Applied Microbiology and Biotechnology

, Volume 103, Issue 23–24, pp 9217–9228 | Cite as

Amelioration of TMAO through probiotics and its potential role in atherosclerosis

  • Ahmad Ud Din
  • Adil Hassan
  • Yuan Zhu
  • Tieying Yin
  • Hans Gregersen
  • Guixue WangEmail author


Atherosclerosis is a major cause of mortalities and morbidities worldwide. It is associated with hyperlipidemia and inflammation, and become chronic by triggering metabolites in different metabolic pathways. Disturbance in the human gut microbiota is now considered a critical factor in the atherosclerosis. Trimethylamine-N-oxide (TMAO) attracts attention and is regarded as a vital contributor in the development of atherosclerosis. TMAO is generated from its dietary precursors choline, carnitine, and phosphatidylcholine by gut microbiota into an intermediate compound known as trimethylamine (TMA), which is then oxidized into TMAO by hepatic flavin monooxygenases. The present review focus on advances in TMAO preventing strategies through probiotics, including, modulation of gut microbiome, metabolomics profile, miRNA, or probiotic antagonistic abilities. Furthermore, possible recommendations based on relevant literature have been presented, which could be applied in probiotics and atherosclerosis-preventing strategies.


Gut microbiota Atherosclerosis TMAO Probiotics TMA lyases 



We are also thankful for the support from the Chongqing Engineering Laboratory in Vascular Implants and the Public Experiment Center of State Bioindustrial Base (Chongqing).

Funding information

This study was supported by grants from the National Natural Science Foundation of China (11572064, 31771599), the National Key Technology R&D Program of China (2016YFC1102305, 2018YFC0114408), and the Fundamental Research Funds for the Central Universities (2018CDPTCG0001-10).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

The article does not contain experiments which include human or animals.


  1. Aron-Wisnewsky J, Julia Z, Poitou C, Bouillot J-L, Basdevant A, Chapman MJ, Clement K, Guerin M (2011) Effect of bariatric surgery-induced weight loss on SR-BI-, ABCG1-, and ABCA1-mediated cellular cholesterol efflux in obese women. J Clin Endocrinol Metab 96(4):1151–1159PubMedGoogle Scholar
  2. Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, Fernandes GR, Tap J, Bruls T, Batto J-M, Bertalan M, Borruel N, Casellas F, Fernandez L, Gautier L, Hansen T, Hattori M, Hayashi T, Kleerebezem M, Kurokawa K, Leclerc M, Levenez F, Manichanh C, Nielsen HB, Nielsen T, Pons N, Poulain J, Qin J, Sicheritz-Ponten T, Tims S, Torrents D, Ugarte E, Zoetendal EG, Wang J, Guarner F, Pedersen O, de Vos WM, Brunak S, Doré J, Meta HITC, Antolín M, Artiguenave F, Blottiere HM, Almeida M, Brechot C, Cara C, Chervaux C, Cultrone A, Delorme C, Denariaz G, Dervyn R, Foerstner KU, Friss C, van de Guchte M, Guedon E, Haimet F, Huber W, van Hylckama-Vlieg J, Jamet A, Juste C, Kaci G, Knol J, Lakhdari O, Layec S, Le Roux K, Maguin E, Mérieux A, Melo Minardi R, M’Rini C, Muller J, Oozeer R, Parkhill J, Renault P, Rescigno M, Sanchez N, Sunagawa S, Torrejon A, Turner K, Vandemeulebrouck G, Varela E, Winogradsky Y, Zeller G, Weissenbach J, Ehrlich SD, Bork P (2011) Enterotypes of the human gut microbiome. Nature 473(7346):174–180PubMedPubMedCentralGoogle Scholar
  3. Ascher S, Reinhardt C (2018) The gut microbiota: an emerging risk factor for cardiovascular and cerebrovascular disease. Eur J Immunol 48(4):564–575PubMedGoogle Scholar
  4. Association AH (2015) Heart disease and stroke statistics–at-a-glance heart disease, stroke and other cardiovascular diseases heart disease, stroke and cardiovascular disease risk factors. AHA 1:7–10Google Scholar
  5. Becattini S, Taur Y, Pamer EG (2016) Antibiotic-induced changes in the intestinal microbiota and disease. Trends Mol Med 22:458–478PubMedPubMedCentralGoogle Scholar
  6. Behnsen J, Deriu E, Sassone-Corsi M, Raffatellu M (2013) Probiotics: properties, examples, and specific applications. Cold Spring Harb Perspect Med 3(3):a010074PubMedPubMedCentralGoogle Scholar
