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  • OUTLOOK

Homing in on an oral link to inflammatory disease

SEM showing gingivitis as green circular shapes

Scanning electron microscope image of a pathogen that causes gingivitis.Credit: Steve Gschmeissner/SPL

A century ago, many medical practitioners in Europe and the United States espoused the idea that the extraction of decaying teeth could stave off a host of disorders ranging from arthritis to schizophrenia. Indeed, some went as far as to simply remove all of a person’s teeth as a pre-emptive measure.

“The idea was that an infection around the teeth could spread to another part of the body,” says Iain Chapple, a periodontist at the University of Birmingham, UK. The practice of pre-emptively removing teeth has long since fallen out of favour — it’s “complete rubbish”, says Chapple. But the core concept that oral health directly influences chronic medical conditions is undergoing a renaissance. Decades of collaborations between dentists, periodontists, physicians and immunologists have provided a clearer picture of the systemic impact of periodontal disease.

The emerging story is one in which bacterially induced inflammation in the gum tissue ignites a poorly regulated immune response that damages tissues and organs throughout the body. “That’s why the argument of taking the teeth out is flawed,” says Chapple. “You need to keep your teeth, but you need to keep them healthy, with low levels of bacteria.”

Many disorders have an inflammatory component. An association between gum infections and conditions such as cardiovascular disease and diabetes is particularly well established. Findings in the past few years have also linked periodontal infection to other conditions, such as Alzheimer’s disease and rheumatoid arthritis. “There is evidence linking about 50 diseases associated with periodontitis,” says Francesco D’Aiuto, a periodontist at University College London.

Decisively confirming these associations — and demonstrating the potential to treat or prevent such disorders through periodontal interventions — has proved challenging. “Some studies are confirming a causal possible link, and others are disputing it or opening up other questions,” says D’Aiuto. But what has become clear is that the consequences of gum disease are not simply the purview of periodontists, and need to be considered as an integral component of overall health.

Tracing trouble to the teeth

One of the earliest contemporary links between periodontal health and systemic disease arose from observations by a team of cardiologists led by Kimmo Mattila at the University of Helsinki. “They noticed that most of the patients that they had on the operating table for heart attacks had really bad teeth,” says Wenche Borgnakke, a dentist at the University of Michigan in Ann Arbor.

Mattila and his colleagues subsequently confirmed1 a significant association between heart attack and poor periodontal health in a case-control study published in 1989. This connection with cardiovascular health has since been extensively investigated. On the basis of current clinical data, D’Aiuto estimates that periodontal disease increases the risk of heart disease by 10–15%.

There is also clear evidence for a link to type 2 diabetes. In 2013, Borgnakke coordinated an influential systematic review of the clinical data2 that offered support for a causal relationship. “We showed that having periodontitis has the effect of raising the blood sugar,” she says. This, in turn, could lead to type 2 diabetes or, in people who already have diabetes, it could worsen blood sugar control and exacerbate the risk of complications such as cardiovascular disease and neuropathy. Causality also applies in the other direction: longitudinal studies have shown that people with type 2 diabetes are two to three times more likely to develop periodontal disease than are people without the disorder3.

These disease relationships have proved tricky to untangle. For one thing, conditions such as cardiovascular disease and diabetes take decades to develop, so costly longitudinal surveys of large numbers of people are needed to track systemic and oral health over many years. Furthermore, to demonstrate causality decisively, these studies would have to deny a cohort of people periodontal care and see how it affects the incidence of disease.

“That’s just an unethical study to run,” says Chapple. “Instead, we end up doing observational studies and shorter-term intervention studies where you might delay the periodontal treatment in the control group for a short time, and then look at surrogate outcomes like stiffness of the arteries.” But even observational studies can offer compelling evidence. For example, a multi-year study by Thomas Van Dyke at the Forsyth Institute in Cambridge, Massachusetts, and his colleagues, published this year4, demonstrated that people initially assessed as having measurable gum inflammation — indicating active periodontitis — were more than twice as likely eventually to have a heart attack, stroke or other cardiovascular event.

Animal studies have provided robust support for the idea that periodontitis can set in motion physiological changes that exacerbate the risk of cardiovascular disease and metabolic syndrome (a cluster of conditions including type 2 diabetes, high blood pressure and obesity), as well as rheumatoid arthritis and other disorders. These conditions share a crucial common thread, according to Van Dyke. “Most non-communicable diseases have an inflammatory component,” he says, “and that’s what periodontal disease is — uncontrolled inflammation.” The question is, how does localized inflammation in the mouth escalate to a full-body crisis?

An unquenchable fire

Everybody has a vibrant bacterial community dwelling in their mouth, including species with known pathogenic potential, such as Porphyromonas gingivalis. Healthy gum tissue offers a robust barrier against infection while being sufficiently porous for our immune systems to keep those bacterial populations in check.

