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Can diet modulate trimethylamine N-oxide (TMAO) production? What do we know so far?

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European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Background

Trimethylamine N-oxide (TMAO) is a metabolite that has attracted attention due to its positive association with several chronic non-communicable diseases such as insulin resistance, atherosclerotic plaque formation, diabetes, cancer, heart failure, hypertension, chronic kidney disease, liver steatosis, cardiac fibrosis, endothelial injury, neural degeneration and Alzheimer's disease. TMAO production results from the fermentation by the gut microbiota of dietary nutrients such as choline and carnitine, which are transformed to trimethylamine (TMA) and converted into TMAO in the liver by flavin-containing monooxygenase 1 and 3 (FMO1 and FMO3). Considering that TMAO is involved in the development of many chronic diseases, strategies have been found to enhance a healthy gut microbiota. In this context, some studies have shown that nutrients and bioactive compounds from food can modulate the gut microbiota and possibly reduce TMAO production.

Objective

This review has as main objective to discuss the studies that demonstrated the effects of food on the reduction of this harmful metabolite.

Methods

All relevant articles until November 2020 were included. The articles were searched in Medline through PubMed.

Results

Both the food is eaten acutely and chronically, by altering the nature of the gut microbiota, influencing colonic TMA production. Furthermore, hepatic production of TMAO by the flavin monooxygenases in the liver may also be influenced by phenolic compounds present in foods.

Conclusion

The evidence presented in this review shows that TMAO levels can be reduced by some bioactive compounds. However, it is crucial to notice that there is significant variation among the studies. Further clinical studies should be conducted to evaluate these dietary components’ effectiveness, dose, and intervention time on TMAO levels and its precursors.

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References

  1. Rinninella E, Cintoni M, Raoul P et al (2019) Food components and dietary habits: keys for a healthy gut microbiota composition. Nutrients. https://doi.org/10.3390/nu11102393

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kim S, Jazwinski SM (2018) The gut microbiota and healthy aging. Gerontology 64:513–520. https://doi.org/10.1159/000490615

    Article  CAS  PubMed  Google Scholar 

  3. Lloyd-Price J, Mahurkar A, Rahnavard G et al (2017) Strains, functions and dynamics in the expanded Human Microbiome Project. Nature 550:61–66. https://doi.org/10.1038/nature23889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Illiano P, Brambilla R, Parolini C (2020) The mutual interplay of gut microbiota, diet and human disease. FEBS J 287:833–855. https://doi.org/10.1111/febs.15217

    Article  CAS  PubMed  Google Scholar 

  5. Walker AW, Sanderson JD, Churcher C et al (2011) High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol 11:7. https://doi.org/10.1186/1471-2180-11-7

    Article  PubMed  PubMed Central  Google Scholar 

  6. Quigley EMM (2013) Gut bacteria in health and disease. Gastroenterol Hepatol (N Y) 9:560–569

    Google Scholar 

  7. Weiss GA, Hennet T (2017) Mechanisms and consequences of intestinal dysbiosis. Cell Mol Life Sci 74:2959–2977. https://doi.org/10.1007/s00018-017-2509-x

    Article  CAS  PubMed  Google Scholar 

  8. Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E (2017) Dysbiosis and the immune system. Nat Rev Immunol 17:219–232. https://doi.org/10.1038/nri.2017.7

    Article  CAS  PubMed  Google Scholar 

  9. Mafra D, Borges N, Alvarenga L et al (2019) Dietary components that may influence the disturbed gut microbiota in chronic kidney disease. Nutrients. https://doi.org/10.3390/nu11030496

    Article  PubMed  PubMed Central  Google Scholar 

  10. Pimenta FS, Luaces-Regueira M, Ton AM et al (2018) Mechanisms of action of kefir in chronic cardiovascular and metabolic diseases. Cell Physiol Biochem 48:1901–1914. https://doi.org/10.1159/000492511

    Article  CAS  PubMed  Google Scholar 

  11. Prakash S, Rodes L, Coussa-Charley M, Tomaro-Duchesneau C (2011) Gut microbiota: next frontier in understanding human health and development of biotherapeutics. Biologics 5:71–86. https://doi.org/10.2147/BTT.S19099

    Article  PubMed  PubMed Central  Google Scholar 

  12. Liu Y, Dai M (2020) Trimethylamine N-oxide generated by the gut microbiota is associated with vascular inflammation: new insights into atherosclerosis. Mediators Inflamm. https://doi.org/10.1155/2020/4634172

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jin M, Qian Z, Yin J et al (2019) The role of intestinal microbiota in cardiovascular disease. J Cell Mol Med 23:2343–2350. https://doi.org/10.1111/jcmm.14195

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bryniarski MA, Hamarneh F, Yacoub R (2019) The role of chronic kidney disease-associated dysbiosis in cardiovascular disease. Exp Biol Med (Maywood) 244:514–525. https://doi.org/10.1177/1535370219826526

    Article  CAS  Google Scholar 

  15. Koeth RA, Wang Z, Levison BS et al (2013) Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19:576–585. https://doi.org/10.1038/nm.3145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang Z, Klipfell E, Bennett BJ et al (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472:57–63. https://doi.org/10.1038/nature09922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Arias N, Arboleya S, Allison J et al (2020) The relationship between choline bioavailability from diet, intestinal microbiota composition, and its modulation of human diseases. Nutrients. https://doi.org/10.3390/nu12082340

