姜黄素通过肠道微生物依赖的三甲胺 N-氧化物（TMAO）途径在小鼠体内的抗动脉粥样硬化作用。

Anti-atherosclerotic effects of geraniin through the gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway in mice.

机构信息

Department of Cardiology, Fujian Provincial Hospital, Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Provincial Center for Geriatrics, Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350001, China.

Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, China.

出版信息

Phytomedicine. 2022 Jul;101:154104. doi: 10.1016/j.phymed.2022.154104. Epub 2022 Apr 16.

DOI:10.1016/j.phymed.2022.154104

PMID:35461005

Abstract

BACKGROUND

Cardiovascular disease is a leading cause of death, which signifies the urgent need for effective anti-atherosclerotic strategies. Gut microbiota-dependent trimethylamine-N-oxide (TMAO) is associated with atherosclerosis, and geraniin, a natural polyphenol with various biological activities, might play key role in this process.

PURPOSE

We aimed to investigate the pharmacological activity of geraniin in atherosclerosis through remodeling the gut microbiota.

METHODS

C57BL/6J ApoE mice were administrated geraniin for 12 weeks. The colon contents were analyzed via 16S rRNA sequencing. Pathological staining was performed to evaluate the atherosclerotic characteristics. Cytokine assays detected the levels of plasma inflammatory cytokines. RAW264.7 cells were cultured in vitro and treated with TMAO. Tandem Mass Tag quantitative proteomics analysis and western blot were performed to investigate the effect of TMAO in macrophages.

RESULTS

The plasma TMAO level in mice significantly decreased after geraniin intervention. The predominant intestinal microflora from geraniin-treated mice were Bacteroides (65.3%) and Firmicutes (30.6%). Pathological staining demonstrated that administration of geraniin attenuated atherosclerotic characteristics. After geraniin treatment, plasma levels of IL-1β, IL-6, and TNF-α in mice were significantly reduced, and IL-10 levels were significantly increased. Proteomics analysis demonstrated the number of differentially expressed proteins after TMAO administration. In vitro study suggested that the atherogenic effect of TMAO could be attributed to changes in CD36, transmembrane protein 106a, apolipoprotein C1, macrophage scavenger receptor types I and II, and alpha-2-macroglobulin.

CONCLUSION

Geraniin might be an effective prospective drug against cardiovascular diseases, and the gut microbiota is a potential target to reduce the risk of atherosclerotic disease.

摘要

背景

心血管疾病是主要的死亡原因，这表明迫切需要有效的抗动脉粥样硬化策略。肠道微生物群依赖的三甲胺 N-氧化物（TMAO）与动脉粥样硬化有关，而具有多种生物学活性的天然多酚根皮苷可能在此过程中发挥关键作用。

目的

我们旨在通过重塑肠道微生物群来研究根皮苷在动脉粥样硬化中的药理活性。

方法

用根皮苷处理 C57BL/6J ApoE 小鼠 12 周。通过 16S rRNA 测序分析结肠内容物。进行病理染色以评估动脉粥样硬化特征。细胞因子测定检测血浆炎症细胞因子水平。在体外培养 RAW264.7 细胞并用 TMAO 处理。进行串联质量标签定量蛋白质组学分析和 Western blot 以研究 TMAO 对巨噬细胞的影响。

结果

根皮苷干预后，小鼠血浆 TMAO 水平显著降低。根皮苷处理小鼠的主要肠道微生物群为拟杆菌（65.3%）和厚壁菌门（30.6%）。病理染色表明，根皮苷给药可减轻动脉粥样硬化特征。根皮苷治疗后，小鼠血浆中 IL-1β、IL-6 和 TNF-α水平显著降低，IL-10 水平显著升高。蛋白质组学分析表明 TMAO 给药后差异表达蛋白的数量。体外研究表明，TMAO 的动脉粥样硬化作用可能归因于 CD36、跨膜蛋白 106a、载脂蛋白 C1、巨噬细胞清道夫受体类型 I 和 II 以及α-2-巨球蛋白的变化。