Advanced Search

Journal of Traditional Chinese Medicine >

2025 , Vol. 45 >Issue 4: 747 - 758

DOI: https://doi.org/10.19852/j.cnki.jtcm.2025.04.005

Original Articles

Huayu Qutan formula (化瘀祛痰方) can improve platelet aggregation in acute coronary syndrome rats by regulating gut microbes to drive trimethylamine/flavin containing monooxygenase 3/trimethylamine N-oxide pathway

  • Ni ZHANG ,
  • Yanxi CHEN ,
  • Lianqun JIA ,
  • Xinya LI ,
  • Yixin MA
Expand
  • 1 Department of Cardiology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, China
    2 First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China
    3 Department of Biochemistry, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China
    4 Chinese Medicine Innovation Engineering Technology Center, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China
Dr. ZHANG Ni, Department of Cardiology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, China. zhang_ni1993@163.com,Telephone: +86-24-82961932

Received date: 2024-07-16

  Accepted date: 2024-11-29

  Online published: 2025-07-25

Supported by

National Natural Science Foundation of China Project: based on the Theory of “the Heart is in Harmony with the Small Intestine” to Explore the Influence and Mechanism of Gut Microbes on High Platelet Reactivity of Acute Coronary Syndrome with Phlegm and Blood Stasis Syndrome(82104841);Education Department of Liaoning Province Young Science and Technology Talents "Seedling" Project: to Explore the Effect and Mechanism of Huayu Qutan Formula on Platelet Function in Acute Coronary Syndrome Patients with Phlegm and Blood Stasis Syndrome after Percutaneous Coronary Intervention based on Intestinal Microbiome(L202039)

Fold

Abstract

OBJECTIVE: To investigate the effects of gut microbes regulation of the trimethylamine (TMA)/flavin containing monooxygenase 3 (FMO3)/trimethylamine N-oxide (TMAO) pathway on platelet aggregation in acute coronary syndrome (ACS) rats and the intervention of Huayu Qutan formula (化瘀祛痰方).

METHODS: The ACS rats with syndrome of phlegm and blood stasis rats were established. Platelet, platelet aggregation, platelet activation markers and TMA/FMO3/ TMAO pathway were detected. Metagenomics technology was employed to analyze the characteristics of the gut microbiota.

RESULTS: Huayu Qutan formula and gut microbes could inhibit high platelet reactivity and regulate the TMA/ FMO3/TMAO pathway. The dominant bacteria in ACS rats including but not limited to the major phyla, Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria, also including some low abundance phyla, Fusobacteria, Verrucomicrobia, Spirochaetes, and Deferribacteres. The dominant bacteria in the Huayu Qutan formula group were Synergistetes, Deferribacteres, Deferribacteraceae, Faecalibacterium and Mucispirillum. In the Huayu Qutan formula combined with fecal bacteria enema group, the dominant bacteria were Verrucomicrobia, Verrucomicrobiae, Akkermansia and Verrucomicrobium. These gut microbiota were correlated with pathways such as Riboflavin metabolism and Arachidonic acid metabolism.

CONCLUSION: Huayu Qutan formula may prevent ACS by modulating gut microbes Synergistetes, Faecalibacterium and Allobaculum, regulating the iron metabolism of Deferribacteres, and driving the TMA/FMO3/TMAO pathway to regulate gut microbiota function, and improving platelet aggregation. Akkermansia may serve as a promising probiotic, which could drive TMA/FMO3/ TMAO pathway to regulate Arachidonic acid metabolism to improve platelet aggregation. The findings of this study provide a theoretical basis for the theory of "the heart is connected with the small intestine".

Key words： acute coronary syndrome; platelet aggregation; gut microbes; Huayu Qutan formula

Cite this article

Ni ZHANG , Yanxi CHEN , Lianqun JIA , Xinya LI , Yixin MA . Huayu Qutan formula (化瘀祛痰方) can improve platelet aggregation in acute coronary syndrome rats by regulating gut microbes to drive trimethylamine/flavin containing monooxygenase 3/trimethylamine N-oxide pathway[J]. Journal of Traditional Chinese Medicine, 2025 , 45(4) : 747 -758 . DOI: 10.19852/j.cnki.jtcm.2025.04.005

