Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota.
Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota.
复制标题
白藜芦醇通过重塑肠道微生物群来调节 TMAO 合成和胆汁酸代谢，从而减轻三甲胺 N-氧化物 (TMAO) 诱导的动脉粥样硬化
作者：
Chen ML;Yi L;Zhang Y;Zhou X;Ran L;Yang J;Zhu JD;Zhang QY;Mi MT
摘要肠道菌群与动脉粥样硬化（AS）密切相关。白藜芦醇（Resveratrol，RSV）是一种天然植物抗毒素，具有抗AS作用，但其作用机制尚不清楚。因此，我们试图确定RSV的抗AS作用是否与肠道微生物群的变化有关。我们发现RSV减弱了ApoE−/−小鼠中三甲胺-N-氧化物（TMAO）诱导的AS。同时，RSV通过抑制小鼠肠道微生物群重构引起的肠道微生物三甲胺（TMA）产生来降低TMAO水平。此外，RSV增加了乳杆菌属和双歧杆菌属的水平，这增加了胆盐水解酶的活性，从而增强了C57 BL/6 J和ApoE−/−小鼠中胆汁酸（BA）的解结合和粪便排泄。这与回肠BA含量降低、肝肠法尼醇X受体（FXR）-成纤维细胞生长因子15（FGF 15）轴抑制、胆固醇7 α-羟化酶（CYP 7A 1）表达增加和肝BA新合成有关。FXR拮抗剂对FGF 15和CYP 7A 1表达的影响与RSV相同，而FXR激动剂消除了RSV诱导的FGF 15和CYP 7A 1表达的变化。在用抗生素治疗的小鼠中，RSV既不降低TMAO水平也不增加肝脏BA合成。此外，RSV诱导的抑制TMAO引起的AS也明显消除抗生素。总之，RSV通过降低TMAO水平和经由肠道微生物群重塑增加肝BA新合成来减弱TMAO诱导的AS，并且BA新合成部分地通过肠肝FXR-FGF 15轴介导。近年来，氧化三甲胺（TMAO）已被确定为一种新的和独立的危险因素，促进动脉粥样硬化（AS）部分通过抑制肝胆汁酸（BA）的合成。肠道微生物群在TMAO诱导的AS的病理生理学中起着关键作用。白藜芦醇（Resveratrol，RSV）是一种具有益生元功效的天然植物抗毒素。越来越多的证据支持这一假设，即生物利用度差的酚类植物化学物质可能主要通过肠道微生物群的重塑起作用。目前的研究表明，RSV通过降低TMAO水平和通过肠道微生物群重塑增加肝脏BA新合成来减弱TMAO诱导的AS。RSV诱导的BA合成部分是通过下调肝肠法尼酯X受体-成纤维细胞生长因子15轴介导的。这些结果为RSV抗AS作用的机制提供了新的见解，并表明肠道微生物群可能成为药理学或饮食干预的有趣目标，以降低心血管疾病的风险。最近，三甲基胺-N-氧化物（TMAO）被确定为部分通过抑制肝胆汁酸（BA）合成而促进动脉粥样硬化（AS）的一种新的独立危险因素。肠道微生物群在TMAO诱导的AS的病理生理学中起着关键作用。白藜芦醇（Resveratrol，RSV）是一种具有益生元功效的天然植物抗毒素。越来越多的证据支持这一假设，即生物利用度差的酚类植物化学物质可能主要通过肠道微生物群的重塑起作用。目前的研究表明，RSV通过降低TMAO水平和通过肠道微生物群重塑增加肝脏BA新合成来减弱TMAO诱导的AS。RSV诱导的肝脏BA新合成部分通过下调肝肠法尼醇X受体-成纤维细胞生长因子15轴介导。这些结果为RSV抗AS作用的机制提供了新的见解，并表明肠道微生物群可能成为药理学或饮食干预的有趣目标，以降低心血管疾病的风险。
ABSTRACT The gut microbiota is found to be strongly associated with atherosclerosis (AS). Resveratrol (RSV) is a natural phytoalexin with anti-AS effects; however, its mechanisms of action remain unclear. Therefore, we sought to determine whether the anti-AS effects of RSV were related to changes in the gut microbiota. We found that RSV attenuated trimethylamine-N-oxide (TMAO)-induced AS in ApoE−/− mice. Meanwhile, RSV decreased TMAO levels by inhibiting commensal microbial trimethylamine (TMA) production via gut microbiota remodeling in mice. Moreover, RSV increased levels of the genera Lactobacillus and Bifidobacterium, which increased the bile salt hydrolase activity, thereby enhancing bile acid (BA) deconjugation and fecal excretion in C57BL/6J and ApoE−/− mice. This was associated with a decrease in ileal BA content, repression of the enterohepatic farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) axis, and increased cholesterol 7a-hydroxylase (CYP7A1) expression and hepatic BA neosynthesis. An FXR antagonist had the same effect on FGF15 and CYP7A1 expression as RSV, while an FXR agonist abolished RSV-induced alterations in FGF15 and CYP7A1 expression. In mice treated with antibiotics, RSV neither decreased TMAO levels nor increased hepatic BA synthesis. Additionally, RSV-induced inhibition of TMAO-caused AS was also markedly abolished by antibiotics. In conclusion, RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling, and the BA neosynthesis was partially mediated through the enterohepatic FXR-FGF15 axis. IMPORTANCE Recently, trimethylamine-N-oxide (TMAO) has been identified as a novel and independent risk factor for promoting atherosclerosis (AS) partially through inhibiting hepatic bile acid (BA) synthesis. The gut microbiota plays a key role in the pathophysiology of TMAO-induced AS. Resveratrol (RSV) is a natural phytoalexin with prebiotic benefits. A growing body of evidence supports the hypothesis that phenolic phytochemicals with poor bioavailability are possibly acting primarily through remodeling of the gut microbiota. The current study showed that RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling. And RSV-induced hepatic BA neosynthesis was partially mediated through downregulating the enterohepatic farnesoid X receptor-fibroblast growth factor 15 axis. These results offer new insights into the mechanisms responsible for RSV’s anti-AS effects and indicate that the gut microbiota may become an interesting target for pharmacological or dietary interventions to decrease the risk of developing cardiovascular diseases. Recently, trimethylamine-N-oxide (TMAO) has been identified as a novel and independent risk factor for promoting atherosclerosis (AS) partially through inhibiting hepatic bile acid (BA) synthesis. The gut microbiota plays a key role in the pathophysiology of TMAO-induced AS. Resveratrol (RSV) is a natural phytoalexin with prebiotic benefits. A growing body of evidence supports the hypothesis that phenolic phytochemicals with poor bioavailability are possibly acting primarily through remodeling of the gut microbiota. The current study showed that RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling. And RSV-induced hepatic BA neosynthesis was partially mediated through downregulating the enterohepatic farnesoid X receptor-fibroblast growth factor 15 axis. These results offer new insights into the mechanisms responsible for RSV’s anti-AS effects and indicate that the gut microbiota may become an interesting target for pharmacological or dietary interventions to decrease the risk of developing cardiovascular diseases.