  7. 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 (2013) Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab 17(1):49–60PubMedPubMedCentralGoogle Scholar
  8. Bennett BJ, Davis RC, Civelek M, Orozco L, Wu J, Qi H, Pan C, Sevag Packard RR, Eskin E, Yan M, Kirchgessner T, Wang Z, Li X, Gregory JC, Hazen SL, Gargalovic PS, Lusis AJ (2016) Correction: genetic architecture of atherosclerosis in mice: a systems genetics analysis of common inbred strains. PLoS Genet 12(3):e1005913PubMedPubMedCentralGoogle Scholar
  9. Broderick TL, Quinney HA, Barker CC, Lopaschuk GD (1993) Beneficial effect of carnitine on mechanical recovery of rat hearts reperfused after a transient period of global ischemia is accompanied by a stimulation of glucose oxidation. Circulation 87(3):972–981PubMedGoogle Scholar
  10. Caesar R, Fåk F, Bäckhed F (2010) Effects of gut microbiota on obesity and atherosclerosis via modulation of inflammation and lipid metabolism. J Intern Med 268(4):320–328PubMedGoogle Scholar
  11. Cannon CP, Braunwald E, McCabe CH, Grayston JT, Muhlestein B, Giugliano RP, Cairns R, Skene AM (2005) Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 352(16):1646–1654PubMedGoogle Scholar
  12. Cebra J, Jiang H, Sterzl J, Tlaskalova-Hogenova H (1999) The role of mucosal microbiota in the development and maintenance of the mucosal immune system. Mucosal Immunol 267Google Scholar
  13. Chen ML, Yi L, Zhang Y, Zhou X, Ran L, Yang J, Zhu JD, Zhang QY, Mi MT (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–e02215PubMedPubMedCentralGoogle Scholar
  14. Chenoll E, Casinos B, Bataller E, Astals P, Echevarria J, Iglesias JR, Balbarie P, Ramon D, Genoves S (2011) Novel probiotic Bifidobacterium bifidum CECT 7366 strain active against the pathogenic bacterium Helicobacter pylori. Appl Environ Microbiol 77(4):1335–1343PubMedPubMedCentralGoogle Scholar
  15. Chetwin E, Manhanzva MT, Abrahams AG, Froissart R, Gamieldien H, Jaspan H, Jaumdally SZ, Barnabas SL, Dabee S, Happel A-U, Bowers D, Davids L, Passmore J-AS, Masson L (2019) Antimicrobial and inflammatory properties of South African clinical Lactobacillus isolates and vaginal probiotics. Sci Rep 9(1):1917Google Scholar
  16. Collins HL, Drazul-Schrader D, Sulpizio AC, Koster PD, Williamson Y, Adelman SJ, Owen K, Sanli T, Bellamine A (2015) L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE transgenic mice expressing CETP. Atherosclerosis 244:29–37PubMedGoogle Scholar
  17. Dalmasso G, Nguyen HTT, Yan Y, Laroui H, Charania MA, Ayyadurai S, Sitaraman SV, Merlin D (2011) Microbiota Modulate Host Gene Expression via MicroRNAs. PLoS ONE 6(4):e19293PubMedPubMedCentralGoogle Scholar
  18. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA (2014) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505(7484):559–563PubMedPubMedCentralGoogle Scholar
  19. DiNicolantonio JJ, Lavie CJ, Fares H, Menezes AR, O’Keefe JH L-carnitine in the secondary prevention of cardiovascular disease: systematic review and meta-analysis. In: Mayo Clin Proc, 2013. vol 88. Elsevier, p 544–551Google Scholar
  20. Du Y, Wang L, Hong B (2015) High-density lipoprotein-based drug discovery for treatment of atherosclerosis. Expert Opin Drug Discovery 10(8):841–855Google Scholar
  21. Dunne C, O’Mahony L, Murphy L, Thornton G, Morrissey D, O’Halloran S, Feeney M, Flynn S, Fitzgerald G, Daly C, Kiely B, O’Sullivan GC, Shanahan F, Collins JK (2001) In vitro selection criteria for probiotic bacteria of human origin: correlation with in vivo findings. Am J Clin Nutr 73(2 Suppl):386S–392SPubMedGoogle Scholar
  22. Falcinelli S, Picchietti S, Rodiles A, Cossignani L, Merrifield DL, Taddei AR, Maradonna F, Olivotto I, Gioacchini G, Carnevali O (2015) Lactobacillus rhamnosus lowers zebrafish lipid content by changing gut microbiota and host transcription of genes involved in lipid metabolism. Sci Rep 5:9336PubMedPubMedCentralGoogle Scholar
  23. Finkelstein EA, Khavjou OA, Thompson H, Trogdon JG, Pan L, Sherry B, Dietz W (2012) Obesity and severe obesity forecasts through 2030. Am J Prev Med 42(6):563–570PubMedGoogle Scholar
