Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota.

Ming-Liang Chen,Qian-Yong Zhang,Jun-Dong Zhu,Xi Zhou,Jining Yang,Man-Tian Mi,Long Yi,Li Ran,Yong Zhang

doi:10.1128/mbio.02210-15

Abstract

ABSTRACTThe 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.

Highlights

The incidence of cardiovascular diseases (CVDs), such as atherosclerosis (AS), is increasing globally and has become an expensive public health issue [1]
Via liquid chromatography-tandem mass spectrometry (LC/MS), we found that peak concentrations of TMA and TMAO occurred 4 h after choline administration and 1 h after TMA administration (Fig. 1A and B)
Dietary choline is metabolized by the intestinal microbiota to TMA, which is further metabolized by flavin monooxygenase (FMO) enzymes, in particular, flavin monooxygenase 3 (FMO3), to produce TMAO in the liver [23]

Summary

Introduction

The incidence of cardiovascular diseases (CVDs), such as atherosclerosis (AS), is increasing globally and has become an expensive public health issue [1]. Many studies have shown that the gut microbiota regulates secondary BA metabolism and BA synthesis in the liver by alleviating the enterohepatic FXR-fibroblast growth factor 15 (FGF15) axis [6, 9]. Sayin et al found that the gut microbiota can reduce the levels of tauro-beta-muricholic acid (T-␤MCA), a naturally occurring FXR antagonist This subsequently inhibits cholesterol 7ahydroxylase (CYP7A1), the rate-limiting enzyme in BA synthesis, by activating FXR-FGF15 signaling and regulating BA metabolism in the liver [5, 11]. Tempol, an antioxidant and protective agent against radiation, can alter the gut microbiome, leading to the accumulation of intestinal T-␤MCA, thereby inhibiting intestinal FXR signaling and decreasing obesity [12] These results indicate that microbiota-targeted therapies could be effective in preventing gut-related diseases, including AS, by regulating BA metabolism via the enterohepatic FXR-FGF15 axis. For the first time, that RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling and that RSV-induced BA neosynthesis was partially mediated through the enterohepatic FXR-FGF15 axis

Methods

Results

Conclusion