Echinacoside alleviates type 2 diabetes mellitus through inhibiting hepatic gluconeogenesis via gut bacterial-fungal trans-kingdom network reconstruction

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-04-22 DOI:10.1016/j.phymed.2025.156802

Li Fan , Jian Liu , Lin Li , Xueping Yang , Qingwei Zhao , Lijuan Zhao

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Abstract

Background

Echinacoside (ECH), a natural phenylethanoid glycoside, has demonstrated protective effects against type 2 diabetes mellitus (T2DM). However, the mechanism underlying the low bioavailability yet advantageous anti-diabetic of ECH remains unresolved.

Purpose

To elucidate the mechanism of ECH against T2DM through gut microbiota-mediated host metabolism for the first time.

Study design and methods

A T2DM mouse model was established using a high-fat diet in combination with streptozotocin injection. The therapeutic effects of ECH against T2DM were evaluated by measuring fasting blood glucose (FBG), insulin resistance, glucose intolerance, blood lipids and organ damage in mice. Fecal 16S rRNA and ITS sequencing techniques were employed to characterize the composition of gut microbiota, followed by analysis of bacterial-fungal trans-kingdom network. Metabolomics was conducted to assess the ECH-induced metabolite profile alterations. Additionally, the predicted mechanism of ECH on T2DM was investigated through measuring the hepatic gluconeogenesis markers and inflammation by western blotting, immunohistochemistry, enzymatic assays and antimicrobial mixture (ABX) experiments.

Results

ECH exhibited significant protective effects against T2DM, as evidenced by reductions in FBG and fasting insulin levels, improvements in glucose and insulin tolerance, attenuations of hyperlipidemia, and alleviation of liver, kidney, and colon damage in T2DM mice. Furthermore, ECH modulated gut microbiota by decreasing the abundances of conditional pathogenic intestinal bacteria (Klebsiella and Escherichia-Shigella) and fungi (Debarymoyces), while increasing beneficial bacteria (Lactobacillus) and fungi (Wallemia and Penicillium). Moreover, ECH could restore the disrupted trans-kingdom network between gut fungi and bacteria, thereby suppressing the inflammation-mediated hepatic gluconeogenesis via downregulation of FBP1, PCK1 and G6PC expression. Correspondingly, ABX experiments indicated that once the regulatory function of gut microbiota imbalance was blocked, the anti-T2DM effects of ECH were weakened, accompanied by a failure to improve the levels of inflammation and key gluconeogenic markers in T2DM mice.

Conclusion

This study presents novel evidence indicating that ECH alleviates T2DM through inhibiting hepatic gluconeogenesis via gut bacterial-fungal trans-kingdom network reconstruction. These findings suggest that ECH may serve as a promising therapeutic strategy for T2DM management, providing new insights for the prevention and treatment of clinical diabetes and its complications.

Abstract Image

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紫锥菊苷通过肠道细菌-真菌跨界网络重建抑制肝脏糖异生，缓解2型糖尿病

背景：dechinacoside （ECH）是一种天然的苯乙醇苷，已被证明对2型糖尿病（T2DM）有保护作用。然而，ECH低生物利用度却具有抗糖尿病优势的机制尚不清楚。目的通过肠道菌群介导的宿主代谢，首次阐明ECH抗2型糖尿病的机制。研究设计与方法采用高脂饮食联合链脲佐菌素注射液建立T2DM小鼠模型。通过测定小鼠空腹血糖（FBG）、胰岛素抵抗、葡萄糖耐受不良、血脂及脏器损伤等指标，评价ECH对T2DM的治疗作用。采用粪便16S rRNA和ITS测序技术表征肠道微生物群的组成，然后分析细菌-真菌跨界网络。采用代谢组学方法评估ech诱导的代谢物谱改变。此外，通过western blotting、免疫组织化学、酶促试验和抗菌混合剂（ABX）实验检测肝脏糖异生标志物和炎症，探讨ECH对T2DM的预测机制。结果乙酰胆碱对T2DM具有显著的保护作用，可以降低T2DM小鼠的空腹血糖和空腹胰岛素水平，改善葡萄糖和胰岛素耐量，降低高脂血症，减轻肝、肾和结肠损伤。此外，ECH通过降低条件致病性肠道细菌（克雷伯氏菌和埃希氏志贺氏菌）和真菌（德巴氏菌）的丰度，同时增加有益细菌（乳酸杆菌）和真菌（瓦利姆菌和青霉菌）的丰度来调节肠道微生物群。此外，ECH可以恢复肠道真菌和细菌之间被破坏的跨界网络，从而通过下调FBP1、PCK1和G6PC的表达来抑制炎症介导的肝脏糖异生。相应的，ABX实验表明，一旦肠道菌群失衡的调节功能被阻断，ECH的抗T2DM作用减弱，同时不能改善T2DM小鼠的炎症水平和关键糖异生标志物。结论本研究提供了新的证据，表明ECH通过肠道细菌-真菌跨界网络重建抑制肝脏糖异生，从而减轻T2DM。这些发现表明，ECH可能作为T2DM治疗的一种有前景的治疗策略，为预防和治疗临床糖尿病及其并发症提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.