  24. Frostegård J (2013) Immunity, atherosclerosis and cardiovascular disease. BMC Med 11(1):117PubMedPubMedCentralGoogle Scholar
  25. Getz Godfrey S, Reardon Catherine A (2018) Diet, microbes, and murine atherosclerosis. Atertio Thromb Vasc Biol 38(10):2269–2271Google Scholar
  26. Gibson FC, Hong C, Chou H, Yumoto H, Chen J, Lien E, Wong J, Genco CA (2004) Innate immune recognition of invasive bacteria accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation 109(22):2801–2806PubMedGoogle Scholar
  27. Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD, Rogers WJ, Crouse JR, Borrowdale SL, Schron E (2005) Azithromycin for the secondary prevention of coronary events. N Engl J Med 352(16):1637–1645PubMedGoogle Scholar
  28. Gregory JC, Buffa JA, Org E, Wang Z, Levison BS, Zhu W, Wagner MA, Bennett BJ, Li L, DiDonato JA (2015) Transmission of atherosclerosis susceptibility with gut microbial transplantation. J Biol Chem 290(9):5647–5660PubMedGoogle Scholar
  29. Hamasalim HJ (2015) The impact of some widely probiotic (Iraqi probiotic) on health and performance. J Biosci Med 3(08):25Google Scholar
  30. Hansson GK, Libby P, Schonbeck U, Yan ZQ (2002) Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 91(4):281–291PubMedGoogle Scholar
  31. Hassan A, Din AU, Zhu Y, Zhang K, Li T, Wang Y, Luo Y, Wang G (2019) Updates in understanding the hypocholesterolemia effect of probiotics on atherosclerosis. Appl Microbiol Biotechnol 103:5993–6006PubMedGoogle Scholar
  32. Holmes E, Kinross J, Gibson GR, Burcelin R, Jia W, Pettersson S, Nicholson JK (2012) Therapeutic modulation of microbiota-host metabolic interactions. Sci Transl Med 4(137):137rv6PubMedGoogle Scholar
  33. Hu S, Dong TS, Dalal SR, Wu F, Bissonnette M, Kwon JH, Chang EB (2011) The microbe-derived short chain fatty acid butyrate targets miRNA-dependent p21 gene expression in human colon cancer. PLoS ONE 6(1):e16221PubMedPubMedCentralGoogle Scholar
  34. Hudault S, Lievin V, Bernet-Camard MF, Servin AL (1997) Antagonistic activity exerted in vitro and in vivo by Lactobacillus casei (strain GG) against Salmonella typhimurium C5 infection. Appl Environ Microbiol 63(2):513–518PubMedPubMedCentralGoogle Scholar
  35. Jäckel S, Kiouptsi K, Lillich M, Hendrikx T, Khandagale A, Kollar B, Hörmann N, Reiss C, Subramaniam S, Wilms E (2017) Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via Toll-like receptor-2. Blood 130(4):542–553PubMedGoogle Scholar
  36. Jameson E, Quareshy M, Chen Y (2018) Methodological considerations for the identification of choline and carnitine-degrading bacteria in the gut. Meth 149:42–48Google Scholar
  37. Jonsson AL, Caesar R, Akrami R, Reinhardt C, Hallenius FF, Boren J, Backhed F (2018) Impact of gut microbiota and diet on the development of atherosclerosis in Apoe−/− mice. Atertio Thromb Vasc Biol 38(10):2318–2326Google Scholar
  38. Ju KH, Sook NJ, Ok SY (2018) Beneficial effects of kimchi, a korean fermented vegetable food, on pathophysiological factors related to atherosclerosis. J Med Food 21(2):127–135Google Scholar
  39. Kalani M, Hodjati H, Sajedi Khanian M, Doroudchi M (2016) Lactobacillus acidophilus increases the anti-apoptotic micro RNA-21 and decreases the pro-inflammatory micro RNA-155 in the LPS-treated human endothelial cells. Probiotics Antimicrob Proteins 8(2):61–72PubMedGoogle Scholar
  40. Kalla R, Ventham NT, Kennedy NA (2015) MicroRNAs: new players in inflammatory bowel disease. Gut 64(6):1008–1008PubMedGoogle Scholar
  41. Kamareddine L, Robins WP, Berkey CD, Mekalanos JJ, Watnick PI (2018) The Drosophila immune deficiency pathway modulates enteroendocrine function and host metabolism. Cell Metab 28(3):449–462.e5PubMedPubMedCentralGoogle Scholar
  42. Karbach SH, Schönfelder T, Brandão I, Wilms E, Hörmann N, Jäckel S, Schüler R, Finger S, Knorr M, Lagrange J (2016) Gut microbiota promote angiotensin II–induced arterial hypertension and vascular dysfunction. JAHA 5(9):e003698PubMedGoogle Scholar
  43. Karlsson FH, Fak F, Nookaew I, Tremaroli V, Fagerberg B, Petranovic D, Backhed F, Nielsen J (2012) Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat Commun 3(1):1245–1245PubMedPubMedCentralGoogle Scholar