References

1. Gach O, El HZ, Lancellotti P. Acute coronary syndrome. Rev Med Liege 2018; 73: 243-50.
2. Wang L, Jin Y. Noncoding RNAs as biomarkers for acute coronary syndrome. Biomed Res Int 2020; 2020: 3298696.
3. Sabouret P, Spadafora L, Fischman D, et al. De-escalation of antiplatelet therapy in patients with coronary artery disease: time to change our strategy? Eur J Intern Med 2023; 110: 1-9.
4. Kwon O, Park DW. Antithrombotic therapy after acute coronary syndromes or percutaneous coronary interventions in east asian populations. JACC Asia 2022; 2: 1-18.
5. Pedersen OB, Pasalic L, Nissen PH, Grove EL, Kristensen SD, Hvas AM. Flow cytometric assessment of changes in platelet reactivity after acute coronary syndrome: a systematic review. Semin Thromb Hemost 2022; 48: 542-51.
6. Alenazy FO, Thomas MR. Novel antiplatelet targets in the treatment of acute coronary syndromes. Platelets 2021; 32: 15-28.
7. Wongsalap Y, Kengkla K, Wilairat P, Ratworawong K, Saokaew S, Wanlapakorn C. Efficacy and safety of different dual antiplatelet strategies in patients undergoing percutaneous coronary intervention: a systematic review and network Meta-analysis. Chronic Dis Transl Med 2023; 9: 299-308.
8. De Luca L, Gragnano F, Calabrò P, Huber K. Balancing benefits and risks of oral antiplatelet strategies in patients with coronary artery diseases: an evolving issue. Curr Probl Cardiol 2023; 48: 102025.
9. Jacob S, Kosaka Y, Bhatlekar S, et al. Mitofusin-2 regulates platelet mitochondria and function. Circ Res 2024; 134: 143-61.
10. Solari FA, Krahn D, Swieringa F, et al. Multi-omics approaches to study platelet mechanisms. Curr Opin Chem Biol 2023; 73: 102253.
11. Ravera S, Signorello MG, Panfoli I. Platelet metabolic flexibility: a matter of substrate and location. Cells 2023; 12: 1802.
12. Kong H, Cen J, Yang X, et al. Research progress in the relationship between trimethylamine oxide and coronary heart disease. Altern Ther Health Med 2024; 30: 220-7.
13. Chen B, Patel S, Bao L, Nadeem D, Krittanawong C. Pro-inflammatory food, gut microbiota, and cardiovascular and pancreatic diseases. Biomolecules 2024; 14: 210.
14. Fang J, Yu CH, Li XJ, et al. Gut dysbiosis in nonalcoholic fatty liver disease: pathogenesis, diagnosis, and therapeutic implications. Front Cell Infect Microbiol 2022; 12: 997018.
15. Piccioni A, de Cunzo T, Valletta F, et al. Gut microbiota and environment in coronary artery disease. Int J Environ Res Public Health 2021; 18: 4242.
16. Xie Z, Liu X, Huang X, et al. Remodelling of gut microbiota by berberine attenuates trimethylamine N-oxide-induced platelet hyperreaction and thrombus formation. Eur J Pharmacol 2021; 911: 174526.
17. Zhang F, Wu LB, Hu L, et al. Study on the central neural pathway and the relationship between the heart and small intestine via a dual neural tracer. PLoS One 2022; 17: e0277644.
18. Anonymous (compiled during Warring States to Western Han Dynasty). Huang Di Nei Jing. Beijing: China Press of Traditional Chinese Medicine, 2013: 14.
19. Qin JM (Ming dynasty), Qin HS (Qing dynasty, Supplement). Zheng Yin Mai Zhi. Beijing: People's Medical Publishing House, 2023: 3.
20. Yi M, Dai X, Li Q, Zhao Y, Nie S, Wang D. 1H-NMR-based metabolomics study on coronary heart disease with blood-stasis syndrome and phlegm syndrome. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2021; 46: 591-600.
21. Liu R, Jiang LJ, Yang Y, et al. Study on syndrome differentiation strategy of phlegm and blood stasis syndromes of coronary heart disease based on expert consultation on medical cases. Ann Palliat Med 2021; 10: 9940-52.
