Berberine ameliorates vascular dysfunction by downregulating TMAO-endoplasmic reticulum stress pathway via gut microbiota in hypertension

IF 6.1 1区 生物学 Q1 MICROBIOLOGY
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Abstract

The gut microbial metabolite trimethylamine N-oxide (TMAO) is regarded as a novel risk factor for hypertension. Berberine (BBR) exerts cardiovascular protective effects by regulating the gut microbiota-metabolite production pathway. However, whether and how BBR alleviates TMAO-induced vascular dysfunction in hypertension remains unclear. In the present study, we observed that plasma TMAO and related bacterial abundance were significantly elevated and negatively correlated with vascular function in 86 hypertensive patients compared with 46 normotensive controls. TMAO activated endoplasmic reticulum stress (ERS) signaling pathway to promote endothelial cell dysfunction and apoptosis in vitro. BBR (100, 200 mg · kg−1 ·d−1) for 4 weeks ameliorates TMAO-induced vascular dysfunction and ERS activation in a choline-angiotensin II hypertensive mouse model. We found that plasma TMAO levels in 15 hypertensive patients treated with BBR (0.4 g, tid) were reduced by 8.8 % and 16.7 % at months 1 and 3, respectively, compared with pretreatment baseline. The oral BBR treatment also improved vascular function and lowered blood pressure. Faecal 16 S rDNA showed that BBR altered the gut bacterial composition and reduced the abundance of CutC/D bacteria in hypertensive mice and patients. In vitro bacterial cultures and enzyme reaction systems indicated that BBR inhibited the biosynthesis of TMAO precursor in the gut microbiota by binding to and inhibiting the activity of CutC/D enzyme. Our results indicate that BBR improve vascular dysfunction at least partially by decreasing TMAO via regulation of the gut microbiota in hypertension.

小檗碱通过肠道微生物群下调 TMAO-内质网应激途径改善高血压患者的血管功能障碍
肠道微生物代谢物三甲胺 N-氧化物(TMAO)被认为是高血压的新型风险因素。小檗碱(BBR)通过调节肠道微生物群-代谢物产生途径发挥保护心血管的作用。然而,小檗碱是否以及如何缓解 TMAO 引起的高血压血管功能障碍仍不清楚。在本研究中,我们观察到,与 46 例正常血压对照组相比,86 例高血压患者的血浆 TMAO 和相关细菌丰度显著升高,且与血管功能呈负相关。TMAO 在体外激活内质网应激(ERS)信号通路,促进内皮细胞功能障碍和凋亡。在胆碱-血管紧张素 II 高血压小鼠模型中,连续 4 周服用 BBR(100、200 毫克 - kg-1 -d-1)可改善 TMAO 诱导的血管功能障碍和 ERS 激活。我们发现,15 名高血压患者接受 BBR(0.4 克,tid)治疗后,血浆中的 TMAO 水平在第 1 个月和第 3 个月分别比治疗前的基线降低了 8.8% 和 16.7%。口服 BBR 还能改善血管功能并降低血压。粪便 16 S rDNA 显示,BBR 改变了高血压小鼠和患者的肠道细菌组成,降低了 CutC/D 细菌的丰度。体外细菌培养和酶反应系统表明,BBR 通过与 CutC/D 酶结合并抑制其活性,抑制了 TMAO 前体在肠道微生物群中的生物合成。我们的研究结果表明,BBR 至少可以通过调节高血压患者的肠道微生物群来减少 TMAO,从而部分改善血管功能障碍。
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
Microbiological research
Microbiological research 生物-微生物学
CiteScore
10.90
自引率
6.00%
发文量
249
审稿时长
29 days
期刊介绍: Microbiological Research is devoted to publishing reports on prokaryotic and eukaryotic microorganisms such as yeasts, fungi, bacteria, archaea, and protozoa. Research on interactions between pathogenic microorganisms and their environment or hosts are also covered.
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