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Since the 1990s an ongoing vast array of articles has been published to validate the oral-systemic connection. As such, it is imperative that dentists stay abreast of current research to best understand new treatments available in the dental field. Also, new frontiers in microbiome research are continually emerging, an area in medicine that can aid dentists in personalizing periodontal and dental treatments so patients may receive optimal care. Up-to-date information published in the past few years has further elucidated the oral-systemic connection.
Research has shown that periodontal disease has a significant impact on overall health. As early as the 1980s, reports were published of the association of periodontal pathogens, such as Actinobacillus actinomycetemcomitans, with subacute endocarditis.1 Such microorganisms were found in endothelial lining and heart valves. Through longitudinal studies, it was concluded that periodontal disease was a risk factor for coronary heart disease and stroke. Also, it is well known that there is a strong relationship between diabetes mellitus, glycemic control, and periodontal disease. In the 1990s, studies by Offenbacher et al determined that periodontitis is a clinically significant risk factor for preterm low birth weight babies.2
In the past decade, the amount of research articles on the oral-systemic health connection has increased exponentially, as microbiological studies have become cheaper and faster to conduct and more accurate. This article explores various areas of research as it pertains to different groups of diseases.
Alzheimer's Disease and Dementia
Poor oral care has been associated with Alzheimer's disease (AD) and dementia, with people with the least number of teeth having a higher risk of onset of disease.3 Dr. Dale Bredesen, director of UCLA's Easton Center for Alzheimer's Disease Research, explains in his book, The End of Alzheimer's, how oral bacteria are found in the brain and contribute to the onset of AD and dementia. It is quite clear today that periodontal pathogens such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia have been found in the brains of patients with AD.4 The presence of these pathogens create a low level of inflammation that results in an atrophy of the brain and a slowdown in cognitive function. Furthermore, oral viruses also can play a role in brain inflammation. Herpes simplex virus (HSV), which lives in the trigeminal ganglion and causes outbreaks on the lips and oral cavity, can sometimes travel upward on the nerve and create inflammation in the brain.5 Bredesen explains that the blood brain barrier can become "leaky," similar to the gut lining or periodontal pocket becoming "leaky" or inflamed. Bacteria, viruses, fungi, and parasites can then cross into the brain and form a biofilm. Brains of AD patients shrink as a protective response to this toxic biofilm.4
Alzheimer's disease also has been called a "neurospirochetosis," because it has been concluded that spirochetes can cause brain atrophy and, thus, dementia.6 Spirochetes were observed in the brain in more than 90% of cases of AD patients. It is thought that spirochetes invade the brain years before there is any clinical manifestation of disease, and that sustained inflammation with deposition of amyloid plaque in the brain over the course of years results in dementia.
Toxins are also an important part of the health of the brain. Recent epidemiological data shows a link of dental amalgams, which can contain up to 50% mercury, to neurological diseases, including AD.7 Bredesen discusses this link and warns against the danger of higher levels of mercury in the brain of an Alzheimer's patient. The changes that occur in AD, which include plaque formation, neurofibrillary tangles, phosphorylated tau proteins, and an inhibition of neurotransmitters, to name a few, are the same changes seen in mercury toxicity.8 More clinical studies of mercury toxicity in dentistry are needed to determine a dose-response relationship to neurobehavioral issues.
