Trimethylamine N-Oxide, the Microbiome, and Heart and Kidney Disease

Annual Review of Nutrition

Volumn 37, Issue , 2017, Pages 157-181

  Zeisel, Steven H ^a   Warrier, Manya ^a  

^a UNIVERSITY OF NORTH CAROLINA   (United States)

Author keywords

Cardiovascular disease; Carnitine; Choline; Gut bacteria; Kidney disease; TMA; TMAO

Indexed keywords

METHYLAMINE; TRIMETHYLOXAMINE;

ANIMAL; BACTERIUM; BLOOD; CHEMICALLY INDUCED; DIET; FEMALE; HEART DISEASE; HUMAN; KIDNEY DISEASE; LIVER; MALE; METABOLISM; MICROFLORA;

ANIMALS; BACTERIA; DIET; FEMALE; HEART DISEASES; HUMANS; KIDNEY DISEASES; LIVER; MALE; METHYLAMINES; MICROBIOTA;

EID: 85027975271     PISSN: 01999885     EISSN: 15454312     Source Type: Book Series    
DOI: 10.1146/annurev-nutr-071816-064732     Document Type: Review

References (138)

1. al-Waiz M, Mikov M, Mitchell SC, Smith RL. 1992. The exogenous origin of trimethylamine in the mouse. Metabolism 41:135-36
2. Al-Waiz M, Mitchell SC, Idle JR, Smith RL. 1987. The metabolism of 14C-labelled trimethylamine and its N-oxide in man. Xenobiotica 17:551-58
3. Albert CM, Hennekens CH, O'Donnell CJ, Ajani UA, Carey VJ, et al. 1998. Fish consumption and risk of sudden cardiac death. JAMA 279:23-28
4. Anderson CW. 1993. DNA damage and the DNA-activated protein kinase. Trends Biochem. Sci. 18:433-37
5. Aron-Wisnewsky J, Clement K. 2016. The gut microbiome, diet, and links to cardiometabolic and chronic disorders. Nat. Rev. Nephrol. 12:169-81
6. Athawale MV, Dordick JS, Garde S. 2005. Osmolyte trimethylamine-N-oxide does not affect the strength of hydrophobic interactions: Origin of osmolyte compatibility. Biophys. J. 89:858-66
7. Bae S, Ulrich CM, Neuhouser ML, Malysheva O, Bailey LB, et al. 2014. Plasma cholinemetabolites and colorectal cancer risk in the Women's Health Initiative Observational Study. Cancer Res. 74:7442-52
8. Bain MA, Faull R, Fornasini G, Milne RW, Evans AM. 2006. Accumulation of trimethylamine and trimethylamine-N-oxide in end-stage renal disease patients undergoing haemodialysis. Nephrol. Dial. Transplant. 21:1300-4
9. Bain MA, Fornasini G, Evans AM. 2005. Trimethylamine: Metabolic, pharmacokinetic and safety aspects. Curr. Drug Metab. 6:227-40
10. Bang HO, Dyerberg J, Nielsen AB. 1971. Plasma lipid and lipoprotein pattern in Greenlandic west-coast Eskimos. Lancet 297:1143-46
11. Barton S, Navarro SL, Buas MF, Schwarz Y, Gu H, et al. 2015. Targeted plasma metabolome response to variations in dietary glycemic load in a randomized, controlled, crossover feeding trial in healthy adults. Food Funct. 6:2949-56
12. Bell JD, Lee JA, Lee HA, Sadler PJ, Wilkie DR, Woodham RH. 1991. Nuclear magnetic resonance studies of blood plasma and urine from subjects with chronic renal failure: Identification of trimethylamine-N-oxide. Biochim. Biophys. Acta 1096:101-7
13. Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, et al. 2013. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 17:49-60
14. Bennion BJ, Daggett V. 2004. Counteraction of urea-induced protein denaturation by trimethylamine N-oxide: A chemical chaperone at atomic resolution. PNAS 101:6433-38
15. Biddinger SB, Hernandez-Ono A, Rask-Madsen C, Haas JT, Aleman JO, et al. 2008. Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab. 7:125-34
16. Bidulescu A, Chambless LE, Siega-Riz AM, Zeisel SH, Heiss G. 2007. Usual choline and betaine dietary intake and incident coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study. BMC Cardiovasc. Disord. 7:20
17. Blesso CN. 2015. Egg phospholipids and cardiovascular health. Nutrients 7:2731-47
