Interdisciplinary Approaches to Understanding and Managing Oral Microbiome Dysbiosis in Relation to Cardiovascular Disease Pathophysiology and Outcomes
Keywords:
Cardiovascular diseases, oral dysbiosis, periodontal infections, atherosclerosis, systemic inflammation.Abstract
Background: The global prevalence of cardiovascular diseases (CVD) has significantly increased over the past three decades, with a notable rise in morbidity and mortality rates. Recent research highlights a potential link between oral health, specifically oral dysbiosis, and cardiovascular outcomes.
Methods: This review synthesizes current literature on the relationship between the oral microbiome and cardiovascular diseases, focusing on atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF). We analyzed epidemiological studies, clinical trials, and mechanistic research to elucidate the pathways through which oral dysbiosis may influence cardiovascular health.
Results: Evidence suggests that periodontal infections contribute to systemic inflammation and bacteremia, facilitating atherogenesis and exacerbating cardiovascular conditions. Notably, specific oral pathogens have been identified in atherosclerotic plaques, indicating a direct connection between oral dysbiosis and ASCVD. Furthermore, interventions such as periodontal treatment have shown promise in reducing inflammatory markers and improving cardiovascular outcomes.
Conclusion: The interplay between oral health and cardiovascular disease underscores the need for an interdisciplinary approach in managing CVD, integrating dental care into cardiovascular risk assessment and treatment strategies. Future research should aim to establish causal relationships and explore therapeutic interventions targeting oral microbiota to mitigate cardiovascular risks.
References
1. Roth, G. A. et al. Global burden of cardiovascular diseases and risk factors, 1990–2019. J. Am. Coll. Cardiol. 76, 2982–3021 (2020).
2. Bowry, A. D., Lewey, J., Dugani, S. B. & Choudhry, N. K. The burden of cardiovascular disease in low- and middle-income countries: epidemiology and management. Can. J. Cardiol. 31, 1151–1159 (2015).
3. Tang, W. H. W., Kitai, T. & Hazen, S. L. Gut microbiota in cardiovascular health and disease. Circ. Res. 120, 1183–1196 (2017).
4. Fan, Y. & Pedersen, O. Gut microbiota in human metabolic health and disease. Nat. Rev. Microbiol. 19, 55–71 (2021).
5. Degruttola, A. K., Low, D., Mizoguchi, A. & Mizoguchi, E. Current understanding of dysbiosis in disease in human and animal models. Inflamm. Bowel Dis. 22, 1137–1150 (2016).
6. Shreiner, A. B., Kao, J. Y. & Young, V. B. The gut microbiome in health and in disease. Curr. Opin. Gastroenterol. 31, 69–75 (2015).
7. Gilbert, J. et al. Current understanding of the human microbiome. Nat. Med. 24, 392–400 (2018).
8. Sender, R., Fuchs, S. & Milo, R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 14, e1002533 (2016).
9. Hasan, N. & Yang, H. Factors affecting the composition of the gut microbiota, and its modulation. PeerJ 7, e7502 (2019).
10. The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).
11. Thaiss, C. A., Zmora, N., Levy, M. & Elinav, E. The microbiome and innate immunity. Nature 535, 65–74 (2016).
12. Honda, K. & Littman, D. R. The microbiota in adaptive immune homeostasis and disease. Nature 535, 75–84 (2016).
13. Nikitakis, N. G., Papaioannou, W., Sakkas, L. I. & Kousvelari, E. The autoimmunity-oral microbiome connection. Oral. Dis. 23, 828–839 (2017).
14. Dhadse, P., Gattani, D. & Mishra, R. The link between periodontal disease and cardiovascular disease: how far we have come in last two decades? J. Indian Soc. Periodontol. 14, 148–154 (2010).
15. Leishman, S. J., Do, H. L. & Ford, P. J. Cardiovascular disease and the role of oral bacteria. J. Oral. Microbiol. 2, 5781 (2010).
16. Kholy, K.El, Genco, R. J. & Dyke, T. E.Van Oral infections and cardiovascular disease. Trends Endocrinol. Metab. 26, 315–321 (2015).
17. Albandar, J. M. & Kingman, A. Gingival recession, gingival bleeding, and dental calculus in adults 30 years of age and older in the United States, 1988-1994. J. Periodontol. 70, 30–43 (1999).
18. Dotre, S. V., Davane, M. S. & Nagoba, B. S. Peridontitis, bacteremia and infective endocarditis: a review study. Arch. Pediatr. Infect. Dis. 5, e41067 (2017).
19. Lockhart, P. B. et al. Bacteremia associated with toothbrushing and dental extraction. Circulation 117, 3118–3125 (2008).
