Skip to main navigation menu Skip to main content Skip to site footer

Research Progress on the Association Between the Oral–Gut Microbiota Axis and Cardiovascular Disease

Abstract

Cardiovascular disease (CVD) remains the leading cause of global mortality despite substantial advances in the pathophysiological understanding and clinical management of this disease. Emerging evidence implicates the oral and intestinal microbiota—two highly complex microbial ecosystems—as critical modulators of cardiovascular homeostasis. These communities are shaped by host immunity, lifestyle, aging, diet, pharmacological agents, and environmental exposure; their dysbiosis has been causally linked to a spectrum of chronic disorders, including CVD. This suggests that the oral and gut microbiota constitute tractable biological targets for CVD intervention. Here, we first delineate the compositional and functional interrelationship between the oral and gut microbiomes. We then summarize mechanistic pathways through which the oral–gut microbiota axis may drive CVD, including (i) direct endothelial invasion, (ii) microbial translocation, (iii) platelet hyperaggregation, (iv) immune-mediated systemic inflammation, and (v) microbial metabolite–host interactions. Finally, we review clinical associations between the oral–gut axis and prevalent CVD phenotypes—atherosclerosis, hypertension, myocardial infarction, and heart failure—and discuss translational perspectives for microbiota-directed therapeutics.

Keywords

Cardiovascular Disease, Oral–Gut Microbiota Axis, Oral Microbiome, Gut Microbiome, Periodontitis

PDF

References

  1. Adak, A., & Khan, M. R. (2019). An insight into gut microbiota and its functionalities. Cellular and Molecular Life Sciences, 76(3), 473-493. https://doi.org/10.1007/s00018-018-2943-4
  2. Aguirre-García, M. M., Amedei, A., Hernández-Ruiz, P., et al. (2024). Cytokine and microbiota profiles in obesity-related hypertension patients. Frontiers in Cellular and Infection Microbiology, 13, 1325261. https://doi.org/10.3389/fcimb.2023.1325261
  3. Amar, S., Wu, S. C., & Madan, M. (2009). Is Porphyromonas gingivalis cell invasion required for atherogenesis? Pharmacotherapeutic implications. The Journal of Immunology, 182(3), 1584-1592. https://doi.org/10.4049/jimmunol.182.3.1584
  4. Armingohar, Z., Jørgensen, J. J., Kristoffersen, A. K., et al. (2014). Bacteria and bacterial DNA in atherosclerotic plaque and aneurysmal wall biopsies from patients with and without periodontitis. Journal of Oral Microbiology, 6, 24208. https://doi.org/10.3402/jom.v6.24208
  5. Baker, J. L., Mark Welch, J. L., Kauffman, K. M., et al. (2024). The oral microbiome: Diversity, biogeography and human health. Nature Reviews Microbiology, 22(2), 89-104. https://doi.org/10.1038/s41579-023-00905-x
  6. Bier, A., Braun, T., Khasbab, R., et al. (2018). A high salt diet modulates the gut microbiota and short chain fatty acids production in a salt-sensitive hypertension rat model. Nutrients, 10(9), 1154. https://doi.org/10.3390/nu10091154
  7. Blancas-Luciano, B. E., Zamora-Chimal, J., da Silva-de Rosenzweig, P. G., et al. (2023). Macrophages immunomodulation induced by Porphyromonas gingivalis and oral antimicrobial peptides. Odontology, 111(4), 778-792. https://doi.org/10.1007/s10266-023-00803-6
  8. Brandsma, E., Kloosterhuis, N. J., Koster, M., et al. (2019). A proinflammatory gut microbiota increases systemic inflammation and accelerates atherosclerosis. Circulation Research, 124(1), 94-100. https://doi.org/10.1161/CIRCRESAHA.118.313234