18. Borrel G, Harris HM, Tottey W, Mihajlovski A, Parisot N, et al. 2012. Genome sequence of "Candidatus Methanomethylophilus alvus" Mx1201, a methanogenic archaeon from the human gut belonging to a seventh order of methanogens. J. Bacteriol. 194:6944-45
19. Brown JM, Hazen SL. 2014. Meta-organismal nutrient metabolism as a basis of cardiovascular disease. Curr. Opin. Lipidol. 25:48-53
20. Brown JM, Hazen SL. 2015. The gut microbial endocrine organ: Bacterially derived signals driving cardiometabolic diseases. Annu. Rev. Med. 66:343-59
21. Brugère JF, Borrel G, Gaci N, Tottey W, O'Toole PW, Malpuech-Brugère C. 2014. Archaebiotics: Proposed therapeutic use of archaea to prevent trimethylaminuria and cardiovascular disease. Gut Microbes 5:5-10
22. Buzello M, Tornig J, Faulhaber J, Ehmke H, Ritz E, Amann K. 2003. The apolipoprotein E knockout mouse: A model documenting accelerated atherogenesis in uremia. J. Am. Soc. Nephrol. 14:311-16
23. Cashman J.R. 2000. Human flavin-containing monooxygenase: Substrate specificity and role in drug metabolism. Curr. Drug Metab. 1:181-91
24. Cashman JR, Xiong Y, Lin J, Verhagen H, van Poppel G, et al. 1999. In vitro and in vivo inhibition of human flavin-containing monooxygenase form 3 (FMO3) in the presence of dietary indoles. Biochem. Pharmacol. 58:1047-55
25. Chao CK, Zeisel SH. 1990. Formation of trimethylamine from dietary choline by Streptococcus sanguis I, which colonizes the mouth. J. Nutr. Biochem. 1:89-97
26. Chebotareva NA. 2007. Effect of molecular crowding on the enzymes of glycogenolysis. Biochemistry 72:1478-90
27. Chen ML, Yi L, Zhang Y, Zhou X, Ran L, et al. 2016. Resveratrol attenuates trimethylamine-Noxide (TMAO)-induced atherosclerosis by regulating TMAO synthesis and bile acid metabolism via remodeling of the gut microbiota. m Bio 7:e02210-15
28. Cho CE, Taesuwan S, Malysheva OV, Bender E, Tulchinsky NF, et al. 2016. Trimethylamine-N-oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: A randomized controlled trial. Mol. Nutr. Food Res. 61(1):1600324
29. Cho SS, Reddy G, Straub JE, Thirumalai D. 2011. Entropic stabilization of proteins by TMAO. J. Phys. Chem. B 115:13401-7
30. Chowdhury R, Stevens S, Gorman D, Pan A, Warnakula S, et al. 2012. Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: Systematic review and meta-analysis. BMJ 345:e6698
31. Collins HL, Drazul-Schrader D, Sulpizio AC, Koster PD, Williamson Y, et al. 2016. L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in Apo E-/-transgenic mice expressing CETP. Atherosclerosis 244:29-37
32. Craciun S, Balskus EP. 2012. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. PNAS 109:21307-12
33. Craig SA. 2004. Betaine in human nutrition. Am. J. Clin. Nutr. 80:539-49
34. Dalmeijer GW, Olthof MR, Verhoef P, Bots ML, van der Schouw YT. 2008. Prospective study on dietary intakes of folate, betaine, and choline and cardiovascular disease risk in women. Eur. J. Clin. Nutr. 62:386-94
35. Dambrova M, Latkovskis G, Kuka J, Strele I, Konrade I, et al. 2016. Diabetes is associated with higher trimethylamine N-oxide plasma levels. Exp. Clin. Endocrinol. Diabetes 124:251-56
36. Dambrova M, Skapare-Makarova E, Konrade I, Pugovics O, Grinberga S, et al. 2013. Meldonium decreases the diet-increased plasma levels of trimethylamine N-oxide, a metabolite associated with atherosclerosis. J. Clin. Pharmacol. 53:1095-98
37. Di Nicolantonio JJ, Lavie CJ, Fares H, Menezes AR, O'Keefe JH. 2013. L-Carnitine in the secondary prevention of cardiovascular disease: Systematic review and meta-analysis. Mayo Clin. Proc. 88:544-51