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rath S, Rud T, Pieper DH, Vital M (2020) Potential TMA-producing bacteria are ubiquitously found in mammalia. Front Microbiol. https://doi.org/10.3389/fmicb.2019.02966

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wang J, Gu X, Yang J et al (2019) Gut microbiota dysbiosis and increased plasma LPS and TMAO levels in patients with preeclampsia. Front Cell Infect Microbiol. https://doi.org/10.3389/fcimb.2019.00409

    Article  PubMed  PubMed Central  Google Scholar 

  20. Xu K-Y, Xia G-H, Lu J-Q et al (2017) Impaired renal function and dysbiosis of gut microbiota contribute to increased trimethylamine-N-oxide in chronic kidney disease patients. Sci Rep. https://doi.org/10.1038/s41598-017-01387-y

    Article  PubMed  PubMed Central  Google Scholar 

  21. Benítez-Páez A, Kjølbæk L, Gómez Del Pulgar EM et al (2019) A multi-omics approach to unraveling the microbiome-mediated effects of arabinoxylan oligosaccharides in overweight humans. mSystems. https://doi.org/10.1128/mSystems.00209-19

    Article  PubMed  PubMed Central  Google Scholar 

  22. Tang WHW, Hazen SL (2017) Microbiome, trimethylamine N-oxide, and cardiometabolic disease. Transl Res 179:108–115. https://doi.org/10.1016/j.trsl.2016.07.007

    Article  CAS  PubMed  Google Scholar 

  23. Oellgaard J, Winther SA, Hansen TS et al (2017) Trimethylamine N-oxide (TMAO) as a new potential therapeutic target for insulin resistance and cancer. Curr Pharm Des 23:3699–3712. https://doi.org/10.2174/1381612823666170622095324

    Article  CAS  PubMed  Google Scholar 

  24. Tan X, Liu Y, Long J et al (2019) Trimethylamine N-oxide aggravates liver steatosis through modulation of bile acid metabolism and inhibition of farnesoid X receptor signaling in nonalcoholic fatty liver disease. Mol Nutr Food Res 63:e1900257. https://doi.org/10.1002/mnfr.201900257

    Article  CAS  PubMed  Google Scholar 

  25. Vogt NM, Romano KA, Darst BF et al (2018) The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease. Alzheimers Res Ther 10:124. https://doi.org/10.1186/s13195-018-0451-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tang WHW, Hazen SL (2014) The contributory role of gut microbiota in cardiovascular disease. J Clin Invest 124:4204–4211. https://doi.org/10.1172/JCI72331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Brown JM, Hazen SL (2015) The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases. Annu Rev Med 66:343–359. https://doi.org/10.1146/annurev-med-060513-093205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tang WHW, Wang Z, Kennedy DJ et al (2015) Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res 116:448–455. https://doi.org/10.1161/CIRCRESAHA.116.305360

    Article  CAS  PubMed  Google Scholar 

  29. Trøseid M, Ueland T, Hov JR 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 277:717–726. https://doi.org/10.1111/joim.12328

    Article  CAS  PubMed  Google Scholar 

  30. Kalagi NA, Abbott KA, Alburikan KA et al (2019) Modulation of circulating trimethylamine N-oxide concentrations by dietary supplements and pharmacological agents: a systematic review. Adv Nutr 10:876–887. https://doi.org/10.1093/advances/nmz012

    Article  PubMed  PubMed Central  Google Scholar 

  31. Goldfarb DS, Modersitzki F, Asplin JR (2007) A randomized, controlled trial of lactic acid bacteria for idiopathic hyperoxaluria. Clin J Am Soc Nephrol 2:745–749. https://doi.org/10.2215/CJN.00600207

    Article  PubMed  Google Scholar 

  32. Zeisel SH, Warrier M (2017) Trimethylamine N-oxide, the microbiome, and heart and kidney disease. Annu Rev Nutr 37:157–181. https://doi.org/10.1146/annurev-nutr-071816-064732

    Article  CAS  PubMed  Google Scholar 

  33. Del Rio D, Rodriguez-Mateos A, Spencer JPE et al (2013) Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid Redox Signal 18:1818–1892. https://doi.org/10.1089/ars.2012.4581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tang WHW, Wang Z, Levison BS et al (2013) Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 368:1575–1584. https://doi.org/10.1056/NEJMoa1109400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Randrianarisoa E, Lehn-Stefan A, Wang X et al (2016) Relationship of serum trimethylamine N-oxide (TMAO) levels with early atherosclerosis in humans. Sci Rep 6:26745. https://doi.org/10.1038/srep26745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Geng J, Yang C, Wang B et al (2018) Trimethylamine N-oxide promotes atherosclerosis via CD36-dependent MAPK/JNK pathway. Biomed Pharmacother 97:941–947. https://doi.org/10.1016/j.biopha.2017.11.016

