Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide

Wang, Zeneng; Tang, W.H. Wilson; Buffa, Jennifer A.; Fu, Xiaoming; Britt, Earl B.; Koeth, Robert A.; Levison, Bruce S.; Fan, Yuwei; Wu, Yuping; Hazen, Stanley L.

doi:10.1093/eurheartj/ehu002

Cited by 478 publications

(435 citation statements)

References 23 publications

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“…Direct ingestion of PC was shown to result in a rise in choline, betaine, and TMAO levels 1, 3. Moreover, previous studies have report that elevated plasma TMAO levels predicted future risk of major adverse cardiovascular events and have a direct mechanistic link to development of cardiovascular disease 1, 2, 3, 4. Extending these observations, in the present prospective study focused exclusively on patients with adjudicated diagnosis of PAD, an upper quartile for TMAO levels (compared with the lowest quartile) had a significant, 1.6‐fold increased risk for future all‐cause mortality, independent of traditional cardiovascular risk factors, inflammation markers, and eGFR.…”

Section: Discussionmentioning

confidence: 98%

Trimethylamine N ‐Oxide and Mortality Risk in Patients With Peripheral Artery Disease

Senthong

Wang

Fan

et al. 2016

JAHA

136

106

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BackgroundProduction of the proatherogenic metabolite, trimethylamine N‐oxide (TMAO), from dietary nutrients by intestinal microbiota enhances atherosclerosis development in animal models and is associated with atherosclerotic coronary artery disease in humans. The utility of studying plasma levels of TMAO to risk stratify in patients with peripheral artery disease (PAD) has not been reported.Methods and ResultsWe examined the relationship between fasting plasma TMAO and all‐cause mortality (5‐year), stratified by subtypes of PAD and presence of coronary artery disease in 935 patients with PAD who underwent elective angiography for cardiac evaluation at a tertiary care hospital. Median plasma TMAO was 4.8 μmol/L (interquartile range, 2.9–8.0 μmol/L). Elevated TMAO levels were associated with 2.7‐fold increased mortality risk (fourth versus first quartiles, hazard ratio 2.86, 95% CI 1.82–3.97, P<0.001). Following adjustments for traditional risk factors, inflammatory biomarkers, and history of coronary artery disease, the highest TMAO quartile remained predictive of 5‐year mortality (adjusted hazard ratio 2.06, 95% CI 1.36–3.11, P<0.001). Similar prognostic value for elevated TMAO was seen for subjects with carotid artery, non–carotid artery, or lower extremity PAD. TMAO provided incremental prognostic value for all‐cause mortality (net reclassification index, 40.22%; P<0.001) and improvement in area under receiver operator characteristic curve (65.7% versus 69.4%; P=0.013).Conclusions TMAO, a pro‐atherogenic metabolite formed by gut microbes, predicts long‐term adverse event risk and incremental prognostic value in patients with PAD. These findings point to the potential for TMAO to help improve selection of high‐risk PAD patients with or without significant coronary artery disease, who likely need more aggressive and specific dietary and pharmacologic therapy.

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Section: Discussionmentioning

confidence: 98%

Trimethylamine N ‐Oxide and Mortality Risk in Patients With Peripheral Artery Disease

Senthong

Wang

Fan

et al. 2016

JAHA

136

106

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“…Specifically, gut microbes were shown to play an obligatory role in trimethylamine N-oxide (TMAO) formation upon processing of common dietary components (e.g., choline in egg yolk or Lcarnitine in meat) both in mice 4,5 and in humans. [6][7][8][9] These studies also demonstrated that TMAO was not merely a biomarker, but it was also a mediator of alterations in cholesterol and sterol metabolism and can directly enhance atherogenesis. 4,5 Pathophysiologically, TMAO may also interact with other host neurohormonal systems, as observed in a rat model whereby angiotensin II infusion in the setting of elevated TMAO levels led to sustained augmentation of BP.…”

