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急性应激通过 GDNF-RET 破坏肠道稳态。

Acute stress disrupts intestinal homeostasis via GDNF-RET.

机构信息

Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

出版信息

Cell Prolif. 2020 Oct;53(10):e12889. doi: 10.1111/cpr.12889. Epub 2020 Aug 17.

DOI:10.1111/cpr.12889
PMID:32808420
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7574880/
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.

摘要

目的

肠嗜铬细胞（EC）与功能性胃肠疾病有关，如 IBS。最近，我们发现胶质细胞衍生的神经营养因子（GDNF）-转染过程中重排（RET）定位于人结肠上皮中的 EC 细胞。在这里，我们研究了 GDNF-RET 在腹泻为主的肠易激综合征（IBS-D）病理生理学中的作用。

材料和方法

通过 ELISA 和免疫组织化学评估 IBS-D 患者和健康对照者活检中的 GDNF。使用包裹-束缚应激（WRS）程序诱导应激，作为急性应激诱导的 IBS 模型。体内和体外评估 GDNF-RET 轴对肠干细胞（ISC）稳态和 EC 细胞数量的作用。

结果

GDNF-RET 在人结肠的 EC 细胞中表达。IBS-D 患者中 GDNF 显著增加。WRS 小鼠结肠中 GDNF-RET 水平增加。WRS 通过 GDNF-RET 扩展 ISC 和分化 EC 细胞来诱导内脏高敏性。此外，GDNF 处理的小鼠重现了 WRS 小鼠的表型。在体外，GDNF 处理以剂量依赖性方式放大了结肠类器官中的 Wnt 信号并增加了 5-羟色胺水平。

结论

我们发现 GDNF-RET 存在于 IBS-D 患者的结肠上皮中。GDNF-RET 在调节 ISC 和 EC 细胞分化中起重要作用。因此，我们的研究结果为治疗 IBS-D 患者提供了 RET 抑制剂作为新的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a7/7574880/271ddfa0fa85/CPR-53-e12889-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a7/7574880/f2d48f5332ce/CPR-53-e12889-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a7/7574880/a5f1e572f049/CPR-53-e12889-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a7/7574880/e0c13858825e/CPR-53-e12889-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a7/7574880/10a5ff1f249d/CPR-53-e12889-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a7/7574880/4779d5673e5d/CPR-53-e12889-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a7/7574880/271ddfa0fa85/CPR-53-e12889-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a7/7574880/f2d48f5332ce/CPR-53-e12889-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a7/7574880/dfe5bf5d2193/CPR-53-e12889-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a7/7574880/a5f1e572f049/CPR-53-e12889-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a7/7574880/271ddfa0fa85/CPR-53-e12889-g007.jpg

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