Gum disease

Alzheimer’s is linked to gum disease – but bad oral health is not the only culprit

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For most people, teeth cleaning may just be a normal part of your daily routine. But what if the way you clean your teeth today, might affect your chances of getting Alzheimer’s disease in years to come?

There is an increasing body of evidence to indicate that gum (periodontal) disease could be a plausible risk factor for Alzheimer’s disease. Some studies even suggest your risk doubles when gum disease persists for ten or more years. Indeed, a new US study published in Science Advances details how a type of bacteria called Porphyromonas gingivalis – or P. gingivalis – which is associated with gum disease, has been found in the brains of patients with Alzheimer’s disease. Tests on mice also showed how the bug spread from their mouth to brain where it destroyed nerve cells.

Image Credit: Africa Studio via Shutterstock

The report in question was carried out and self-funded by founders of a US pharmaceutical company Cortexyme, which is researching the cause of Alzheimer’s and other degenerative disorders. Scientists from the San Francisco drug firm will launch a human trial later this year.

WHAT IS GUM DISEASE?

The first phase of gum disease is called gingivitis. This occurs when the gums become inflamed in response to the accumulation of bacterial plaque on the surface of the teeth.

Gingivitis is experienced by up to half of all adults but is generally reversible. If gingivitis is left untreated, “sub-gingival pockets” form between the tooth and gum, which are filled by bacteria. These pockets indicate that gingivitis has converted to periodontitis. At this stage, it becomes almost impossible to eliminate the bacteria, though dental treatment can help control their growth.

The risks of gum disease are significantly increased in people with poor oral hygiene. And factors such as smoking, medication, genetics, food choices, puberty and pregnancy can all contribute towards the development of the condition.

rushing your teeth at least twice a day and flossing regularly can help to keep gum disease at bay. - Image Credit: AUWAU PHOTO via Shutterstock
rushing your teeth at least twice a day and flossing regularly can help to keep gum disease at bay.

Though it is important to remember that gum disease is not just the work of P. gingivalis alone. A group of organisms including Treponema denticola, Tanerella forsythia and other bacteria also play a role in this complex oral disease.

MOUTH BRAIN CONNECTION

At the University of Central Lancashire, we were the first to make the connection with P. gingivalis and fully diagnosed Alzheimer’s disease. Subsequent studies have also found this bacteria – which is responsible for many forms of gum disease – can migrate from the mouth to the brain in mice. And on entry to the brain, P. gingivalis can reproduce all of the characteristic features of Alzheimer’s disease.

The recent US research which found the bacteria of chronic gum disease in the brains of Alzheimer’s disease patients gives additional very strong research-based evidence – but it must be interpreted in context. And the fact of the matter is that Alzheimer’s disease is linked with a number of other conditions and not just gum disease.

Existing research shows that other types of bacteria and the Herpes type I virus can also be found in Alzheimer’s disease brains. People with Down’s syndrome are also at a higher risk of developing Alzheimer’s disease, as are people who have had a severe head injury. Research also shows that several conditions associated with cardiovascular disease can increase the risk of Alzheimer’s disease. This suggests there are many causes with one endpoint – and scientists are still trying to figure out the connection.

This endpoint results in the same symptoms of Alzheimer’s: poor memory and behavioural changes. This also occurs alongside plaque buildup in the grey matter of the brain and what’s known as “neurofibrillary tangles”. These are the debris left from the collapse of a neuron’s internal skeleton. These occur when a protein can no longer perform its function of stabilising the cell structure.

BRUSH YOUR TEETH

The latest research adds more evidence to the theory that gum disease is one of the things that can lead to Alzheimer’s disease. But before you start panic brushing your teeth, it’s important to remember that not everyone who suffers from gum disease develops Alzheimer’s disease and not all who suffer from Alzheimer’s disease have gum disease.

To find out who is “at risk”, scientists now need to develop tests that can show the dentist who to target. Dental clinicians can then advise those people as to how they can reduce the risk of developing Alzheimer’s disease through better management of their oral health. But until then, regularly brushing your teeth and maintaining good oral hygeine is recommended.

COPD Exacerbated by Gum Disease

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Severe gum disease has been linked to the progression of chronic obstructive pulmonary disease, or COPD. However, it is not fully understood how the connection plays out in the immune system. Now, a new study reveals immune system cells that play a key role in the microbial link between COPD and gum disease. Researchers from Sichuan University, in China, report that bacteria associated with gum disease promote COPD through the activation of two types of cells, γδ T cells and M2 macrophages.

The findings are published in mSystems in an article titled, “Periodontitis aggravates COPD through the activation of γδ T cell and M2 macrophage.”

