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, No.138, Xianlin Road, Qixia District, Nanjing, 210023, PR China.
Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xi'an, 712046, Shaanxi Province, PR China.
J Ethnopharmacol. 2020 Mar 1;249:112423. doi: 10.1016/j.jep.2019.112423. Epub 2019 Nov 22.
Euphorbia kansui is a toxic Chinese herbal medicine and exhibits promising treatment to the malignant ascites (MA) in its traditional use. Ingenane-type and jastrophane-type diterpenes are demonstrated to be responsible for the toxicity and efficacy of kansui. Two representative compounds, kansuiphorin C (KPC) and kansuinin A (KA) in each type were proved to effectively reduce the ascites. The biological and toxicological effects are closely associated with the gastrointestinal tract, but the possible mechanism and related metabolic functions of KPC and KA treating MA through modulating the gut microbiota remain unclear.
To investigate the possible mechanism and related metabolism of KPC and KA ameliorating malignant ascites through modulating gut microbiota.
MA rats and normal rats were divided into different groups and administrated with KPC, KA, and positive drug, respectively. 16S rDNA gene sequencing and metagenomes analysis combined with the quantification of short-chain fatty acids of feces were performed to reflect the modulation of gut microbiota. Then, the metabolites of KPC and KA in rat feces under the normal and pathological circumstances were detected by ultra-fast liquid chromatography coupled with MS/MS detector (UFLC-MS/MS) to explore the in-vivo bacterial biotransformation.
KPC and KA were modulatory compounds for gut microbiota. The richness of Lactobacillus and the decreased abundance of Helicobacter involved in the carbohydrate metabolism and amino acid metabolism could be responsible for their prohibitory effects on malignant ascites. KPC exhibited stronger modulation of gut microbiota through making the abundance of Helicobacter about 3.5 times lower than KA. Besides, in-vivo microbial biotransformation of KPC and KA contained oxidation, hydrolysis, dehydration, and methylation to form metabolites of lower polarity. Besides, at the dosage of 10 mg kg, the toxicity of both compounds had weaker influences on the gut microbiota of normal rats.
KPC and KA could ameliorate malignant ascites by modulating gut microbiota mainly containing the increase of Lactobacillus and the decrease of Helicobacter and related carbohydrate and amino acid metabolism, providing a basis for their promising clinical usage.
甘遂是一种有毒的中药，在传统用途中显示出对恶性腹水（MA）有治疗作用。已证明 ingene 型和 jatrophane 型二萜类化合物是甘遂毒性和疗效的原因。这两种类型的两种代表性化合物， kansuiphorin C（KPC）和 kansuinin A（KA），已被证明可有效减少腹水。生物和毒理学作用与胃肠道密切相关，但 KPC 和 KA 通过调节肠道微生物群治疗 MA 的可能机制和相关代谢功能尚不清楚。
研究 KPC 和 KA 通过调节肠道微生物群改善恶性腹水的可能机制和相关代谢。
将 MA 大鼠和正常大鼠分为不同组，分别给予 KPC、KA 和阳性药物。进行 16S rDNA 基因测序和宏基因组分析，并结合粪便短链脂肪酸的定量，以反映肠道微生物群的调节。然后，通过超快速液相色谱与 MS/MS 检测器（UFLC-MS/MS）检测 KPC 和 KA 在正常和病理情况下大鼠粪便中的代谢物，以探索体内细菌的生物转化。
KPC 和 KA 是肠道微生物群的调节化合物。参与碳水化合物代谢和氨基酸代谢的 Lactobacillus 丰度增加和 Helicobacter 丰度降低可能是它们抑制恶性腹水的原因。KPC 通过使 Helicobacter 的丰度降低约 3.5 倍，对肠道微生物群的调节作用更强。此外，KPC 和 KA 的体内微生物生物转化包含氧化、水解、脱水和甲基化，形成低极性的代谢物。此外，在 10mg/kg 剂量下，两种化合物的毒性对正常大鼠的肠道微生物群的影响较弱。
KPC 和 KA 通过调节肠道微生物群主要增加 Lactobacillus 和减少 Helicobacter 及其相关的碳水化合物和氨基酸代谢来改善恶性腹水，为其在临床应用中的良好前景提供了依据。