20. Lockhart, P. B. et al. Poor oral hygiene as a risk factor for infective endocarditis-related bacteremia. J. Am. Dent. Assoc. 140, 1238–1244 (2009).
21. Bartova, J. et al. Periodontitis as a risk factor of atherosclerosis. J. Immunol. Res. 2014, 636893 (2014).
22. Gorelick, P. B. Stroke prevention therapy beyond antithrombotics: unifying mechanisms in ischemic stroke pathogenesis and implications for therapy: an invited review. Stroke 33, 862–875 (2002).
23. Raber-Durlacher, J. E. et al. Periodontal status and bacteremia with oral viridans streptococci and coagulase negative staphylococci in allogeneic hematopoietic stem cell transplantation recipients: a prospective observational study. Support. Care Cancer 21, 1621–1627 (2013).
24. Forner, L., Larsen, T., Kilian, M. & Holmstrup, P. Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal inflammation. J. Clin. Periodontol. 33, 401–407 (2006).
25. Sreedevi, M., Ramesh, A. & Dwarakanath, C. Periodontal status in smokers and nonsmokers: a clinical, microbiological, and histopathological study. Int. J. Dent. 2012, 571590 (2012).
26. Libby, P. et al. Atherosclerosis. Nat. Rev. Dis. Prim. 5, 56 (2019).
27. Cosselman, K. E., Navas-Acien, A. & Kaufman, J. D. Environmental factors in cardiovascular disease. Nat. Rev. Cardiol. 12, 627–642 (2015).
28. Zühlke, L. et al. Cardiovascular medicine and research in sub-Saharan Africa: challenges and opportunities. Nat. Rev. Cardiol. 16, 642–644 (2019).
29. Weber, C. & Noels, H. Atherosclerosis: current pathogenesis and therapeutic options. Nat. Med. 17, 1410–1422 (2011).
30. Sanz, M. et al. Periodontitis and cardiovascular diseases: consensus report. J. Clin. Periodontol. 47, 268–288 (2020).
31. DeStefano, F., Anda, R. F., Kahn, H. S., Williamson, D. F. & Russell, C. M. Dental disease and risk of coronary heart disease and mortality. BMJ 306, 688–691 (1993).
32. Dietrich, T., Sharma, P. & Walter, C. The epidemiological evidence behind the association between periodontitis and incident atherosclerotic cardiovascular disease. J. Clin. Periodontol. 40 (Suppl. 14), S70–S84 (2013).
33. Sen, S., Giamberardino, L. D. & Moss, K. Periodontal disease, regular dental care use, and incident ischemic stroke. Stroke 49, 355–362 (2018).
34. Cowan, L. T., Lakshminarayan, K. & Lutsey, P. L. Periodontal disease and incident venous thromboembolism: the Atherosclerosis Risk in Communities study. J. Clin. Periodontol. 46, 12–19 (2019).
35. Humphrey, L. L., Fu, R. & Buckley, D. I. Periodontal disease and coronary heart disease incidence: a systematic review and meta-analysis. J. Gen. Intern. Med. 23, 2079–2086 (2008).
36. Mattila, K. J., Nieminen, M. S. & Valtonen, V. V. Association between dental health and acute myocardial infarction. BMJ 298, 779–781 (1989).
37. Chen, Y. W. et al. Periodontitis may increase the risk of peripheral arterial disease. Eur. J. Vasc. Endovasc. Surg. 35, 153–158 (2008).
38. Cauley, J. A., Kassem, A. M., Lane, N. E. & Thorson, S. Prevalent peripheral arterial disease and inflammatory burden. BMC Geriatr. 16, 213 (2016).
39. Soto‐Barreras, U., Olvera‐Rubio, J. O. & Loyola‐Rodriguez, J. P. Peripheral arterial disease associated with caries and periodontal disease. J. Periodontol. 84, 486–494 (2013).
40. Chandy, S., Joseph, K. & Sankaranarayanan, A. Evaluation of C-reactive protein and fibrinogen in patients with chronic and aggressive periodontitis: a clinico-biochemical study. J. Clin. Diagn. Res. 11, ZC41–ZC45 (2017).
41. Fentoglu, O. & Bozkurt, F. Y. The bi-directional relationship between periodontal disease and hyperlipidemia. Eur. J. Dent. 2, 142–146 (2008).
42. Golpasand, H. L., Zakavi, F., Hajizadeh, F. & Saleki, M. The association between hyperlipidemia and periodontal infection. Iran. Red. Crescent Med. J. 16, e6577 (2014).