38. Dridi B, Fardeau ML, Ollivier B, Raoult D, Drancourt M. 2012. Methanomassiliicoccus luminyensis gen. nov., sp. Nov., a methanogenic archaeon isolated from human faeces. Int. J. Syst. Evol. Microbiol. 62:1902-7
39. Dumas ME, Barton RH, Toye A, Cloarec O, Blancher C, et al. 2006. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. PNAS 103:12511-16
40. Dyerberg J, Bang HO, Hjorne N. 1975. Fatty acid composition of the plasma lipids in Greenland Eskimos. Am. J. Clin. Nutr. 28:958-66
41. Falony G, Vieira-Silva S, Raes J. 2015. Microbiology meets big data: The case of gut microbiota-derived trimethylamine. Annu. Rev. Microbiol. 69:305-21
42. Flanagan JL, Simmons PA, Vehige J, Willcox MD, Garrett Q. 2010. Role of carnitine in disease. Nutr. Metab. 7:30
43. Fukami K, Yamagishi S, Sakai K, Kaida Y, Yokoro M, et al. 2015. Oral L-carnitine supplementation increases trimethylamine-N-oxide but reduces markers of vascular injury in hemodialysis patients. J. Cardiovasc. Pharmacol. 65:289-95
44. Gao X, Liu X, Xu J, Xue C, Xue Y, Wang Y. 2014. Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet. J. Biosci. Bioeng. 118:476-81
45. Hai X, Landeras V, Dobre MA, De Oreo P, Meyer TW, Hostetter TH. 2015. Mechanism of prominent trimethylamine oxide (TMAO) accumulation in hemodialysis patients. PLOS ONE 10:e0143731
46. Haissman JM, Knudsen A, Hoel H, Kjaer A, Kristoffersen US, et al. 2016. Microbiota-dependentmarker TMAO is elevated in silent ischemia but is not associated with first-time myocardial infarction in HIV infection. J. Acquir. Immune Defic. Syndr. 1999 71:130-36
47. Hand SC, Carpenter JF. 1986. p H-Induced hysteretic properties of phosphofructokinase purified from rat myocardium. Am. J. Physiol. 250:R505-11
48. Hand SC, Somero GN. 1982. Urea and methylamine effects on rabbit muscle phosphofructokinase. Catalytic stability and aggregation state as a function of p H and temperature. J. Biol. Chem. 257:734-41
49. Hartiala J, Bennett BJ, Tang WH, Wang Z, Stewart AF, et al. 2014. Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and L-carnitine. Arterioscler. Thromb. Vasc. Biol. 34:1307-13
50. He K, Song Y, Daviglus ML, Liu K, Van Horn L, et al. 2004. Fish consumption and incidence of stroke: A meta-analysis of cohort studies. Stroke. 35:1538-42
51. He K, Song Y, Daviglus ML, Liu K, Van Horn L, et al. 2004. Accumulated evidence on fish consumption and coronary heart disease mortality: A meta-analysis of cohort studies. Circulation 109:2705-11
52. Herlaar E, Brown Z. 1999. p38 MAPK signalling cascades in inflammatory disease. Trends Mol. Med. 5:439-47
53. Hsu WY, Lo WY, Lai CC, Tsai FJ, Tsai CH, et al. 2007. Rapid screening assay of trimethylaminuria in urine with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Rapid Commun. Mass Spectrom. 21:1915-19
54. Hu FB, Bronner L, Willett WC, Stampfer MJ, Rexrode KM, et al. 2002. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA 287:1815-21
55. Huo T, Cai S, Lu X, Sha Y, Yu M, Li F. 2009. Metabonomic study of biochemical changes in the serum of type 2 diabetes mellitus patients after the treatment of metformin hydrochloride. J. Pharm. Biomed. Anal. 49:976-82
56. Inst.Med., Natl. Acad. 1998. Choline. In Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline, 1:390-422. Washington, DC: Natl. Acad.
57. Jawien J, Nastalek P, Korbut R. 2004. Mousemodels of experimental atherosclerosis. J. Physiol. Pharmacol. 55:503-17
58. Johnson DW. 2008. A flow injection electrospray ionization tandem mass spectrometric method for the simultaneous measurement of trimethylamine and trimethylamine N-oxide in urine. J. Mass Spectrom. 43:495-99
