Mistry Rima H, Verkade Henkjan J, Tietge Uwe J F
From the Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, The Netherlands.
Arterioscler Thromb Vasc Biol. 2017 Mar;37(3):419-422. doi: 10.1161/ATVBAHA.116.308306. Epub 2017 Jan 5.
The intestinal microbiota is emerging as a clinically relevant modulator of atherosclerotic risk. Reverse cholesterol transport (RCT) is an atheroprotective metabolic pathway. How the microbiota impacts RCT has not been investigated. Therefore, the aim of this study was to characterize (cholesterol) metabolism and RCT in germ-free mice compared with conventional mice.
In chow-fed germ-free mice, plasma cholesterol was unchanged, whereas liver cholesterol content was higher (1.5-fold; <0.05) than in conventional controls. Biliary secretion of cholesterol (2-fold; <0.001) and bile acids (3-fold; <0.001) was substantially increased in the germ-free model, whereas fecal neutral sterol excretion was unaltered, and fecal bile acid excretion was decreased (<0.01). However, fecal bile acid profiles of germ-free mice were dominated by the presence of β-muricholic acid (<0.001), pointing toward a higher contribution of the alternative acidic pathway to total bile acid synthesis in these mice. As expected, secondary bile acids were absent in the germ-free model. In vivo macrophage-to-feces RCT was increased >2-fold (<0.01) in the absence of intestinal bacteria.
These data demonstrate that the absence of the intestinal microbiota stimulates RCT >2-fold. Thereby, our results support the importance of intestinal bacteria for metabolic regulation and indicate that specific targeting of the microbiota bears therapeutic potential to prevent and treat cardiovascular disease.
肠道微生物群正成为动脉粥样硬化风险的临床相关调节因子。逆向胆固醇转运（RCT）是一条抗动脉粥样硬化的代谢途径。微生物群如何影响RCT尚未得到研究。因此，本研究的目的是与常规小鼠相比，对无菌小鼠的（胆固醇）代谢和RCT进行表征。
在喂食普通饲料的无菌小鼠中，血浆胆固醇未发生变化，而肝脏胆固醇含量比常规对照小鼠高1.5倍（P<0.05）。在无菌模型中，胆固醇的胆汁分泌增加了2倍（P<0.001），胆汁酸分泌增加了3倍（P<0.001），而粪便中性固醇排泄未改变，粪便胆汁酸排泄减少（P<0.01）。然而，无菌小鼠的粪便胆汁酸谱以β-鼠胆酸为主（P<0.001），表明在这些小鼠中，替代酸性途径对总胆汁酸合成的贡献更大。正如预期的那样，无菌模型中不存在次级胆汁酸。在没有肠道细菌的情况下，体内巨噬细胞到粪便的RCT增加了2倍以上（P<0.01）。
这些数据表明，肠道微生物群的缺失会使RCT增加2倍以上。因此，我们的结果支持肠道细菌对代谢调节的重要性，并表明对微生物群的特异性靶向具有预防和治疗心血管疾病的治疗潜力。