22. Galli M, Andreotti F, Sabouret P, Gragnano F. 2023 ESC guidelines on ACS: what is new in antithrombotic therapy? Eur Heart J Cardiovasc Pharmacother 2023; 9: 595-6.
23. Heemskerk JWM, West J. Emerging technologies for understanding platelet diversity. Arterioscler Thromb Vasc Biol 2022; 42: 540-52.
24. Van der Meijden PEJ, Heemskerk JWM. Platelet biology and functions: new concepts and clinical perspectives. Nat Rev Cardiol 2019; 16: 166-79.
25. Fei YX, Wang SQ, Yang LJ, et al. Salvia miltiorrhiza Bunge (Danshen) extract attenuates permanent cerebral ischemia through inhibiting platelet activation in rats. J Ethnopharmacol 2017; 207: 57-66.
26. Li L, Chen H, Shen A, et al. Ligustrazine inhibits platelet activation via suppression of the Akt pathway. Int J Mol Med 2019; 43: 575-82.
27. Zhang D, Qiao W, Zhao Y, Fang H, Xu D, Xia Q. Curdione attenuates thrombin-induced human platelet activation: β1-tubulin as a potential therapeutic target. Fitoterapia 2017; 116: 106-15.
28. Zhu W, Gregory JC, Org E, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 2016; 165: 111-24.
29. Hasan RA, Koh AY, Zia A. The gut microbiome and thromboembolism. Thromb Res 2020; 189: 77-87.
30. Emonds JJ, Ringel C, Reinicke M, et al. Influence of trimethylamine N-Oxide on platelet activation. Nutrients 2022; 14: 3261.
31. Nam HS. Gut microbiota and ischemic stroke: the role of trimethylamine N-Oxide. J Stroke 2019; 21: 151-59.
32. Canyelles M, Borràs C, Rotllan N, Tondo M, Escolà-Gil JC, Blanco-Vaca F. Gut microbiota-derived TMAO: a causal factor promoting atherosclerotic cardiovascular disease? Int J Mol Sci 2023; 24: 1940.
33. Ivashkin VT, Kashukh YA. Impact of L-carnitine and phosphatidylcholine containing products on the proatherogenic metabolite TMAO production and gut microbiome changes in patients with coronary artery disease. Vopr Pitan 2019; 88: 25-33.
34. Ge X, Zheng L, Zhuang R, et al. The gut microbial metabolite trimethylamine N-Oxide and hypertension risk: a systematic review and dose-response Meta-analysis. Adv Nutr 2020; 11: 66-76.
35. Duttaroy AK. Role of gut microbiota and their metabolites on atherosclerosis, hypertension and human blood platelet function: a review. Nutrients 2021; 13: 144.
36. Massey W, Osborn LJ, Banerjee R, et al. Flavin-containing monooxygenase 3 (FMO3) is critical for dioxin-induced reorganization of the gut microbiome and host insulin sensitivity. Metabolites 2022; 12: 364.
37. Zhang WQ, Wang YJ, Zhang A, et al. TMA/TMAO in hypertension: novel horizons and potential therapies. J Cardiovasc Transl Res 2021; 14: 1117-24.
38. Zhang Y, Wang Y, Ke B, Du J. TMAO: how gut microbiota contributes to heart failure. Transl Res 2021; 228: 109-25.
39. Tang WH, Wang Z, Li XS, et al. Increased trimethylamine N-Oxide portends high mortality risk independent of glycemic control in patients with type 2 diabetes mellitus. Clin Chem 2017; 63: 297-306.
40. Witkowski M, Weeks TL, Hazen SL. Gut microbiota and cardiovascular disease. Circ Res 2020; 127: 553-70.
41. Verhaar BJH, Prodan A, Nieuwdorp M, Muller M. Gut microbiota in hypertension and atherosclerosis: a review. Nutrients 2020; 12: 2982.
42. Khan I, Khan I, Jianye Z, et al. Exploring blood microbial communities and their influence on human cardiovascular disease. J Clin Lab Anal 2022; 36: e24354.
43. Cui L, Zhao T, Hu H, Zhang W, Hua X. Association study of gut flora in coronary heart disease through high-throughput sequencing. Biomed Res Int 2017; 2017: 3796359.
