Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta-Analysis of Prospective Studies

Yoriko Heianza, Wenjie Ma, JoAnn E Manson, Kathryn M Rexrode, Lu Qi, Yoriko Heianza, Wenjie Ma, JoAnn E Manson, Kathryn M Rexrode, Lu Qi

Abstract

Background: Gut microbial metabolites have been implicated as novel risk factors for cardiovascular events and premature death. The strength and consistency of associations between blood concentrations of the gut microbial metabolites, trimethylamine-N-oxide (TMAO) and its precursors, with major adverse cardiovascular events (MACE) or death have not been comprehensively assessed. We quantified associations of blood concentrations of TMAO and its precursors with risks of MACE and mortality.

Methods and results: PubMed and Embase databases were searched up, and a total of 19 prospective studies from 16 publications (n=19 256, including 3315 incident cases) with quantitative estimates of the associations of TMAO with the development of MACE or death were included in our main analysis. Multivariate-adjusted relative risks (RRs) were used when these were available. Elevated concentrations of TMAO were associated with a pooled RR of 1.62 (95% CI, 1.45, 1.80; Pheterogeneity=0.2; I2=23.5%) for MACE compared with low TMAO levels, and 1 study of black participants influenced the heterogeneity of the association. After excluding the data of blacks, the RRs were not different according to body mass index, prevalence of diabetes mellitus, history of cardiovascular diseases, and kidney dysfunction. Furthermore, elevated TMAO concentrations were associated with a pooled RR of 1.63 (1.36, 1.95) for all-cause mortality. Individuals with elevated concentrations of TMAO precursors (l-carnitine, choline, or betaine) had an approximately 1.3 to 1.4 times higher risk for MACE compared to those with low concentrations.

Conclusions: Elevated concentrations of TMAO and its precursors were associated with increased risks of MACE and all-cause mortality independently of traditional risk factors.

Keywords: major adverse cardiovascular events; meta‐analysis; risk; trimethylamine N‐oxide.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1
Figure 1
Selection of studies for meta‐analysis. MACE indicates major adverse cardiovascular events; TMAO, trimethylamine N‐oxide.
Figure 2
Figure 2
Pooled relative risks of high trimethylamine N‐oxide (TMAO) levels for the risk of major adverse clinical events/death (A) and all‐cause mortality (B). Dashed lines represent the overall effect, and gray boxes represent weight. ES indicates effect size; RR, relative risk.
Figure 3
Figure 3
Pooled relative risks of elevated concentrations of l‐carnitine or choline (A) and betaine (B) for major adverse cardiovascular events/death. Dashed lines represent the overall effect, and gray boxes represent weight. ES indicates effect size; RR, relative risk.