43. Herzberg, M. C. Platelet-streptococcal interactions in endocarditis. Crit. Rev. Oral. Biol. Med. 7, 222–236 (1996).
44. Nakano, K., Nomura, R., Matsumoto, M. & Ooshima, T. Roles of oral bacteria in cardiovascular diseases – from molecular mechanisms to clinical cases: cell-surface structures of novel serotype k streptococcus mutans strains and their correlation to virulence. J. Pharmacol. Sci. 113, 120–125 (2010).
45. Schenkein, H. A. & Loos, B. G. Inflammatory mechanisms linking periodontal diseases to cardiovascular diseases. J. Clin. Periodontol. 40 (Suppl. 14), S51–S69 (2013).
46. Hashizume-Takizawa, T., Yamaguchi, Y. & Kobayashi, R. Oral challenge with Streptococcus sanguinis induces aortic inflammation and accelerates atherosclerosis in spontaneously hyperlipidemic mice. Biochem. Biophys. Res. Commun. 520, 507–513 (2019).
47. Chhibber-Goel, J., Singhal, V. & Bhowmik, D. Linkages between oral commensal bacteria and atherosclerotic plaques in coronary artery disease patients. NPJ Biofilms Microbiomes 2, 7 (2016).
48. Radaic, A. & Kapila, Y. L. The oralome and its dysbiosis: new insights into oral microbiome–host interactions. Comp. Struct. Biotechnol. J. 19, 1335–1360 (2021).
49. Schenkein, H. A., Papapanou, P. N., Genco, R. & Sanz, M. Mechanisms underlying the association between periodontitis and atherosclerotic disease. Periodontol 83, 90–106 (2000).
50. Pussinen, P. J. et al. Endotoxemia, immune response to periodontal pathogens, and systemic inflammation associate with incident cardiovascular disease events. Arterioscler. Thromb. Vasc. Biol. 27, 1433–1439 (2007).
51. Aarabi, G., Heydecke, G. & Seedorf, U. Roles of oral infections in the pathomechanism of atherosclerosis. Int. J. Mol. Sci. 19, 1978 (2018).
52. Saini, R., Marawar, P. P., Shete, S. & Periodontitis, S. S. A true infection. J. Glob. Infect. Dis. 1, 149–150 (2009).
53. Borén, J. et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur. Heart J. 41, 2313–2330 (2020).
54. Virani, S. S. et al. 2021 ACC expert consensus decision pathway on the management of ASCVD risk reduction in patients with persistent hypertriglyceridemia. J. Am. Coll. Card. 78, 960–993 (2021).
55. Rosenson, R. S. et al. HDL and atherosclerotic cardiovascular disease: genetic insights into complex biology. Nat. Rev. Cardiol. 15, 9–19 (2018).
56. Sammalkorpi, K., Valtonen, V., Kerttula, Y., Nikkila, E. & Taskinen, M. R. Changes in serum lipoprotein pattern induced by acute infections. Metabolism 37, 859–865 (1988).
57. Popa, C., Netea, M. G., van Riel, P. L., van der Meer, J. W. & Stalenhoef, A. F. The role of TNF-α in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. J. Lipid Res. 48, 751–762 (2007).
58. Berbee, J. F., Havekes, L. M. & Rensen, P. C. Apolipoproteins modulate the inflammatory response to lipopolysaccharide. J. Endotoxin Res. 11, 97–103 (2005).
59. Auerbach, B. J. & Parks, J. S. Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin: cholesterol acyltransferase and lipase deficiency. J. Biol. Chem. 264, 10264–10270 (1989).
60. Feingold, K. R., Memon, R. A., Moser, A. H., Shigenaga, J. K. & Grunfeld, C. Endotoxin and interleukin-1 decrease hepatic lipase mRNA levels. Atherosclerosis 142, 379–387 (1999).
61. Khovidhunkit, W. et al. Apolipoproteins A-IV and A-V are acute-phase proteins in mouse HDL. Atherosclerosis 176, 37–44 (2004).
62. Hossain, E. et al. Lipopolysaccharide augments the uptake of oxidized LDL by up-regulating lectin-like oxidized LDL receptor-1 in macrophages. Mol. Cell Biochem. 400, 29–40 (2015).
63. Levine, B., Kalman, J. & Mayer, L. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N. Engl. J. Med. 323, 236–241 (1990).
64. Mann, D. L. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ. Res. 116, 1254–1268 (2015).
65. Liu, L., Wang, Y. & Cao, Z. Y. Up-regulated TLR4 in cardiomyocytes exacerbates heart failure after long-term myocardial infarction. J. Cell Mol. Med. 19, 2728–2740 (2015).
