1. Kau, A. L., Ahern, P. P., Griffin, N. W., Goodman, A. L. & Gordon, J. I. Human nutrition, the gut microbiome and the immune system. Nature 474, 327–336 (2011).

2. Blaser, M. J. The microbiome revolution. J. Clin. Invest. 124, 4162–4165 (2014).

3. Fischbach, M. A. & Segre, J. A. Signaling in host-associated microbial communities. Cell 164, 1288–1300 (2016).

4. Aron-Wisnewsky, J. & Clément, K. The gut microbiome, diet, and links to cardiometabolic and chronic disorders. Nat. Rev. Nephrol. 12, 169–181 (2016).

5. Schroeder, B. O. & Bäckhed, F. Signals from the gut microbiota to distant organs in physiology and disease. Nat. Med. 22, 1079–1089 (2016).

6. Koopen, A. M., Groen, A. K. & Nieuwdorp, M. Human microbiome as therapeutic intervention target to reduce cardiovascular disease risk. Curr. Opin. Lipidol. 27, 615–622 (2016).

7. Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).

8. Tang, W. H. W. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1584 (2013).

9. Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).

10. Wang, Z. et al. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur. Heart J. 35, 904–910 (2014).

11. Tang, W. H. W. et al. 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, 1908–1914 (2014).

12. Tang, W. H. W. et al. 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 (2015).

13. Tang, W. H. W. et al. Intestinal microbiota–dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J. Card. Fail. 21, 91–96 (2015).

14. Organ, C. L. et al. Choline diet and its gut microbe–derived metabolite, trimethylamine N-oxide, exacerbate pressure overload–induced heart failure. Circ. Heart Fail. 9, e002314 (2016).

15. Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016).

16. Senthong, V. et al. 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 (2016).

17. Warrier, M. et al. The TMAO-generating enzyme flavin monooxygenase 3 is a central regulator of cholesterol balance. Cell Rep. 10, 326–338 (2015).

18. Seldin, M. M. et al. Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-κB. J. Am. Heart Assoc. 5, e002767 (2016).

19. Li, T., Chen, Y., Gua, C. & Li, X. Elevated circulating trimethylamine N-oxide levels contribute to endothelial dysfunction in aged rats through vascular inflammation and oxidative stress. Front. Physiol. 8, 350 (2017).

20. Yue, C. et al. Trimethylamine N-oxide prime NLRP3 inflammasome via inhibiting ATG16L1-induced autophagy in colonic epithelial cells. Biochem. Biophys. Res. Commun. 490, 541–551 (2017).

21. Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015).

22. Fusaro, M. et al. Vitamin K plasma levels determination in human health. Clin. Chem. Lab. Med 55, 789–799 (2017).

23. Jäckel, S. et al. Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via Toll-like receptor-2. Blood 130, 542–553 (2017).

24. Zhu, W., Wang, Z., Tang, W. H. W. & Hazen, S. L. Gut microbe-generated trimethylamine N-oxide from dietary choline is prothrombotic in subjects. Circulation 135, 1671–1673 (2017).

25. Heianza, Y., Ma, W., Manson, J. E., Rexrode, K. M. & Qi, L. Gut microbiota metabolites and risk of major adverse cardiovascular disease events and death: a systematic review and meta-analysis of prospective studies. J. Am. Heart Assoc. 6, e004947 (2017).

26. Schiattarella, G. G. et al. 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 (2017).

27. Qi, J. et al. Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies. J. Cell. Mol. Med. 22, 185–194 (2018).

28. Brown, J. M. & Hazen, S. L. Targeting of microbe-derived metabolites to improve human health: The next frontier for drug discovery. J. Biol. Chem. 292, 8560–8568 (2017).

29. Dolphin, C. T., Janmohamed, A., Smith, R. L., Shephard, E. A. & Phillips, I. R. Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nat. Genet. 17, 491–494 (1997).

30. Bennett, B. J. et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 17, 49–60 (2013).

31. Phillips, G. B. The lipid composition of human bile. Biochim. Biophys. Acta 41, 361–363 (1960).

32. Craciun, S., Marks, J. A. & Balskus, E. P. Characterization of choline trimethylamine-lyase expands the chemistry of glycyl radical enzymes. ACS Chem. Biol. 9, 1408–1413 (2014).

33. Romano, K. A., Vivas, E. I., Amador-Noguez, D. & Rey, F. E. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. MBio 6, e02481 (2015).