“COPD is a chronic systemic inflammatory disease with high morbidity and mortality,” wrote the researchers. “Periodontitis exacerbates COPD progression; however, the immune mechanisms by which periodontitis affects COPD remain unclear. Here, by constructing periodontitis and COPD mouse models, we demonstrated that periodontitis and COPD could mutually aggravate disease progression. For the first time, we found that the progression was associated with the activation of γδ T cells and M2 macrophages, and M2 polarization of macrophages was affected by γδ T cells activation.”

“By enhancing periodontal therapy and targeting the inhibition of γδ T cells and M2 macrophages [we] may be able to help control the progression of COPD,” said microbiologist Boyu Tang, PhD, who led the study with microbiologist Yan Li, PhD.

Periodontitis is a chronic infectious disease, and previous studies have found that it’s a risk factor for a raft of diseases, including diabetes, hypertension, some cancers, cardiovascular disease, and COPD.

Previous studies, including some led by Li and Tang, have established that the oral bacteria Porphyromonas gingivalis plays an important role in gum disease. For the current study, Li, Tang, and their colleagues used mouse models to show how those bacteria could aggravate progression of COPD. In one experiment, they showed that mice infected with both periodontitis and COPD had worse progression of COPD than mice infected with COPD alone.

In another experiment, they observed that in mice orally infected with P. gingivalis, the bacteria migrated to and infected lung tissue, leading to a significant, observable change in the lung microbiota. Further observations using flow cytometry and immunofluorescence revealed that periodontitis promoted the expansion of the immune cells in the lung tissue. Finally, in experiments using mouse lung tissue, the group connected the dots by showing that P. gingivalis could activate the immune cells, promoting their ability to produce cytokines associated with worsening COPD.

The researchers noted that the decrease in lung function and increase in immune cells was more modest than they’d predicted, but that could be an artifact of the experimental setup. The team created COPD animal models using exposure to cigarette smoke. “If the cigarette smoke exposure could be extended for a longer period of time, these changes might be more pronounced,” Li said. In future studies, Li said that the group plans to investigate how increases in smoke exposure might affect the immune response.

“We’ll further carry out additional studies on human subjects to confirm the mechanism,” Li said. They plan to recruit patients with both conditions and offer periodontitis treatment, then compare lung function and immune cell counts before and after. “Our finding could lead to a potential new strategy for treating COPD.”

Can Probiotics Help With Gum Disease?

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More than 700 kinds of bacteria can live in your mouth — some helpful, and some harmful. Don’t run for your toothbrush or mouthwash just yet. As long as they’re in balance, the “good” kind keep the “bad” ones from hurting you.

But if that balance gets out of whack, the harmful ones can take hold and lead to gum disease.

You might have heard how good bacteria in certain foods and supplements (called probiotics) may help with this kind of imbalance in your gut. Well, scientists are finding that they may help fight gum disease in much the same way.

That might give you and your dentist another tool to use to treat or prevent gum issues along with the standard ones.

How Does the Imbalance Happen?

Researchers are still trying to sort out what lets the harmful bacteria go to work in your mouth. The triggers can include:

  • Not taking care of your teeth and gums. This lets the bad bacteria multiply and shifts the balance.
  • A weak immune system. This can affect the way the bacteria in your mouth relate to one another and give the harmful kind an advantage.
  • Your body’s genetic blueprint. Some people may not have enough of the helpful bacteria, or they may be more likely to have the bad kind.
  • Dry mouth. Your saliva has substances that help fight harmful bacteria. But some medicines, like painkillers and decongestants, can affect how much you have.

How Does That Lead to Gum Disease?

An imbalance of bacteria can affect your body’s defenses and keep your white blood cells from killing harmful bacteria. Those bacteria can inflame your gums. That inflammation, in turn, gives off chemicals that feed bad bacteria, which multiply. More bacteria inflame your gums and start to eat away at the bone that anchors your teeth.

If this goes on long enough, your gums and the bone that supports your teeth can be ruined. You might end up losing teeth.

It also can set you up for tooth decay and bad breath. Researchers think it also may help cause oral cancer.

And if you have too many harmful bacteria in your mouth, they can move to other parts of your body and may be linked to:

Probiotics and Gum Disease

A group of helpful bacteria called lactobacilli can fight several kinds of bad bacteria and may help restore a healthy balance in your mouth.

Researchers put some of this bacteria into chewing gum and asked people with the gum disease gingivitis to use it every day. (With gingivitis, your gums are red and swollen and bleed easily.) After 2 weeks, the teeth of the people in the study had less plaque — the clear, sticky film that can cause cavities or gum disease.

