Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis

Schiattarella, Gabriele Giacomo; Sannino, Anna; Toscano, Evelina; Giugliano, Giuseppe; Gargiulo, Giuseppe; Franzone, Anna; Trimarco, Bruno; Esposito, Giovanni; Perrino, Cinzia

doi:10.1093/eurheartj/ehx342

Cited by 437 publications

(355 citation statements)

References 44 publications

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“…2 Recent animal and human data in PCOS showed alterations in composition of gut microbiota in PCOS, partly associated with androgen excess. [13][14][15] Even though limited studies have reported dysbiosis in PCOS, to the best of our knowledge, no data are available on gut microbiota-derived metabolites and impact of any treatment on those in the syndrome. 8,9 Trimethylamine N-oxide (TMAO) is the most well-known gut microbiota-related cardiometabolic risk factor which is highly related to atherosclerotic cardiovascular disease, type 2 diabetes and gestational diabetes mellitus.…”

Section: Introductionmentioning

confidence: 99%

“…Elevated circulating concentrations of both TMAO and its precursors are associated with increased risk of adverse cardiovascular events, independently of traditional risk factors. [13][14][15] Even though limited studies have reported dysbiosis in PCOS, to the best of our knowledge, no data are available on gut microbiota-derived metabolites and impact of any treatment on those in the syndrome. The primary aim of this study was to determine whether microbiota-related cardiometabolic risk markers are altered in PCOS.…”

Section: Introductionmentioning

confidence: 99%

“…It has been suggested that TMAO could serve as a novel and independent biomarker in humans for development of atherosclerosis and prediction of cardiovascular morbidity and mortality 10,[13][14][15]. It has been suggested that TMAO could serve as a novel and independent biomarker in humans for development of atherosclerosis and prediction of cardiovascular morbidity and mortality 10,[13][14][15].…”

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confidence: 99%

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Circulating gut microbiota metabolite trimethylamine N‐oxide and oral contraceptive use in polycystic ovary syndrome

Eyüpoğlu

Guzelce

Açıkgöz

et al. 2019

Clinical Endocrinology

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Objectives: Polycystic ovary syndrome (PCOS) is associated with an increased cardiometabolic risk that might not necessarily translate into adverse cardiovascular outcome later in life. Recently, alterations in gut microbial composition have been reported in the syndrome. Microbiota-dependent metabolite trimethylamine N-oxide (TMAO) and its precursors are closely linked with development of atherosclerotic cardiovascular disease, independently of traditional risk factors. We aimed to assess whether TMAO and its precursors are altered in PCOS and to determine potential impact of treatment on these metabolites. Design: Prospective study.Patients: Twenty-seven overweight/obese patients with PCOS and 25 age-and BMImatched healthy control women.Measurements: At baseline, fasting serum TMAO and its precursors were measured after a 3-day standardized diet. Patients received 3-month OC therapy along with general dietary advice after which all measurements were repeated. Results: Patients had higher total testosterone (T) and free androgen index (FAI)whereas whole-body fat mass, fasting plasma glucose, insulin and lipids were similar between the groups. PCOS group showed significantly higher serum levels of TMAO and its precursors; choline, betaine and carnitine. TMAO and choline showed correlations with T. After 3 months of OC use, TMAO and its precursors significantly decreased along with reductions in BMI, T and FAI. Conclusions:This study reports for the first time that TMAO and its precursors are elevated in PCOS which might contribute to increased cardiometabolic risk of the syndrome and that short-term OC use along with lifestyle intervention is associated with reduction of these microbiome-dependent metabolites. K E Y W O R D Scardiometabolic risk, microbiome, oral contraceptives, polycystic ovary syndrome, trimethylamine N-oxide | 811 EYUPOGLU Et aL.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Circulating gut microbiota metabolite trimethylamine N‐oxide and oral contraceptive use in polycystic ovary syndrome

Eyüpoğlu

Guzelce

Açıkgöz

et al. 2019

Clinical Endocrinology

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“…Obesity is one of the most important predictors of CVD and T 2 DM, and from an etiologic point of view, it is important to elucidate whether the associations between TMAO and CVD or other NCDs are established via an independent association between TMAO and obesity as a prognostic cardio‐metabolic risk factor. While no summarized evidence regarding the associations between obesity and TMAO is available, there are several meta‐analyses regarding the association between increased TMAO levels and risk of CVD mortality and T 2 DM . It should also be noted that no study is available to summarize the association between TMAO and obesity measurements.…”

