Potential effects of natural dietary compounds on trimethylamine N-oxide (TMAO) formation and TMAO-induced atherosclerosis
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide. Recently, trimethylamine N-oxide (TMAO) is identified to be highly associated with CVD development and exacerbates atherosclerosis by several mechanisms. TMAO is a gut microbiota-dependent metabolite formed from dietary quaternary amines, mainly choline and carnitine. These trimethylamine (TMA)-containing compounds are first converted to TMA by enzymes in gut microbiota and subsequently metabolized by the host hepatic enzymes to TMAO. As the microbiome is the source of TMAO, administration of broad spectrum antibiotics shows marked decrease in TMAO levels. However, antibiotics may possess many possible undesirable side effects and chronic treatment consideration effects of antibiotic resistance in bacteria. Thus, studies have focused on the alternative strategies, including use of natural dietary compounds to reduce elevated TMAO levels and prevent atherogenesis. Natural dietary compounds have been studied for their beneficial health effects for decades. Diet and nutritional interventions based on the use of natural bioactive compounds is an effective strategy for remodeling gut microbiota composition and improving human health. This review focuses on the mechanisms by which TMAO promote atherosclerosis, the microbes that contribute to TMA formation, the enzymes involved, and the potential of natural dietary compounds that contribute to TMAO reduction and attenuate TMAO-induced atherosclerosis.
References
Adams, D.H., and Shaw, S. (1994). Leucocyte-endothelial interactions and regulation of leucocyte migration. Lancet. 343(8901): 831–836.
Asatoor, A.M., and Simenhoff, M.L. (1965). The origin of urinary dimethylamine. Biochim. Biophys. Acta. 111(2): 384–392.
Baker, F.D., Papiska, H.R., and Campbell, L.L. (1962). Choline fermentation by Desulfovibrio desulfuricans. J. Bacteriol. 84: 973–978.
Banikazemi, Z., Haji, H.A., Mohammadi, M., Taheripak, G., Iranifar, E., Poursadeghiyan, M., Moridikia, A., Rashidi, B., Taghizadeh, M., and Mirzaei, H. (2018). Diet and cancer prevention: Dietary compounds, dietary microRNAs, and dietary exosomes. J. Cell. Biochem. 119(1): 185–196.
Bennett, B.J., Vallim, T.Q.D., Wang, Z.N., Shih, D.M., Meng, Y.H., Gregory, J., Allayee, H., Lee, R., Graham, M., Crooke, R., Edwards, P.A., Hazen, S.L., and Lusis, A.J. (2013). Trimethylamine-N-Oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 17(1): 49–60.
Boutagy, N.E., Neilson, A.P., Osterberg, K.L., Smithson, A.T., Englund, T.R., Davy, B.M., Hulver, M.W., and Davy, K.P. (2015). Probiotic supplementation and trimethylamine-N-oxide production following a high-fat diet. Obesity. 23(12): 2357–2363.
Cardona, F., Andres-Lacueva, C., Tulipani, S., Tinahones, F.J., and Queipo-Ortuno, M.I. (2013). Benefits of polyphenols on gut microbiota and implications in human health. J. Nutr. Biochem. 24(8): 1415–1422.
Chen, M.L., Yi, L., Zhang, Y., Zhou, X., Ran, L., Yang, J.N., Zhu, J.D., Zhang, Q.Y., and Mi, M.T. (2016). Resveratrol attenuates trimethylamine-N-oxide (TMAO)-induced atherosclerosis by regulating TMAO synthesis and bile acid metabolism via remodeling of the gut microbiota. mBio. 7(2): e02210–15.
Conlon, M.A., and Bird, A.R. (2015). The impact of diet and lifestyle on gut microbiota and human health. Nutrients. 7(1): 17–44.
Craciun, S., and Balskus, E.P. (2012). Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc. Natl. Acad. Sci. U. S. A. 109(52): 21307–21312.
De La Huerga, J., Popper, H., and Steigmann, F. (1951). Urinary excretion of choline and trimethylamines after intravenous administration of choline in liver diseases. J. Lab. Clin. Med. 38(6): 904–910.
Degirolamo, C., Rainaldi, S., Bovenga, F., Murzilli, S., and Moschetta, A. (2014). Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Rep. 7(1): 12–18.
Dore, J., Simren, M., Buttle, L., and Guarner, F. (2013). Hot topics in gut microbiota. United Eur. Gastroent. 1(5): 311–318.