66. Tsukamoto, H., Takeuchi, S. & Kubota, K. Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1–IKKε–IRF3 axis activation. J. Biol. Chem. 293, 10186–10201 (2018).
67. Sandek, A., Bjarnason, I. & Volk, H. D. Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure. Int. J. Cardiol. 157, 80–85 (2012).
68. Ser, H. L., Letchumanan, V., Goh, B. H., Wong, S. H. & Lee, L. H. The use of fecal microbiome transplant in treating human diseases: too early for poop? Front. Microbiol. 12, 519836 (2021).
69. Gupta, S., Allen-Vercoe, E. & Petrof, E. O. Fecal microbiota transplantation: in perspective. Ther. Adv. Gastroenterol. 9, 229–239 (2016).
70. Aron-Wisnewsky, J. et al. Major microbiota dysbiosis in severe obesity: fate after bariatric surgery. Gut 68, 70–82 (2019).
71. Debédat, J., Clément, K. & Aron-Wisnewsky, J. Gut microbiota dysbiosis in human obesity: impact of bariatric surgery. Curr. Obes. Rep. 8, 229–242 (2019).
72. Džunková, M. et al. Salivary microbiome composition changes after bariatric surgery. Sci. Rep. 10, 20086 (2020).
73. Stefura, T. et al. Changes in the composition of oral and intestinal microbiota after sleeve gastrectomy and Roux-en-Y gastric bypass and their impact on outcomes of bariatric surgery. Obes. Surg. 32, 1439–1450 (2022).
74. Durand, R. et al. Dental caries are positively associated with periodontal disease severity. Clin. Oral. Investig. 23, 3811–3819 (2019).
75. Kilian, M. The oral microbiome – friend or foe? Eur. J. Oral. Sci. 126, 5–12 (2018).
76. Sälzer, S., Graetz, C., Dörfer, C. E., Slot, D. E. & Weijden, F. A. Contemporary practices for mechanical oral hygiene to prevent periodontal disease. Periodontology 84, 35–44 (2000).
77. Chapple, I. L. C. et al. Primary prevention of periodontitis: managing gingivitis. J. Clin. Periodontol. 42 (Suppl. 16), S71–S76 (2015).
78. Innes, N. & Fee, P. A. Is personal oral hygiene advice effective in preventing coronal dental caries? Evid. Based Dent. 20, 52–53 (2019).
79. Ten Cate, J. M. & Featherstone, J. Mechanistic aspects of the interactions between fluoride and dental enamel. Crit. Rev. Oral. Biol. Med. 2, 283–296 (1991).
80. Joshipura, K., Muñoz-Torres, F., Fernández-Santiago, J., Patel, R. P. & Lopez-Candales, A. Over-the-counter mouthwash use, nitric oxide and hypertension risk. Blood Press. 29, 103–112 (2020).
81. Kapil, V. et al. Physiological role for nitrate-reducing oral bacteria in blood pressure control. Free. Radic. Biol. Med. 55, 93–100 (2013).
82. Dagher, A. & Hannan, N. Mouthwash: more harm than good? Br. Dent. J. 226, 240 (2019).
83. D’Aiuto, F. et al. Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial. Lancet Diabetes Endocrinol. 6, 954–965 (2018).
84. Cavero-Redondo, I., Peleteiro, B., Alvarez-Bueno, C., Rodriguez-Artalejo, F. & Martinez-Vizcaino, V. Glycated haemoglobin A1c as a risk factor of cardiovascular outcomes and all-cause mortality in diabetic and non-diabetic populations: a systematic review and meta-analysis. BMJ Open 7, e015949 (2017).
85. Mulhall, H., Huck, O. & Amar, S. Porphyromonas gingivalis, a long-range pathogen: systemic impact and therapeutic implications. Microorganisms 8, 869 (2020).
86. Wong, J. M. W. et al. Gut microbiota, diet, and heart disease. J. AOAC Int. 95, 24–30 (2012).
87. Hara, H., Haga, S., Aoyama, Y. & Kiriyama, S. Short-chain fatty acids suppress cholesterol synthesis in rat liver and intestine. J. Nutr. 129, 942–948 (1999).
88. Granado-Serrano, A. B. et al. Faecal bacterial and short-chain fatty acids signature in hypercholesterolemia. Sci. Rep. 9, 1772 (2019).
89. Parada Venegas, D. et al. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front. Immunol. 10, 277 (2019).
Published
How to Cite
Issue
Section
License

This work is licensed under a Creative Commons Attribution 4.0 International License.
CC Attribution 4.0