Oral Biofilms and the Systemic Connection
Tracking the health implications of inflammation due to periodontal disease
Gregori M. Kurtzman, DDS, MAGD, DICOI
Research has demonstrated a direct link between oral health and systemic disease that is becoming stronger as further evidence is produced. The American Dental Association highlighted 200 possible connections between systemic diseases and oral health.1 Poor oral hygiene habits and the resulting worsening periodontal conditions lead to a situation locally within periodontal pockets that can have negative repercussions throughout the entire body. Microbiology has demonstrated that specific, harmful microorganisms are always present in periodontal disease and that certain people are predisposed to harboring these oral organisms, increasing health risks. Evidence linking periodontal disease and chronic inflammation to certain major health conditions, including cardiovascular and renal issues, diabetes, osteoporosis, and pulmonary disorders, is presented here.
Formation and Effects of Biofilm
More than 700 different species of bacteria typically reside in the mouth. Most are considered innocuous, but some of these microorganisms have been identified as pathogenic. The mouth is the perfect incubator for bacteria, which can double in number in a few hours if left undisturbed. As bacteria increase in number, they quickly create an intricate network of protective layers (ie, matrix) and channels that develops into biofilm, previously referred to as “plaque.” Dental biofilm is the major cause of periodontal disease.
This aggregation of bacteria works together as a community, producing specific proteins and enzymes by way of quorum sensing, utilizing oral fluids as the vector for transmission.2 Quorum sensing is a cell-to-cell communication mechanism that synchronizes gene expression in biofilm in reaction to the density of population cells. Via quorum sensing, the bacteria in biofilm have the ability to regulate numerous processes. These can include secreting specific enzymes to activate or deactivate the genes of other bacteria.
The bacteria in biofilm and their byproducts provoke an immune response from the host, which sends white blood cells (WBC) to the site to kill the invading bacteria, resulting in localized inflammation in the surrounding gingiva. Using quorum sensing, the bacteria have the ability to confuse the defending WBC chemotactically by releasing chemicals into the environment, rendering the immune response ineffective. Because neutrophils, a type of WBC, have a 3-day life cycle,3 if they do not engulf a bacterium and destroy it within that timeframe, they lyse and die. The neutrophil elastase enzyme that was intended to kill the bacteria are now available to turn on the very tissue they were meant to protect.4 Dentally, this translates into periodontal bone loss and a deepening of the pockets and inflammation.
There is increasing evidence that indicates patients with periodontal disease also have a much higher risk of developing cardiovascular and other systemic issues than those individuals who take preventive measures to eliminate and control the biofilm in their mouths. Harmful strains of bacteria in biofilm can enter the bloodstream during the inflammatory response and can travel to other areas of the body, exerting a distant systemic effect that has been linked to numerous diseases.
Cardiovascular Disease (CVD)
CVD, an umbrella term for heart and blood vessel conditions (eg, atherosclerosis, coronary heart disease, stroke, myocardial infarction) is the result of a complex set of genetic and environmental factors.5 These genetic factors include age, lipid metabolism, obesity, hypertension, and diabetes. Environmental risk factors include socioeconomic status, exercise, stress, diet, smoking, and chronic infections. The classic risk factors such as hypertension, hypercholesterolemia, and cigarette smoking may only account for one half to two thirds of the incidence of CVD.6 Evidence linking chronic infection and inflammation to CVD has been increasing; the inflammation caused by biofilm may be a predisposing factor as well.7,8
The connection between oral bacteria and cardiac disease is not a recent development in the literature. Oral bacteria, specifically the cariogenic Streptococcus mutans and the periodontitis-inducing Porphyromonas gingivalis, induce platelet aggregation, which leads to thrombus formation.9 Studies have reported one or more periodontal pathogens found in 42% of the atheromas in patients with severe periodontal disease.10 Deshpande reported that P gingivalis actively can adhere to and invade fetal bovine heart endothelial cells and aortic endothelial cells.11 A 14-year study found patients with periodontitis had a 25% higher risk to develop CVD than their healthy counterparts.12 Men younger than 50 years with periodontal disease demonstrate 72% more risk to develop CVD. Additionally, periodontal disease increased risk for both fatal and non-fatal strokes two-fold.13,14 Despite strong evidence of an association between periodontal disease and CVD, it is unknown if it is a direct causal relationship.