    Article  CAS  PubMed  Google Scholar 

  37. Zhu W, Gregory JC, Org E et al (2016) Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165:111–124. https://doi.org/10.1016/j.cell.2016.02.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Seldin MM, Meng Y, Qi H et al (2016) Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-κB. J Am Heart Assoc. https://doi.org/10.1161/JAHA.115.002767

    Article  PubMed  PubMed Central  Google Scholar 

  39. Canyelles M, Tondo M, Cedó L et al (2018) Trimethylamine N-oxide: a link among diet, gut microbiota, gene regulation of liver and intestine cholesterol homeostasis and HDL function. Int J Mol Sci. https://doi.org/10.3390/ijms19103228

    Article  PubMed  PubMed Central  Google Scholar 

  40. Liu H, Pathak P, Boehme S, Chiang JYL (2016) Cholesterol 7α-hydroxylase protects the liver from inflammation and fibrosis by maintaining cholesterol homeostasis. J Lipid Res 57:1831–1844. https://doi.org/10.1194/jlr.M069807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ding L, Chang M, Guo Y et al (2018) Trimethylamine-N-oxide (TMAO)-induced atherosclerosis is associated with bile acid metabolism. Lipids Health Dis 17:286. https://doi.org/10.1186/s12944-018-0939-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mafune A, Iwamoto T, Tsutsumi Y 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 20:731–739. https://doi.org/10.1007/s10157-015-1207-y

    Article  CAS  PubMed  Google Scholar 

  43. Senthong V, Wang Z, Li XS 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. https://doi.org/10.1161/JAHA.115.002816

    Article  PubMed  PubMed Central  Google Scholar 

  44. Tang WHW, Wang Z, Shrestha K 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. https://doi.org/10.1016/j.cardfail.2014.11.006

    Article  CAS  PubMed  Google Scholar 

  45. Wang Z, Tang WHW, Buffa JA et al (2014) Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur Heart J 35:904–910. https://doi.org/10.1093/eurheartj/ehu002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schiattarella GG, Sannino A, Toscano E et al (2017) Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis. Eur Heart J 38:2948–2956. https://doi.org/10.1093/eurheartj/ehx342

    Article  CAS  PubMed  Google Scholar 

  47. Farhangi MA (2020) Gut microbiota-dependent trimethylamine N-oxide and all-cause mortality: Findings from an updated systematic review and meta-analysis. Nutrition 78:110856. https://doi.org/10.1016/j.nut.2020.110856

    Article  CAS  PubMed  Google Scholar 

  48. Rexidamu M, Li H, Jin H, Huang J (2019) Serum levels of Trimethylamine-N-oxide in patients with ischemic stroke. Biosci Rep. https://doi.org/10.1042/BSR20190515

    Article  PubMed  PubMed Central  Google Scholar 

  49. Tong M, Neusner A, Longato L et al (2009) Nitrosamine exposure causes insulin resistance diseases: relevance to type 2 diabetes mellitus, non-alcoholic steatohepatitis, and Alzheimer’s disease. J Alzheimers Dis 17:827–844

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Shan Z, Sun T, Huang H et al (2017) Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes. Am J Clin Nutr 106:888–894. https://doi.org/10.3945/ajcn.117.157107

    Article  CAS  PubMed  Google Scholar 

  51. Li P, Zhong C, Li S et al (2018) Plasma concentration of trimethylamine-N-oxide and risk of gestational diabetes mellitus. Am J Clin Nutr 108:603–610. https://doi.org/10.1093/ajcn/nqy116

    Article  PubMed  PubMed Central  Google Scholar 

  52. Zhuang R, Ge X, Han L et al (2019) Gut microbe–generated metabolite trimethylamine N-oxide and the risk of diabetes: A systematic review and dose-response meta-analysis. Obes Rev 20:883–894. https://doi.org/10.1111/obr.12843

    Article  CAS  PubMed  Google Scholar 

  53. Webster AC, Nagler EV, Morton RL, Masson P (2017) Chronic kidney disease. Lancet 389:1238–1252. https://doi.org/10.1016/S0140-6736(16)32064-5

    Article  PubMed  Google Scholar 

  54. Lau WL, Savoj J, Nakata MB, Vaziri ND (2018) Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins. Clin Sci (Lond) 132:509–522. https://doi.org/10.1042/CS20171107

    Article  CAS  Google Scholar 

  55. Li DY, Wilson Tang WH (2018) Contributory role of gut microbiota and their metabolites towards cardiovascular complications in chronic kidney disease. Semin Nephrol 38:193–205. https://doi.org/10.1016/j.semnephrol.2018.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hsu C-N, Yang H-W, Hou C-Y et al (2020) Maternal adenine-induced chronic kidney disease programs hypertension in adult male rat offspring: implications of nitric oxide and gut microbiome derived metabolites. Int J Mol Sci. https://doi.org/10.3390/ijms21197237

    Article  PubMed  PubMed Central  Google Scholar 

  57. Pelletier CC, Croyal M, Ene L et al (2019) Elevation of trimethylamine-N-oxide in chronic kidney disease: contribution of decreased glomerular filtration rate. Toxins (Basel). https://doi.org/10.3390/toxins11110635

