肠道微生物群在贝派地酸抗高脂血症中的作用：贝派地酸治疗调节的新候选靶点。

Role of gut microbiota in bempedoic acid against hyperlipidemia: a new candidate target for bempedoic acid on the therapeutic regulation.

作者信息

Zhang Wei-Jian, Wang Jian, Ouyang Zi-Qi, Luo Sen-Rong, Chen Zhi-Kai, He Yuan-Kang, Luo Mu-Jin, Liao Xu-Xing

机构信息

Department of Neurosurgery, First People's Hospital of Foshan, Foshan, Guangdong, China.

Department of Translational Medicine Research Institute, First People's Hospital of Foshan, Foshan, Guangdong, China.

出版信息

Front Pharmacol. 2025 Jun 3;16:1584273. doi: 10.3389/fphar.2025.1584273. eCollection 2025.

DOI:10.3389/fphar.2025.1584273

PMID:40529499

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12170663/

Abstract

BACKGROUND

Bempedoic acid (BA), an oral synthetic dicarboxylic acid derivative, has been widely used to treat patients with hyperlipidemia who are intolerant to statins. Both clinical and preclinical studies have reported the protective effects of BA against hyperlipidemia. However, the mechanisms of BA for hyperlipidemia treatment remain largely obscured. This study aimed to evaluate the effects of BA on hyperlipidemia and investigate the mechanism underlying its correlation with gut microbiota and serum metabolite regulation.

METHODS

Four-week-old male C57BL/6J mice were fed a high-fat diet (HFD) and treated with BA daily for 20 weeks. Biochemical changes of serum were assessed, covering lipid metabolism, inflammation, and endothelial function. Moreover, 16S rRNA sequencing of gut microbiota as well as untargeted metabolomics analysis of serum were performed.

RESULTS

The results showed that BA exerted potent efficacy against hyperlipidemia by attenuating serum lipid profiles, inhibiting vascular inflammation, and improving endothelial function. 16S rRNA sequencing revealed that BA improved the disorder of gut microbiota biodiversity. Specifically, BA significantly enriched the abundance of , , , and , which were closely associated with BA's therapeutic effects. Serum metabolomics analysis indicated that BA recovered the disturbances of serum metabolic phenotypes. A total of 20 differential metabolites were significantly regulated by BA treatment, suggesting that BA might exert effects by ameliorating relevant metabolic pathways, including bile acid biosynthesis, glycerophospholipid metabolism, β-oxidation of fatty acids and sphingolipid metabolism.

CONCLUSION

Taken together, the present study demonstrated that BA could inhibit the development of hyperlipidemia, and its protective effects may be related to alterations in gut microbiota composition and changes in serum metabolite abundances.

摘要

背景

贝派地酸（BA）是一种口服合成二羧酸衍生物，已广泛用于治疗对他汀类药物不耐受的高脂血症患者。临床和临床前研究均报道了BA对高脂血症的保护作用。然而，BA治疗高脂血症的机制仍 largely obscured。本研究旨在评估BA对高脂血症的影响，并探讨其与肠道微生物群和血清代谢物调节相关性的潜在机制。

方法

给4周龄雄性C57BL/6J小鼠喂食高脂饮食（HFD），并每天用BA治疗20周。评估血清的生化变化，包括脂质代谢、炎症和内皮功能。此外，进行了肠道微生物群的16S rRNA测序以及血清的非靶向代谢组学分析。

结果

结果表明，BA通过降低血清脂质水平、抑制血管炎症和改善内皮功能，对高脂血症发挥了显著疗效。16S rRNA测序显示，BA改善了肠道微生物群生物多样性的紊乱。具体而言，BA显著富集了、、和的丰度，这些与BA的治疗效果密切相关。血清代谢组学分析表明，BA恢复了血清代谢表型的紊乱。共有20种差异代谢物受到BA治疗的显著调节，表明BA可能通过改善相关代谢途径发挥作用，包括胆汁酸生物合成、甘油磷脂代谢、脂肪酸β氧化和鞘脂代谢。