Falony, G., Vieira-Silva, S., and Raes, J. (2015). Microbiology meets big data: The case of gut microbiota-derived trimethylamine. Annu. Rev. Microbiol. 69: 305–321.
Flanagan, J.L., Simmons, P.A., Vehige, J., Willcox, M.D.P., and Garrett, Q. (2010). Role of carnitine in disease. Nutr. Metab. (Lond.). 7(1): 30.
Hayward, H.R., and Stadtman, T.C. (1959). Anaerobic degradation of choline. I. Fermentation of choline by an anaerobic, cytochrome-producing bacterium, Vibrio cholinicus n. sp. J. Bacteriol. 78: 557–561.
He, Z., and Chen, Z.Y. (2018). The origin of trimethylamine-N-oxide (TMAO) and its role in development of atherosclerosis. J. Food Bioact. 2: 28–36.
Huber, S.A., Sakkinen, P., Conze, D., Hardin, N., and Tracy, R. (1999). Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscl. Throm. Vas. 19(10): 2364–2367.
Jessup, W., Krithairides, L., and Stocker, R. (2004). Lipid oxidation in atherogenesis: an overview. Biochem. Soc. Trans. 32(1): 134–138.
Koenig, W., and Khuseyinova, N. (2007). Biomarkers of atherosclerotic plaque instability and rupture. Arterioscl. Throm. Vas. 27(1): 15–26.
Koeth, R.A., Levison, B.S., Culley, M.K., Buffa, J.A., Wang, Z., Gregory, J.C., Org, E., Wu, Y., Li, L., Smith, J.D., Tang, W.H.W., DiDonato, J.A., Lusis, A.J., and Hazen, S.L. (2014). gamma-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab. 20(5): 799–812.
Koeth, R.A., Wang, Z.E., Levison, B.S., Buffa, J.A., Org, E., Sheehy, B.T., Britt, E.B., Fu, X.M., Wu, Y.P., Li, L., Smith, J.D., DiDonato, J.A., Chen, J., Li, H.Z., Wu, G.D., Lewis, J.D., Warrier, M., Brown, J.M., Krauss, R.M., Tang, W.H.W., Bushman, F.D., Lusis, A.J., and Hazen, S.L. (2013). Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19(5): 576–585.
Krueger, S.K., and Williams, D.E. (2005). Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol. Ther. 106(3): 357–387.
Lee, W.J., and Hase, K. (2014). Gut microbiota-generated metabolites in animal health and disease. Nat. Chem. Biol. 10(6): 416–424.
Lehtio, L., and Goldman, A. (2004). The pyruvate formate lyase family: sequences, structures and activation. Protein Eng. Des. Sel. 17(6): 545–552.
Li, D.Y., and Tang, W.H.W. (2017). Gut microbiota and atherosclerosis. Curr Atheroscler Rep. 19(10): 39.
Liu, T.X., Niu, H.T., and Zhang, S.Y. (2015). Intestinal microbiota metabolism and atherosclerosis. Chin. Med. J. 128(20): 2805–2811.
Martinez-del Campo, A., Bodea, S., Hamer, H.A., Marks, J.A., Haiser, H.J., Turnbaugh, P.J., and Balskus, E.P. (2015). Characterization and detection of a widely distributed gene cluster that predicts anaerobic choline utilization by human gut bacteria. mBio. 6(2): e00042–15.
Meadows, J.A., and Wargo, M.J. (2015). Carnitine in bacterial physiology and metabolism. Microbiology. 161(6): 1161–1174.
O'Connor, S., Taylor, C., Campbell, L.A., Epstein, S., and Libby, P. (2001). Potential infectious etiologies of atherosclerosis: A multifactorial perspective. Emerg. Infect. Dis. 7(5): 780–788.
Parkin, K.L., and Hultin, H.O. (1982). Fish Muscle Microsomes Catalyze the Conversion of Trimethylamine Oxide to Dimethylamine and Formaldehyde. FEBS Lett. 139(1): 61–64.
Pekala, J., Patkowska-Sokola, B., Bodkowski, R., Jamroz, D., Nowakowski, P., Lochynski, S., and Librowski, T. (2011). L-Carnitine - metabolic functions and meaning in humans life. Curr. Drug Metab. 12(7): 667–678.
Qiao, Y., Sun, J., Xia, S.F., Tang, X., Shi, Y.H., and Le, G.W. (2014). Effects of resveratrol on gut microbiota and fat storage in a mouse model with high-fat-induced obesity. Food Funct. 5(6): 1241–1249.