But if the microbial ecosystem located between tooth and gum becomes overgrown or imbalanced, the resulting immune response can quickly become problematic. Mariano Sanz, a periodontist at the Complutense University of Madrid, notes that this initial wave of acute inflammation is an important natural defence mechanism. “The problem is when the inflammation becomes chronic,” he says, noting that this state arises when the immune system is unable to clear excess pathogenic bacteria effectively in a short time. Immune cells recruited to the gum secrete cytokines and other molecules that stimulate a broader inflammatory response. This also compromises the integrity of the gum, allowing oral bacteria to leak through. “When they get into the bloodstream, they prime and activate neutrophils,” says Chapple. These are the white blood cells that, along with other such cells called monocytes, serve as first responders for the innate immune system, triggering a rapid inflammatory reaction in response to infection. The invading bacteria themselves also produce toxins such as lipopolysaccharide, which further ramp up inflammation.

Although initially localized to the mouth, the combined effects of these various signals entering the bloodstream can trigger a robust whole-body inflammatory response, coordinated by various molecules secreted by the liver. This systemic inflammatory response is normally short-lived, and does not contribute meaningfully to chronic disease. For that to happen, the inflammatory state must be sustained for an extended period of time.

Close up of a man opening his mouth wide while a dentist insert a tool ready for cleaning

A person undergoes an oral cleaning treatment at a dental hygienist’s office.Credit: E+/Getty

George Hajishengallis, an immunologist at the University of Pennsylvania in Philadelphia, and his collaborators have developed a model that might explain how this acute inflammatory reaction turns into a chronic problem. They call it ‘trained immunity’, and the core idea is that the innate immune response to infection naturally establishes a kind of memory in the immune progenitor cells that live in our bone marrow. Such memory is a well-established feature of the adaptive immune system, in which antibodies and T cells are trained to recognize a specific disease-related target. However, this mechanism has been identified only in the past few years in the innate immune response, which tends to be much broader in scope. As with the adaptive immune system, this memory enables a more rapid response to future encounters once the initial infection has cleared. But this alarm system can go wrong if the infection lingers, such as in unhealthy gum tissue. “Periodontal disease-associated systemic inflammation can be not only sensed, but also memorized by the bone marrow,” says Hajishengallis.

This renders the bone marrow extremely sensitive to the steady influx of inflammatory signals and bacterial contents that continually issue from the mouth in cases of untreated periodontal disease. “If you take peripheral blood from periodontitis patients and stimulate their monocytes and neutrophils with lipopolysaccharide, the production of inflammatory cytokines is much, much higher than in a periodontally healthy individual,” says Hajishengallis. His group is currently accumulating evidence to demonstrate how this hyperactive immunity might give high-risk individuals the final nudge required to develop chronic diseases, or amplify severity in people with existing conditions.

This inflammatory response is also a two-way street. For example, Chapple notes that poorly controlled type 2 diabetes can enable the progression of periodontal disease by providing fuel for the inflammatory response in the gum tissue. “It’s the hyperglycaemia — glucose fires up inflammation, and you get these metabolic by-products forming that delay healing,” he says. And as the inflammatory response to oral pathogens increases, it promotes further release of sugar to fuel the immune system’s counter-attack. “That makes the diabetes much harder to control,” says Chapple, “and therefore the cardiovascular, kidney and other complications of diabetes are all worse in patients with periodontitis.”

A bug in the system

The oral bacteria themselves can also contribute directly to systemic disease. Every time we brush our teeth, eat hard foods or get a dental cleaning, a certain number of bacteria become detached from the teeth and are swallowed or enter the circulation. Our immune system can normally handle this, but in the mouths of people with gum inflammation, the problem becomes chronic, with potentially harmful species entering the bloodstream in much greater numbers. The presence of these bacteria might not only heighten the inflammatory response but also inflict damage in other ways.

Porphyromonas gingivalis is not the only such bad actor, but it is the most well-studied, and it has been described as a keystone pathogen that has tentative links to a number of chronic diseases. Chapple says that although this anaerobic species is typically present in low numbers even in healthy mouths, increased exposure to blood in inflamed gums provides a crucial source of iron that essentially activates the bacteria. Once set in motion, P. gingivalis can actively contribute to the disruption of endothelial cell layers — worsening periodontal damage — but it can also infiltrate other host cells, including immune cells.

Some studies have demonstrated that P. gingivalis might even hijack certain subsets of immune cell5, forcing them to travel elsewhere in the body. “Instead of disintegrating and becoming metabolized inside, they use the cells as taxi cabs,” says Borgnakke. Destinations seem to include the plaques that accumulate in the blood vessels of people with cardiovascular disease. These bacteria have been detected repeatedly here. Hajishengallis points out that a number of studies in animal models have demonstrated that P. gingivalis can potentially promote the onset or worsening of atherosclerosis — although it is unclear whether this is a major contributing factor in the periodontitis–cardiovascular disease risk.

Even more worryingly, P. gingivalis can readily cross the blood–brain barrier that generally prevents pathogens and toxins from damaging the central nervous system. A 2019 study by Stephen Dominy at the drug company Cortexyme, based in South San Francisco, California, and Jan Potempa at the University of Louisville in Kentucky has provided intriguing evidence that the presence of this bacterium in the brain can contribute to Alzheimer’s disease6. Epidemiological data have previously linked periodontal disease to increased risk of developing and dying from Alzheimer’s. But Dominy and Potempa demonstrated that P. gingivalis in the brain could drive this process directly by fuelling inflammation and the production of enzymes that promote the accumulation of tau and β-amyloid — proteins strongly linked to the pathology of Alzheimer’s disease.