    Article  Google Scholar 

  58. Rhee EP, Clish CB, Ghorbani A et al (2013) A combined epidemiologic and metabolomic approach improves CKD prediction. J Am Soc Nephrol 24:1330–1338. https://doi.org/10.1681/ASN.2012101006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Stubbs JR, House JA, Ocque AJ et al (2016) Serum trimethylamine-N-oxide is elevated in CKD and correlates with coronary atherosclerosis burden. J Am Soc Nephrol 27:305–313. https://doi.org/10.1681/ASN.2014111063

    Article  CAS  PubMed  Google Scholar 

  60. Li D, Ke Y, Zhan R et al (2018) Trimethylamine-N-oxide promotes brain aging and cognitive impairment in mice. Aging Cell 17:e12768. https://doi.org/10.1111/acel.12768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sonnenburg JL, Bäckhed F (2016) Diet-microbiota interactions as moderators of human metabolism. Nature 535:56–64. https://doi.org/10.1038/nature18846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Turnbaugh PJ, Ridaura VK, Faith JJ et al (2009) the effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic Mice. Science Translational Medicine 1:6ra14. https://doi.org/10.1126/scitranslmed.3000322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen J, Guo Y, Gui Y, Xu D (2018) Physical exercise, gut, gut microbiota, and atherosclerotic cardiovascular diseases. Lipids Health Dis 17:17. https://doi.org/10.1186/s12944-017-0653-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lyu M, Wang Y-F, Fan G-W et al (2017) Balancing herbal medicine and functional food for prevention and treatment of cardiometabolic diseases through modulating gut microbiota. Front Microbiol 8:2146. https://doi.org/10.3389/fmicb.2017.02146

    Article  PubMed  PubMed Central  Google Scholar 

  65. Cheynier V (2005) Polyphenols in foods are more complex than often thought. Am J Clin Nutr 81:223S-229S. https://doi.org/10.1093/ajcn/81.1.223S

    Article  CAS  PubMed  Google Scholar 

  66. Crozier A, Jaganath IB, Clifford MN (2009) Dietary phenolics: chemistry, bioavailability and effects on health. Nat Prod Rep 26:1001–1043. https://doi.org/10.1039/b802662a

    Article  CAS  PubMed  Google Scholar 

  67. Henning SM, Yang J, shao P et al (2017) Health benefit of vegetable/fruit juice-based diet: Role of microbiome. Sci Rep 7:2167. https://doi.org/10.1038/s41598-017-02200-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Caro-Gómez E, Sierra JA, Escobar JS et al (2019) green coffee extract improves cardiometabolic parameters and modulates gut microbiota in high-fat-diet-fed ApoE-/- mice. Nutrients. https://doi.org/10.3390/nu11030497

    Article  PubMed  PubMed Central  Google Scholar 

  69. Kemperman RA, Bolca S, Roger LC, Vaughan EE (2010) Novel approaches for analysing gut microbes and dietary polyphenols: challenges and opportunities. Microbiology (Reading, Engl) 156:3224–3231. https://doi.org/10.1099/mic.0.042127-0

    Article  CAS  Google Scholar 

  70. Stapleton PD, Shah S, Ehlert K et al (2007) The beta-lactam-resistance modifier (-)-epicatechin gallate alters the architecture of the cell wall of Staphylococcus aureus. Microbiology (Reading, Engl) 153:2093–2103. https://doi.org/10.1099/mic.0.2007/007807-0

    Article  CAS  Google Scholar 

  71. Smith AH, Zoetendal E, Mackie RI (2005) Bacterial mechanisms to overcome inhibitory effects of dietary tannins. Microb Ecol 50:197–205. https://doi.org/10.1007/s00248-004-0180-x

    Article  CAS  PubMed  Google Scholar 

  72. Cianciosi D, Forbes-Hernández TY, Afrin S et al (2018) Phenolic compounds in honey and their associated health benefits: a review. Molecules. https://doi.org/10.3390/molecules23092322

    Article  PubMed  PubMed Central  Google Scholar 

  73. Sirerol JA, Rodríguez ML, Mena S et al (2016) Role of natural stilbenes in the prevention of cancer. Oxid Med Cell Longev 2016:3128951. https://doi.org/10.1155/2016/3128951

    Article  CAS  PubMed  Google Scholar 

  74. Messina F, Guglielmini G, Curini M et al (2015) Effect of substituted stilbenes on platelet function. Fitoterapia 105:228–233. https://doi.org/10.1016/j.fitote.2015.07.009

    Article  CAS  PubMed  Google Scholar 

  75. Barreca D, Gattuso G, Bellocco E et al (2017) Flavanones: Citrus phytochemical with health-promoting properties. BioFactors 43:495–506. https://doi.org/10.1002/biof.1363

    Article  CAS  PubMed  Google Scholar 

  76. Chen M, Yi L, Zhang Y et al (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:e02210-02215. https://doi.org/10.1128/mBio.02210-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Annunziata G, Maisto M, Schisano C et al (2019) Effects of grape pomace polyphenolic extract (Taurisolo®) in reducing TMAO serum levels in humans: preliminary results from a randomized, placebo-controlled. Cross-Over Study Nutr. https://doi.org/10.3390/nu11010139