Another study found that lozenges with the same kind of bacteria also helped with inflammation and plaque.

If you have gum disease or are worried about it, talk with your dentist about whether a probiotic like this might be good for you. But remember that the most important things you can do to guard against gum disease are to brush and floss your teeth.

Gum disease linked to increased stroke risk: What’s new?

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A new study has shown an independent association between periodontal disease and incident stroke risk. What’s interesting is routine dental care can attenuate the stroke risk.

“The more severe the periodontal disease, the higher the risk of future stroke is,” said primary investigator Dr Souvik Sen from the University of South Carolina School of Medicine in Columbia, South Carolina, US. However, individuals who regularly attend the dentist had half the stroke risk of those who do not receive regular dental care.”

Periodontal disease characterized by increased inflammation, for example, gingivitis and severe periodontitis had the strongest association with stroke risk. “The risk is about two to three times higher in individuals with severe [periodontal] disease,” said Sen. “The risk [brought about by gum disease] is similar to that of high blood pressure.”

The study involved 10,362 middle-aged individuals with no history of previous stroke participating in the Atherosclerosis Risk in Communities (ARIC) study.  The pattern of their dental visits was classified as regular (more than once a year) or episodic (only when needed or never). Within 15 years of follow-up, 584 individuals had an incident of ischaemic stroke. [Stroke 2018;doi: 10.1161/STROKEAHA.117.018990]

Selected individuals from the ARIC study (n=6,736) were included in the ancillary dental ARIC study and were assessed and classified into seven periodontal profile classes (PPCs), from A to G (healthy to severe periodontal disease). Of these, 299 went on to have an incident ischaemic stroke in the follow-up period.

Risk lower with regular dental care

The incidence of ischaemic stroke per 1,000 person-years was 1.29 for PPC-A (the reference healthy group without periodontal disease), 2.82 for PPC-B (mild periodontal disease), 4.80 for PPC-C (high gingival index score), 3.81 for PPC-D (tooth loss), 3.50 for PPC-E (posterior disease), 4.78 for PPC-F (severe tooth loss), and 5.03 for PPC-G (severe periodontal disease).

Periodontal disease was significantly associated with cardioembolic stroke (hazard ratio, 2.6, 95 percent confidence interval [CI], 1.2–5.6) and thrombotic stroke (HR, 2.2, 95 percent CI, 1.3–3.8), but not lacunar strokes.

Regular dental users had a lower risk of stroke (crude hazard ratio [HR], 0.52] vs episodic users. The risk remained lower for regular dental users after adjusting for age, sex, BMI, hypertension, diabetes, smoking, race/centre, low-density lipoprotein level, and other factors (adjusted HR, 0.77).

Oral and heart health: The connection

Association cannot prove causation. However, more studies have shown that the bacteria found in gum disease, for example, Streptococcus sanguinis, can attach to the bloodstream and damage the heart valves, resulting in endocarditis.

“Our findings support the link between gum disease and stroke. The mechanism is to do with atherosclerosis and/or atrial fibrillation,” said Sen.  “Of note, good dental hygiene can mitigate the risk. The message is that good regular dental care, including a thorough home cleaning routine with brushing and flossing and regular dentist visits, can do more for heart health.”

Dear women, pay attention to oral hygiene if you’re trying to conceive

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The finding is independent of other risk factors contributing to conception, such as age, current smoking, and socioeconomic status.

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Researchers advise fertile women to take care of their oral health.

If you’re trying to conceive, it might be a good idea to pay attention to your oral care routine. A common bacterium associated with gum disease may delay conception in young women, warns a new study. “Our results encourage young women of fertile age to take care of their oral health and attend periodontal evaluations regularly,” said one of the researchers Susanna Paju of the University of Helsinki in Finland.

Periodontal (gum) disease is an inflammatory reaction to a bacterial infection below the gum line. The study involved 256 healthy non-pregnant women (mean age 29.2 years, range 19 to 42) who had discontinued contraception in order to become pregnant. They were enrolled from the general community from Southern Finland.

Participants were followed-up to establish whether they did or did not become pregnant during the observation period of 12 months. Porphyromonas gingivalis, a bacterium associated with periodontal diseases, was significantly more frequently detected in the saliva among women who did not become pregnant during the one-year follow-up period than among those who did, according to the study published in the Journal of Oral Microbiology.

The levels of salivary and serum antibodies against this pathogen were also significantly higher in women who did not become pregnant. Statistical analysis showed that the finding was independent of other risk factors contributing to conception, such as age, current smoking, socioeconomic status, bacterial vaginosis, previous deliveries, or clinical periodontal disease.