34. Martínez-del Campo, A. et al. Characterization and detection of a widely distributed gene cluster that predicts anaerobic choline utilization by human gut bacteria. MBio 6, e00042–15 (2015).

35. Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015).

36. Furie, B. & Furie, B. C. Mechanisms of thrombus formation. N. Engl. J. Med. 359, 938–949 (2008).

37. Bobadilla, R. V. Acute coronary syndrome: focus on antiplatelet therapy. Crit. Care Nurse 36, 15–27 (2016).

38. Levine, G. N. et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Thorac. Cardiovasc. Surg. 152, 1243–1275 (2016).

39. Jennings, L. K. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb. Haemost. 102, 248–257 (2009).

40. Manchikanti, L. et al. Assessment of bleeding risk of interventional techniques: a best evidence synthesis of practice patterns and perioperative management of anticoagulant and antithrombotic therapy. Pain. Physician 16, SE261–SE318 (2013).

41. Cohen, M. Expanding the recognition and assessment of bleeding events associated with antiplatelet therapy in primary care. Mayo Clin. Proc. 84, 149–160 (2009).

42. Bodea, S., Funk, M. A., Balskus, E. P. & Drennan, C. L. Molecular basis of C–N bond cleavage by the glycyl radical enzyme choline trimethylamine-lyase. Cell Chem. Biol. 23, 1206–1216 (2016).

43. Chen, M. L. et al. 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–e02215 (2016).

44. Walsh, C. T. Suicide substrates, mechanism-based enzyme inactivators: recent developments. Annu. Rev. Biochem. 53, 493–535 (1984).

45. Hazen, S. L., Zupan, L. A., Weiss, R. H., Getman, D. P. & Gross, R. W. Suicide inhibition of canine myocardial cytosolic calcium-independent phospholipase A2. Mechanism-based discrimination between calcium-dependent and -independent phospholipases A2. J. Biol. Chem. 266, 7227–7232 (1991).

46. Sandhu, S. S. & Chase, T. Jr. Aerobic degradation of choline by Proteus mirabilis: enzymatic requirements and pathway. Can. J. Microbiol. 32, 743–750 (1986).

47. Romano, K. A. et al. Metabolic, epigenetic, and transgenerational effects of gut bacterial choline consumption. Cell Host Microbe 22, 279–290.e7 (2017).

48. Nemzek, J. A., Bolgos, G. L., Williams, B. A. & Remick, D. G. Differences in normal values for murine white blood cell counts and other hematological parameters based on sampling site. Inflamm. Res. 50, 523–527 (2001).

49. Koeth, R. A. et al. γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of l-carnitine to TMAO. Cell Metab. 20, 799–812 (2014).

50. Liu, Y., Jennings, N. L., Dart, A. M. & Du, X.-J. Standardizing a simpler, more sensitive and accurate tail bleeding assay in mice. World J. Exp. Med. 2, 30–36 (2012).

51. Derrien, M., Belzer, C. & de Vos, W. M. Akkermansia muciniphila and its role in regulating host functions. Microb. Pathog. 106, 171–181 (2017).

52. Gachet, C. Antiplatelet drugs: which targets for which treatments? J. Thromb. Haemost. 13, S313–S322 (2015).

53. Osbourn, A. E. & Field, B. Operons. Cell. Mol. Life Sci. 66, 3755–3775 (2009).

54. Craciun, S. & Balskus, E. P. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc. Natl Acad. Sci. USA 109, 21307–21312 (2012).

55. Berthoumieux, S. et al. Shared control of gene expression in bacteria by transcription factors and global physiology of the cell. Mol. Syst. Biol. 9, 634 (2013).

56. Clarke, D. D. Fluoroacetate and fluorocitrate: mechanism of action. Neurochem. Res. 16, 1055–1058 (1991).

57. Imhann, F. et al. Proton pump inhibitors affect the gut microbiome. Gut 65, 740–748 (2016).

58. Rogers, M. A. M. & Aronoff, D. M. The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. Clin. Microbiol. Infect. 22, 178.e1–178.e9 (2016).

59. Maier, L. et al. Extensive impact of nonantibiotic drugs on human gut bacteria. Nature 555, 623–628 (2018).

60. Wu, H. et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23, 850–858 (2017).

61. Wang, Z. et al. Measurement of trimethylamine-N-oxide by stable isotope dilution liquid chromatography tandem mass spectrometry. Anal. Biochem. 455, 35–40 (2014).