59. Kaysen GA, Johansen KL, Chertow GM, Dalrymple LS, Kornak J, et al. 2015. Associations of trimethylamine N-oxide with nutritional and inflammatory biomarkers and cardiovascular outcomes in patients new to dialysis. J. Ren. Nutr. 25:351-56
60. Kim KB, Yang JY, Kwack SJ, Park KL, Kim HS, et al. 2010. Toxicometabolomics of urinary biomarkers for human gastric cancer in a mouse model. J. Toxicol. Environ. Health Part A 73:1420-30
61. Kim RB, Morse BL, Djurdjev O, Tang M, Muirhead N, et al. 2016. Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events. Kidney Int. 89:1144-52
62. Koeth RA, Levison BS, Culley MK, Buffa JA, Wang Z, et al. 2014. ?-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab. 20:799-812
63. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, et al. 2013. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19:576-85
64. Koukouritaki SB, Simpson P, Yeung CK, Rettie AE, Hines RN. 2002. Human hepatic flavin-containing monooxygenases 1 (FMO1) and 3 (FMO3) developmental expression. Pediatr. Res. 51:236-43
65. Kromhout D, Bosschieter EB, de Lezenne Coulander C. 1985. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N. Engl. J. Med. 312:1205-9
66. Kuhn T, Rohrmann S, Sookthai D, Johnson T, Katzke V, et al. 2017. Intra-individual variation of plasma trimethylamine-N-oxide (TMAO), betaine, and choline over 1 year. Clin. Chem. Lab. Med. 55:261-68
67. Kuka J, Liepinsh E, Makrecka-Kuka M, Liepins J, Cirule H, et al. 2014. Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation. Life Sci. 117:84-92
68. Lee MB, Storer MK, Blunt JW, Lever M. 2006. Validation of 1H NMR spectroscopy as an analytical tool for methylamine metabolites in urine. Clin. Chim. Acta 365:264-69
69. Lever M, George PM, Slow S, Bellamy D, Young JM, et al. 2014. Betaine and trimethylamine-N-oxide as predictors of cardiovascular outcomes show different patterns in diabetes mellitus: An observational study. PLOS ONE 9:e114969
70. Li X, Chen Y, Liu J, Yang G, Zhao J, et al. 2012. Serum metabolic variables associated with impaired glucose tolerance induced by high-fat-high-cholesterol diet in Macaca mulatta. Exp. Biol. Med. 237:1310-21
71. Mackay RJ, Mc Entyre CJ, Henderson C, Lever M, George PM. 2011. Trimethylaminuria: Causes and diagnosis of a socially distressing condition. Clin. Biochem. Rev. 32:33-43
72. Mafune A, Iwamoto T, Tsutsumi Y, Nakashima A, Yamamoto I, et al. 2016. Associations among serum trimethylamine-N-oxide (TMAO) levels, kidney function and infarcted coronary artery number in patients undergoing cardiovascular surgery: A cross-sectional study. Clin. Exp. Nephrol. 20:731-39
73. Martin FP, Wang Y, Sprenger N, Yap IK, Lundstedt T, et al. 2008. Probiotic modulation of symbiotic gut microbial-host metabolic interactions in a humanized microbiome mouse model. Mol. Syst. Biol. 4:157
74. Massy ZA, Ivanovski O, Nguyen-Khoa T, Angulo J, Szumilak D, et al. 2005. Uremia accelerates both atherosclerosis and arterial calcification in apolipoprotein E knockout mice. J. Am. Soc. Nephrol. 16:109-16
75. Mente A, Chalcraft K, Ak H, Davis AD, Lonn E, et al. 2015. The relationship between trimethylamine-N-oxide and prevalent cardiovascular disease in a multiethnic population living in Canada. Can. J. Cardiol. 31:1189-94
76. Meyer KA, Benton TZ, Bennett BJ, Jacobs DR, Lloyd-Jones DM, et al. 2016. Themicrobiota-dependent metabolite trimethylamine N-oxide (TMAO) and coronary artery calcium in the Coronary Artery Risk Development in Young Adults Study (CARDIA). J. Am. Heart Assoc. 5:e003970