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confidence: 90%

“…6 Although elevated circulating L-carnitine and choline/betaine levels (all substrates of TMAO production) were also associated with future risk, their prognostic values were primarily restricted to those with concomitant elevated TMAO levels. 4,7 Over the past decades, there have been reports from small cohorts (n,20) that have observed that circulating TMAO levels are elevated in patients with ESRD and CKD. 12,13 In our cohort, TMAO levels remained elevated in CKD (eGFR,60 ml/min per 1.73 m 2 , calculated using the Modification of Diet in Renal Disease equation; n5583) compared with patients without CKD, and the prognostic value for TMAO in predicting future mortality risk remained robust in the CKD cohort even after adjustment for traditional risk factors.…”

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confidence: 99%

Trimethylamine N-Oxide as a Novel Therapeutic Target in CKD

Tang

2016

Journal of the American Society of Nephrology

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“…Moreover, high serum TMAO concentrations have been observed to strongly associate with incident cardiovascular events in humans with preserved kidney function, [8][9][10][11] providing solid clinical evidence to support a link between TMAO and cardiovascular pathology. Both L-carnitine and choline are metabolized by intestinal bacteria to trimethylamine, a metabolite which is absorbed from the intestine and subsequently oxidized via hepatic flavin monooxygenase enzymes to form TMAO.…”

mentioning

confidence: 91%

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Stubbs

House

Ocque

et al. 2016

Journal of the American Society of Nephrology

341

319

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Trimethlyamine-N-oxide (TMAO) was recently identified as a promoter of atherosclerosis. Patients with CKD exhibit accelerated development of atherosclerosis; however, no studies have explored the relationship between TMAO and atherosclerosis formation in this group. This study measured serum concentrations and urinary excretion of TMAO in a CKD cohort (n=104), identified the effect of renal transplant on serum TMAO concentration in a subset of these patients (n=6), and explored the cross-sectional relationship between serum TMAO and coronary atherosclerosis burden in a separate CKD cohort (n=220) undergoing coronary angiography. Additional exploratory analyses examined the relationship between baseline serum TMAO and long-term survival after coronary angiography. Serum TMAO concentrations demonstrated a strong inverse association with eGFR (r 2 =0.31, P,0.001). TMAO concentrations were markedly higher in patients receiving dialysis (median [interquartile range], 94.4 mM [54.8-133.0 mM] for dialysis-dependent patients versus 3.3 mM [3.1-6.0 mM] for healthy controls; P,0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min-max] 71.2 mM [29.2-189.7 mM] pretransplant versus 11.4 mM [8.9-20.2 mM] posttransplant; P=0.03). TMAO concentration was an independent predictor for coronary atherosclerosis burden (P=0.02) and predicted long-term mortality independent of traditional cardiac risk factors (hazard ratio, 1.26 per 10 mM increment in TMAO concentration; 95% confidence interval, 1.13 to 1.40; P,0.001). In conclusion, serum TMAO concentrations substantially increase with decrements in kidney function, and this effect is reversed by renal transplantation. Increased TMAO concentrations correlate with coronary atherosclerosis burden and may associate with long-term mortality in patients with CKD undergoing coronary angiography. Patients with CKD have a high prevalence of cardiovascular comorbidities, which primarily contributes to the exceedingly high mortality in this group. 1,2 For example, the 5-year survival for ESRD patients receiving dialysis is approximately 35%, with .50% of the mortality in this group resulting directly from cardiovascular causes. 1 It is well established that CKD patients exhibit a disproportionate burden of atherosclerosis as compared with individuals having normal kidney function. [2][3][4][5] Furthermore, a higher prevalence of traditional risk factors for the development of atherosclerosis, such as hypertension, diabetes and hyperlipidemia, only partially accounts for the accelerated atherosclerosis in CKD patients, leading to the hypothesis that unique risk factors must be present in this population. 6,7

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Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide

Abstract: Elevated plasma levels of choline and betaine are each associated with incident MACE risk independent of traditional risk factors. However, high choline and betaine levels are only associated with higher risk of future MACE with concomitant increase in TMAO.

Cited by 478 publications

References 23 publications

Trimethylamine N ‐Oxide and Mortality Risk in Patients With Peripheral Artery Disease

Trimethylamine N ‐Oxide and Mortality Risk in Patients With Peripheral Artery Disease

Trimethylamine N-Oxide as a Novel Therapeutic Target in CKD

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

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