  44. Kasahara K, Tanoue T, Yamashita T, Yodoi K, Matsumoto T, Emoto T, Mizoguchi T, Hayashi T, Kitano N, Sasaki N (2017) Commensal bacteria at the crossroad between cholesterol homeostasis and chronic inflammation in atherosclerosis. J Lipid Res 58(3):519–528PubMedPubMedCentralGoogle Scholar
  45. Kawashima T, Hayashi K, Kosaka A, Kawashima M, Igarashi T, Tsutsui H, Tsuji NM, Nishimura I, Hayashi T, Obata A (2011) Lactobacillus plantarum strain YU from fermented foods activates Th1 and protective immune responses. Int Immunopharmacol 11(12):2017–2024PubMedGoogle Scholar
  46. Ke Y, Li D, Zhao M, Liu C, Liu J, Zeng A, Shi X, Cheng S, Pan B, Zheng L, Hong H (2018) Gut flora-dependent metabolite Trimethylamine-N-oxide accelerates endothelial cell senescence and vascular aging through oxidative stress. Free Radic Biol Med 116:88–100PubMedGoogle Scholar
  47. 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 (2013) Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19(5):576–585PubMedPubMedCentralGoogle Scholar
  48. 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 (2014) gamma-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab 20(5):799–812PubMedPubMedCentralGoogle Scholar
  49. Koren O, Spor A, Felin J, Fak F, Stombaugh J, Tremaroli V, Behre CJ, Knight R, Fagerberg B, Ley RE (2011) Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc Natl Acad Sci U S A 108:4592–4598PubMedGoogle Scholar
  50. Krautkramer KA, Kreznar JH, Romano KA, Vivas EI, Barrett-Wilt GA, Rabaglia ME, Keller MP, Attie AD, Rey FE, Denu JM (2016) Diet-microbiota interactions mediate global epigenetic programming in multiple host tissues. Mol Cell 64(5):982–992PubMedPubMedCentralGoogle Scholar
  51. Kuka J, Liepinsh E, Makrecka-Kuka M, Liepins J, Cirule H, Gustina D, Loza E, Zharkova-Malkova O, Grinberga S, Pugovics O, Dambrova M (2014) Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation. Life Sci 117(2):84–92PubMedGoogle Scholar
  52. Kurilshikov A, van den Munckhof ICL, Chen L, Bonder MJ, Schraa K, Rutten JHW, Riksen NP, de Graaf J, Oosting M, Sanna S, Joosten LAB, van der Graaf M, Brand T, Koonen DPY, van Faassen M, Slagboom PE, Xavier RJ, Kuipers F, Hofker MH, Wijmenga C, Netea MG, Zhernakova A, Fu J (2019) Gut microbial associations to plasma metabolites linked to cardiovascular phenotypes and risk. Circ Res 124(12):1808–1820PubMedGoogle Scholar
  53. Leblanc JG, Milani C, De Giori GS, Sesma F, Van Sinderen D, Ventura M (2013) Bacteria as vitamin suppliers to their host: a gut microbiota perspective. Curr Opin Biotechnol 24(2):160–168PubMedGoogle Scholar
  54. Lehr H-A, Sagban TA, Ihling C, Zähringer U, Hungerer K-D, Blumrich M, Reifenberg K, Bhakdi S (2001) Immunopathogenesis of atherosclerosis Endotoxin accelerates atherosclerosis in rabbits on hypercholesterolemic diet. Circ 104(8):914–920Google Scholar
  55. Li DY, Tang WHW (2017) Gut microbiota and atherosclerosis. Curr Atheroscler Rep 19(10):39PubMedGoogle Scholar
  56. Libby P (2013) Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 368(21):2004–2013PubMedGoogle Scholar
  57. Libby P, Lichtman AH, Hansson GK (2013) Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity 38(6):1092–1104PubMedPubMedCentralGoogle Scholar
  58. Lievin V, Peiffer I, Hudault S, Rochat F, Brassart D, Neeser JR, Servin AL (2000) Bifidobacterium strains from resident infant human gastrointestinal microflora exert antimicrobial activity. Gut 47(5):646–652PubMedPubMedCentralGoogle Scholar
  59. Liu J, Gu Z, Lu W, Hu D, Zhao X, Huang H, Zhang H, Zhao J, Chen W (2018a) Multiple mechanisms applied by Lactobacillus pentosus AT6 to mute the lethal effects of Salmonella in a mouse model. Food Funct 9(5):2787–2795Google Scholar
  60. Liu J, Hu D, Chen Y, Huang H, Zhang H, Zhao J, Gu Z, Chen W (2018b) Strain-specific properties of Lactobacillus plantarum for prevention of Salmonella infection. Food Funct 9(7):3673–3682PubMedGoogle Scholar