Autoimmune Diseases
An association between rheumatoid arthritis (RA) and periodontitis has been known since the early 1900s, but the possible mechanism through which these two conditions are connected has only recently been understood. P. gingivalis found in the synovial tissues releases an enzyme that causes a change in certain proteins, and autoimmune antibodies develop against such proteins.9 Significantly higher amounts of Treponema and Prevotella species, which are considered spirochetes, also have been found in RA patients when compared to healthy patients.10 Aggregatibacter actinomycetemcomitansalso has been linked to RA, triggering symptoms through production of leukotoxin A. Interestingly, one case study reported antibiotic treatment that resulted in the patient being symptom-free even 1 year later.11
Psoriasis is a chronic autoimmune disease that has certain environmental triggers. Periodontitis can play a significant role in the onset of psoriasis. Untreated periodontitis can exacerbate the condition or result in anti-psoriasis treatment being ineffective.12
Systemic lupus erythematosus (SLE) is an autoimmune disease that results in tissue damage with side effects on the heart, joints, skin, liver, kidneys, and periodontium. The etiology of SLE is believed to be partly due to dysbiosis and environmental triggers. A recent study found that severe periodontal pathogens, specifically Treponema denticola and Tannerella forsythia, were increased significantly in patients with SLE and active periodontal disease, and these periodontal pathogens increased systemic proinflammatory cytokines, which may exacerbate SLE.13 A meta-analysis study also found that there is an increased risk of periodontitis in patients with SLE as compared to healthy patients.14
Cancers
A recently published meta-analysis studied 490 papers that reported an association between periodontitis and various cancers. A statistically significant association was found for digestive tract cancers, pancreatic cancer, prostate cancer, breast cancer, uterine cancer, lung cancer, hematological cancer, esophagus/oropharyngeal cancer, and non-Hodgkin's lymphoma.15 More studies, however, are needed to determine the exact association between periodontitis and cancer.
A cohort study monitored patients with moderate to severe periodontitis between 2001 and 2010.16 The study concluded that periodontitis patients had a 77% increased risk of cancer versus patients without periodontitis. Women with periodontitis had significantly higher risk of breast cancer, and men with periodontitis had significantly higher risk of prostate and blood cancer.
Several studies assessed the association between breast cancer and periodontitis.17 Exactly how periodontitis plays a role in cancer is not completely understood. However, some researchers suggest that chronic inflammation from ongoing infections by specific bacteria and viruses is one of the foremost causes of cancers.18 In line with this theory, several articles have shown that F. nucleatum, a well-known periodontal pathogen, plays an important role in the development of oral, colorectal, and esophageal cancer.18 F. nucleatum and P. gingivalis have been detected in oral cancer cells. Large amounts of P. gingivalis have been recovered from oral squamous cell carcinoma.19 There is a direct relationship between P. gingivalis and carcinogenesis. P. gingivalis has been shown to upregulate specific receptors on cancer cells to promote metastasis and chemoresistance to anti-cancer agents. It can accelerate cellular proliferation of oral cancer by affecting gene expression of certain inflammatory proteins.20 P. gingivalis can play a role in precancerous gastrointestinal (GI) lesions, esophageal squamous cell carcinoma, and head and neck (larynx, throat, lip, mouth, and salivary glands) carcinoma.19
A recent meta-analysis of nine studies concluded that periodontitis was associated with a relative increased risk of mortality from GI cancer as well as pancreatic cancer.21
Cardiovascular Diseases
More than 70 million Americans are diagnosed annually with cardiovascular diseases (CVDs), including high blood pressure, myocardial infarction (MI), and angina pectoris. While dentists may be aware of the correlation between CVDs and periodontitis, recent studies have been performed to determine if periodontal treatment can prevent CVD. In an assessment of 34 randomized controlled trials and reviews, scientists concluded that periodontal treatment can prevent CVD.22
The severity of periodontitis plays a role in its association with MI. In a study that looked at patients with moderate to severe periodontitis, it was concluded that the risk of an acute episode of MI was two to four times greater for these patients than for patients without periodontitis, with those in the severe group having the highest risk.23
The endothelial lining of the peripheral vasculature is affected by the presence of periodontal pathogens, especially P. gingivalis.24 Data shows that outer membrane vesicles produced by P. gingivalis cause an increase in vascular permeability, which leads to vascular disease.25 One particular 10-year study of 64,960 patients demonstrated that intensive periodontal treatment reduced the incidence of spontaneous cranial hemorrhage and, thus, mortality rates.26
Hypertension recently has been linked to periodontitis independent of common risk factors such as older age, smoking, and obesity.27 An imbalance in the oral and GI microbiome plays an important role in this association. Gingival bleeding was consistently associated with a slight increase (+2.6 mm Hg) in systolic blood pressure compared with no gingival bleeding.28 Also, the same study showed that unstable periodontitis was associated with uncontrollable high blood pressure. This indicates that periodontal evaluation is important in controlling hypertension.