    Article  Google Scholar 

  78. Annunziata G, Maisto M, Schisano C et al (2019) Effect of grape pomace polyphenols with or without pectin on TMAO Serum levels assessed by LC/MS-based assay: a preliminary clinical study on overweight/obese subjects. Front Pharmacol 10:575. https://doi.org/10.3389/fphar.2019.00575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bresciani L, Dall’Asta M, Favari C et al (2018) An in vitro exploratory study of dietary strategies based on polyphenol-rich beverages, fruit juices and oils to control trimethylamine production in the colon. Food Funct 9:6470–6483. https://doi.org/10.1039/c8fo01778f

    Article  CAS  PubMed  Google Scholar 

  80. Hsu C-N, Chang-Chien G-P, Lin S et al (2019) Targeting on gut microbial metabolite trimethylamine-N-oxide and short-chain fatty acid to prevent maternal high-fructose-diet-induced developmental programming of hypertension in adult male offspring. Mol Nutr Food Res 63:e1900073. https://doi.org/10.1002/mnfr.201900073

    Article  CAS  PubMed  Google Scholar 

  81. Li Q, Chen H, Zhang M et al (2019) Altered short chain fatty acid profiles induced by dietary fiber intervention regulate AMPK levels and intestinal homeostasis. Food Funct 10:7174–7187. https://doi.org/10.1039/c9fo01465a

    Article  CAS  PubMed  Google Scholar 

  82. Angelino D, Carregosa D, Domenech-Coca C et al (2019) 5-(Hydroxyphenyl)-γ-valerolactone-sulfate, a key microbial metabolite of flavan-3-ols, is able to reach the brain: evidence from different in silico, in vitro and in vivo experimental models. Nutrients. https://doi.org/10.3390/nu11112678

    Article  PubMed  PubMed Central  Google Scholar 

  83. Sinopoli A, Calogero G, Bartolotta A (2019) Computational aspects of anthocyanidins and anthocyanins: a review. Food Chem 297:124898. https://doi.org/10.1016/j.foodchem.2019.05.172

    Article  CAS  PubMed  Google Scholar 

  84. Liu S, You L, Zhao Y, Chang X (2018) Wild Lonicera caerulea berry polyphenol extract reduces cholesterol accumulation and enhances antioxidant capacity in vitro and in vivo. Food Res Int 107:73–83. https://doi.org/10.1016/j.foodres.2018.02.016

    Article  CAS  PubMed  Google Scholar 

  85. Chen P-Y, Li S, Koh Y-C et al (2019) Oolong tea extract and citrus peel polymethoxyflavones reduce transformation of l-carnitine to trimethylamine-N-oxide and decrease vascular inflammation in l-carnitine feeding mice. J Agric Food Chem 67:7869–7879. https://doi.org/10.1021/acs.jafc.9b03092

    Article  CAS  PubMed  Google Scholar 

  86. Tenore GC, Caruso D, Buonomo G et al (2019) Lactofermented annurca apple puree as a functional food indicated for the control of plasma lipid and oxidative amine levels: results from a randomised clinical trial. Nutrients. https://doi.org/10.3390/nu11010122

    Article  PubMed  PubMed Central  Google Scholar 

  87. Lim T, Ryu J, Lee K et al (2020) Protective effects of black raspberry (Rubus occidentalis) extract against hypercholesterolemia and hepatic inflammation in rats fed high-fat and high-choline diets. Nutrients. https://doi.org/10.3390/nu12082448

    Article  PubMed  PubMed Central  Google Scholar 

  88. Angiletta CJ, Griffin LE, Steele CN et al (2018) Impact of short-term flavanol supplementation on fasting plasma trimethylamine N-oxide concentrations in obese adults. Food Funct 9:5350–5361. https://doi.org/10.1039/c8fo00962g

    Article  CAS  PubMed  Google Scholar 

  89. Białecka-Florjańczyk E, Fabiszewska A, Zieniuk B (2018) Phenolic acids derivatives—biotechnological methods of synthesis and bioactivity. Curr Pharm Biotechnol 19:1098–1113. https://doi.org/10.2174/1389201020666181217142051

    Article  CAS  PubMed  Google Scholar 

  90. Kumar N, Goel N (2019) Phenolic acids: natural versatile molecules with promising therapeutic applications. Biotechnol Rep (Amst) 24:e00370. https://doi.org/10.1016/j.btre.2019.e00370

    Article  Google Scholar 

  91. Dall’Acqua S, Stocchero M, Boschiero I, et al (2016) New findings on the in vivo antioxidant activity of Curcuma longa extract by an integrated (1)H NMR and HPLC-MS metabolomic approach. Fitoterapia 109:125–131. https://doi.org/10.1016/j.fitote.2015.12.013

    Article  CAS  Google Scholar 

  92. Dalla Via A, Gargari G, Taverniti V et al (2019) Urinary TMAO levels are associated with the taxonomic composition of the gut microbiota and with the choline TMA-lyase gene (cutC) harbored by Enterobacteriaceae. Nutrients. https://doi.org/10.3390/nu12010062

