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

Chen, Mingliang; Lv, Yi; Zhang, Yong; Zhou, Xi; Ran, Li; Yang, Jining; Zhu, Jingjing; Zhang, Qianyong; Mi, Mantian

doi:10.1128/mbio.02210-15

Cited by 564 publications

(502 citation statements)

References 49 publications

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“…We confirmed previously detected associations between TMAO and the abundance of Peptococcaceae ( P = 4.67 × 10 −4 ) and Prevotella ( P = 0.004) (Fig. 2) [12, 35]. Interestingly, we also observed a negative association between TMAO and the abundance of common gut commensal Faecalibacterium prausnitzii ( P = 0.006; FDR <0.08).…”

Section: Resultssupporting

confidence: 90%

Relationships between gut microbiota, plasma metabolites, and metabolic syndrome traits in the METSIM cohort

et al. 2017

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BackgroundThe gut microbiome is a complex and metabolically active community that directly influences host phenotypes. In this study, we profile gut microbiota using 16S rRNA gene sequencing in 531 well-phenotyped Finnish men from the Metabolic Syndrome In Men (METSIM) study.ResultsWe investigate gut microbiota relationships with a variety of factors that have an impact on the development of metabolic and cardiovascular traits. We identify novel associations between gut microbiota and fasting serum levels of a number of metabolites, including fatty acids, amino acids, lipids, and glucose. In particular, we detect associations with fasting plasma trimethylamine N-oxide (TMAO) levels, a gut microbiota-dependent metabolite associated with coronary artery disease and stroke. We further investigate the gut microbiota composition and microbiota–metabolite relationships in subjects with different body mass index and individuals with normal or altered oral glucose tolerance. Finally, we perform microbiota co-occurrence network analysis, which shows that certain metabolites strongly correlate with microbial community structure and that some of these correlations are specific for the pre-diabetic state.ConclusionsOur study identifies novel relationships between the composition of the gut microbiota and circulating metabolites and provides a resource for future studies to understand host–gut microbiota relationships.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1194-2) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 90%

Relationships between gut microbiota, plasma metabolites, and metabolic syndrome traits in the METSIM cohort

et al. 2017

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“…Therefore, the changes in urinary amino acids and derivatives revealed by the metabolomic analysis may imply a resveratrol-induced modulation of the gut flora in men with metabolic syndrome. This is in accordance with studies in rodents where resveratrol has been shown to modulate the gut microbiota directly [41,42,43]. …”

Section: Discussionsupporting

confidence: 92%

Comprehensive Metabolomic Analysis in Blood, Urine, Fat, and Muscle in Men with Metabolic Syndrome: A Randomized, Placebo-Controlled Clinical Trial on the Effects of Resveratrol after Four Months’ Treatment

Korsholm

Kjær

Ørnstrup

et al. 2017

IJMS

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Resveratrol possesses several beneficial metabolic effects in rodents, while the effects of resveratrol in humans remain unclear. Therefore, we performed a non-targeted comprehensive metabolomic analysis on blood, urine, adipose tissue, and skeletal muscle tissue in middle-aged men with metabolic syndrome randomized to either resveratrol or placebo treatment for four months. Changes in steroid hormones across all four matrices were the most pronounced changes observed. Resveratrol treatment reduced sulfated androgen precursors in blood, adipose tissue, and muscle tissue, and increased these metabolites in urine. Furthermore, markers of muscle turnover were increased and lipid metabolism was affected, with increased intracellular glycerol and accumulation of long-chain saturated, monounsaturated, and polyunsaturated (n3 and n6) free fatty acids in resveratrol-treated men. Finally, urinary derivatives of aromatic amino acids, which mainly reflect the composition of the gut microbiota, were altered upon resveratrol treatment. In conclusion, the non-targeted metabolomics approach applied to four different matrices provided evidence of subtle but robust effects on several metabolic pathways following resveratrol treatment for four months in men with metabolic syndrome—effects that, for the most part, would not have been detected by routine analyses. The affected pathways should be the focus of future clinical trials on resveratrol’s effects, and perhaps particularly the areas of steroid metabolism and the gut microbiome.

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“…Treatment with RSV resulted in an increase in Bacteroidetes abundance at the expense of Firmicutes in choline-treated apoE −/− mice. Serum TMA and TMAO levels were much lower in RSV-treated mice fed with choline than in those in the control group [55]. …”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Trimethylamine N-Oxide: The Good, the Bad and the Unknown

Velasquez

Ramezani

Manal

et al. 2016

Toxins

373

316

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Trimethylamine N-oxide (TMAO) is a small colorless amine oxide generated from choline, betaine, and carnitine by gut microbial metabolism. It accumulates in the tissue of marine animals in high concentrations and protects against the protein-destabilizing effects of urea. Plasma level of TMAO is determined by a number of factors including diet, gut microbial flora and liver flavin monooxygenase activity. In humans, a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events and death is reported. The atherogenic effect of TMAO is attributed to alterations in cholesterol and bile acid metabolism, activation of inflammatory pathways and promotion foam cell formation. TMAO levels increase with decreasing levels of kidney function and is associated with mortality in patients with chronic kidney disease. A number of therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that utilize TMAO as substrate and the development of target-specific molecules with varying level of success. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies examining the cellular signaling in physiology and pathological states in order to establish the role of TMAO in health and disease in humans.

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

Cited by 564 publications

References 49 publications

Relationships between gut microbiota, plasma metabolites, and metabolic syndrome traits in the METSIM cohort

Relationships between gut microbiota, plasma metabolites, and metabolic syndrome traits in the METSIM cohort

Comprehensive Metabolomic Analysis in Blood, Urine, Fat, and Muscle in Men with Metabolic Syndrome: A Randomized, Placebo-Controlled Clinical Trial on the Effects of Resveratrol after Four Months’ Treatment

Trimethylamine N-Oxide: The Good, the Bad and the Unknown

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