Gut Microbiota Modulation Attenuated the Hypolipidemic Effect of Simvastatin in High-Fat/Cholesterol-Diet Fed Mice.
Gut Microbiota Modulation Attenuated the Hypolipidemic Effect of Simvastatin in High-Fat/Cholesterol-Diet Fed Mice.
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DOI：
10.1021/acs.jproteome.6b00984
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发表时间：
2017-05-05
影响因子：
4.4
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
He X;Zheng N;He J;Liu C;Feng J;Jia W;Li H
临床上观察到辛伐他汀的降血脂作用存在个体差异，代谢组学研究揭示了细菌衍生代谢物的变化与治疗结果之间的联系。在目前的研究中，我们调查了辛伐他汀不同反应背后的肠道微生物参与的机制。雄性C57BL/6J小鼠给予高脂/高脂饮食(HFD)8周后，口服辛伐他汀(20 mg/kg，1次/d)，连续4周，同时给予或不给予抗生素(100 mg/kg亚胺培南：西司他丁钠)。我们观察到辛伐他汀可降低高脂饲料喂养小鼠的血清TC、LDL、HDL和TG水平，但这种作用可被改变肠道微生物区系组成的抗生素所减弱。随后的代谢组学研究表明，肠道微生物区系调节改变了辛伐他汀治疗小鼠的血清代谢和胆汁酸谱。此外，我们的结果显示辛伐他汀刺激高脂饲料喂养的小鼠肝脏细胞色素P7A1、细胞色素P7B1和法尼醇X受体(FXR)的表达，而这些基因的表达受到肠道微生物区系调节的影响。综上所述，我们的结果表明，辛伐他汀的降血脂作用与肠道微生物区系的组成有关，而辛伐他汀通过肠道微生物区系调节的降脂作用与抑制调节胆固醇合成胆汁酸的肝脏细胞色素P7A1、细胞色素P7B1和FXR蛋白有关。
Interindividual differences in hypolipidemic effect of simvastatin are observed in clinic, and metabolomic studies have uncovered the association between variations of bacterial-derived metabolites and therapeutic outcomes. In current study, we investigated the gut microbial-involved mechanisms underlying the different responses to simvastatin. Male C57BL/6J mice were given high-fat/cholesterol diet (HFD) 8 weeks and then orally administered simvastatin (20 mg/kg, once a day) for 4 weeks with or without antibiotic (100 mg/kg Imipenem : Cilastatin Sodium). We observed simvastatin reduced the levels of serum TC, LDL, HDL and TG in HFD-fed mice, but this effect was attenuated by antibiotic which altered gut microbiota composition. Subsequent metabolomic study indicated that gut microbiota modulation changed the serum metabolic and bile acid profiles in simvastatin-treated mice. Moreover, our results showed that simvastatin stimulated the expression of hepatic CYP7A1, CYP7B1 and Farnesoid X receptor (FXR) in HFD-fed mice, which were impaired by gut microbiota modulation. In summary, our results revealed that the hypolipidemic effect of simvastatin was correlated with the composition of gut microbiota, and the attenuated hypolipidemic effect of simvastatin by gut microbiota modulation was associated with the suppression on hepatic CYP7A1, CYP7B1 and FXR proteins that regulate bile acids synthesis from cholesterol.
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影响因子：
4.3
作者：
Li H;He J;Jia W
通讯作者：
Jia W
影响因子：
14.9
作者：
Ludwig, W;Strunk, O;Schleifer, KH
通讯作者：
Schleifer, KH
影响因子：
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作者：
Aura, Anna-Marja;Mattila, Ismo;Oksman-Caldentey, Kirsi-Marja
通讯作者：
Oksman-Caldentey, Kirsi-Marja
影响因子：
3.2
作者：
Soupene, Eric;Borja, Mark S.;Kuypers, Frans A.
通讯作者：
Kuypers, Frans A.
影响因子：
4.4
作者：
Schloss, Patrick D.;Westcott, Sarah L.;Weber, Carolyn F.
通讯作者：
Weber, Carolyn F.