    Article  PubMed  PubMed Central  Google Scholar 

  93. Latkovskis G, Makarova E, Mazule M et al (2018) Loop diuretics decrease the renal elimination rate and increase the plasma levels of trimethylamine-N-oxide. Br J Clin Pharmacol 84:2634–2644. https://doi.org/10.1111/bcp.13728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wu W-K, Panyod S, Ho C-T et al (2015) Dietary allicin reduces transformation of L-carnitine to TMAO through impact on gut microbiota. J Funct Foods 15:408–417. https://doi.org/10.1016/j.jff.2015.04.001

    Article  CAS  Google Scholar 

  95. Kanhere M, Chassaing B, Gewirtz AT, Tangpricha V (2018) Role of vitamin D on gut microbiota in cystic fibrosis. J Steroid Biochem Mol Biol 175:82–87. https://doi.org/10.1016/j.jsbmb.2016.11.001

    Article  CAS  PubMed  Google Scholar 

  96. Obeid R, Awwad HM, Kirsch SH et al (2017) Plasma trimethylamine-N-oxide following supplementation with vitamin D or D plus B vitamins. Mol Nutr Food Res. https://doi.org/10.1002/mnfr.201600358

    Article  PubMed  Google Scholar 

  97. Bislev LS, Sundekilde UK, Kilic E et al (2020) Circulating levels of muscle-related metabolites increase in response to a daily moderately high dose of a vitamin D3 supplement in women with vitamin D insufficiency—secondary analysis of a randomized placebo-controlled trial. Nutrients 12:1310. https://doi.org/10.3390/nu12051310

    Article  CAS  PubMed Central  Google Scholar 

  98. Barrea L, Muscogiuri G, Annunziata G et al (2019) A new light on vitamin D in obesity: a novel association with trimethylamine-N-oxide (TMAO). Nutrients. https://doi.org/10.3390/nu11061310

    Article  PubMed  PubMed Central  Google Scholar 

  99. Missailidis C, Sørensen N, Ashenafi S et al (2019) Vitamin D and phenylbutyrate supplementation does not modulate gut derived immune activation in HIV-1. Nutrients. https://doi.org/10.3390/nu11071675

    Article  PubMed  PubMed Central  Google Scholar 

  100. Augustin LSA, Aas A-M, Astrup A et al (2020) dietary fibre consensus from the international carbohydrate quality consortium (ICQC). Nutrients. https://doi.org/10.3390/nu12092553

    Article  PubMed  PubMed Central  Google Scholar 

  101. Li Q, Wu T, Liu R et al (2017) Soluble dietary fiber reduces trimethylamine metabolism via gut microbiota and co-regulates host AMPK pathways. Mol Nutr Food Res. https://doi.org/10.1002/mnfr.201700473

    Article  PubMed  PubMed Central  Google Scholar 

  102. Cheng W, Lu J, Li B et al (2017) Effect of functional oligosaccharides and ordinary dietary fiber on intestinal microbiota diversity. Front Microbiol 8:1750. https://doi.org/10.3389/fmicb.2017.01750

    Article  PubMed  PubMed Central  Google Scholar 

  103. Liu W-C, Yang M-C, Wu Y-Y et al (2018) Lactobacillus plantarum reverse diabetes-induced Fmo3 and ICAM expression in mice through enteric dysbiosis-related c-Jun NH2-terminal kinase pathways. PLoS ONE. https://doi.org/10.1371/journal.pone.0196511

    Article  PubMed  PubMed Central  Google Scholar 

  104. Hill E, Sapa H, Negrea L et al (2020) Effect of oat β-glucan supplementation on chronic kidney disease: a feasibility study. J Renal Nutr 30:208–215. https://doi.org/10.1053/j.jrn.2019.06.012

    Article  CAS  Google Scholar 

  105. Baugh ME, Steele CN, Angiletta CJ et al (2018) Inulin supplementation does not reduce plasma trimethylamine N-Oxide concentrations in individuals at risk for type 2 diabetes. Nutrients. https://doi.org/10.3390/nu10060793

    Article  PubMed  PubMed Central  Google Scholar 

  106. Reid G (2016) Probiotics: definition, scope and mechanisms of action. Best Pract Res Clin Gastroenterol 30:17–25. https://doi.org/10.1016/j.bpg.2015.12.001

    Article  CAS  PubMed  Google Scholar 

  107. Fadhlaoui K, Arnal M-E, Martineau M et al (2020) Archaea, specific genetic traits, and development of improved bacterial live biotherapeutic products: another face of next-generation probiotics. Appl Microbiol Biotechnol 104:4705–4716. https://doi.org/10.1007/s00253-020-10599-8

    Article  CAS  PubMed  Google Scholar 

  108. Moludi J, Maleki V, Jafari-Vayghyan H et al (2020) Metabolic endotoxemia and cardiovascular disease: a systematic review about potential roles of prebiotics and probiotics. Clin Exp Pharmacol Physiol 47:927–939. https://doi.org/10.1111/1440-1681.13250

    Article  CAS  PubMed  Google Scholar 

  109. Qiu L, Tao X, Xiong H et al (2018) Lactobacillus plantarum ZDY04 exhibits a strain-specific property of lowering TMAO via the modulation of gut microbiota in mice. Food Funct 9:4299–4309. https://doi.org/10.1039/c8fo00349a