77. Miao J, Ling AV, Manthena PV, Gearing ME, Graham MJ, et al. 2015. Flavin-containingmonooxygenase 3 as a potential player in diabetes-associated atherosclerosis. Nat. Commun. 6:6498
78. Millard HR, Musani SK, Dibaba DT, Talegawkar SA, Taylor HA, et al. 2016. Dietary choline and betaine; associations with subclinical markers of cardiovascular disease risk and incidence of CVD, coronary heart disease and stroke: The Jackson Heart Study. Eur. J. Nutr. doi:10.1007/s00394-016-1296-8
79. Miller CA, Corbin KD, da Costa KA, Zhang S, Zhao X, et al. 2014. Effect of egg ingestion on trimethylamine-N-oxide production in humans: A randomized, controlled, dose-response study. Am. J. Clin. Nutr. 100:778-86
80. Mills GA, Walker V, Mughal H. 1999. Quantitative determination of trimethylamine in urine by solidphase microextraction and gas chromatography-mass spectrometry. J. Chromatogr. B Biomed. Sci. Appl. 723:281-85
81. Missailidis C, Hallqvist J, Qureshi AR, Barany P, Heimburger O, et al. 2016. Serum trimethylamine-Noxide is strongly related to renal function and predicts outcome in chronic kidney disease. PLOS ONE 11:e0141738
82. Mitchell SC, Smith RL. 2001. Trimethylaminuria: The fish malodor syndrome. Drug Metab. Dispos. 29:517-21
83. Mondul AM, Moore SC, Weinstein SJ, Karoly ED, Sampson JN, Albanes D. 2015. Metabolomic analysis of prostate cancer risk in a prospective cohort: The Alpha-Tocolpherol, Beta-Carotene Cancer Prevention (ATBC) Study. Int. J. Cancer 137:2124-32
84. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, et al. 2016. Heart disease and stroke statistics-2016 update: A report from the American Heart Association. Circulation 133:e38-360
85. Mueller DM, Allenspach M, Othman A, Saely CH, Muendlein A, et al. 2015. Plasma levels of trimethylamine-N-oxide are confounded by impaired kidney function and poor metabolic control. Atherosclerosis 243:638-44
86. Nagatomo Y, Tang WH. 2015. Intersections between microbiome and heart failure: Revisiting the gut hypothesis. J. Card. Fail. 21:973-80
87. Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. 1994. Apo E-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler. Thromb. Vasc. Biol. 14:133-40
88. Nnane IP, Damani LA. 2001. Pharmacokinetics of trimethylamine in rats, including the effects of a synthetic diet. Xenobiotica 31:749-55
89. Obeid R, Awwad HM, Rabagny Y, Graeber S, Herrmann W, Geisel J. 2016. Plasma trimethylamine N-oxide concentration is associated with choline, phospholipids, and methyl metabolism. Am. J. Clin. Nutr. 103:703-11
90. Organ CL, Otsuka H, Bhushan S, Wang Z, Bradley J, et al. 2016. Choline diet and its gut microbederived metabolite, trimethylamine N-oxide, exacerbate pressure overload-induced heart failure. Circ. Heart Fail. 9:e002314
91. Paul S, Patey GN. 2007. Structure and interaction in aqueous urea-trimethylamine-N-oxide solutions. J. Am. Chem. Soc. 129:4476-82
92. Posada-Ayala M, Zubiri I, Martin-Lorenzo M, Sanz-Maroto A, Molero D, et al. 2014. Identification of a urine metabolomic signature in patients with advanced-stage chronic kidney disease. Kidney Int. 85:103-11
93. Rhee EP, Clish CB, Ghorbani A, Larson MG, Elmariah S, et al. 2013. A combined epidemiologic and metabolomic approach improves CKD prediction. J. Am. Soc. Nephrol. 24:1330-38
94. Rohrmann S, Linseisen J, Allenspach M, von Eckardstein A, Muller D. 2016. Plasma concentrations of trimethylamine-N-oxide are directly associated with dairy food consumption and low-grade inflammation in a German adult population. J. Nutr. 146:283-89
