100 years ago, many medical professionals in Europe and the United States believed that pulling teeth with tooth decay could prevent a whole host of other diseases from arthritis to schizophrenia. Some therefore went so far as to remove all their patients' teeth – as a precaution.
"It was believed at the time that an infection around the teeth could spread to other regions of the body, " says Iain Chapple of the University of Birmingham in England. As a periodontist, he deals with the periodontal apparatus, which keeps the teeth stable in the jaw. These include, among other things, gums, root skin and the bony tooth compartment in the jaw.
The practice of precautionary tooth removal quickly came into disrepute. "That was also complete nonsense," says Chapple. However, the underlying assumption that oral health may have a direct impact on chronic diseases is experiencing a renaissance today.
Series: good for the tongue
Whether talking, eating, smiling or kissing: Our mouth is virtually constantly in motion. How important it is that he stays healthy, many still notice only when the first aches and pains make themselves felt, such as caries, gingivitis or nasty aphthae. Oral and dental care can have far-reaching consequences for the entire body – even with diseases such as Alzheimer's, heart disease and Covid-19, it is now associated. Find out what optimal oral hygiene looks like, what contribution the oral microbiome makes and what makes the oral mucosa so special in our series »Healthy in the mouth«:
The decades of cooperation between dentists, periodontologists, doctors and immunologists has drawn a sharper picture of how diseases of the tooth keeper apparatus can affect the rest of the body. Today it is known that bacterial inflammation of the gums can trigger a poorly regulated immune response, which in turn damages tissue and organs throughout the body. "So taking your teeth out is not a solution," says Chapple, you should rather keep it. "But you also have to keep them healthy."
Many diseases have an inflammatory component. A connection with gingivitis has been well proven, especially for cardiovascular diseases and diabetes. But also Alzheimer's and rheumatoid arthritis seem to be associated with an inflammation of the dental bed, called periodontitis. "There is evidence of about 50 diseases associated with periodontitis," says Francesco D'Aiuto, a periodontist at University College London.
To demonstrate a clear connection between the diseases - and thus consider that treatments in the gums can treat or prevent other diseases - but is not child's play. "While some studies confirm a causal context, others are in questioning it again," says D'Aiuto. One thing is clear: the consequences of gum diseases do not only belong to the area of responsibility of dentists. They are an integral part of general health.
Do gingivitis make the entire body sick?
At the end of the 1980s, a research team led by Kimmo Mattila from the University of Helsinki described one of the first scientifically well-documented links between periodontal health and systemic diseases. "The heart surgeons found that most of their heart patients had really bad teeth," says dentist Wenche Borgnakke of the University of Michigan in Ann Arbor. In a case-control study published in 1989, Mattila and his colleagues confirmed that the risk of heart attack is significantly influenced by the health of the dental bed. Since then, the relationship has been extensively investigated. Based on the current data, D'Aiuto estimates that periodontal diseases increase the risk of heart disease by ten to 15 percent.
In addition, there are significant indications of a connection between gum infections and type 2 diabetes. In 2013, Borgnakke and her colleagues released an influential systematic analysis of clinical data that demonstrated a causal connection. "We were able to show that periodontitis increases blood sugar," she says. As a result, type 2 diabetes could arise. In people who already have diabetes, the blood sugar setting, which in turn increases the risk of complications such as cardiovascular diseases and diseases of the peripheral nervous system. Conversely, examinations over a longer period of time within longitudinal studies have shown that people with type 2 diabetes develop two to three times more frequent periodontal diseases.
How the different diseases are related is extremely difficult to disguise. Diseases such as cardiovascular diseases and diabetes only arise for decades after the first dental problems. Exstined longitudinal studies with a large number of subjects would be required to observe the health of teeth and body for many years. In addition, some test subjects should not be treated with gum infections. Only on them could it be clearly determined what effects diseases of the tooth bed have on the development of other diseases.
"That would simply be an unethical study," says periodontist Chapple. "Instead, we conduct observational studies and short-term intervention studies in which we delay periodontal treatment in the control group for a short period of time and then look at factors such as the stiffness of the arteries as a substitute." In fact, such observational studies can also provide meaningful data. For example, a multi-year study published by Thomas Van and his colleagues at the Forsyth Institute in Cambridge, Massachusetts, in 2021. In it, the authors report that people with proven gingivitis – an indication of active periodontitis – had twice as high a risk of developing cardiovascular disease, especially a heart attack or stroke.
Animal studies also support the assumption that inflammation of the dental bed increases the risk of developing cardiovascular diseases, a metabolic syndrome (the common occurrence of type 2 diabetes, hypertension and obesity) or rheumatoid arthritis. According to Van Dyke, the clinical pictures have a decisive commonality. "Most non-communicable diseases have an inflammatory component," he says. This is exactly what periodontitis is - an uncontrolled inflammation. The question is: how can local inflammation in the mouth become a crisis in the rest of the body?
Inflammation that persists poses a problem.