References

    1. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472:57–63.
    1. Koeth RA, Levison BS, Culley MK, Buffa JA, Wang Z, Gregory JC, Org E, Wu Y, Li L, Smith JD, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. gamma‐Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L‐carnitine to TMAO. Cell Metab. 2014;20:799–812.
    1. Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368:1575–1584.
    1. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, Didonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WHW, Bushman FD, Lusis AJ, Hazen SL. Intestinal microbiota metabolism of L‐carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19:576–585.
    1. Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ. Trimethylamine‐N‐oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013;17:49–60.
    1. Mente A, Chalcraft K, Ak H, Davis AD, Lonn E, Miller R, Potter MA, Yusuf S, Anand SS, McQueen MJ. The relationship between trimethylamine‐N‐oxide and prevalent cardiovascular disease in a multiethnic population living in Canada. Can J Cardiol. 2015;31:1189–1194.
    1. Lever M, George PM, Slow S, Bellamy D, Young JM, Ho M, McEntyre CJ, Elmslie JL, Atkinson W, Molyneux SL, Troughton RW, Frampton CM, Richards AM, Chambers ST. Betaine and trimethylamine‐N‐oxide as predictors of cardiovascular outcomes show different patterns in diabetes mellitus: an observational study. PLoS One. 2014;9:e114969.
    1. Tang WH, Wang Z, Fan Y, Levison B, Hazen JE, Donahue LM, Wu Y, Hazen SL. Prognostic value of elevated levels of intestinal microbe‐generated metabolite trimethylamine‐N‐oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol. 2014;64:1908–1914.
    1. Wang Z, Tang WH, Buffa JA, Fu X, Britt EB, Koeth RA, Levison BS, Fan Y, Wu Y, Hazen SL. Prognostic value of choline and betaine depends on intestinal microbiota‐generated metabolite trimethylamine‐N‐oxide. Eur Heart J. 2014;35:904–910.
    1. Kaysen GA, Johansen KL, Chertow GM, Dalrymple LS, Kornak J, Grimes B, Dwyer T, Chassy AW, Fiehn O. Associations of trimethylamine N‐oxide with nutritional and inflammatory biomarkers and cardiovascular outcomes in patients new to dialysis. J Ren Nutr. 2015;25:351–356.
    1. Tang WH, Wang Z, Kennedy DJ, Wu Y, Buffa JA, Agatisa‐Boyle B, Li XS, Levison BS, Hazen SL. Gut microbiota‐dependent trimethylamine N‐oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res. 2015;116:448–455.
    1. Tang WH, Wang Z, Shrestha K, Borowski AG, Wu Y, Troughton RW, Klein AL, Hazen SL. Intestinal microbiota‐dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J Card Fail. 2015;21:91–96.
    1. Troseid M, Ueland T, Hov JR, Svardal A, Gregersen I, Dahl CP, Aakhus S, Gude E, Bjorndal B, Halvorsen B, Karlsen TH, Aukrust P, Gullestad L, Berge RK, Yndestad A. Microbiota‐dependent metabolite trimethylamine‐N‐oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med. 2015;277:717–726.
    1. Mueller DM, Allenspach M, Othman A, Saely CH, Muendlein A, Vonbank A, Drexel H, von Eckardstein A. Plasma levels of trimethylamine‐N‐oxide are confounded by impaired kidney function and poor metabolic control. Atherosclerosis. 2015;243:638–644.
    1. Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, Li L, Fu X, Wu Y, Mehrabian M, Sartor RB, McIntyre TM, Silverstein RL, Tang WH, DiDonato JA, Brown JM, Lusis AJ, Hazen SL. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell. 2016;165:111–124.
    1. Suzuki T, Heaney LM, Bhandari SS, Jones DJ, Ng LL. Trimethylamine N‐oxide and prognosis in acute heart failure. Heart. 2016;102:841–848.
    1. Skagen K, Troseid M, Ueland T, Holm S, Abbas A, Gregersen I, Kummen M, Bjerkeli V, Reier‐Nilsen F, Russell D, Svardal A, Karlsen TH, Aukrust P, Berge RK, Hov JE, Halvorsen B, Skjelland M. The carnitine‐butyrobetaine‐trimethylamine‐N‐oxide pathway and its association with cardiovascular mortality in patients with carotid atherosclerosis. Atherosclerosis. 2016;247:64–69.
    1. Missailidis C, Hallqvist J, Qureshi AR, Barany P, Heimburger O, Lindholm B, Stenvinkel P, Bergman P. Serum trimethylamine‐N‐oxide is strongly related to renal function and predicts outcome in chronic kidney disease. PLoS One. 2016;11:e0141738.