  9. Brito-Monzani, J. O., Sanches, I. C., Bernardes, N., et al. (2018). Hypertension induces additional cardiometabolic impairments and attenuates aerobic exercise training adaptations in fructose-fed ovariectomized rats. Hypertension Research, 41(2), 88-95. https://doi.org/10.1038/s41440-017-0009-6
  10. Bruno, A. S., Lopes, P. D. D., de Oliveira, K. C. M., et al. (2021). Vascular inflammation in hypertension: Targeting lipid mediators unbalance and nitrosative stress. Current Hypertension Reviews, 17(1), 35-46. https://doi.org/10.2174/1573402117666210118101622
  11. Caradonna, E., Abate, F., Schiano, E., et al. (2025). Trimethylamine-N-Oxide (TMAO) as a rising-star metabolite: Implications for human health. Metabolites, 15(4), 220. https://doi.org/10.3390/metabo15040220
  12. Carrizales-Sepúlveda, E. F., Ordaz-Farías, A., Vera-Pineda, R., et al. (2018). Periodontal disease, systemic inflammation and the risk of cardiovascular disease. Heart, Lung and Circulation, 27(11), 1327-1334. https://doi.org/10.1016/j.hlc.2018.05.102
  13. Chen, B. Y., Li, Y. L., Lin, W. Z., et al. (2023). Integrated omic analysis of human plasma metabolites and microbiota in a hypertension cohort. Nutrients, 15(9), 2074. https://doi.org/10.3390/nu15092074
  14. Chen, B. Y., Lin, W. Z., Li, Y. L., et al. (2023). Roles of oral microbiota and oral-gut microbial transmission in hypertension. Journal of Advanced Research, 43, 147-161. https://doi.org/10.1016/j.jare.2022.03.007
  15. Chen, Z., Wang, B., Dong, J., et al. (2021). Gut microbiota-derived l-histidine/imidazole propionate axis fights against the radiation-induced cardiopulmonary injury. International Journal of Molecular Sciences, 22(21), 11436. https://doi.org/10.3390/ijms222111436
  16. Chhibber-Goel, J., Singhal, V., Bhowmik, D., et al. (2016). Linkages between oral commensal bacteria and atherosclerotic plaques in coronary artery disease patients. NPJ Biofilms and Microbiomes, 2, 7. https://doi.org/10.1038/npjbiofilms.2016.7
  17. Costa, C. F. F. A., Correia-de-Sá, T., Araujo, R., et al. (2024). The oral-gut microbiota relationship in healthy humans: Identifying shared bacteria between environments and age groups. Frontiers in Microbiology, 15, 1475159. https://doi.org/10.3389/fmicb.2024.1475159
  18. Deng, H., Gong, Y., Chen, Y., et al. (2022). Porphyromonas gingivalis lipopolysaccharide affects the angiogenic function of endothelial progenitor cells via Akt/FoxO1 signaling. Journal of Periodontal Research, 57(4), 859-868. https://doi.org/10.1111/jre.13020
  19. Deshpande, R. G., Khan, M. B., & Genco, C. A. (1998). Invasion of aortic and heart endothelial cells by Porphyromonas gingivalis. Infection and Immunity, 66(11), 5337-5343. https://doi.org/10.1128/IAI.66.11.5337-5343.1998
  20. DeStefano, F., Anda, R. F., Kahn, H. S., et al. (1993). Dental disease and risk of coronary heart disease and mortality. BMJ, 306(6879), 688-691. https://doi.org/10.1136/bmj.306.6879.688
  21. Dilek, N., Papapetropoulos, A., Toliver-Kinsky, T., et al. (2020). Hydrogen sulfide: An endogenous regulator of the immune system. Pharmacological Research, 161, 105119. https://doi.org/10.1016/j.phrs.2020.105119
  22. Dong, J., Li, Y., Xiao, H., et al. (2021). Oral microbiota affects the efficacy and prognosis of radiotherapy for colorectal cancer in mouse models. Cell Reports, 37(4), 109886. https://doi.org/10.1016/j.celrep.2021.109886
  23. Duttaroy, A. K. (2021). Role of gut microbiota and their metabolites on atherosclerosis, hypertension and human blood platelet function: A review. Nutrients, 13(1), 144. https://doi.org/10.3390/nu13010144