Three biologic mechanisms explain the association between periodontal disease and CVD. First, periodontal diseases release bacteria that may enter the circulation, invading the heart and vascular tissue, causing harmful effects. People with higher levels of bacteria in their mouths tend to have thicker carotid arteries, an indicator of CVD.15 A systemic study reported that antibody response to periodontal bacteria was associated with coronary heart disease,16 and periodontal bacteria have been found in samples of plaque removed from arteries.17,18 Bacteria in the plaque near diseased gingiva appears to induce clumping of blood platelets, which can then cause the clotting and blockages that can lead to heart attacks or strokes. Second, the body’s response to the periodontal infection includes production of inflammatory mediators, which travel through the circulatory system and may cause harmful effects on the heart and blood vessels. Inflammatory mediators such as lipoprotein and triglycerides are significantly higher in patients with periodontitis than in control groups.19 Additionally, increased levels of C-reactive protein, which is considered a biomarker for inflammation, were associated with periodontitis. Clotting is increased as levels of C-reactive protein increase, which is associated with an elevated risk of heart disease.220Third, bacterial products, such as lipopolysaccharides, enter the blood stream, causing harmful effects on the blood vessels and heart.21
Periodontal disease’s emergence as a potential risk factor for CVD is leading to a convergence in oral and medical care. Proper management of oral health may very well be key to prevention of cardiac disease or worsening of existing heart conditions. In addition, more frequent prophylaxis, such as antibiotics before dental procedures, may be indicated in those patients who have gingival issues combined with a history of cardiac disease, including those with prosthetic cardiac valves, previous endocarditis history, some types of congenital heart disease, and previous cardiac transplant with valvular disease.
Chronic Kidney Disease (CKD)
CVD and CKD share many risk factors, and it appears that inflammation also links periodontitis to the development of kidney disease.22 Pathogens found in oral biofilms have been shown to have the ability to adhere to and invade coronary endothelial cells, leading to atheroma formation and impaired vasculature relaxation. Many researchers postulate that periodontal disease exerts similar effects within the vasculature of the kidney.23
Chronic renal disease is a progressive loss in renal function. Symptoms of diminishing kidney function are nonspecific and may include feeling generally unwell and experiencing a reduced appetite. CKD is identified by a blood test for creatinine. Increased levels of creatinine indicate a falling glomerular filtration rate and a decreased ability of the kidneys to excrete waste products. The most common causes of CKD are diabetes mellitus, hypertension, and glomerulonephritis, which together cause approximately 75% of all adult cases.24
CKD patients are characterized by a few well-established risk factors of periodontal disease. These include poor oral hygiene and diabetes.25 A strong correlation appears to exist between patients on dialysis and the high number of patients suffering from gingivitis (46%) and severe periodontitis (35%).26 Interestingly, the correlation appears to be bi-directional, as patients with CKD have higher prevalence of periodontal disease. Both diseases are associated with chronic low-level inflammation, and periodontitis may lead to endothelial dysfunction, which plays a role in the pathogenesis of kidney disease.27 The negative effects of systemic inflammation on kidney function could occur during active periodontal infection. Inflammation has been reported to be an important predictor of low serum albumin levels among dialysis patients.28
Diabetes
Diabetes is a significant public health problem, affecting 9.3% of the US population (29.1 million patients). It has been estimated that 8.1 million (27.8%) patients with diabetes go undiagnosed.29 The Centers for Disease Control and Prevention reports diabetes diagnoses have increased by more than 3 million in almost 2 years.
Periodontal disease is more common in patients with diabetes. Those with diabetes have twice the risk for periodontal disease of those without the metabolic disorder. In addition, periodontal disease is more prevalent, progresses more rapidly, and is often more severe in patients with type I or type II diabetes.30,31 Periodontal disease is classified as the sixth most common complication of diabetes. Conversely, diabetes is a strong, well-established risk factor for severe periodontal disease.
Patients with periodontal infections have worse glycemic control over time. Grossi reported that in cases of severe periodontal disease, an increase in the severity of diabetes mellitus is reported, and this complicates metabolic control.32 Cytokines secreted because of chronic inflammation are associated with insulin resistance. An infection-mediated cycle of cytokine synthesis and secretion by chronic stimulus from products of biofilm may amplify cytokine response. This helps explain the increase in tissue destruction seen in diabetic periodontitis as well as how periodontal disease may complicate the severity of diabetes.
