Fan Li, Liu Jian, Li Lin, Yang Xueping, Zhao Qingwei, Zhao Lijuan
Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational Research, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational Research, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Phytomedicine. 2025 Jul;142:156802. doi: 10.1016/j.phymed.2025.156802. Epub 2025 Apr 22.
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.
To elucidate the mechanism of ECH against T2DM through gut microbiota-mediated host metabolism for the first time.
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.
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.
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.
紫锥菊苷（ECH）是一种天然苯乙醇苷，已显示出对2型糖尿病（T2DM）的保护作用。然而，ECH生物利用度低却具有抗糖尿病优势的潜在机制仍未得到解决。
首次阐明ECH通过肠道微生物群介导的宿主代谢对抗T2DM的机制。
通过高脂饮食联合链脲佐菌素注射建立T2DM小鼠模型。通过测量小鼠空腹血糖（FBG）、胰岛素抵抗、葡萄糖耐量、血脂和器官损伤来评估ECH对T2DM的治疗效果。采用粪便16S rRNA和ITS测序技术表征肠道微生物群的组成，随后分析细菌 - 真菌跨域网络。进行代谢组学以评估ECH诱导的代谢物谱变化。此外，通过蛋白质免疫印迹、免疫组织化学、酶活性测定和抗生素混合物（ABX）实验测量肝脏糖异生标志物和炎症，研究ECH对T2DM的预测机制。
ECH对T2DM表现出显著的保护作用，表现为T2DM小鼠的FBG和空腹胰岛素水平降低、葡萄糖和胰岛素耐受性改善、高脂血症减轻以及肝脏、肾脏和结肠损伤减轻。此外，ECH通过降低条件致病性肠道细菌（克雷伯菌属和大肠埃希菌 - 志贺菌属）和真菌（德巴利酵母属）的丰度，同时增加有益细菌（乳杆菌属）和真菌（瓦勒酵母属和青霉属）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破坏的跨域网络，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。相应地，ABX实验表明，一旦肠道微生物群失衡的调节功能被阻断，ECH的抗T2DM作用就会减弱，同时无法改善T2DM小鼠的炎症水平和关键糖异生标志物。
本研究提供了新的证据，表明ECH通过肠道细菌 - 真菌跨域网络重建抑制肝脏糖异生来减轻T2DM。这些发现表明，ECH可能是一种有前途的T2DM治疗策略，为临床糖尿病及其并发症的预防和治疗提供了新的见解。