Pregnancy Complications
Subgingival dental plaque biofilm can have a negative effect on pregnancy if periodontal pathogens are present. In women with periodontitis, periodontal pathogens can reach to the fetus and placenta through circulation and, in turn, upregulate the inflammatory pathways systemically. This can induce preterm labor and also restrict the growth of the fetus.29 What is interesting is that certain oral bacteria have been identified to have more of an influence than others. High IgG serum levels of P. gingivalis have been associated with higher incidence of low birth weight infants than other periodontal pathogens.30 P. gingivalis is associated with other adverse pregnancy outcomes, such as preeclampsia, spontaneous abortion, gestational diabetes, and even misconception.31 The molecular mechanisms through which this periodontal pathogen alters the tissues and induces inflammation have been detailed.31
The good news is that periodontal therapy during pregnancy helps reduce the adverse systemic side effects of periodontitis. A meta-analysis published in 2019 concluded that periodontal treatment during pregnancy reduces the risks of perinatal mortality and preterm birth and does not have any adverse side effects.32
Respiratory Diseases
With regard to respiratory conditions, it has been shown that most patients are able to tolerate pathogens, but in a weakened, immunocompromised patient these same pathogens may be life-threatening.33 The oral cavity is a reservoir of more than 600 different microbial species. The maintenance of proper oral hygiene, therefore, is critical to control oral biofilm. Poor oral hygiene is associated with increased anaerobic bacteria in the lungs of patients with pneumonia and an increase in mortality.34 Increased dry mouth is also significantly associated with a higher rate of anaerobes present in the lungs.34
A recent systematic review examined the association between asthma and periodontal disease in adults. Asthmatic patients presented a higher incidence of periodontal diseases, especially gingivitis.35
Periodontal treatment helps reduce the severity of respiratory issues in asthmatic patients. In a study of 4,771 asthmatic adults the subjects were followed over almost 6 years. It was found that periodontal treatment reduced the incidence of hospitalization and intensive care unit admissions for adverse respiratory issues and mortality in these patients, clearly demonstrating the contribution of good oral health in decreasing asthmatic events.36
Periodontal Disease and Mortality
Since the 1960s scientists have been interested in learning whether oral disease, and in particular periodontitis, indeed affects the lifespan of humans. From the US Department of Veterans Affairs (VA) dental longitudinal study results, it was concluded that for subjects with alveolar bone loss of more than 21% the risk of dying increased by 70%.37 What is interesting about this 25+ years follow-up study is that periodontitis increased the risk of mortality more than smoking.
More recently, a total of 57 studies that included 5.71 million participants were examined by two independent reviewers. Periodontitis and edentulism were confirmed to be associated with an increased risk of all-cause mortality.38
In the medical community, anti-aging means early detection and treatment of age-related conditions with the goal of prolonging a vibrant life. Thus, in essence, early detection and treatment of periodontitis is an anti-aging strategy.39
The Microbiome's Role in Human Health
The human mouth is colonized by a multitude of organisms. On and in the human body are 10 times more organisms than human cells.40 For many years these trillions of creatures have been underestimated, but their behavior and importance in health and disease are becoming increasingly understood. Most of these microorganisms live in the mouth and digestive tract and include primarily bacteria, but also fungi, viruses, and protozoa. A genetic transfer of information occurs between the biofilm and human cells. The genetic information of all the microorganisms living on and in the human body is called the microbiome. Interestingly, the expression of one's genes is influenced by one's microbiome.41
The National Institutes of Health launched the Human Microbiome Project in 2008 as part of the Human Genome Project.40 In the past, studying the microbiome through culturing techniques was difficult, because bacteria would not survive. Today, testing is easier, and dead or fragments of bacteria can be easily identified in saliva and washed away by gingival crevicular fluid.