Treatment of periodontitis appears to improve glycemic control.33 Thus, control of the periodontal infection and associated biofilm should be part of the standard treatment for the diabetic patient.
Osteoporosis
Periodontal bone loss may progress more rapidly in patients with osteoporosis. Evidence has established a correlation between periodontitis and bone metabolism.34 Early diagnosis of reduced bone mineral density (BMD), even before to the establishment of a significant negative impact on the periodontal tissues, might be important. Smoking and menopausal status were reported not to alter these associations.35
Periodontitis and osteoporosis are two diseases that increase in intensity with age. Findings suggest that periodontal changes can be associated with osteoporosis in postmenopausal women and there is an increase in both conditions as the patient ages.36 Periodontitis is associated with resorption of the alveolar bone and osteoporosis is characterized by bone loss leading to structural bone transformation. Some studies have established a relationship between osteoporosis and periodontitis based on pocket depth and clinical attachment loss.37 However, other investigators have reported that periodontal patients with low BMD may have increased risk of alveolar bone loss based on radiographic analysis but not necessarily attachment level or probing depth.38,39
Medications taken by patients with osteoporosis should be considered before any operative procedures. Intravenous bisphosphonates create a greater risk for the patient than oral bisphosphonates for bone issues and the potential of osteonecrosis of the jaw (ONJ) due to lower vascularity of the jawbone. Sites with increased bone turnover, such as extraction sites or areas of periodontal inflammation, are exposed to higher bisphosphonate doses than the remaining alveolar ridge and may explain greater the susceptibility of such areas to ONJ.40,41
Pulmonary Disease
Periodontal biofilm is a reservoir of bacteria and a source of lower airway infections, especially in older patients or those who are debilitated. Bacteria in biofilm can innoculate the respiratory tract when aspirated by the patient. The severity of the oral disease is correlated with the pathogenicity of the bacteria in the oral biofilm. Periodontal pathogens and the presence of cariogenic bacteria are significant risk factors for aspiration pneumonia.
The highest risk patients for respiratory infection (pneumonia and bronchitis) are medically compromised patients with or without respiratory disease who are unable to perform adequate oral homecare. There is strong evidence that elderly patients may be at increased risk of pulmonary issues related to periodontal disease especially as they pass the seventh decade of life, when general health diminishes as well as their ability to render homecare. Evaluation of 328 articles published over an 11-year period reported linking oral hygiene to oral health care–associated pneumonia or respiratory tract infection in elderly people. The authors reported, “There is good evidence that mechanical oral hygiene practices reduce the progression or occurrence of respiratory diseases in high-risk elderly people in nursing homes or hospitals. Mechanical oral hygiene practices may prevent the death of about 1 in 10 elderly residents of nursing homes from health care–associated pneumonia.”42
Meticulous oral homecare is critical in preventing these oral infections by minimizing the potential of aspirating biofilm into the pulmonary system. One author reported, “Oral hygiene intervention significantly reduced occurrence of pneumonia in institutionalized subjects.”43 Additionally, frequent tooth brushing and preoperative use of 0.12% chlorhexidine mouthrinse or gel reduced nosocomial respiratory tract infections.44 Therefore, it may be of general benefit that all elderly patients be placed on chlorhexidine daily rinses as a preventive measure. It has also been demonstrated that use of low concentration peroxides in custom trays has a positive affect on oral biofilms, reducing the bacterial load and decreasing pathogenic material that may be aspirated. This may be a more predictable approach in elderly patients who lack manual dexterity to perform oral homecare with a toothbrush.
Conclusion
Plaque is the traditional term that has been used to describe the soft material on the teeth and within the pockets. Today we recognize that plaque, now called biofilm, is a much more complex material that functions through coordination of bacteria within a protective slime. Many years of data and research has demonstrated that the oral biofilm causing periodontal disease has distant systemic affects and has been connected to numerous medical conditions. The health conditions examined here are not the only ones associated with periodontal disease. Evidence also links prostate disease, colon cancer, pancreatic cancer, and poor pregnancy outcomes (preterm birth and low birth weight) to periodontal disease to varying degrees; a full review of all conditions was beyond the scope of this article. Periodontal treatment is evolving to be a major component of full-body medical care and controlling the associated biofilm yields better overall systemic health.
