2. Academic Validation
  3. Acute stress disrupts intestinal homeostasis via GDNF-RET

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

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.

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