Synergistic effect of Euphorbia kansui stir-fried with vinegar and bile acids on malignant ascites effusion through modulation of gut microbiota

Shengyun Dai; Shikang Zhou; Yonghui Ju; Weifeng Yao; Yuping Tang; Jian Zheng; Shuangcheng Ma; Yi Zhang; Li Zhang

doi:10.3389/fphar.2023.1249910

Synergistic effect of Euphorbia kansui stir-fried with vinegar and bile acids on malignant ascites effusion through modulation of gut microbiota

Front Pharmacol. 2023 Nov 9:14:1249910. doi: 10.3389/fphar.2023.1249910. eCollection 2023.

Authors

Shengyun Dai^#¹, Shikang Zhou^#², Yonghui Ju³, Weifeng Yao², Yuping Tang⁴, Jian Zheng¹, Shuangcheng Ma¹, Yi Zhang², Li Zhang²

Affiliations

¹ Institute for Control of Chinese Traditional Medicine and Ethnic Medicine, National Institute for Food and Drug Control, Beijing, China.
² Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine and Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, China.
³ School of Medicine and Chemical Materials, Zhenjiang College, Zhenjiang, China.
⁴ College of Pharmacy and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an, China.

^# Contributed equally.

Abstract

Background: Toxic Euphorbia kansui (EK) is employed to treat malignant ascites effusion (MAE). EK stir-fried with vinegar (VEK) has been demonstrated to reduce toxicity due to its preserved water-expelling effect. This was demonstrated to be correlated with gut microbiota. Therein, bile acids (BAs) have a bidirectional relationship with the gut microbiota. Therefore, the aim of this study is to explore whether BA-mediated gut microbiota influences the water-expelling effect of VEK against MAE. Methods: The MAE rat model was established by intraperitoneal injection of Walker-256 tumor cells. A reliable simultaneous method for the determination of 15 bile acids in rat feces using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was established and applied to analyze the fecal BAs in rats treated with VEK. The screened BA was then administered to VEK-treated MAE rats. The water-expelling effect was evaluated using histopathological analysis, biochemical examination, inflammatory factors in ascites, urine volume, ascites amount, and intestinal aquaporin expression. The microbial composition was determined using 16S rRNA sequencing, and the contents of bile acids were finally measured. Results: VEK decreased the content of fecal deoxycholic acid (DCA), lithocholic acid (LCA), and taurocholic acid (TCA) while increasing the content of ursodeoxycholic acid (UDCA). VEK alleviated liver, stomach, and intestinal injuries; oxidative damage; and inflammation, which were further ameliorated with UDCA intervention. VEK alleviated MAE by increasing the fecal water content, urine volume, and AQP3 protein expression and decreasing the urine levels of Na⁺, K⁺, and Cl^-. This was retained with the intervention of UDCA. UDCA and VEK regulated the BA metabolism disorder to a certain extent. Analysis of gut microbiota showed that VEK increased the abundance of Lactobacillus and decreased that of Prevotella_9 in MAE rats. The combined administration of UDCA and VEK showed a better modulation of the microbiota structure than that of VEK alone, and the effect of this administration reached closer to the reference state. Conclusion: The water-expelling effect of VEK did not directly depend on the BA-mediated gut microbiota. However, VEK and BAs had a synergistic effect on malignant ascites effusion through the regulation of the gut microbiota. These results provided a scientific basis for the reasonable usage of VEK and the novel combination treatment strategy of VEK and UDCA.

Keywords: Euphorbia kansui; bile acids; gut microbiota; malignant ascites; water-expelling effect.

Grants and funding

This research was financially supported by the National Natural Science Foundation of China (82374039, 81673599). This research was also supported by a 333 High-level Talents Training Project funded by Jiangsu Province (BRA2020071), the Natural Science Foundation of the Jiangsu Higher Educatioin Institutions of China (23KJB360006), and the Natural Science Foundation of Jiangsu Province (SBK2023022246, SBK2020021421).