  24. Ehteshami, A., Shirban, F., Bagherniya, M., et al. (2024). The association between high-density lipoproteins and periodontitis. Current Medicinal Chemistry, 31(39), 6407-6428. https://doi.org/10.2174/0929867331666230718152238
  25. Esposito, S., McGuinness, L. R., Sharma, P., et al. (2025). Trimethylamine N-oxide (TMAO) acutely alters ionic currents but does not increase cardiac cell death. Frontiers in Physiology, 16, 1505813. https://doi.org/10.3389/fphys.2025.1505813
  26. Fernandes, C. P., Oliveira, F. A., Silva, P. G., et al. (2014). Molecular analysis of oral bacteria in dental biofilm and atherosclerotic plaques of patients with vascular disease. International Journal of Cardiology, 174(3), 710-712. https://doi.org/10.1016/j.ijcard.2014.04.201
  27. Fitzgerald, K. A., & Kagan, J. C. (2020). Toll-like receptors and the control of immunity. Cell, 180(6), 1044-1066. https://doi.org/10.1016/j.cell.2020.02.041
  28. Gan, G., Zhang, R., Lu, B., et al. (2023). Gut microbiota may mediate the impact of chronic apical periodontitis on atherosclerosis in apolipoprotein E-deficient mice. International Endodontic Journal, 56(1), 53-68. https://doi.org/10.1111/iej.13836
  29. Gangula, P., Ravella, K., Chukkapalli, S., et al. (2015). Polybacterial periodontal pathogens alter vascular and gut BH4/nNOS/NRF2-phase II enzyme expression. PLoS ONE, 10(6), e0129885. https://doi.org/10.1371/journal.pone.0129885
  30. Giri, S., Uehara, O., Takada, A., et al. (2022). The effect of Porphyromonas gingivalis on the gut microbiome of mice in relation to aging. Journal of Periodontal Research, 57(6), 1256-1266. https://doi.org/10.1111/jre.13058
  31. Hayashi, C., Madrigal, A. G., Liu, X., et al. (2010). Pathogen-mediated inflammatory atherosclerosis is mediated in part via Toll-like receptor 2-induced inflammatory responses. Journal of Innate Immunity, 2(4), 334-343. https://doi.org/10.1159/000314686
  32. He, Z., Kwek, E., Hao, W., et al. (2021). Hawthorn fruit extract reduced trimethylamine-N-oxide (TMAO)-exacerbated atherogenesis in mice via anti-inflammation and anti-oxidation. Nutrition & Metabolism, 18(1), 6. https://doi.org/10.1186/s12986-020-00535-8
  33. Huang, Y., Liao, Y., Luo, B., et al. (2020). Non-surgical periodontal treatment restored the gut microbiota and intestinal barrier in apolipoprotein E mice with periodontitis. Frontiers in Cellular and Infection Microbiology, 10, 498. https://doi.org/10.3389/fcimb.2020.00498
  34. Jia, X., Xu, W., Zhang, L., et al. (2021). Impact of gut microbiota and microbiota-related metabolites on hyperlipidemia. Frontiers in Cellular and Infection Microbiology, 11, 634780. https://doi.org/10.3389/fcimb.2021.634780
  35. Jiang, S., Shui, Y., Cui, Y., et al. (2021). Gut microbiota dependent trimethylamine N-oxide aggravates angiotensin II-induced hypertension. Redox Biology, 46, 102115. https://doi.org/10.1016/j.redox.2021.102115
  36. Joshi, V., Matthews, C., Aspiras, M., et al. (2014). Smoking decreases structural and functional resilience in the subgingival ecosystem. Journal of Clinical Periodontology, 41(11), 1037-1047. https://doi.org/10.1111/jcpe.12300
  37. Koh, A., Molinaro, A., Ståhlman, M., et al. (2018). Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell, 175(4), 947-961.e17. https://doi.org/10.1016/j.cell.2018.09.055
  38. Kozarov, E. V., Dorn, B. R., Shelburne, C. E., et al. (2005). Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. Arteriosclerosis, Thrombosis, and Vascular Biology, 25(3), e17-e18. https://doi.org/10.1161/01.ATV.0000155018.51734.7a
