Recent studies have pointed to the connection between gut microbiota and cardiovascular disease (CVD) in mouse models. With the aim to investigate the importance of metabolic crosstalk between the gut microbiota and the host in the development of CVD, a recent study, led by Dr. Man-tian Mi from the Research Centre for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University in Chongqing (China), has found that the anti-atherosclerosis effects of resveratrol (RSV) – a plant-based natural phenolic compound used to fight pathogens such as fungi and bacteria – are related to changes in the gut microbiota of mice.
Researchers found in mice that RSV reduced trimethylamine-N-oxide (TMAO) levels by inhibiting gut microbial TMA synthesis via modifying gut microbiota, thus attenuating TMAO-induced atherosclerosis. TMAO generation involves the gut microbiota, which first metabolizes dietary sources of choline-really abundant in a western diet-to trimethylamine (TMA). Thereafter, TMA is carried via the portal circulation to the liver, where is converted by a family of hepatic flavin monooxygenases (FMOs) into TMAO. (An association of TMAO and thrombosis potential has been observed in several clinical studies).
In a previous study, it was demonstrated that the gut microbe-dependent metabolite TMAO directly increased platelet hyperreactivity and thrombosis potential in in vivo carotid artery thrombosis models, suggesting new potential therapeutic targets for the prevention of adverse cardiovascular event risk. Based on this mechanistic link between specific dietary nutrients, gut microbes and thrombosis risk, Ming-liang Chen et al. conducted experiments in mice to determine whether the protective effect of resveratrol against atherosclerosis was related to changes in the gut microbiota. Resveratrol is a natural polyphenol mainly found in grapes, berries and a wide range of fruits and it has been reported to have prebiotic benefits and beneficial properties in atherosclerotic heart diseases. For the first time here, the researchers demonstrated that resveratrol attenuated TMAO-induced atherosclerosis by decreasing TMA generation and subsequent TMAO synthesis, and by increasing bile acid (BA) deconjugation and fecal excretion through remodelling the composition of gut microbiota. Specifically, resveratrol modulated gut microbiota composition through increasing the Bacteroidetes-to-Firmicutes ratios, significantly inhibiting the growth of Prevotella, and increasing the proportions of Bacteroides, Lactobacillus, Bifidobacterium, and Akkermansia in mice. Resveratrol increased bile salt hydrolase (BSH) enzyme activity by gut microbiota remodelling, which promoted the generation of unconjugated BAs from conjugated BAs and enhanced faecal BA loss. Resveratrol-induced faecal BA loss led to a decrease in ileal BA content, with the subsequent increase in BA neosynthesis that contributes to cholesterol homeostasis and finally results in attenuating AS. Resveratrol-mediated BA neosynthesis was partially modulated by downregulation of the gut-liver FXR-FGF15 axis.
“Our results offer new insights into the mechanisms responsible for resveratrol’s anti-atherosclerosis effects and indicate that gut microbiota may become an interesting target for pharmacological or dietary interventions to decrease the risk of developing cardiovascular diseases”, said Dr. Man-tian Mi, principal investigator of the study.
In the context of CVD in humans, it is also important to take into account that gut microbiota is related to metabolic profiles of symptomatic AS. For instance, in atherosclerosis, the abundance of certain oral microbial taxa was correlated with plasma cholesterol levels (n=30).
To sum up, gut microbiota may be an important player in atherosclerosis. As CVDs are the second leading cause of death worldwide, modifying the gut microbiota emerges as a promising way to prevent CVD mortality, especially in high-risk patients like those undergoing cardiac surgery or those who have multiple obstructed blood vessels in the brain. Although animal studies support anti-atherosclerosis effects of RSV, there is a lack of evidence available in recent human studies. For instance, a recent meta-analysis of 6 randomized controlled trials by Liu et al. did not find a blood pressure lowering effect of RSV in hypertensive patients.
Chen ML, Yi L, Zhang Y, et al. Resveratrol attenuates trimethylamine-N-oxide (TMAO)-induced atherosclerosis by regulating TMAO synthesis and bile acid metabolism via remodeling of the gut microbiota. MBio. 2016;7(2).doi:10.1128/mBio.02210-15.
Koren O, Spor A, Felin J, et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc Natl Acad Sci U S A. 2011;108(Suppl. 1):4592-8.
Liu Y, Ma W, Zhang P, He S, Huang D. Effect of resveratrol on blood pressure: a meta-analysis of randomized controlled trials. Clin Nutr. 2015;34(1):27-34.
Zhu W, Gregory JC, Org E, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell. 2016;165(1):111-24.
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