95. Rohrmann S, Overvad K, Bueno-de-Mesquita HB, Jakobsen MU, Egeberg R, et al. 2013. Meat consumption andmortality-results from the European Prospective Investigation into Cancer and Nutrition. BMC Med. 11:63
96. Romano KA, Vivas EI, Amador-Noguez D, Rey FE. 2015. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-Noxide. m Bio 6:e02481
97. Schugar RC, Brown JM. 2015. Emerging roles of flavinmonooxygenase 3 in cholesterolmetabolism and atherosclerosis. Curr. Opin. Lipidol. 26:426-31
98. Seibel BA, Walsh PJ. 2002. Trimethylamine oxide accumulation in marine animals: Relationship to acylglycerol storage. J. Exp. Biol. 205:297-306
99. Seldin MM, Meng Y, Qi H, Zhu W, Wang Z, et al. 2016. Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-?B. J. Am. Heart Assoc. 5:e002767
100. Senthong V, Li XS, Hudec T, Coughlin J, Wu Y, et al. 2016. Plasma trimethylamine N-oxide, a gut microbe-generated phosphatidylcholine metabolite, is associated with atherosclerotic burden. J. Am. Coll. Cardiol. 67:2620-28
101. Senthong V, Wang Z, Li XS, Fan Y, Wu Y, et al. 2016. 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. 5:e002816
102. Shih DM, Wang Z, Lee R, Meng Y, Che N, et al. 2015. Flavin containingmonooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis. J. Lipid Res. 56:22-37
103. Shimizu M, Cashman JR, Yamazaki H. 2007. Transient trimethylaminuria related to menstruation.BMC Med. Genet. 8:2
104. Spence JD, Urquhart BL, Bang H. 2016. Effect of renal impairment on atherosclerosis: Only partially mediated by homocysteine. Nephrol. Dial. Transplant 31:937-44
105. Street TO, Bolen DW, Rose GD. 2006. A molecular mechanism for osmolyte-induced protein stability. PNAS 103:13997-4002
106. Stubbs JR, House JA, Ocque AJ, Zhang S, Johnson C, et al. 2016. Serum trimethylamine-N-oxide is elevated in CKD and correlates with coronary atherosclerosis burden. J. Am. Soc. Nephrol. 27:305-13
107. Svensson BG, Akesson B, Nilsson A, Paulsson K. 1994. Urinary excretion of methylamines in men with varying intake of fish from the Baltic Sea. J. Toxicol. Environ. Health 41:411-20
108. Tang WH. 2016. Trimethylamine N-oxide as a novel therapeutic target in CKD. J. Am. Soc. Nephrol. 27:8-10
109. Tang WH, Wang Z, Kennedy DJ, Wu Y, Buffa JA, et al. 2015. Gutmicrobiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ. Res. 116:448-55
110. Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, et al. 2013. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368:1575-84
111. Tang WH, Wang Z, Shrestha K, Borowski AG, Wu Y, et al. 2015. Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J. Card. Fail. 21:91-96
112. Thibodeaux CJ, van der Donk WA. 2012. Converging on a mechanism for choline degradation. PNAS 109:21184-85
113. Treacy EP, Akerman BR, Chow LM, Youil R, Bibeau C, et al. 1998. Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum. Mol. Genet. 7:839-45
114. Troseid M, Hov JR, Nestvold TK, Thoresen H, Berge RK, et al. 2016. Major increase in microbiotadependent proatherogenicmetabolite TMAOone year after bariatric surgery. Metab. Syndr. Relat.Disord. 14:197-201
115. Troseid M, Ueland T, Hov JR, Svardal A, Gregersen I, et al. 2015. Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J. Intern. Med. 277:717-26
116. US Dep. Aric. 2008. USDA Database for the Choline Content of Common Foods, Release 2. Washington, DC: US Dep. Agric. https://www.ars.usda.gov/northeast-area/beltsville-md/beltsvillehuman-nutrition-research-center/nutrient-data-laboratory/docs/usda-database-for-the-cholinecontent-of-common-foods-release-2-2008/