  61. Liu, H., Chen, X., Hu, X., Niu, H., Tian, R., Wang, H., Pang, H., Jiang, L., Qiu, B., Chen, X. and Zhang, Y., 2019. Alterations in the gut microbiome and metabolism with coronary artery disease severity. Microbiome, 7(1), p.68.Google Scholar
  62. Lo J, Abbara S, Shturman L, Soni A, Wei J, Rocha-Filho JA, Nasir K, Grinspoon SK (2010) Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men. AIDS (London, England) 24(2):243Google Scholar
  63. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461(7268):1282–1286PubMedPubMedCentralGoogle Scholar
  64. McKenna LB, Schug J, Vourekas A, McKenna JB, Bramswig NC, Friedman JR, Kaestner KH (2010) MicroRNAs control intestinal epithelial differentiation, architecture, and barrier function. Gastroenterology 139(5):1654–1664 1664 e1PubMedPubMedCentralGoogle Scholar
  65. McNelis JC, Olefsky JM (2014) Macrophages, immunity, and metabolic disease. Immunity 41(1):36–48PubMedGoogle Scholar
  66. Mendelsohn AR, Larrick JW (2013) Dietary modification of the microbiome affects risk for cardiovascular disease. Rejuvenation Res 16(3):241–244PubMedGoogle Scholar
  67. Miska EA (2005) How microRNAs control cell division, differentiation and death. Curr Opin Genet Dev 15(5):563–568PubMedGoogle Scholar
  68. Mohammadi A, Vahabzadeh Z, Jamalzadeh S, Khalili T (2018) Trimethylamine-N-oxide, as a risk factor for atherosclerosis, induces stress in J774A.1 murine macrophages. Adv Med Sci 63(1):57–63PubMedGoogle Scholar
  69. Mozaffarian D, Wu JH (2011) Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol 58(20):2047–2067PubMedGoogle Scholar
  70. Muoio DM, Noland RC, Kovalik J-P, Seiler SE, Davies MN, DeBalsi KL, Ilkayeva OR, Stevens RD, Kheterpal I, Zhang J (2012) Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metab 15(5):764–777PubMedPubMedCentralGoogle Scholar
  71. Murray CJ, Lopez AD (1997) Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 349(9063):1436–1442PubMedGoogle Scholar
  72. Nagpal R, Wang S, Ahmadi S, Hayes J, Gagliano J, Subashchandrabose S, Kitzman DW, Becton T, Read R, Yadav H (2018) Human-origin probiotic cocktail increases short-chain fatty acid production via modulation of mice and human gut microbiome. Sci Rep 8(1):12649PubMedPubMedCentralGoogle Scholar
  73. Namkin K, Zardast M, Basirinejad F (2016) Saccharomyces Boulardii in Helicobacter Pylori eradication in children: a randomized trial from Iran. Iran J Pediatr 26(1):e3768PubMedPubMedCentralGoogle Scholar
  74. Nunes C (1994) Microbial probiotics and their utilization in husbandry. Rev Portuguesa de Cie Vet 89(512):166–174Google Scholar
  75. 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(3):703–711PubMedGoogle Scholar
  76. Ohira H, Tsutsui W, Fujioka Y (2017) Are short chain fatty acids in gut microbiota defensive players for inflammation and atherosclerosis? J Atheroscler Thromb 24(7):660–672PubMedPubMedCentralGoogle Scholar
  77. Org E, Mehrabian M, Lusis AJ (2015) Unraveling the environmental and genetic interactions in atherosclerosis: central role of the gut microbiota. Atherosclerosis 241(2):387–399PubMedPubMedCentralGoogle Scholar
  78. Organ CL, Otsuka H, Bhushan S, Wang Z, Bradley J, Trivedi R, Polhemus DJ, Tang WW, Wu Y, Hazen SL (2016) Choline diet and its gut microbe–derived metabolite, trimethylamine N-oxide, exacerbate pressure overload–induced heart failure. Circ Heart Fail 9(1):e002314PubMedGoogle Scholar
  79. Pacifico L, Osborn J, Bonci E, Romaggioli S, Baldini R, Chiesa C (2014) Probiotics for the treatment of Helicobacter pylori infection in children. World J Gastroenterol 20(3):673–683PubMedPubMedCentralGoogle Scholar
  80. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464(7285):59–65PubMedPubMedCentralGoogle Scholar
  81. Quin C, Estaki M, Vollman DM, Barnett JA, Gill SK, Gibson DL (2018) Probiotic supplementation and associated infant gut microbiome and health: a cautionary retrospective clinical comparison. Sci Rep 8(1):8283PubMedPubMedCentralGoogle Scholar
  82. Randrianarisoa E, Lehn-Stefan A, Wang X, Hoene M, Peter A, Heinzmann SS, Zhao X, Konigsrainer I, Konigsrainer A, Balletshofer B, Machann J, Schick F, Fritsche A, Haring HU, Xu G, Lehmann R, Stefan N (2016) Relationship of serum trimethylamine N-oxide (TMAO) levels with early atherosclerosis in humans. Sci Rep 6:26745PubMedPubMedCentralGoogle Scholar