The oral microbiome was first identified by Dutchman Antony van Leeuwenhoek in 1674. He looked at his own dental plaque through a microscope that he built himself. The microbiome of the mouth is the second largest in humans after the gut and, compared with all other organs, is the most diverse in terms of microbial species. The mouth provides a favorable environment for the growth of bacteria: a constant temperature and moisture from saliva. A pH of 6.5 to 7 is beneficial for most species of bacteria. The bacteria are able to stay hydrated and nourished. To re-establish balance in a flared-up periodontal environment it is crucial that clinicians recognize this ideal oral environment for bacteria.
It is important to understand exactly how the microbiome is interconnected to the human body. Every time gingival bleeding occurs it presents an opportunity for microorganisms, especially pathogenic ones such as P. gingivalis, to enter the bloodstream and find a new home somewhere else, such as the joints, brain, lungs, blood vessel walls, or placenta.
Interestingly, the concept of oral pathogens causing inconspicuous systemic effects is not new. A British physician, William Hunter, presented the idea that oral microbes could cause several systemic conditions that were chronic in nature. He named it the focal infection theory.33 Dr. Hunter warned against dental procedures that could trap bacteria in a tooth, as pathogens could then travel into the jawbone and give rise to systemic disease. He recognized that the degree of systemic effect was determined by the aggressiveness of the microbe, as well as the host's susceptibility, which is now known as genetic predisposition. Dr. Hunter believed that these microbes trapped in the body produced toxins and different reactions in different tissues, giving rise to certain low-grade symptoms. The focal infection theory became widely accepted in Britain and the United States. The downside is that at the time, the recommended solution was tooth extraction at the site of a cavity or periodontal disease. Today, salivary diagnostics may be used to pinpoint the different microbes present in the oral cavity. Practitioners need to recognize the importance of knowing what kind of periodontal pathogens patients are presenting with.
Altering Clinical Treatment
Given the vast amount of research that is now available on the oral microbiome and its relationship to oral health, clinicians need to consider how clinical treatment may be altered to fit today's knowledge. Many articles focus on individual pathogens, such as the stealth Porphyromonas gingivalis, Fusobacterium nucleatum, Prevotella intermedia, and Treponemasp.to name a few, that are known culprits in systemic diseases, including cancer. Early detection of these organisms as well as viruses that can increase the risks of cancer is important.
In the dental office, testing can be done relatively easily via salivary diagnostics. A simple 1-minute swish-and-expectorate test can be administered to identify different periodontal pathogens, candida, HSV, and human papillomavirus in the oropharynx. Based on the test results, the patient can then be informed whether there is a high, moderate, or low risk of systemic presence of these microorganisms. Often times, high amounts of a certain pathogen can be detected in young patients with gingivitis, in whom bone loss has not yet developed. This early detection and subsequent timely treatment can help prevent not only the progression to periodontal disease, but also perhaps a systemic predisposition to certain chronic diseases.
Conclusion
Going forward, the ideal goal of periodontal therapy will be to shift the biofilm from a pathogenic community to a healthy, resilient community. More studies are needed in this area to personalize periodontal protocols based on the patient's oral bacterial fingerprint. Periodontal treatments typically have concentrated on eradicating all bacteria equally; however, more recently an emphasis has been placed on rebuilding a healthy biofilm. The oral use of probiotics and prebiotics as adjuncts to periodontal treatment has shown promising results in the past few years and needs to be explored further.
About the Author
Sanda Moldovan, DDS, MS, CNS
Founder and Chief Executive Officer, Orasana, Inc.;Private Practice, Beverly Hills, California; Diplomate, American Academy of Periodontology
Queries to the author regarding this course may be submitted to authorqueries@aegiscomm.com.
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