44. Sanchez-Alcoholado L, Castellano-Castillo D, Jordan-Martinez L, et al. Role of gut microbiota on cardiometabolic parameters and immunity in coronary artery disease patients with and without type-2 diabetes mellitus. Front Microbiol 2017; 8: 1936.
45. Peng Y, Zhang N, Li WJ, et al. Correlations of changes in inflammatory factors, glucose and lipid metabolism indicators and adiponectin with alterations in intestinal flora in rats with coronary heart disease. Eur Rev Med Pharmacol Sci 2020; 24: 10118-25.
46. Peeling RW, Mabey D, Chen XS, Garcia PJ. Syphilis. Lancet 2023; 402: 336-46.
47. Mathur H, Beresford TP, Cotter PD. Health benefits of lactic acid bacteria (LAB) fermentates. Nutrients 2020; 12: 1679.
48. Martín R, Rios-Covian D, Huillet E, et al. Faecalibacterium: a bacterial genus with promising human health applications. FEMS Microbiol Rev 2023; 47: fuad039.
49. Yang HT, Jiang ZH, Yang Y, et al. Faecalibacterium prausnitzii as a potential antiatherosclerotic microbe. Cell Commun Signal 2024; 22: 54.
50. Wang H, Reddy ST, Fogelman AM. The role of gut-derived oxidized lipidsand bacterial lipopolysaccharide in systemic infammation and atherosclerosis. Curr Opin Lipidol 2022; 33: 277-82.
51. Zheng Z, Lyu W, Ren Y, et al. Allobaculum involves in the modulation of intestinal ANGPTLT 4 expression in mice treated by high-fat diet. Front Nutr 2021; 8: 690138.
52. Park S, Kim I, Han SJ, et al. Oral porphyromonas gingivalis infection affects intestinal microbiota and promotes atherosclerosis. J Clin Periodontol 2023; 50: 1553-67.
53. Herp S, Durai Raj AC, Salvado Silva M, Woelfel S, Stecher B. The human symbiont mucispirillum schaedleri: causality in health and disease. Med Microbiol Immunol 2021; 210: 173-79.
54. Li Y, Luan Y, Yue X, et al. Effects of codonopis bulleynana forest ex diels on deferribacteres in constipation predominant intestine tumor: differential analysis. Saudi J Biol Sci 2019; 26: 395-401.
55. Corredor Z, Suarez-Molina A, Fong C, Cifuentes-C L, Guauque-Olarte S. Presence of periodontal pathogenic bacteria in blood of patients with coronary artery disease. Sci Rep 2022; 12: 1241.
56. Lledós M, Prats-Sánchez L, Llucià-Carol L, et al. Ischaemic stroke patients present sex differences in gut microbiota. Eur J Neurol 2023; 30: 3497-506.
57. Kuhn KA, Schulz HM, Regner EH, et al. Bacteroidales recruit IL-6-producing intraepithelial lymphocytes in the colon to promote barrier integrity. Mucosal Immunol 2018; 11: 357-68.
58. Zhao N, Wang Y, Ma Y, et al. Jia-Wei-Si-Miao-Yong-An decoction modulates intestinal flora and metabolites in acute coronary syndrome model. Front Cardiovasc Med 2023; 9: 1038273.
59. Burakova I, Smirnova Y, Gryaznova M, et al. The effect of short-term consumption of lactic acid bacteria on the gut microbiota in obese people. Nutrients 2022; 14: 3384.
60. Zhang T, Li Q, Cheng L, Buch H, Zhang F. Akkermansia muciniphila is a promising probiotic. Microb Biotechnol 2019; 12: 1109-25.
61. Jian H, Liu Y, Wang X, Dong X, Zou X. Akkermansia muciniphila as a next-generation probiotic in modulating human metabolic homeostasis and disease progression: a role mediated by gut-liver-brain axes? Int J Mol Sci 2023; 24: 3900.
62. Cani PD, Depommier C, Derrien M, Everard A, de Vos WM. Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms. Nat Rev Gastroenterol Hepatol 2022; 19: 625-37.
63. Xing YQ, Li JX, Yuan YL, Mao TY. The combination of gut microbiota-depleted treatment and fecal microbiota transplantation is an important strategy to verify the efficacy of traditional Chinese medicine though modulation of gut dysbiosis. J Tradit Chin Med 2024; 44: 222-3.
Options
Outlines

/

〈 〉