    Article  CAS  PubMed  Google Scholar 

  110. Qiu L, Yang D, Tao X et al (2017) Enterobacter aerogenes ZDY01 attenuates choline-induced trimethylamine N-oxide levels by remodeling gut microbiota in mice. J Microbiol Biotechnol 27:1491–1499. https://doi.org/10.4014/jmb.1703.03039

    Article  CAS  PubMed  Google Scholar 

  111. Hsu C-N, Hou C-Y, Chan JYH et al (2019) Hypertension programmed by perinatal high-fat diet: effect of maternal gut microbiota-targeted therapy. Nutrients. https://doi.org/10.3390/nu11122908

    Article  PubMed  PubMed Central  Google Scholar 

  112. Malik M, Suboc TM, Tyagi S et al (2018) Lactobacillus plantarum 299v supplementation improves vascular endothelial function and reduces inflammatory biomarkers in men with stable coronary artery disease. Circ Res 123:1091–1102. https://doi.org/10.1161/CIRCRESAHA.118.313565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Borges NA, Stenvinkel P, Bergman P et al (2019) Effects of probiotic supplementation on trimethylamine-N-oxide plasma levels in hemodialysis patients: a pilot study. Probiotics Antimicrob Proteins 11:648–654. https://doi.org/10.1007/s12602-018-9411-1

    Article  CAS  PubMed  Google Scholar 

  114. Tripolt NJ, Leber B, Triebl A et al (2015) Effect of Lactobacillus casei Shirota supplementation on trimethylamine-N-oxide levels in patients with metabolic syndrome: an open-label, randomized study. Atherosclerosis 242:141–144. https://doi.org/10.1016/j.atherosclerosis.2015.05.005

    Article  CAS  PubMed  Google Scholar 

  115. Boutagy NE, Neilson AP, Osterberg KL et al (2015) Probiotic supplementation and trimethylamine-N-oxide production following a high-fat diet. Obesity (Silver Spring) 23:2357–2363. https://doi.org/10.1002/oby.21212

    Article  CAS  Google Scholar 

  116. Wang Q-J, Shen Y-E, Wang X et al (2020) Concomitant memantine and Lactobacillus plantarum treatment attenuates cognitive impairments in APP/PS1 mice. Aging 12:628–649. https://doi.org/10.18632/aging.102645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Chen S, Jiang P, Yu D et al (2020) Effects of probiotic supplementation on serum trimethylamine-N-oxide level and gut microbiota composition in young males: a double-blinded randomized controlled trial. Eur J Nutr. https://doi.org/10.1007/s00394-020-02278-1

    Article  PubMed  PubMed Central  Google Scholar 

  118. Montrucchio C, De Nicolò A, D’Ettorre G et al (2020) Serum trimethylamine-N-oxide concentrations in people living with HIV and the effect of probiotic supplementation. Int J Antimicrob Agents 55:105908. https://doi.org/10.1016/j.ijantimicag.2020.105908

    Article  CAS  PubMed  Google Scholar 

  119. Martin F-PJ, Wang Y, Sprenger N et al (2008) Probiotic modulation of symbiotic gut microbial-host metabolic interactions in a humanized microbiome mouse model. Mol Syst Biol 4:157. https://doi.org/10.1038/msb4100190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Chen K, Zheng X, Feng M et al (2017) Gut microbiota-dependent metabolite trimethylamine N-oxide contributes to cardiac dysfunction in western diet-induced obese mice. Front Physiol. https://doi.org/10.3389/fphys.2017.00139

    Article  PubMed  PubMed Central  Google Scholar 

  121. Wan Y, Wang F, Yuan J et al (2019) Effects of dietary fat on gut microbiota and faecal metabolites, and their relationship with cardiometabolic risk factors: a 6-month randomised controlled-feeding trial. Gut 68:1417–1429. https://doi.org/10.1136/gutjnl-2018-317609

    Article  CAS  PubMed  Google Scholar 

  122. Mori A, Goto A, Kibe R et al (2019) Comparison of the effects of four commercially available prescription diet regimens on the fecal microbiome in healthy dogs. J Vet Med Sci 81:1783–1790. https://doi.org/10.1292/jvms.19-0055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Boutagy NE, Neilson AP, Osterberg KL et al (2015) Short-term high-fat diet increases postprandial trimethylamine-N-oxide in humans. Nutr Res 35:858–864. https://doi.org/10.1016/j.nutres.2015.07.002

    Article  CAS  PubMed  Google Scholar 

  124. Genoni A, Christophersen CT, Lo J et al (2019) Long-term Paleolithic diet is associated with lower resistant starch intake, different gut microbiota composition and increased serum TMAO concentrations. Eur J Nutr. https://doi.org/10.1007/s00394-019-02036-y

    Article  PubMed  PubMed Central  Google Scholar 

  125. Bergeron N, Williams PT, Lamendella R et al (2016) Diets high in resistant starch increase plasma levels of trimethylamine-N-oxide, a gut microbiome metabolite associated with CVD risk. Br J Nutr 116:2020–2029. https://doi.org/10.1017/S0007114516004165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Griffin LE, Djuric Z, Angiletta CJ et al (2019) A Mediterranean diet does not alter plasma trimethylamine N-oxide concentrations in healthy adults at risk for colon cancer. Food Funct 10:2138–2147. https://doi.org/10.1039/c9fo00333a