    1. Stubbs JR, House JA, Ocque AJ, Zhang S, Johnson C, Kimber C, Schmidt K, Gupta A, Wetmore JB, Nolin TD, Spertus JA, Yu AS. Serum trimethylamine‐N‐oxide is elevated in CKD and correlates with coronary atherosclerosis burden. J Am Soc Nephrol. 2016;27:305–313.
    1. Kim RB, Morse BL, Djurdjev O, Tang M, Muirhead N, Barrett B, Holmes DT, Madore F, Clase CM, Rigatto C, Levin A, Can PI. Advanced chronic kidney disease populations have elevated trimethylamine N‐oxide levels associated with increased cardiovascular events. Kidney Int. 2016;89:1144–1152.
    1. Senthong V, Wang Z, Li XS, Fan Y, Wu Y, Tang WH, Hazen SL. Intestinal microbiota‐generated metabolite trimethylamine‐N‐oxide and 5‐year mortality risk in stable coronary artery disease: the contributory role of intestinal microbiota in a COURAGE‐like patient cohort. J Am Heart Assoc. 2016;5:e002816 DOI: .
    1. Shafi T, Powe NR, Meyer TW, Hwang S, Hai X, Melamed ML, Banerjee T, Coresh J, Hostetter TH. Trimethylamine N‐oxide and cardiovascular events in hemodialysis patients. J Am Soc Nephrol. 2017;28:321–331.
    1. Robinson‐Cohen C, Newitt R, Shen DD, Rettie AE, Kestenbaum BR, Himmelfarb J, Yeung CK. Association of FMO3 variants and trimethylamine N‐oxide concentration, disease progression, and mortality in CKD patients. PLoS One. 2016;11:e0161074.
    1. Ottiger M, Nickler M, Steuer C, Odermatt J, Huber A, Christ‐Crain M, Henzen C, Hoess C, Thomann R, Zimmerli W, Mueller B, Schuetz P. Trimethylamine‐N‐oxide (TMAO) predicts fatal outcomes in community‐acquired pneumonia patients without evident coronary artery disease. Eur J Intern Med. 2016;36:67–73.
    1. Senthong V, Wang Z, Fan Y, Wu Y, Hazen SL, Tang WH. Trimethylamine N‐oxide and mortality risk in patients with peripheral artery disease. J Am Heart Assoc. 2016;5:e004237 DOI: .
    1. Tang WH, Wang Z, Li XS, Fan Y, Li DS, Wu Y, Hazen SL. Increased trimethylamine N‐oxide portends high mortality risk independent of glycemic control in patients with type 2 diabetes mellitus. Clin Chem. 2017;63:297–306.
    1. Dambrova M, Latkovskis G, Kuka J, Strele I, Konrade I, Grinberga S, Hartmane D, Pugovics O, Erglis A, Liepinsh E. Diabetes is associated with higher trimethylamine N‐oxide plasma levels. Exp Clin Endocrinol Diabetes. 2016;124:251–256.
    1. Bain MA, Faull R, Fornasini G, Milne RW, Evans AM. Accumulation of trimethylamine and trimethylamine‐N‐oxide in end‐stage renal disease patients undergoing haemodialysis. Nephrol Dial Transplant. 2006;21:1300–1304.
    1. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB. Meta‐analysis of observational studies in epidemiology: a proposal for reporting. Meta‐analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283:2008–2012.
    1. Kip KE, Hollabaugh K, Marroquin OC, Williams DO. The problem with composite end points in cardiovascular studies: the story of major adverse cardiac events and percutaneous coronary intervention. J Am Coll Cardiol. 2008;51:701–707.
    1. Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle‐Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta‐analyses. 2014 Available at: . Accessed May 7, 2016.
    1. Higgins JP. Commentary: heterogeneity in meta‐analysis should be expected and appropriately quantified. Int J Epidemiol. 2008;37:1158–1160.
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ. 2003;327:557–560.
    1. Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med. 1997;127:820–826.
    1. Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta‐analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol. 2000;53:1119–1129.
    1. Greenland S, Longnecker MP. Methods for trend estimation from summarized dose‐response data, with applications to meta‐analysis. Am J Epidemiol. 1992;135:1301–1309.
    1. Scalbert A, Brennan L, Manach C, Andres‐Lacueva C, Dragsted LO, Draper J, Rappaport SM, van der Hooft JJ, Wishart DS. The food metabolome: a window over dietary exposure. Am J Clin Nutr. 2014;99:1286–1308.
    1. Wong JM. Gut microbiota and cardiometabolic outcomes: influence of dietary patterns and their associated components. Am J Clin Nutr. 2014;100(suppl 1):369S–377S.