  39. Li, J., Zhao, F., Wang, Y., et al. (2017). Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome, 5(1), 14. https://doi.org/10.1186/s40168-016-0222-x
  40. Li, Y., Liu, Y., Cui, J., et al. (2024). Oral-gut microbial transmission promotes diabetic coronary heart disease. Cardiovascular Diabetology, 23(1), 123. https://doi.org/10.1186/s12933-024-02188-1
  41. Lin, J., Huang, D., Xu, H., et al. (2022). Macrophages: A communication network linking Porphyromonas gingivalis infection and associated systemic diseases. Frontiers in Immunology, 13, 952040. https://doi.org/10.3389/fimmu.2022.952040
  42. Litwin, M., & Kułaga, Z. (2021). Obesity, metabolic syndrome, and primary hypertension. Pediatric Nephrology, 36(4), 825-837. https://doi.org/10.1007/s00467-020-04580-3
  43. Liu, X. R., Xu, Q., Xiao, J., et al. (2020). Role of oral microbiota in atherosclerosis. Clinica Chimica Acta, 506, 191-195. https://doi.org/10.1016/j.cca.2020.03.033
  44. Magrin, G. L., Strauss, F. J., Benfatti, C. A. M., et al. (2020). Effects of short-chain fatty acids on human oral epithelial cells and the potential impact on periodontal disease: A systematic review of in vitro studies. International Journal of Molecular Sciences, 21(14), 4895. https://doi.org/10.3390/ijms21144895
  45. Maki, K. A., Kazmi, N., Barb, J. J., et al. (2021). The oral and gut bacterial microbiomes: Similarities, differences, and connections. Biological Research for Nursing, 23(1), 7-20. https://doi.org/10.1177/1099800420941600
  46. Manrique, C., Lastra, G., Whaley-Connell, A., et al. (2005). Hypertension and the cardiometabolic syndrome. The Journal of Clinical Hypertension, 7(8), 471-476. https://doi.org/10.1111/j.1524-6175.2005.04546.x
  47. Marcano, R., Rojo, M. Á., Cordoba-Diaz, D., et al. (2021). Pathological and therapeutic approach to endotoxin-secreting bacteria involved in periodontal disease. Toxins, 13(8), 533. https://doi.org/10.3390/toxins13080533
  48. Mougeot, J. C., Stevens, C. B., Paster, B. J., et al. (2017). Porphyromonas gingivalis is the most abundant species detected in coronary and femoral arteries. Journal of Oral Microbiology, 9(1), 1281562. https://doi.org/10.1080/20002297.2017.1281562
  49. Murugesan, S., Al Ahmad, S. F., Singh, P., et al. (2020). Profiling the salivary microbiome of the Qatari population. Journal of Translational Medicine, 18(1), 127. https://doi.org/10.1186/s12967-020-02291-2
  50. Nearing, J. T., DeClercq, V., Van Limbergen, J., et al. (2020). Assessing the variation within the oral microbiome of healthy adults. mSphere, 5(5), e00451-20. https://doi.org/10.1128/mSphere.00451-20
  51. Nikitakis, N. G., Papaioannou, W., Sakkas, L. I., et al. (2017). The autoimmunity-oral microbiome connection. Oral Diseases, 23(7), 828-839. https://doi.org/10.1111/odi.12589
  52. Park, S. Y., Hwang, B. O., Lim, M., et al. (2021). Oral-gut microbiome axis in gastrointestinal disease and cancer. Cancers, 13(9), 2124. https://doi.org/10.3390/cancers13092124
  53. Pushalkar, S., Paul, B., Li, Q., et al. (2020). Electronic cigarette aerosol modulates the oral microbiome and increases risk of infection. iScience, 23(3), 100884. https://doi.org/10.1016/j.isci.2020.100884
  54. Rabot, S., Membrez, M., Bruneau, A., et al. (2010). Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. The FASEB Journal, 24(12), 4948-4959. https://doi.org/10.1096/fj.10-164921
  55. Rizzo, A. A. (1967). The possible role of hydrogen sulfide in human periodontal disease. I. Hydrogen sulfide production in periodontal pockets. Periodontics, 5(5), 233-236.