117. Wallrabenstein I, Kuklan J, Weber L, Zborala S, Werner M, et al. 2013. Human trace amine-associated receptor TAAR5 can be activated by trimethylamine. PLOS ONE 8:e54950
118. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, et al. 2011. Gut florametabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472:57-63
119. Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, et al. 2015. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163:1585-95
120. Wang Z, Tang WH, Buffa JA, Fu X, Britt EB, et al. 2014. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur. Heart J. 35:904-10
121. Warrier M, Shih DM, Burrows AC, Ferguson D, Gromovsky AD, et al. 2015. The TMAO-generating enzyme flavin monooxygenase 3 is a central regulator of cholesterol balance. Cell Rep. 10:326-38
122. Wojciechowski P, Tangri N, Rigatto C, Komenda P. 2016. Risk prediction in CKD: The rational alignment of health care resources in CKD 4/5 care. Adv. Chronic Kidney Dis. 23:227-30
123. Xu J, Zhang J, Cai S, Dong J, Yang JY, Chen Z. 2009. Metabonomics studies of intact hepatic and renal cortical tissues from diabetic db/db mice using high-resolution magic-angle spinning 1H NMR spectroscopy. Anal. Bioanal. Chem. 393:1657-68
124. Xu R, Wang Q, Li L. 2015. A genome-wide systems analysis reveals strong link between colorectal cancer and trimethylamine N-oxide (TMAO), a gut microbial metabolite of dietary meat and fat. BMC Genom. 16(Suppl. 7):S4
125. Zeisel SH. 2006. Choline: Critical role during fetal development and dietary requirements in adults. Annu. Rev. Nutr. 26:229-50
126. Zeisel SH, Da Costa KA. 1986. Increase in human exposure tomethylamine precursors of N-nitrosamines after eating fish. Cancer Res. 46:6136-38
127. Zeisel SH, da Costa KA, La Mont JT. 1988. Mono-, di-and trimethylamine in human gastric fluid: Potential substrates for nitrosodimethylamine formation. Carcinogenesis 9:179-81
128. Zeisel SH, da Costa KA, Youssef M, Hensey S. 1989. Conversion of dietary choline to trimethylamine and dimethylamine in rats: Dose-response relationship. J. Nutr. 119:800-4
129. Zeisel SH, Mar M-H, Howe JC, Holden JM. 2003. Erratum: Concentrations of choline-containing compounds and betaine in common foods J. Nutr. 133:1302-7.
130. Erratum. 2003. J. Nutr. 133:2918
131. Zeisel SH, Mar MH, Howe JC, Holden JM. 2003. Concentrations of choline-containing compounds and betaine in common foods. J. Nutr. 133:1302-7
132. Zeisel SH, Wishnok JS, Blusztajn JK. 1983. Formation of methylamines from ingested choline and lecithin. J. Pharmacol. Exp. Ther. 225:320-24
133. Zhang AQ, Mitchell S, Smith R. 1995. Fish odour syndrome: Verification of carrier detection test. J. Inherit. Metab. Dis. 18:669-74
134. Zhang J, Cashman JR. 2006. Quantitative analysis of FMO gene m RNA levels in human tissues. Drug Metab. Dispos. 34:19-26
135. Zhao X, Zeisel SH, Zhang S. 2015. Rapid LC-MRM-MS assay for simultaneous quantification of choline, betaine, trimethylamine, trimethylamine N-oxide, and creatinine in human plasma and urine. Electrophoresis 36:2207-14
136. Zheng Y, Li Y, Rimm EB, Hu FB, Albert CM, et al. 2016. Dietary phosphatidylcholine and risk of allcause and cardiovascular-specific mortality among US women and men. Am. J. Clin. Nutr. 104:173-80
137. Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, et al. 2016. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165:111-24
138. Zhu Y, Jameson E, Crosatti M, Schafer H, Rajakumar K, et al. 2014. Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota. PNAS 111:4268-73