  83. Rath S, Heidrich B, Pieper DH, Vital M (2017) Uncovering the trimethylamine-producing bacteria of the human gut microbiota. Microbiome 5(1):54PubMedPubMedCentralGoogle Scholar
  84. Rauch U, Osende JI, Fuster V, Badimon JJ, Fayad Z, Chesebro JH (2001) Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences. Ann Intern Med 134(3):224–238PubMedGoogle Scholar
  85. Ridlon JM, Kang D, Hylemon PB (2006) Bile salt biotransformations by human intestinal bacteria. J Lipid Res 47(2):241–259PubMedGoogle Scholar
  86. Ringseis R, Keller J, Eder K (2012) Role of carnitine in the regulation of glucose homeostasis and insulin sensitivity: evidence from in vivo and in vitro studies with carnitine supplementation and carnitine deficiency. Eur J Nutr 51(1):1–18PubMedGoogle Scholar
  87. Rivière A, Selak M, Lantin D, Leroy F, De Vuyst L (2016) Bifidobacteria and butyrate-producing colon bacteria: importance and strategies for their stimulation in the human gut. Front Microbiol 7(979)Google Scholar
  88. Rodríguez-Nogales A, Algieri F, Garrido-Mesa J, Vezza T, Utrilla MP, Chueca N, Garcia F, Olivares M, Rodríguez-Cabezas ME, Gálvez J (2017) Differential intestinal anti-inflammatory effects of Lactobacillus fermentum and Lactobacillus salivarius in DSS mouse colitis: impact on microRNAs expression and microbiota composition. Mol Nutr Food Res 61(11):1700144Google Scholar
  89. 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-N-oxide. MBio 6(2):e02481–e02414PubMedPubMedCentralGoogle Scholar
  90. Ross R (1999) Atherosclerosis--an inflammatory disease. N Engl J Med 340(2):115–126PubMedPubMedCentralGoogle Scholar
  91. Sanz Y, Santacruz A, Gauffin P (2010) Gut microbiota in obesity and metabolic disorders. Proc Nutr Soc 69(03):434–441PubMedGoogle Scholar
  92. Schickel R, Boyerinas B, Park SM, Peter ME (2008) MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene 27(45):5959–5974PubMedGoogle Scholar
  93. Sekirov I, Russell SL, Antunes LC, Finlay BB (2010) Gut microbiota in health and disease. Physiol Rev 90(3):859–904PubMedGoogle Scholar
  94. Seldin MM, Meng Y, Qi H, Zhu W, Wang Z, Hazen SL, Lusis AJ, Shih DM (2016) Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-κB. J Am Heart Assoc 5(2):e002767PubMedPubMedCentralGoogle Scholar
  95. Serban M-C, Sahebkar A, Mikhailidis DP, Toth PP, Jones SR, Muntner P, Blaha MJ, Andrica F, Martin SS, Borza C, Lip GYH, Ray KK, Rysz J, Hazen SL, Banach M (2016) Impact of L-carnitine on plasma lipoprotein(a) concentrations: a systematic review and meta-analysis of randomized controlled trials. Sci Rep 6:19188PubMedPubMedCentralGoogle Scholar
  96. Shang R, Sun Z, Li H (2014) Effective dosing of L-carnitine in the secondary prevention of cardiovascular disease: a systematic review and meta-analysis. BMC Cardiovasc Disord 14(1):1Google Scholar
  97. Sharon G, Garg N, Debelius JW, Knight R, Dorrestein PC, Mazmanian SK (2014) Specialized metabolites from the microbiome in health and disease. Cell Metab 20(5):719–730PubMedPubMedCentralGoogle Scholar
  98. Shreiner AB, Kao JY, Young VB (2015) The gut microbiome in health and in disease. Curr Opin Gastroenterol 31(1):69–75PubMedPubMedCentralGoogle Scholar
  99. Sichetti M, De Marco S, Pagiotti R, Traina G, Pietrella D (2018) Anti-inflammatory effect of multi-strain probiotic formulation ( l. rhamnosus, b. lactis and b. longum). NutritionGoogle Scholar
  100. Skelly AN, Sato Y, Kearney S, Honda K (2019) Mining the microbiota for microbial and metabolite-based immunotherapies. Nat Rev ImmunolGoogle Scholar
  101. Spinler SA, Cziraky MJ, Willey VJ, Tang F, Maddox TM, Thomas T, Dueñas GG, Virani SS (2015) Frequency of attainment of low-density lipoprotein cholesterol and non–high-density lipoprotein cholesterol goals in cardiovascular clinical practice (from the National Cardiovascular Data Registry PINNACLE Registry). Am J Cardiol 116(4):547–553PubMedGoogle Scholar