Every human being harbors a diverse bacterial population in his mouth. This also includes species with known pathogenic potential such as Porphyromonas gingivalis. A healthy gum tissue provides a robust barrier against infections. At the same time, it is permeable enough so that the immune system can keep the bacterial populations in check.
If the microbial ecosystem between teeth and gums gets out of balance, the resulting immune response can quickly get out of hand. Mariano Sanz, periodontologist at the University of Complutense Madrid, sees an important and natural defense mechanism in acute inflammation. "You only have a problem when the inflammation becomes chronic," he says. This condition occurs when the immune system is no longer able to effectively eliminate excess harmful bacteria in a short time. Then the immune molecules immigrated to the gums pour out signal molecules such as cytokines that trigger a general inflammatory reaction. The inflammatory reaction also affects the permeability of the gums so that more bacteria can immigrate into the tissue from the mouth.
"When pathogens get into the bloodstream, activate so -called neutrophil granulocytes," says Chapple. Together with other defense cells, the monozytes, these immune cells form the first line of defense of the innate immune system. If there is an infection, a quick inflammatory reaction. The inflammation is additionally boosted by toxins such as lipopolysaccharides that produce the penetrated bacteria. If the different cells and messenger substances get into the bloodstream, you can trigger a strong inflammatory reaction throughout the body. Most of the time, this systemic inflammation is only of short duration and does not contribute significantly to the development of chronic diseases. To do this, the inflammation must last over a longer period of time.
George Hajishengallis is an immunologist at the University of Pennsylvania in Philadelphia. Together with his employees, he has developed a model that could explain how an acute inflammatory reaction from the chronic problem. They call the core idea "trained immunity": If the body is infected with a pathogen, the innate immune system creates a kind of memory protocol in the precursor cells of the immune system based in the bone marrow. It has been known for a long time that the immune system acquired in the course of life builds such an immunogal. It trains antibodies and T cells to recognize components of pathogens, the antigens. For the innate immune response, an immunognight has only been described in recent years. Both memories allow a faster immune response to future encounters with pathogens that have already been successfully combated. "The bone marrow can not only perceive periodontitis -associated systemic inflammation, it can also remember," says Hajishengallis.
However, the alarm system can fail if an infection lasts longer – for example, in chronically inflamed gum tissue. The bone marrow is extremely sensitive to the inflammatory signaling molecules and bacterial toxins that flow into the bloodstream during untreated periodontitis. "If peripheral blood is taken from periodontitis patients and the monocytes and neutrophils contained therein are stimulated with lipopolysaccharide, they produce many more inflammatory signals than in people without gum problems," says Hajishengallis. Currently, his group is gathering evidence on how this hyperactive immunity can trigger chronic diseases or exacerbate an existing condition.
Conversely, a poorly set type 2 diabetes can also promote the progression of periodontal disease, says Chaaple. »This is the reaction to sugar - glucose fueled the inflammation. This creates metabolic products that delay the healing, «he says. The inflammation in turn promotes the additional release of sugar to support the counterattack of the immune system. "It makes it much more difficult to control diabetes," says Chapple. "That is why cardiovascular, kidney-related and other complications of diabetes are all more pronounced in patients with periodontitis."
On the trail of the culprits
Oral bacteria can also directly contribute to the development of systemic diseases. Every time you brush your teeth, eat hard foods or go to clean your teeth, some of the bacteria detaches from the teeth and is swallowed or enters the bloodstream through other routes. Normally, the immune system can cope with this well, but in people with gingivitis, the problem becomes chronic. Then potentially harmful types of bacteria migrate into the bloodstream in much larger numbers than usual and harm the body.
Porphyromonas gingivalis is not the only bad guy of the oral cavity, but it is the best studied. The bacterium is considered a key pathogen and is associated with a whole range of chronic diseases. Although this anaerobic species also occurs in small numbers in healthy mouths, says Chapple. However, if the gums are inflamed and bleed more, the iron from the blood activates the bacteria. Once activated, P. gingivalis can contribute to the destruction of the inner cell layer of blood vessels – making periodontal inflammation even worse – and infiltrate other host cells, including immune cells.
Some studies have shown that P. Gingivalis can even kidnap certain subgroups from immune cells and force them to hike to other parts of the body. "Instead of being dissolved and metabolized by the immune cells, the bacteria use the cells as a taxi," says dentist Borgnakke. The destinations apparently include calcification of the blood vessels that arise in cardiovascular diseases. According to the immunologist Hajishengallis, a number of animal experiments show that P. Gingivalis may also promote the origin or worsening of atherosclerosis.
As if that weren't enough, P. gingivalis easily crosses the blood-brain barrier that normally prevents pathogens and toxins from damaging the central nervous system. A 2019 study has provided evidence that the bacterium in the brain may contribute to Alzheimer's disease. The study was conducted by Stephen Dominy of the drug manufacturer Cortexyme based in South San Francisco, California, and Jan Potempa of the University of Louisville in Kentucky. Previously, epidemiological data suggested a link between periodontal disease and an increased risk of Alzheimer's disease. The results of Dominy and Potempa indicate that P. gingivalis directly drives this process in the brain: it promotes inflammation and the production of enzymes that promote the accumulation of tau- and β-amyloid – proteins that play a central role in the development of Alzheimer's disease.