  56. Roca-Millan, E., González-Navarro, B., Sabater-Recolons, M. M., et al. (2018). Periodontal treatment on patients with cardiovascular disease: Systematic review and meta-analysis. Medicina Oral, Patología Oral y Cirugía Bucal, 23(6), e681-e690. https://doi.org/10.4317/medoral.22233
  57. Roth, G. A., Mensah, G. A., Johnson, C. O., et al. (2020). Global burden of cardiovascular diseases and risk factors, 1990-2019: Update from the GBD 2019 study. Journal of the American College of Cardiology, 76(25), 2982-3021. https://doi.org/10.1016/j.jacc.2020.11.010
  58. Roth, G. A., Moser, B., Huang, S. J., et al. (2006). Infection with a periodontal pathogen induces procoagulant effects in human aortic endothelial cells. Journal of Thrombosis and Haemostasis, 4(10), 2256-2261. https://doi.org/10.1111/j.1538-7836.2006.02128.x
  59. Roth, G. A., Moser, B., Roth-Walter, F., et al. (2007). Infection with periodontal pathogen increases mononuclear cell adhesion to human aortic endothelial cells. Atherosclerosis, 190(2), 271-281. https://doi.org/10.1016/j.atherosclerosis.2006.03.022
  60. Ruan, Q., Guan, P., Qi, W., et al. (2023). Porphyromonas gingivalis regulates atherosclerosis through an immune pathway. Frontiers in Immunology, 14, 1103592. https://doi.org/10.3389/fimmu.2023.1103592
  61. Sayols-Baixeras, S., Dekkers, K. F., Baldanzi, G., et al. (2023). Streptococcus species abundance in the gut is linked to subclinical coronary atherosclerosis in 8973 participants from the SCAPIS cohort. Circulation, 148(6), 459-472. https://doi.org/10.1161/CIRCULATIONAHA.123.063914
  62. Schmidt, T. S., Hayward, M. R., Coelho, L. P., et al. (2019). Extensive transmission of microbes along the gastrointestinal tract. eLife, 8, e42693. https://doi.org/10.7554/eLife.42693
  63. Segata, N., Haake, S. K., Mannon, P., et al. (2012). Composition of the adult digestive tract bacterial microbiome based on seven mouth surfaces, tonsils, throat and stool samples. Genome Biology, 13(6), R42. https://doi.org/10.1186/gb-2012-13-6-r42
  64. Shiheido, Y., Maejima, Y., Suzuki, J. I., et al. (2016). Porphyromonas gingivalis, a periodontal pathogen, enhances myocardial vulnerability, thereby promoting post-infarct cardiac rupture. Journal of Molecular and Cellular Cardiology, 99, 123-137. https://doi.org/10.1016/j.yjmcc.2016.08.015
  65. Tan, X., Wang, Y., & Gong, T. (2023). The interplay between oral microbiota, gut microbiota and systematic diseases. Journal of Oral Microbiology, 15(1), 2213112. https://doi.org/10.1080/20002297.2023.2213112
  66. Tsai, H. J., Tsai, W. C., Hung, W. C., et al. (2021). Gut microbiota and subclinical cardiovascular disease in patients with type 2 diabetes mellitus. Nutrients, 13(8), 2679. https://doi.org/10.3390/nu13082679
  67. Turnbaugh, P. J., Ley, R. E., Mahowald, M. A., et al. (2006). An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, 444(7122), 1027-1031. https://doi.org/10.1038/nature05414
  68. Vanhatalo, A., Blackwell, J. R., L'Heureux, J. E., et al. (2018). Nitrate-responsive oral microbiome modulates nitric oxide homeostasis and blood pressure in humans. Free Radical Biology and Medicine, 124, 21-30. https://doi.org/10.1016/j.freeradbiomed.2018.05.078
  69. Verma, D., Garg, P. K., & Dubey, A. K. (2018). Insights into the human oral microbiome. Archives of Microbiology, 200(4), 525-540. https://doi.org/10.1007/s00203-018-1505-3