Disclosure
Gregori M. Kurtzman, DDS, MAGD, DICOI, has no relevant conflicts of interest to disclose.
About the Author
Gregori M. Kurtzman, DDS, MAGD, DICOI
Private Practice
Silver Spring, Maryland
References
1. Loos BG. Systemic effects of periodontitis. Int J Dent Hyg. 2006;4(suppl 1):34-38; discussion 50-52.
2. Hojo K, Nagaoka S, Ohshima T, Maeda N. Bacterial interactions in dental biofilm development. J Dent Res. 2009;88(11):982-990.
3. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nature Review. 1013(13):159-175.
4. White blood cell enzyme contributes to inflammation and obesity. Medical Xpress website. http://medicalxpress.com/news/2013-04-white-blood-cell-enzyme-contributes.html. April 2, 2013. Accessed January 7, 2016.
5. Herzberg MC, Weyer MW. Dental plaque, platelets, and cardiovascular diseases. Ann Periodontol. 1998;3(1):151-160.
6. Scannapieco FA. Position paper of The American Academy of Periodontology: periodontal disease as a potential risk factor for systemic diseases. J Periodontol. 1998;69(7):841-850.
7. Syrjänen J. Vascular diseases and oral infections. J Clin Periodontol. 1990;17(7 pt 2):497-500.
8. Valtonen VV. Infection as a risk factor for infarction and atherosclerosis. Ann Med. 1991;23(5):539-543.
9. Nomura R, Otsugu M, Naka S, et al. Contribution of the interaction of Streptococcus mutans serotype k strains with fibrinogen to the pathogenicity of infective endocarditis. Infect Immun. 2014;82(12):5223-5234.
10. Haraszthy VI, Zambon JJ, Trevisan M, et al. Identification of pathogens in atheromatous plaques [abstract 273]. Dent Res. 1998;77(spec. iss. B):666.
11. Deshpande RG, Khan MB, Genco CA. Invasion of aortic and heart endothelial cells by Porphyromonas gingivalis. Infect Immun. 1998;66(11):5337-5343.
12. 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. 2010;14(3):148-154.
13. Baker L. Poor oral health increases stroke risk, UB study finds. www.buffalo.edu/imsd/about-imsd/the-buffalo-niagara-region.host.html/content/shared/university/news/news-center-releases/2000/10/4917.detail.html. October 25, 2000. Accessed January 7, 2016.
14. Persson GR, Imfeld T.: Periodontitis and cardiovascular disease. Ther Umsch. 2008 Feb;65(2):121-6.
15. Desvarieux M, Demmer RT, Rundek T, et al. Periodontal microbiota and carotid intima-media thickness: the Oral Infections and Vascular Disease Epidemiology Study (INVEST). Circulation. 2005;111(5):576-582.
16. Beck JD, Eke P, Heiss G, et al. Periodontal disease and coronary heart disease: a reappraisal of the exposure. Circulation. 2005;112(1):19-24.
17. Joshipura KJ, Hung HC, Rimm EB, et al. Periodontal disease, tooth loss, and incidence of ischemic stroke. Stroke. 2003;34(1):47-52.
18. Chiu B. Multiple infections in carotid atherosclerotic plaques. Am Heart J. 1999;138(5 pt 2):S534-S536.
19. Loesche WJ, Schork A, Terpenning MS, et al. The relationship between dental disease and cerebral vascular accident in elderly United States veterans. Ann Periodontol. 1998;3(1):161-174.
20. Wu T, Trevisan M, Genco RJ, et al. Examination of the relation between periodontal health status and cardiovascular risk factors: serum total and high density lipoprotein cholesterol, C-reactive protein, and plasma fibrinogen. Am J Epidemiol. 2000;151(3):273-282.
21. Lavigne SE. The Canadian Dental Hygienists Association. Your mouth—portal to your body: Canadian Dental Hygienists Association position paper on the links between oral health and general health: Part I. Probe. 2004;38(3):114-134.
22. Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet. 2005;366(9499):1809-1820.