The enzymes produced by P. gingivalis could also provoke the onset of rheumatoid arthritis. In this autoimmune disease, antibodies attack the body's own proteins in the joints, which are usually ignored by the immune system. In many cases, the antibodies attack proteins with a specific modification, citrullination. Numerous studies have now shown that P. gingivalis facilitates such modifications. "These experiments provide compelling evidence that the enzymes of P. gingivalis form citrullinates and are therefore likely to play a role in rheumatoid arthritis," says British paradontologist D'Aiuto.
But even if many evidence steer the track on P. Gingivalis, the bacterium alone does not trigger periodontitis or its systemic consequences - it is still essential for the development of illness. "There are four or five other pathogens of the tooth bed that can manipulate the immune system in such a way that vulnerable people develop an inflammatory disease faster or an existing illness progresses faster," says D'iuto. Some researchers, including Chapple, warn against measuring the bacteria too great. "The inflammation nourishes the harmful microbes and the harmful microbes feed the inflammation," says Chapple. "In order to break through this vicious circle, an intervention from outside is needed."
Reduced inflammation may minimize the likelihood of developing other diseases.
The idea of preventing a heart attack with a visit to the dentist is, of course, tempting. "It's much easier to get your teeth cleaned than to lose 50 pounds," Van Dyke jokes. So far, however, research has not been able to prove that the treatment of gum disease has a more general clinical benefit.
On the one hand, the construction of the necessary studies is difficult. In the control group, at least temporarily, any kind of intervention on the tooth bed should be omitted. In addition, clear measurement variables must be defined beforehand that demonstrate the effectiveness of periodontal treatment. In a controversial study from 2013, no clinical benefit for patients with diabetes could be found who received periodontitis treatment. However, the study was roughly faulty, Borgnakke says. "The treatment was limited to a certain number of sessions," she says. In addition, the researchers involved did not define how much dental plaque is removed or how strongly gum inflammation had to decrease so that therapy was considered successful. This made it impossible to draw clear conclusions.
However, recent research results give rise to optimism. In a study from 2020, Sanz and his colleagues report that periodontal treatment brings measurable advantages for people with metabolic syndrome. "The treatment of periodontitis led to a significant reduction in high blood pressure and to a significant reduction in the glycosylated hemoglobin," says Sanz. Glycolyzed hemoglobin is usually measured to control the blood sugar level of type 2 diabetes in the long term. As early as 2018, D'Aiuto and colleagues had observed similar things in people with severe periodontitis and type 2 diabetes. They even found indications that the treatment improves kidney and cardiovascular health. Borgnakke emphasizes that the data from such studies would be summarized that effective periodontal treatment in people with diabetes can reduce glycosylated hemoglobin to the same extent as taking a diabetes medication.
The data basis is still missing for the effectiveness of dental treatments in other periodontitis -associated diseases. Some ongoing studies are currently examining the benefits for people with rheumatoid arthritis, including one of Sanz. "We see whether the dental treatment of patients who suffer from rheumatoid arthritis and periodontitis reduces the release of autoantibodies," says Sanz. "So far, the results look good."
Van Dyke's research group pursues another strategy. The scientists want to develop medication that suppress the excessive inflammatory reaction caused by gum diseases. The long -term use of common inflammatory inhibitors would be too risky due to the holistic damping of the immune system. That is why Van Dyke focuses on a class of anti -inflammatory molecules that his research colleague, the pharmacologist Charles Serhan from Harvard Medical School in Boston, has identified. These molecules "reverse the inflammatory process and bring it back into balance," explains van Dyke. The active ingredients would only have a biological effect if the inflammation is active. "If these substances are given to a healthy test animal without inflammation, they do nothing at all." At the beginning of this year, Van Dyke's team was able to demonstrate in a phase 1 study that such a preparation securely reduces the inflammatory markers of gum diseases. Further effectiveness studies are planned for the near future.
Periodontitis is just one of many factors that can lead to diseases in healthy people. Borgnakke hopes that the new findings will bring a stronger exchange between the departments involved in medicine. »The mouth is absolutely to be understood as part of the body. It is really a shame that studies in studies are now so much differentiated between medicine and dentistry, «she says. The good news: that seems to be slow. At a cardiological congress in 2019, Chappe was surprised by the great interest of the doctors in new knowledge of periodontal and general health. "Some even subscribed to periodontal magazines," he says. "They are fully behind it."
This article is part of "Nature Outlook: Oral Health", an editorially independent side dish that was produced by third parties.
© Springer Nature Outlook: Oral Health, 10.1038/d41586-021-02918-4, 2021
