Background:Despite the availability of various classes of antihypertensive medications, a large proportion of hypertensive individuals remain resistant to treatments. The reason for what contributes to low efficacy of antihypertensive medications in these individuals is elusive. The knowledge that gut microbiota is involved in pathophysiology of hypertension and drug metabolism led us to hypothesize that gut microbiota catabolize antihypertensive medications and compromised their blood pressure (BP)-lowering effects.Methods and Results:To test this hypothesis, we examined the BP responses to a representative ACE (angiotensin-converting enzyme) inhibitor quinapril in spontaneously hypertensive rats (SHR) with or without antibiotics. BP-lowering effect of quinapril was more pronounced in the SHR+antibiotics, indicating that gut microbiota of SHR lowered the antihypertensive effect of quinapril. Depletion of gut microbiota in the SHR+antibiotics was associated with decreased gut microbial catabolism of quinapril as well as significant reduction in the bacterial genus Coprococcus. C. comes, an anaerobic species of Coprococcus, harbored esterase activity and catabolized the ester quinapril in vitro. Co-administration of quinapril with C. comes reduced the antihypertensive effect of quinapril in the SHR. Importantly, C. comes selectively reduced the antihypertensive effects of ester ramipril but not nonester lisinopril.Conclusions:Our study revealed a previously unrecognized mechanism by which human commensal C. comes catabolizes ester ACE inhibitors in the gut and lowers its antihypertensive effect.

中文翻译：

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鉴定损害酯类血管紧张素转换酶抑制剂降血压作用的肠道共生菌

背景：尽管有各种类型的抗高血压药物可供使用，但仍有很大一部分高血压患者对治疗有抵抗力。导致这些人抗高血压药物疗效低下的原因尚不清楚。肠道微生物群参与高血压和药物代谢的病理生理学这一知识使我们假设肠道微生物群分解代谢抗高血压药物并损害其降压 (BP) 作用。方法和结果：为了检验这一假设，我们检查了 BP 反应在有或没有抗生素的自发性高血压大鼠 (SHR) 中使用代表性的 ACE（血管紧张素转换酶）抑制剂喹那普利。喹那普利的降压作用在 SHR+ 抗生素中更为明显，表明 SHR 的肠道微生物群降低了喹那普利的抗高血压作用。SHR+抗生素中肠道微生物群的消耗与喹那普利的肠道微生物分解代谢减少以及细菌属的显着减少有关粪球菌。C. comes是粪球菌的一种厌氧菌，具有酯酶活性并在体外分解代谢酯喹那普利。喹那普利与梭状芽孢杆菌的共同给药降低了喹那普利在 SHR 中的抗高血压作用。重要的是，C. 来选择性地降低酯雷米普利而非非酯赖诺普利的抗高血压作用。结论：我们的研究揭示了一种以前未被认识的机制，人类共生C. 来分解代谢肠道中的酯 ACE 抑制剂并降低其抗高血压作用。