Rath, S., Heidrich, B., Pieper, D.H., and Vital, M. (2017). Uncovering the trimethylamine-producing bacteria of the human gut microbiota. Microbiome. 5(1): 54.
Rebouche, C.J., and Chenard, C.A. (1991). Metabolic-fate of dietary carnitine in human adults - identification and quantification of urinary and fecal metabolites. J. Nutr. 121(4): 539–546.
Rebouche, C.J., Mack, D.L., and Edmonson, P.F. (1984). L-Carnitine dissimilation in the gastrointestinal tract of the rat. Biochemistry. 23(26): 6422–6426.
Romano, K.A., Vivas, E.I., Amador-Noguez, D., and Rey, F.E. (2015). Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. mBio. 6(2): e02481–14.
Ross, R. (1999). Atherosclerosis—An Inflammatory Disease. New Engl. J. Med. 340(2): 115–126.
Seim, H., Löster, H., Claus, R., Kleber, H.P., and Strack, E. (1982). Splitting of the C-N bond in carnitine by an enzyme (trimethylamine forming) from membranes of Acinetobacter calcoaceticus. FEMS Microbiol. Lett. 15(3): 165–167.
Seldin, M.M., Meng, Y.H., Qi, H.X., Zhu, W.F., Wang, Z.E., Hazen, S.L., Lusis, A.J., and Shih, D.M. (2016). Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-kappa B. J. Am. Heart Assoc. 5(2): e002767.
Shah, P.K. (2003). Mechanisms of plaque vulnerability and rupture. J. Am. Coll. Cardiol. 41(4 Suppl S): 15S-22S.
Siddens, L.K., Henderson, M.C., VanDyke, J.E., Williams, D.E., and Krueger, S.K. (2008). Characterization of mouse flavin-containing monooxygenase transcript levels in lung and liver, and activity of expressed isoforms. Biochem. Pharmacol. 75(2): 570–579.
Tang, W.H.W., Wang, Z.E., Levison, B.S., Koeth, R.A., Britt, E.B., Fu, X.M., Wu, Y.P., and Hazen, S.L. (2013). Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. New Engl. J. Med. 368(17): 1575–1584.
Tippani, R., Prakhya, L.J.S., Porika, M., Sirisha, K., Abbagani, S., and Thammidala, C. (2013). Pterostilbene as a potential novel telomerase inhibitor: Molecular docking studies and its in vitro evaluation. Curr. Pharm. Biotechnol. 14(12): 1027–1035.
Treacy, E.P., Akerman, B.R., Chow, L.M.L., Youil, R., Bibeau, C., Lin, J., Bruce, A.G., Knight, M., Danks, D.M., Cashman, J.R., and Forrest, S.M. (1998). Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum. Mol. Genet. 7(5): 839–845.
Wang, Z., Klipfell, E., Bennett, B.J., Koeth, R., Levison, B.S., Dugar, B., Feldstein, A.E., Britt, E.B., Fu, X., Chung, Y.M., Wu, Y., Schauer, P., Smith, J.D., Allayee, H., Tang, W.H., DiDonato, J.A., Lusis, A.J., and Hazen, S.L. (2011). Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472(7341): 57–63.
Wang, Z., Roberts, A.B., Buffa, J.A., Levison, B.S., Zhu, W., Org, E., Gu, X., Huang, Y., Zamanian-Daryoush, M., Culley, M.K., DiDonato, A.J., Fu, X., Hazen, J.E., Krajcik, D., DiDonato, J.A., Lusis, A.J., and Hazen, S.L. (2015). Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163(7): 1585–1595.
Wang, Z., Tang, W.H., Buffa, J.A., Fu, X., Britt, E.B., Koeth, R.A., Levison, B.S., Fan, Y., Wu, Y., and Hazen, S.L. (2014). Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur. Heart J. 35(14): 904–910.
Zeisel, S.H., Wishnok, J.S., and Blusztajn, J.K. (1983). Formation of methylamines from ingested choline and lecithin. J. Pharmacol. Exp. Ther. 225(2): 320–324.
Zhu, Y.J., Jameson, E., Crosatti, M., Schafer, H., Rajakumar, K., Bugg, T.D.H., and Chen, Y. (2014). Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota. Proc. Natl. Acad. Sci. U. S. A. 111(11): 4268–4273.
京公网安备11010802044758号