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Leal-Witt MJ, Llobet M, Samino S et al (2018) Lifestyle intervention decreases urine trimethylamine N-oxide levels in prepubertal children with obesity. Obesity (Silver Spring) 26:1603–1610. https://doi.org/10.1002/oby.22271

    Article  CAS  Google Scholar 

  128. Wang F, Xu J, Jakovlić I et al (2019) Dietary betaine reduces liver lipid accumulation via improvement of bile acid and trimethylamine-N-oxide metabolism in blunt-snout bream. Food Funct 10:6675–6689. https://doi.org/10.1039/C9FO01853K

    Article  CAS  PubMed  Google Scholar 

  129. Park JE, Miller M, Rhyne J et al (2019) Differential effect of short-term popular diets on TMAO and other cardio-metabolic risk markers. Nutr Metab Cardiovasc Dis 29:513–517. https://doi.org/10.1016/j.numecd.2019.02.003

    Article  CAS  PubMed  Google Scholar 

  130. Thøgersen R, Rasmussen MK, Sundekilde UK et al (2020) Background diet influences TMAO concentrations associated with red meat intake without influencing apparent hepatic TMAO-related activity in a porcine model. Metabolites. https://doi.org/10.3390/metabo10020057

    Article  PubMed  PubMed Central  Google Scholar 

  131. Erickson ML, Malin SK, Wang Z et al (2019) Effects of lifestyle intervention on plasma trimethylamine N-oxide in obese adults. Nutrients. https://doi.org/10.3390/nu11010179

    Article  PubMed  PubMed Central  Google Scholar 

  132. Mitchell SM, Milan AM, Mitchell CJ et al (2019) Protein intake at twice the RDA in older men increases circulatory concentrations of the microbiome metabolite trimethylamine-N-oxide (TMAO). Nutrients. https://doi.org/10.3390/nu11092207

    Article  PubMed  PubMed Central  Google Scholar 

  133. Crimarco A, Springfield S, Petlura C et al (2020) A randomized crossover trial on the effect of plant-based compared with animal-based meat on trimethylamine-N-oxide and cardiovascular disease risk factors in generally healthy adults: Study With Appetizing Plantfood—Meat Eating Alternative Trial (SWAP-MEAT). Am J Clin Nutr 112:1188–1199. https://doi.org/10.1093/ajcn/nqaa203

    Article  PubMed  PubMed Central  Google Scholar 

  134. Missimer A, Fernandez ML, DiMarco DM et al (2018) Compared to an oatmeal breakfast, two eggs/day increased plasma carotenoids and choline without increasing trimethyl amine N-oxide concentrations. J Am Coll Nutr 37:140–148. https://doi.org/10.1080/07315724.2017.1365026

    Article  CAS  PubMed  Google Scholar 

  135. Wu T, Gao Y, Hao J et al (2020) Capsanthin extract prevents obesity, reduces serum TMAO levels and modulates the gut microbiota composition in high-fat-diet induced obese C57BL/6J mice. Food Res Int 128:108774. https://doi.org/10.1016/j.foodres.2019.108774

    Article  CAS  PubMed  Google Scholar 

  136. Bordoni L, Sawicka AK, Szarmach A et al (2020) A Pilot Study on the effects of l-carnitine and trimethylamine-N-oxide on platelet mitochondrial DNA methylation and CVD biomarkers in aged women. Int J Mol Sci. https://doi.org/10.3390/ijms21031047

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Figure of this review was created with the aid of Canva.

Funding

This work was supported, in part, by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001 and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (Process E-26/203.269/2017).

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  1. Postgraduate Program in Nutrition Sciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil

    Karen Salve Coutinho-Wolino, Denise Mafra & Milena Barcza Stockler-Pinto

  2. Postgraduate Program in Cardiovascular Sciences, Faculty of Medicine, Fluminense Federal University, Niterói, Brazil

    Ludmila F. M. de F. Cardozo, Denise Mafra & Milena Barcza Stockler-Pinto

  3. Division of Nutrition, Pedro Ernesto University Hospital, State University of Rio de Janeiro (UERJ), Rio de Janeiro, Brazil

    Viviane de Oliveira Leal

  4. Postgraduate Program in Medical Sciences, Faculty of Medicine, Fluminense Federal University, Niterói, Brazil

    Denise Mafra

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  1. Karen Salve Coutinho-Wolino
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KSC-W: Idea for the article, literature search, data analysis, drafted and/or critically revised the work. LFMFC: Data analysis, drafted and/or critically revised the work. VOL: Data analysis, drafted and/or critically revised the work. DM: Data analysis, drafted and/or critically revised the work. MBS-P: Idea for the article, data analysis, drafted and/or critically revised the work.

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Coutinho-Wolino, K.S., de F. Cardozo, L.F.M., de Oliveira Leal, V. et al. Can diet modulate trimethylamine N-oxide (TMAO) production? What do we know so far?. Eur J Nutr 60, 3567–3584 (2021). https://doi.org/10.1007/s00394-021-02491-6

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