  70. Viafara-García, S. M., Morantes, S. J., Chacon-Quintero, Y., et al. (2019). Repeated Porphyromonas gingivalis W83 exposure leads to release pro-inflammatory cytokines and angiotensin II in coronary artery endothelial cells. Scientific Reports, 9(1), 19379. https://doi.org/10.1038/s41598-019-55800-9
  71. Wang, B., Qiu, J., Lian, J., et al. (2021). Gut metabolite Trimethylamine-N-Oxide in atherosclerosis: From mechanism to therapy. Frontiers in Cardiovascular Medicine, 8, 723886. https://doi.org/10.3389/fcvm.2021.723886
  72. Wang, J., Chen, P., Cao, Q., et al. (2022). Traditional Chinese medicine ginseng dingzhi decoction ameliorates myocardial fibrosis and high glucose-induced cardiomyocyte injury by regulating intestinal flora and mitochondrial dysfunction. Oxidative Medicine and Cellular Longevity, 2022, 9205908. https://doi.org/10.1155/2022/9205908
  73. Wang, J., Geng, X., Sun, J., et al. (2019). The risk of periodontitis for peripheral vascular disease: A systematic review. Reviews in Cardiovascular Medicine, 20(2), 81-89. https://doi.org/10.31083/j.rcm.2019.02.52
  74. Wang, J., Zhang, H., He, J., et al. (2022). The role of the gut microbiota in the development of ischemic stroke. Frontiers in Immunology, 13, 845243. https://doi.org/10.3389/fimmu.2022.845243
  75. Wang, L., Wang, S., Zhang, Q., et al. (2022). The role of the gut microbiota in health and cardiovascular diseases. Molecular Biomedicine, 3(1), 30. https://doi.org/10.1186/s43556-022-00091-2
  76. Wang, Q., Zhao, L., Xu, C., et al. (2019). Fusobacterium nucleatum stimulates monocyte adhesion to and transmigration through endothelial cells. Archives of Oral Biology, 100, 86-92. https://doi.org/10.1016/j.archoralbio.2019.02.013
  77. Wang, Z., Haslam, D. E., Sawicki, C. M., et al. (2024). Saliva, plasma, and multifluid metabolomic signatures of periodontal disease, type 2 diabetes progression, and markers of glycemia and dyslipidemia among Puerto Rican adults with overweight and obesity. Journal of the American Heart Association, 13(15), e033350. https://doi.org/10.1161/JAHA.123.033350
  78. Wessler, B. S., Lai, Y. H. L., Kramer, W., et al. (2015). Clinical prediction models for cardiovascular disease: Tufts predictive analytics and comparative effectiveness clinical prediction model database. Circulation: Cardiovascular Quality and Outcomes, 8(4), 368-375. https://doi.org/10.1161/CIRCOUTCOMES.115.001693
  79. Xie, H., Qin, Z., Ling, Z., et al. (2023). Oral pathogen aggravates atherosclerosis by inducing smooth muscle cell apoptosis and repressing macrophage efferocytosis. International Journal of Oral Science, 15(1), 26. https://doi.org/10.1038/s41368-023-00231-9
  80. Xie, M., Tang, Q., Nie, J., et al. (2020). BMAL1-downregulation aggravates Porphyromonas gingivalis-induced atherosclerosis by encouraging oxidative stress. Circulation Research, 126(6), e15-e29. https://doi.org/10.1161/CIRCRESAHA.119.315502
  81. Yan, X., Jin, J., Su, X., et al. (2020). Intestinal flora modulates blood pressure by regulating the synthesis of intestinal-derived corticosterone in high salt-induced hypertension. Circulation Research, 126(7), 839-853. https://doi.org/10.1161/CIRCRESAHA.119.316394
  82. Zeng, X. T., Leng, W. D., Lam, Y. Y., et al. (2016). Periodontal disease and carotid atherosclerosis: A meta-analysis of 17,330 participants. International Journal of Cardiology, 203, 1044-1051. https://doi.org/10.1016/j.ijcard.2015.11.092
  83. Zhao, M., Wei, H., Li, C., et al. (2022). Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy. Nature Communications, 13(1), 1757. https://doi.org/10.1038/s41467-022-29060-7