23. Bascones-Martínez A, Muñoz-Corcuera M, Noronha S, et al. Host defense mechanisms against bacterial aggression in periodontal disease: Basic mechanisms. Med Oral Patol Oral Cir Bucal. 2009; 14(12):e680-e685.
24. Palmer BF. Management of hypertension in patients with chronic kidney disease and diabetes mellitus. Am J Med. 2008;121(8 suppl):s16-s22.
25. DePaola DP, ed. Periodontitis and renal disease. Colgate Oral Care Report. 2007;17(4).
26. Buhlin K, Bárány P, Heimbürger O, et al. Oral health and pro-inflammatory status in end-stage renal disease patients. Oral Health Prev Dent. 2007;5(3):235-244.
27. Rahmati MA, Craig RG, Homel P, et al. Serum markers of periodontal disease status and inflammation in hemodialysis patients. Am J Kidney Dis. 2002;40(5):983-989.
28. Grubbs V, Plantinga LC, Crews DC, et al. Vulnerable populations and the association between periodontal and chronic kidney disease. Clin J Am Soc Nephrol. 2011;6(4):711-717.
29. National Diabetes Statistics Report, 2014. Centers for Disease Control and Prevention website. https://www.cdc.gov/diabetes/pdfs/library/diabetesreportcard2014.pdf. Accessed November 6, 2015.
30. Kim EK, Lee SG, Choi YH, et al. Association between diabetes-related factors and clinical periodontal parameters in type-2 diabetes mellitus. BMC Oral Health. 2013;13:64.
31. Stanko P, Izakovicova Holla L. Bidirectional association between diabetes mellitus and inflammatory periodontal disease. A review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014; 158(1):35-38.
32. Grossi SG, Genco RJ. Periodontal disease and diabetes mellitus: a two-way relationship. Ann Periodontol. 1998;3(1)51-61.
33. Taylor GW, Burt BA, Becker MP, et al. Severe periodontitis and risk for poor glycemic control in patients with non-insulin-dependent diabetes mellitus. J Periodontol. 1996;67(10 suppl):1085-1093.
34. Martelli FS, Martelli M, Rosati C, Fanti E. Vitamin D: relevance in dental practice. Clin Cases Miner Bone Metab. 2014;11(1):15-19.
35. Pepelassi E, Nicopoulou-Karayianni K, Archontopoulou AD, et al. The relationship between osteoporosis and periodontitis in women aged 45-70 years. Oral Dis. 2012;18(4):353-359.
36. Pereira FM, Rodrigues VP, de Oliveira AE, et al. Association between periodontal changes and osteoporosis in postmenopausal women. Climacteric. 2015;18(2):311-315.
37. Aspalli SS, Shetty VS, Parab PG, et al. Osteoporosis and periodontitis: is there a possible link? Indian J Dent Res. 2014;25(3):316-320.
38. Esfahanian V, Shamami MS, Shamami MS. Relationship between osteoporosis and periodontal disease: review of the literature. J Dent (Tehran). 2012;9(4):256-264.
39. Martínez-Maestre MÁ, González-Cejudo C, Machuca G, et al. Periodontitis and osteoporosis: a systematic review. Climacteric. 2010;13(6):523-529.
40. Cheong S, Sun S, Kang B, et al. Bisphosphonate uptake in areas of tooth extraction or periapical disease. J Oral Maxillofac Surg. 2014;72(12):2461-2468.
41. Cheng A, Daly CG, Logan RM, et al. Alveolar bone and the bisphosphonates. Aust Dent J. 2009;54 (suppl 1):S51-S61.
42. Rosenblum R Jr. Oral hygiene can reduce the incidence of and death resulting from pneumonia and respiratory tract infection. J Am Dent Assoc. 2010;141(9):1117-1118.
43. Scannapieco FA, Bush RB, Paju S. Associations between periodontal disease and risk for nosocomial bacterial pneumonia and chronic obstructive pulmonary disease. A systematic review. Ann Periodontol. 2003;8(1):54-69.
44. Sjögren P, Nilsson E, Forsell M, et al. A systemic review of the preventive effect of oral hygiene on pneumonia and respiratory tract infection in elderly people in hospitals and nursing homes: effect estimates and methodological quality of randomized controlled trials. J Am Geriatr Soc. 2008;56(11):2124-2130.
