expressed in EC cells in human colon. GDNF was significantly increased in IBS-D patients. WRS mice showed increased GDNF-RET levels in colon. WRS induced visceral hypersensitivity by expanding of ISC and differentiation of EC cell via GDNF-RET. Furthermore, GDNF-treated mice recapitulated the phenotype of WRS mice. In vitro, GDNF treatment amplified Wnt signal and increased serotonin levels in colonic organoids in a dose-dependent manner.

Conclusions: We identified GDNF-RET was presented in colonic epithelium of patients with IBS-D. GDNF-RET played important roles in regulating ISC and EC cell differentiation. Our findings, thus, provide RET inhibitor as new therapeutic targets for treatment of patients with IBS-D.

Keywords
enterochromaffin cell; intestinal stem cell niche; neurotrophic factor; visceral hypersensitivity.
Products