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健脾饮通过调节胰高血糖素样肽-1、减少钠/氢交换体3的泛素化和磷酸化来减轻乳糖诱导的大鼠慢性腹泻。

Jian-Pi-Yin decoction attenuates lactose-induced chronic diarrhea in rats by regulating GLP-1 and reducing NHE3 ubiquitination and phosphorylation.

作者信息

Ma Jin-Xin, Chen Ting, Xue Hong, Zhang Min, Li Zhong-Yu, Li Xuan, Wang Yi-Tian, Kang Nan, Wang Feng-Yun, Tang Xu-Dong

机构信息

Department of Gastroenterology, Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Zhongzhi Dong Lu, Haidian District, Beijing, 100091, China.

Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China.

出版信息

Heliyon. 2023 Jun 30;9(7):e17444. doi: 10.1016/j.heliyon.2023.e17444. eCollection 2023 Jul.

DOI:10.1016/j.heliyon.2023.e17444
PMID:37539150
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10395042/
Abstract

OBJECTIVES

Jian-Pi-Yin decoction (JPY), a prescription derived from the traditional Chinese medicine Shen-Ling-Bai-Zhu-San, has shown good clinical efficacy in the treatment of diarrhea caused by lactose intolerance. However, the mechanism of action of JPY in the treatment of diarrhea is not fully understood.

DESIGN

In this study, a rat diarrhea model was induced by high lactose feeding combined with standing on a small platform to investigate the ameliorating effect of JPY on hyper lactose-induced diarrhea in rats and its possible mechanism.

METHODS

The rat model of hyper lactose diarrhea was given high, medium, and low doses of JPY and the positive control drug Smida by gavage for 1 week. At the same time, NAH exchanger 3 (NHE3) inhibitor Tenapanor was administered orally for 3 weeks. Body weight, food intake, water intake, grip strength, and severity of diarrhea symptoms were measured in rats throughout the study. The serum, colon, and jejunum tissues of the model and drug-treated rats were collected for histopathological examination and analysis of relevant indicators.

RESULTS

JPY significantly alleviated the symptoms of fatigue, diet reduction and diarrhea in the model group. Glucagon-like peptide-1 (GLP-1) and cyclic adenosine monophosphate (cAMP) expression were also down-regulated after JPY treatment. JPY can significantly promote NHE3 in intestinal tissues of rats with diarrhea, and the mechanism is related to the decrease of GLP-1, inhibition of cAMP/PKA pathway activation, an increase of ubiquitin-specific protease 7 (USP7) and USP10 expression, and decrease of NHE3 ubiquitination and phosphorylation.

CONCLUSION

JPY can reduce the expression of GLP-1, reduce the ubiquitination and phosphorylation of NHE3, regulate the expression of NHE3, at least partly improve ion transport in the intestinal epithelium, and improve the imbalance of electrolyte absorption, thus significantly reducing the diarrhea symptoms of rats with high lactose combined with small platform standing.

INNOVATION

In this study, we explored the mechanism of intestinal GLP-1 activation of cAMP/PKA signaling pathway from multiple dimensions, and increased its expression by reducing phosphorylation and ubiquitination of NHE3, thereby treating chronic diarrhea associated with lactose intolerance.

摘要

目的

健脾饮（JPY）是源自中药参苓白术散的方剂，在治疗乳糖不耐受引起的腹泻方面已显示出良好的临床疗效。然而，JPY治疗腹泻的作用机制尚未完全明确。

设计

在本研究中，通过高乳糖喂养结合站在小平台上诱导大鼠腹泻模型，以研究JPY对高乳糖诱导的大鼠腹泻的改善作用及其可能机制。

方法

对高乳糖腹泻大鼠模型分别给予高、中、低剂量的JPY及阳性对照药物思密达，灌胃给药1周。同时，口服钠氢交换体3（NHE3）抑制剂替那帕诺3周。在整个研究过程中测量大鼠的体重、食物摄入量、饮水量、握力和腹泻症状严重程度。收集模型组和药物治疗组大鼠的血清、结肠和空肠组织进行组织病理学检查及相关指标分析。

结果

JPY显著减轻模型组的疲劳、饮食减少和腹泻症状。JPY治疗后胰高血糖素样肽-1（GLP-1）和环磷酸腺苷（cAMP）表达也下调。JPY可显著促进腹泻大鼠肠道组织中NHE3的表达，其机制与GLP-1降低、cAMP/PKA信号通路激活受抑制、泛素特异性蛋白酶7（USP7）和USP10表达增加、NHE3泛素化和磷酸化减少有关。

结论

JPY可降低GLP-1表达，减少NHE3的泛素化和磷酸化，调节NHE3表达，至少部分改善肠上皮离子转运，改善电解质吸收失衡，从而显著减轻高乳糖结合小平台站立大鼠的腹泻症状。

创新点

本研究从多个维度探讨肠道GLP-1激活cAMP/PKA信号通路的机制，并通过减少NHE3的磷酸化和泛素化增加其表达，从而治疗与乳糖不耐受相关的慢性腹泻。

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