  102. Srinivasa S, Fitch KV, Lo J, Kadar H, Knight R, Wong K, Abbara S, Gauguier D, Capeau J, Boccara F (2015) Plaque burden in HIV-infected patients is associated with serum intestinal microbiota-generated trimethylamine. AIDS (London, England) 29(4):443PubMedPubMedCentralGoogle Scholar
  103. Stepankova R, Tonar Z, Bartova J, Nedorost L, Rossman P, Poledne R, Schwarzer M, Tlaskalova-Hogenova H (2010) Absence of microbiota (germ-free conditions) accelerates the atherosclerosis in ApoE-deficient mice fed standard low cholesterol diet. J Atheroscler Thromb 17(8):796–804PubMedGoogle Scholar
  104. Stock J (2013) Gut microbiota: an environmental risk factor for cardiovascular disease. Atherosclerosis 229(2):440–442PubMedGoogle Scholar
  105. Štofilová J, Szabadosová V, Hrčková G, Salaj R, Bertková I, Hijová E, Strojný L, Bomba A (2015) Co-administration of a probiotic strain Lactobacillus plantarum LS/07 CCM7766 with prebiotic inulin alleviates the intestinal inflammation in rats exposed to N,N-dimethylhydrazine. Int Immunopharmacol 24(2):361–368PubMedGoogle Scholar
  106. Tang WHW, Hazen SL (2014) The contributory role of gut microbiota in cardiovascular disease. J Clin Invest 124(10):4204–4211PubMedPubMedCentralGoogle Scholar
  107. Tang WW, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL (2013) Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 368(17):1575–1584PubMedPubMedCentralGoogle Scholar
  108. Tang WH, Wang Z, Fan Y, Levison B, Hazen JE, Donahue LM, Wu Y, Hazen SL (2014) 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 64(18):1908–1914PubMedGoogle Scholar
  109. Tang WW, Wang Z, Shrestha K, Borowski AG, Wu Y, Troughton RW, Klein AL, Hazen SL (2015) Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J Card Fail 21(2):91–96PubMedGoogle Scholar
  110. Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, Girard R, Zeineddine HA, Lightle R, Moore T (2017) Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature 545(7654):305–310PubMedPubMedCentralGoogle Scholar
  111. Tang WHW, Li DY, Hazen SL (2019) Dietary metabolism, the gut microbiome, and heart failure. Nat Rev Cardiol 16(3):137–154PubMedGoogle Scholar
  112. Trøseid M, Ueland T, Hov J, Svardal A, Gregersen I, Dahl C, Aakhus S, Gude E, Bjørndal B, Halvorsen B (2015) Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med 277(6):717–726PubMedGoogle Scholar
  113. Ursell LK, Haiser HJ, Van Treuren W, Garg N, Reddivari L, Vanamala J, Dorrestein PC, Turnbaugh PJ, Knight R (2014) The intestinal metabolome: an intersection between microbiota and host. Gastroenterology 146(6):1470–1476PubMedPubMedCentralGoogle Scholar
  114. Ussher JR, Lopaschuk GD, Arduini A (2013) Gut microbiota metabolism of L-carnitine and cardiovascular risk. Atherosclerosis 231(2):456–461PubMedGoogle Scholar
  115. Valdesvarela L, Hernandezbarranco AM, Ruasmadiedo P, Gueimonde M (2016) Effect of Bifidobacterium upon Clostridium difficile growth and toxicity when co-cultured in different prebiotic substrates. Front Microbiol 7:738Google Scholar
  116. Vikram A, Kim Y-R, Kumar S, Li Q, Kassan M, Jacobs JS, Irani K (2016) Vascular microRNA-204 is remotely governed by the microbiome and impairs endothelium-dependent vasorelaxation by downregulating Sirtuin1. Nat Commun 7:12565PubMedPubMedCentralGoogle Scholar
  117. Viles-Gonzalez JF, Fuster V, Badimon JJ (2004) Atherothrombosis: a widespread disease with unpredictable and life-threatening consequences. Eur Heart J 25(14):1197–1207PubMedGoogle Scholar
  118. Virchow R (1989) Cellular pathology. As based upon physiological and pathological histology. Lecture XVI--Atheromatous affection of arteries. 1858. Nutr Rev 47(1):23–25PubMedGoogle Scholar
  119. 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 (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472(7341):57–63PubMedPubMedCentralGoogle Scholar
  120. Wang J, Tang H, Zhang C, Zhao Y, Derrien M, Rocher E, van-Hylckama Vlieg JET, Strissel K, Zhao L, Obin M, Shen J (2014a) Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice. Isme J 9:1PubMedPubMedCentralGoogle Scholar