Enzymes produced by P. gingivalis could also contribute to the onset of rheumatoid arthritis. This autoimmune disease arises from the generation of antibodies that attack ‘self’ proteins in the joint tissue that would normally be ignored by the immune system. In many cases, such antibodies target proteins that have undergone a modification known as citrullination — and numerous studies have now demonstrated that P. gingivalis can facilitate such modifications (see, for example, ref. 7). “Those experiments produce quite convincing, compelling evidence that P. gingivalis enzymes clearly citrullinate and can play a role in rheumatoid arthritis,” says D’Aiuto.

But even if many roads seem to converge on P. gingivalis, this bacterium alone is neither necessary nor sufficient to drive periodontitis or its systemic consequences. “You could name another four or five bad periodontal pathogens that could all trigger an immune condition that might lead to faster progression or development of an inflammatory disease in susceptible individuals,” says D’Aiuto. And some researchers, including Chapple, caution more generally against ascribing too much of this process to bacteria in particular. “It’s all about the inflammation,” Chapple says. “The inflammation feeds the bad microbes, the bad microbes feed the inflammation, and you need an intervention that sort of breaks that chain reaction.”

Taking a bite out of disease risk

The idea of being able to prevent a heart attack with a visit to the dentist is inherently appealing. “It’s a lot easier to get your teeth cleaned than to lose 50 pounds,” jokes Van Dyke. But just as it has proved tough to decisively link chronic disease to periodontal health, researchers have struggled to demonstrate the broader clinical benefits of treating gum disease.

Part of the problem is the need to withhold periodontal intervention — even if temporarily — in the control group for any trial. Furthermore, such studies also need to establish clear metrics that can demonstrate the efficacy of the periodontal treatment. In one controversial case, a study published in JAMA in 2013 reported no clinical benefit for people with diabetes who received treatment for their periodontitis8. But the study was fundamentally flawed, contends Borgnakke. “The treatment was limited to a certain number of sessions,” she says, and there were no benchmarks for plaque removal or gum inflammation to indicate what would be considered a successful result. That made it impossible to draw any conclusions on clinical outcomes. “These patients had so much gum disease at the end of treatment, they fulfilled the criteria to start the intervention study in the first place,” says Chapple.

More-recent research has offered greater cause for optimism. In a randomized controlled trial by Sanz and his colleagues, published in 2020, periodontal treatment produced measurable benefits in people with metabolic syndrome9. “Treating periodontitis significantly diminished their high blood pressure, and the levels of glycated haemoglobin were significantly decreased,” Sanz says, referring to a common clinical indicator for control of blood sugar levels in type 2 diabetes. D’Aiuto and his colleagues observed similar clinical benefits in a 2018 clinical trial of people with severe periodontitis and type 2 diabetes, with indications that treatment also improved renal and cardiovascular health10. Borgnakke points out that data from such studies have collectively shown that effective periodontal treatment can achieve the same level of reduction in glycated haemoglobin in people with diabetes as can the addition of a conventional drug to the treatment regimen.

Data are still lacking for oral interventions against other periodontitis-associated conditions, but a number of studies are now under way, including one by Sanz exploring the potential benefits for people with rheumatoid arthritis. “We are evaluating whether treating these patients with both rheumatoid arthritis and periodontitis will diminish the levels of autoantibodies,” says Sanz, “and we are getting very nice results so far.”

Van Dyke’s team is pursuing an alternative strategy, based on the development of drugs that can quell the hyperactive inflammatory state induced by periodontal disease. Long-term use of existing anti-inflammatory drugs can be dangerous because of the broad inhibitory effects on the immune system. Van Dyke is instead focusing on a class of inflammation-resolving molecule identified by his collaborator Charles Serhan, a pharmacologist at Harvard Medical School in Boston, Massachusetts. These molecules “reverse the inflammatory process and drive it back to homeostasis”, explains Van Dyke, adding that they exert a biological effect only when inflammation is active. “If you give these compounds to a healthy animal that has no inflammation, they do absolutely nothing,” he says. Earlier this year, his team demonstrated in a phase I trial that one such formulation can safely reduce inflammatory markers of gum disease11, and is planning to pursue efficacy trials in the near future.

Periodontitis is just one of many factors that can push a healthy person towards developing disease. But Borgnakke hopes that these new findings will lead to greater crosstalk between disparate branches of medicine. “The mouth is so much part of the body, and it is really a shame that it has become so separated in studies between medicine and dentistry,” she says. The good news is that this situation seems to be changing. Chapple notes that, at a 2019 cardiology conference, he was surprised at the strong interest shown by doctors in discussing the latest links to periodontal health. “Some of them even get the periodontal journals,” he says. “They’re real believers.”

doi: https://doi.org/10.1038/d41586-021-02918-4

This article is part of Nature Outlook: Oral health, an editorially independent supplement produced with the financial support of third parties. About this content.

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