    1. Claesson MJ, Jeffery IB, Conde S, Power SE, O'Connor EM, Cusack S, Harris HM, Coakley M, Lakshminarayanan B, O'Sullivan O, Fitzgerald GF, Deane J, O'Connor M, Harnedy N, O'Connor K, O'Mahony D, van Sinderen D, Wallace M, Brennan L, Stanton C, Marchesi JR, Fitzgerald AP, Shanahan F, Hill C, Ross RP, O'Toole PW. Gut microbiota composition correlates with diet and health in the elderly. Nature. 2012;488:178–184.
    1. Kong LC, Holmes BA, Cotillard A, Habi‐Rachedi F, Brazeilles R, Gougis S, Gausseres N, Cani PD, Fellahi S, Bastard JP, Kennedy SP, Dore J, Ehrlich SD, Zucker JD, Rizkalla SW, Clement K. Dietary patterns differently associate with inflammation and gut microbiota in overweight and obese subjects. PLoS One. 2014;9:e109434.
    1. Cotillard A, Kennedy SP, Kong LC, Prifti E, Pons N, Le Chatelier E, Almeida M, Quinquis B, Levenez F, Galleron N, Gougis S, Rizkalla S, Batto JM, Renault P; Consortium ANRM , Dore J, Zucker JD, Clement K, Ehrlich SD. Dietary intervention impact on gut microbial gene richness. Nature. 2013;500:585–588.
    1. Tang WH, Hazen SL. The contributory role of gut microbiota in cardiovascular disease. J Clin Invest. 2014;124:4204–4211.
    1. Liu TX, Niu HT, Zhang SY. Intestinal microbiota metabolism and atherosclerosis. Chin Med J. 2015;128:2805–2811.
    1. Tang WH, Hazen SL. Microbiome, trimethylamine N‐oxide, and cardiometabolic disease. Transl Res. 2017;179:108–115.
    1. Wilson A, McLean C, Kim RB. Trimethylamine‐N‐oxide: a link between the gut microbiome, bile acid metabolism, and atherosclerosis. Curr Opin Lipidol. 2016;27:148–154.
    1. Kucirka LM, Grams ME, Lessler J, Hall EC, James N, Massie AB, Montgomery RA, Segev DL. Association of race and age with survival among patients undergoing dialysis. JAMA. 2011;306:620–626.
    1. Kahn MR, Robbins MJ, Kim MC, Fuster V. Management of cardiovascular disease in patients with kidney disease. Nat Rev Cardiol. 2013;10:261–273.
    1. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI. A core gut microbiome in obese and lean twins. Nature. 2009;457:480–484.
    1. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444:1022–1023.
    1. Zhernakova A, Kurilshikov A, Bonder MJ, Tigchelaar EF, Schirmer M, Vatanen T, Mujagic Z, Vila AV, Falony G, Vieira‐Silva S, Wang J, Imhann F, Brandsma E, Jankipersadsing SA, Joossens M, Cenit MC, Deelen P, Swertz MA, Weersma RK, Feskens EJ, Netea MG, Gevers D, Jonkers D, Franke L, Aulchenko YS, Huttenhower C, Raes J, Hofker MH, Xavier RJ, Wijmenga C, Fu J. Population‐based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science. 2016;352:565–569.
    1. Sonnenburg JL, Backhed F. Diet‐microbiota interactions as moderators of human metabolism. Nature. 2016;535:56–64.
    1. Zheng Y, Li Y, Rimm EB, Hu FB, Albert CM, Rexrode KM, Manson JE, Qi L. Dietary phosphatidylcholine and risk of all‐cause and cardiovascular‐specific mortality among US women and men. Am J Clin Nutr. 2016;104:173–180.
    1. Warrier M, Shih DM, Burrows AC, Ferguson D, Gromovsky AD, Brown AL, Marshall S, McDaniel A, Schugar RC, Wang Z, Sacks J, Rong X, Vallim TA, Chou J, Ivanova PT, Myers DS, Brown HA, Lee RG, Crooke RM, Graham MJ, Liu X, Parini P, Tontonoz P, Lusis AJ, Hazen SL, Temel RE, Brown JM. The TMAO‐generating enzyme flavin monooxygenase 3 is a central regulator of cholesterol balance. Cell Rep. 2015;10:326–338.
    1. Senthong V, Li XS, Hudec T, Coughlin J, Wu Y, Levison B, Wang Z, Hazen SL, Tang WH. Plasma trimethylamine N‐oxide, a gut microbe‐generated phosphatidylcholine metabolite, is associated with atherosclerotic burden. J Am Coll Cardiol. 2016;67:2620–2628.
    1. Seldin MM, Meng Y, Qi H, Zhu W, Wang Z, Hazen SL, Lusis AJ, Shih DM. Trimethylamine N‐oxide promotes vascular inflammation through signaling of mitogen‐activated protein kinase and nuclear factor‐kappaB. J Am Heart Assoc. 2016;5:e002767 DOI: .
    1. Lever M, Slow S. The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism. Clin Biochem. 2010;43:732–744.

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