  121. Wang Z, Tang WW, Buffa JA, Fu X, Britt EB, Koeth RA, Levison BS, Fan Y, Wu Y, Hazen SL (2014b) Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur Heart J:ehu002Google Scholar
  122. Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, Org E, Gu X, Huang Y, Zamanian-Daryoush M, Culley MK, Didonato AJ, Fu X, Hazen JE, Krajcik D, Didonato JA, Lusis AJ, Hazen SL (2015) Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163(7):1585–1595PubMedPubMedCentralGoogle Scholar
  123. Wang S, Xia GH, He Y, Liao SX, Yin J, Sheng HF, Zhou HW (2016) Distribution characteristics of trimethylamine N-oxide and its association with gut microbiota. Nan Fang Yi Ke Da Xue Xue Bao 36(4):455–460PubMedGoogle Scholar
  124. Westerterp M, Berbée JF, Pires NM, van Mierlo GJ, Kleemann R, Romijn JA, Havekes LM, Rensen PC (2007) Apolipoprotein CI is crucially involved in lipopolysaccharide-induced atherosclerosis development in apolipoprotein E–knockout mice. Circ 116(19):2173–2181Google Scholar
  125. WHO (2002) Guidelines for the evaluation of probiotics in food. World Health OrganizationGoogle Scholar
  126. Winek K, Engel O, Koduah P, Heimesaat MM, Fischer A, Bereswill S, Dames C, Kershaw O, Gruber AD, Curato C (2016) Depletion of cultivatable gut microbiota by broad-spectrum antibiotic pretreatment worsens outcome after murine stroke. Stroke 47(5):1354–1363PubMedPubMedCentralGoogle Scholar
  127. Wu GD, Chen J, Hoffmann C, Bittinger K, Chen Y-Y, Keilbaugh SA, Bewtra M, Knights D, Walters WA, Knight R (2011) Linking long-term dietary patterns with gut microbial enterotypes. Science 334(6052):105–108PubMedPubMedCentralGoogle Scholar
  128. Xu Z, Knight R (2015) Dietary effects on human gut microbiome diversity. Br J Nutr 113:S1–S5PubMedPubMedCentralGoogle Scholar
  129. Xue X, Cao AT, Cao X, Yao S, Carlsen ED, Soong L, Liu CG, Liu X, Liu Z, Duck LW (2014) Downregulation of microRNA-107 in intestinal CD11c(+) myeloid cells in response to microbiota and proinflammatory cytokines increases IL-23p19 expression. Eur J Immunol 44(3):673–682PubMedPubMedCentralGoogle Scholar
  130. Yee Kwan C, Kirjavainen P, Pirkka, Yan P, Chen, El-Nezami P, Hani (2012) Probiotics and atherosclerosis–a new challenge? Microb Ecol Health Dis 23(1):18576Google Scholar
  131. Yin J, Liao SX, He Y, Wang S, Xia GH, Liu FT, Zhu JJ, You C, Chen Q, Zhou L, Pan SY, Zhou HW (2015) Dysbiosis of gut microbiota with reduced trimethylamine-N-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack. J Am Heart Assoc 4(11)Google Scholar
  132. Yörük M, Gül M, Hayirli A, Macit M (2004) The effects of supplementation of humate and probiotic on egg production and quality parameters during the late laying period in hens. Poult Sci 83(1):84–88PubMedGoogle Scholar
  133. Zheng Y, Li Y, Rimm EB, Hu FB, Albert CM, Rexrode KM, Manson JE, Qi L (2016) Dietary phosphatidylcholine and risk of all-cause and cardiovascular-specific mortality among US women and men. Am J Clin Nutr 104(1):173–180PubMedPubMedCentralGoogle Scholar
  134. Zhu W, Gregory Jill C, Org E, Buffa Jennifer A, Gupta N, Wang Z, Li L, Fu X, Wu Y, Mehrabian M, Sartor RB, McIntyre Thomas M, Silverstein Roy L, Tang WHW, DiDonato JA, Brown JM, Lusis Aldons J, Hazen Stanley L (2016) Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165(1):111–124PubMedPubMedCentralGoogle Scholar
  135. Zhu Y, Li T, Din AU, Hassan A, Wang Y, Wang G (2019) Beneficial effects of Enterococcus faecalis in hypercholesterolemic mice on cholesterol transportation and gut microbiota. Appl Microbiol Biotechnol 103(7):3181–3191PubMedGoogle Scholar
  136. Zinedine A, Faid M, Benlemlih M (2005) In vitro reduction of aflatoxin B1 by strains of lactic acid bacteria isolated from Moroccan sourdough bread. Int J Agric Biol 7(1):67–70Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Ahmad Ud Din
    • 1
  • Adil Hassan
    • 1
  • Yuan Zhu
    • 1
  • Tieying Yin
    • 1
  • Hans Gregersen
    • 1
  • Guixue Wang
    • 1
    Email author
  1. 1.Key Laboratory for Bio-rheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular ImplantsBioengineering College of Chongqing UniversityChongqingChina

Personalised recommendations