Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis

Wang, Zeneng; Roberts, Anjeanette; Buffa, Jennifer A.; Levison, Bruce S.; Zhu, Weifei; Org, Elin; Gu, Xiaodong; Huang, Ying; Zamanian-Daryoush, Maryam; Culley, Miranda K.; DiDonato, Anthony J.; Fu, Xiaoming; Hazen, Jennie E; Krajcik, Daniel; DiDonato, Joseph A.; Lusis, Aldons J.; Hazen, Stanley L.

doi:10.1016/j.cell.2015.11.055

Cited by 1,066 publications

(912 citation statements)

References 35 publications

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“…The present study shows that elevated TMAO levels at time of MI is further associated with poor outcome. Moreover, a non-lethal choline analogue to inhibit bacterial production of trimethylamine, in turn reducing the levels of circulating TMAO [29], has been recently described, and intervention studies using this or similar compounds will be important to address the causative role of TMAO on coronary artery disease and outcomes in the future. In an initial investigation into TMAO kinetics post-acute MI in a small cohort, circulating TMAO levels were observed to rise and stabilize between day 1 and 5 post-admission.…”

Section: Discussionmentioning

confidence: 99%

Trimethylamine N-oxide and Risk Stratification after Acute Myocardial Infarction

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Trimethylamine N-oxide and Risk Stratification after Acute Myocardial Infarction

et al. 2017

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“…This hypothesis, described in detail below, has recently been supported by substantial evidence in animals and humans (Wang, et al, 2011;Koeth et al, 2013;Tang et. al., 2013;Jonsson and Bäckhed;Troseid, et al, 2015;Wang et al, 2015;Warrier, et al, 2015). Briefly, trimethylamine (TMA)-containing dietary compounds, found mainly in meat, milk, some fish, and other animal foods (e.g., lecithin, choline, betaine, carnitine) are converted by TMA lyases (lyases) in gut bacteria to TMA, which is absorbed and then oxidized by hepatic flavin mono-oxygenase 3 (FMO3) to the toxic trimethylamine N-oxide (TMAO).…”

Section: Introductionmentioning

confidence: 99%

New Insight into the Dietary Cause of Atherosclerosis: Implications for Pharmacology

Spector¹

2016

Journal of Pharmacology and Experimental Therapeutics

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At present, the guideline approach to the medical treatment and prevention of atherosclerotic cardiovascular disease (ASCVD) is to classify patients by risk and treat the known risk factors (contributory causes), e.g., hypertension, diabetes, obesity, smoking, and poor diet, as appropriate. All high-risk patients should receive statins. This approach has had substantial success but ASCVD still remains the number one cause of death in the United States. Until recently, the underlying cause of ASCVD remained unknown, although a potential dietary cause was suggested by the fact that vegetarians, especially vegans, have a much lower incidence of ASCVD than animal flesh eaters. Recently, consistent with the vegetarian data, substantial evidence for a cause of ASCVD in animals and humans has been discovered. Trimethylamine (TMA)-containing dietary compounds in meat, milk, and other animal foods (e.g., lecithin, choline, and carnitine) are converted by closely related gut bacterial TMA lyases to TMA, which is absorbed and converted predominantly by flavin mono-oxygenase 3 to the toxic trimethylamine N-oxide (TMAO). TMAO causes atherosclerosis in animals and is elevated in patients with coronary heart disease. Inhibition of bacterial lyases in mice prevents TMA and secondarily TMAO formation and atherosclerosis, strong evidence for the TMAO hypothesis. At present, the challenge for the pharmaceutical industry is to discover and develop a potent "broad spectrum" bacterial lyase inhibitor that, along with diet and exercise, could, if the TMAO hypothesis is correct, revolutionize the preventive treatment of ASCVD.

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“…In a recent, study Wang et al [19] demonstrated that 3,3-dimethyl-1-butanol (DMB), a structural analog of choline, blocks the intestinal TMA formation through the inhibition of the microbial TMA lyase, and results in reduced TMAO levels. Thus, 'drugging the microbiome' with DMB may be a novel approach for the prevention/treatment of atherosclerosis (Figure 3).…”

Section: Atherosclerosis and Thrombosis Riskmentioning

confidence: 99%

“…Inhibition of intestinal microbial trimethylamine (TMA) synthesis by 3,3-dimethyl-1-butanol (DMB) and attenuation of atherosclerosis [19].…”

Section: Journal Of Healthcare Communications Issn 2472-1654mentioning

confidence: 99%

The Microbiome: a Key Player in Human Health and Disease

Blum¹

2017

J Healthc Commun

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Until recently, human microbiology was based on the identification of single microbes, such as bacteria, fungi and viruses, frequently isolated from patients with acute or chronic infections. Novel culture-independent molecular biochemical analyses (genomics, transcriptomics, proteomics, metabolomics) now allow to detect and classify the diverse microorganisms in a given ecosystem (microbiota), such as the gastrointestinal tract, the skin, the airway system, the urogenital tract and others, and to assess all genomes in these ecosystems (microbiome) as well as their gene products. These analyses revealed that each individual has its own microbiota that plays a role in health, such as in immunity, neurological signalling, biosynthesis of vitamins or steroid hormones as well as the metabolism of drugs. In addition, they greatly contributed to the recent understanding of the role of the microbiome in the pathogenesis of a wide range of human diseases. It is to be expected that these new insights will translate into diagnostic, therapeutic and preventive perspectives in the context of personalized/precision medicine.

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Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis

Cited by 1,066 publications

References 35 publications

Trimethylamine N-oxide and Risk Stratification after Acute Myocardial Infarction

Trimethylamine N-oxide and Risk Stratification after Acute Myocardial Infarction

New Insight into the Dietary Cause of Atherosclerosis: Implications for Pharmacology

The Microbiome: a Key Player in Human Health and Disease

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