Huang Yujie, Xu Weiqi, Dong Wei, Chen Guijie, Sun Yi, Zeng Xiaoxiong
College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China; School of Public Health, Guizhou Medical University, Guiyang 561113, Guizhou, China.
College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China.
J Adv Res. 2025 Jun;72:17-35. doi: 10.1016/j.jare.2024.06.027. Epub 2024 Jul 3.
INTRODUCTION: The human gut microbiome plays a pivotal role in health and disease, notably through its interaction with bile acids (BAs). BAs, synthesized in the liver, undergo transformation by the gut microbiota upon excretion into the intestine, thus influencing host metabolism. However, the potential mechanisms of dicaffeoylquinic acids (DiCQAs) from Ilex kudingcha how to modulate lipid metabolism and inflammation via gut microbiota remain unclear. OBJECTIVES AND METHODS: The objectives of the present study were to investigate the regulating effects of DiCQAs on diabetes and the potential mechanisms of action. Two mice models were utilized to investigate the anti-diabetic effects of DiCQAs. Additionally, analysis of gut microbiota structure and functions was conducted concurrently with the examination of DiCQAs' impact on gut microbiota carrying the bile salt hydrolase (BSH) gene, as well as on the enterohepatic circulation of BAs and related signaling pathways. RESULTS: Our findings demonstrated that DiCQAs alleviated diabetic symptoms by modulating gut microbiota carrying the BSH gene. This modulation enhanced intestinal barrier integrity, increased enterohepatic circulation of conjugated BAs, and inhibited the farnesoid X receptor-fibroblast growth factor 15 (FGF15) signaling axis in the ileum. Consequently, the protein expression of hepatic FGFR4 fibroblast growth factor receptor 4 (FGFR4) decreased, accompanied by heightened BA synthesis, reduced hepatic BA stasis, and lowered levels of hepatic and plasma cholesterol. Furthermore, DiCQAs upregulated glucolipid metabolism-related proteins in the liver and muscle, including v-akt murine thymoma viral oncogene homolog (AKT)/glycogen synthase kinase 3-beta (GSK3β) and AMP-activated protein kinase (AMPK), thereby ameliorating hyperglycemia and mitigating inflammation through the down-regulation of the MAPK signaling pathway in the diabetic group. CONCLUSION: Our study elucidated the anti-diabetic effects and mechanism of DiCQAs from I. kudingcha, highlighting the potential of targeting gut microbiota, particularly Acetatifactor sp011959105 and Acetatifactor muris carrying the BSH gene, as a therapeutic strategy to attenuate FXR-FGF15 signaling and ameliorate diabetes.
引言：人类肠道微生物群在健康和疾病中起着关键作用，特别是通过其与胆汁酸（BAs）的相互作用。胆汁酸在肝脏中合成，排泄到肠道后会被肠道微生物群转化，从而影响宿主代谢。然而，苦丁茶中的二咖啡酰奎宁酸（DiCQAs）如何通过肠道微生物群调节脂质代谢和炎症的潜在机制仍不清楚。 目的和方法：本研究的目的是探讨DiCQAs对糖尿病的调节作用及其潜在作用机制。利用两种小鼠模型研究DiCQAs的抗糖尿病作用。此外，在检测DiCQAs对携带胆汁盐水解酶（BSH）基因的肠道微生物群的影响以及对胆汁酸肝肠循环和相关信号通路的同时，对肠道微生物群的结构和功能进行了分析。 结果：我们的研究结果表明，DiCQAs通过调节携带BSH基因的肠道微生物群来减轻糖尿病症状。这种调节增强了肠道屏障的完整性，增加了结合胆汁酸的肝肠循环，并抑制了回肠中的法尼醇X受体-成纤维细胞生长因子15（FGF15）信号轴。因此，肝脏成纤维细胞生长因子受体4（FGFR4）的蛋白表达下降，同时胆汁酸合成增加，肝脏胆汁酸淤积减少，肝脏和血浆胆固醇水平降低。此外，DiCQAs上调了肝脏和肌肉中与糖脂代谢相关的蛋白质，包括v-akt小鼠胸腺瘤病毒癌基因同源物（AKT）/糖原合酶激酶3-β（GSK3β）和AMP激活蛋白激酶（AMPK），从而通过下调糖尿病组中的丝裂原活化蛋白激酶（MAPK）信号通路来改善高血糖和减轻炎症。 结论：我们的研究阐明了苦丁茶中DiCQAs的抗糖尿病作用及其机制，突出了以肠道微生物群为靶点，特别是携带BSH基因的醋酸杆菌属sp011959105和醋酸杆菌属小鼠作为一种治疗策略来减弱FXR-FGF15信号并改善糖尿病的潜力。
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