Section: Introductionmentioning

confidence: 99%

Gut microbiota‐derived metabolite trimethylamine N‐oxide (TMAO) potentially increases the risk of obesity in adults: An exploratory systematic review and dose‐response meta‐ analysis

et al. 2020

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Summary It has been suggested that trimethylamine N‐oxide (TMAO) is associated with increased risk of diabetes and cardiovascular disease (CVD) morbidity and mortality. However, it is not known whether increased TMAO concentrations is associated with obesity. In the current study, we summarized the evidence related to the association of circulating TMAO with the risk of obesity measurements, including body mass index (BMI), waist circumference (WC), and waist‐to‐hip ratio (WHR) in a two‐class and dose‐response meta‐analysis of observational studies. A systematic search carried out in PubMed, SCOPUS, Cochrane, and ProQuest through September 30, 2019 resulted in 12 eligible studies which were included in the current meta‐synthesis. In these studies, BMI was reported but there were no reports of WC or WHR. Meta‐analysis of two‐class variables and dose‐response meta‐analysis of continuous variables were performed. Subgroup analysis and meta‐regression were also performed to identify the source of heterogeneity. There was a dose‐response association between circulating TMAO concentration and increased BMI in studies involving healthy individuals (P nonlinearity = .007), while no evidence of departure from linearity was observed according to study design or among patients with CVD. Results showed the highest category of TMAO was associated with 0.56 kg/m2 increase in BMI (weighted mean difference [WMD], 0.563; CI, 0.026‐1.100; P = .04). The results of the current meta‐analysis revealed a positive association between circulating TMAO and obesity as presented by increased BMI. Moreover, a dose‐dependent association between circulating TMAO and obesity was also identified in apparently healthy individuals. This is the first meta‐analysis to reveal positive dose‐dependent associations between circulating TMAO concentration and obesity.

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“…19 It is also known from epidemiological studies that specific methylated amines are associated with the risk for cardiovascular diseases, for instance ADMA 20,21 or TMAO. [22][23][24][25] TMAO is also a striking example of the recently recognized importance of the gut microbiota for foodrelated health issues. 26,27 In summary, this compound class is of high relevance and an interesting target for all studies related to nutrition, physical activity, and health.…”

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confidence: 99%

Targeted ultra‐performance liquid chromatography/tandem mass spectrometric quantification of methylated amines and selected amino acids in biofluids

Roggensack

Merz

Dick

et al. 2020

Rapid Comm Mass Spectrometry

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Rationale Methylated amino compounds and basic amino acids are important analyte classes with high relevance in nutrition, physical activity and physiology. Reliable and easy quantification methods covering a variety of metabolites in body fluids are a prerequisite for efficient investigations in the field of food and nutrition. Methods Targeted ultra‐performance liquid chromatography/tandem mass spectrometric (UHPLC/MS) analysis was performed using HILIC separation and timed ESI‐MRM detection, combined with a short sample preparation. Calibration in urine and blood plasma was achieved by matrix‐matched standards, isotope‐labelled internal standards and standard addition. The method was fully validated and the performance was evaluated using a subset from the Karlsruhe Metabolomics and Nutrition (KarMeN) study. Results Within this method, a total of 30 compounds could be quantified simultaneously in a short run of 9 min in both body fluids. This covers a variety of free amino compounds which are present in very different concentrations. The method is easy, precise and robust, and has a broad working range. As a proof of principle, literature‐based associations of certain metabolites with dietary intake of respective foods were clearly confirmed in the KarMeN subset. Conclusions Overall, the method turned out to be well suited for application in nutrition studies, as shown for the example of food intake biomarkers in KarMeN. Application to a variety of questions such as food‐related effects or physical activity will support future studies in the context of nutrition and health.

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Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis

Abstract: This is the first systematic review and meta-analysis demonstrating the positive dose-dependent association between TMAO plasma levels and increased cardiovascular risk and mortality.

Cited by 437 publications

References 44 publications

Circulating gut microbiota metabolite trimethylamine N‐oxide and oral contraceptive use in polycystic ovary syndrome

Circulating gut microbiota metabolite trimethylamine N‐oxide and oral contraceptive use in polycystic ovary syndrome

Gut microbiota‐derived metabolite trimethylamine N‐oxide (TMAO) potentially increases the risk of obesity in adults: An exploratory systematic review and dose‐response meta‐ analysis

Targeted ultra‐performance liquid chromatography/tandem mass spectrometric quantification of methylated amines and selected amino acids in biofluids

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