Women who had P. gingivalis in the saliva and higher saliva or serum antibody concentrations against this bacterium had a three-fold hazard for not becoming pregnant compared to their counterparts. Increased hazard was nearly four-fold if more than one of these qualities and clinical signs of periodontitis were present.

“Our study does not answer the question on possible reasons for infertility but it shows that periodontal bacteria may have a systemic effect even in lower amounts, and even before clear clinical signs of gum disease can be seen,” Paju said, adding, “More studies are needed to explain the mechanisms behind this association. Young women are encouraged to take care of their oral health and maintain good oral hygiene when they are planning pregnancy.”

Gum disease opens up the body to a host of infections

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For centuries, the mouth and the body have been disconnected — at least when it comes to health care. Through the Middle Ages and beyond, teeth fell under the care of barbers, who could shave a customer and pull a molar with equal skill. In the 1700s, French surgeon Pierre Fauchard published the Treatise on Teeth, establishing dentistry as its own science.

Across the channel in England, as physicians gained stature in the 19th century, surgeons and dentists engaged in a power struggle. In the modern United States, after medicine became linked to employer insurance and Medicare, the fissure between medicine and dentistry widened. Insurance coverage began at the throat.

So when Salomon Amar, a periodontal specialist at Boston University, began exploring links between oral bacteria and heart disease in animal studies in the late 1990s, reactions were lukewarm. “Many cardiologists thought we were a bit crazy,” he says. Skepticism still abounds, but the same molecular tools that have dramatically changed understanding of the gut microbiome are now allowing scientists to track and examine bacteria in the mouth. Advocates of a connection between the artery disease atherosclerosis and microbes are hoping to find convincing proof of their suspicions, while exploring links between ailing gums and other conditions, including cancer, arthritis, diabetes and even Alzheimer’s disease.

The work has profound implications for public health, given that more than 65 million American adults are thought to have periodontal disease, which occurs when bacterial overgrowth inflames the gums and can lead to erosion of gums and bone. If it turns out that periodontal decay drives other diseases, doctors would have a new, and relatively simple, means of prevention.

Wenche Borgnakke, a dental researcher at the University of Michigan in Ann Arbor, has been making this case for years, citing “solid evidence that periodontal treatment has an effect on systemic disease.” Shepoints to a study published last year in the journal Medicine comparing patients on dialysis who received periodontal treatment with those who did not. Those getting treatment had an almost 30 percent lower risk of pneumonia and hospitalization from infections. Another study published earlier this year found that gum disease is associated with a roughly 10 percent higher mortality over 10 years among patients with kidney problems.

Researchers working in the field often point out that about half of all deaths from atherosclerosis occur in people who do not have any classic risk factors, such as high cholesterol or obesity. Something else — something as yet unknown — is also contributing to heart disease. Even the root cause of many cancers is largely unexplained. Most women with breast cancer, for instance, have no risk factors other than older age. SaysJean Wactawski-Wende, a cancer epidemiologist at the State University of New York at Buffalo: “The more I work on oral health and cancer, the more I think, ‘Oh my gosh, I’ve got to keep my teeth clean.’ ”

Foul mouth

To date, more than 500 scientific papers have weighed in on the connection between atherosclerosis and gum disease. Officially, the theory remains “biologically plausible,” but unproven, according to the American Heart Association’s formal position. Some concepts are undisputed: For one, the microbes that live in the mouth don’t stay in the mouth. The simple act of brushing allows bacteria clinging to the teeth and gums to leak into the bloodstream.

As the posters at the dentist’s office attest, neglected oral hygiene encourages bacterial growth, allowing the microbes to breed on and between teeth, as well as under the gums. What the illustrations don’t show is that these microorganisms form a biofilm, a tough microbial community bound together with sugar molecules in a thin coating. This is the plaque your dentist warns you about.

“If you do not brush your teeth, it will sit there and accumulate. As that plaque gets thicker and thicker, there is less and less oxygen in the deepest layers,” Borgnakke says. Safely sheltered, the innermost plaque starts to favor anaerobic bacteria, which, when they escape into the blood, can survive in the oxygen-starved nooks and crannies deep inside the body.

As plaque builds up, gums get irritated, swell and draw more blood into the distressed tissue. Eventually, chemicals produced by the biofilm break down the thin layer of cells that form a boundary between the gums and the blood vessels. Periodontitis officially occurs when gum and bone tissue starts to deteriorate. The space between the tooth and gums forms a pocket; dentists measure the depth of the pockets to determine the severity of infection. “We usually think of an infection as some bug from the outside that attacks the body,” says Borgnakke. “In this case, it’s an internal infection.”

It was once thought that only a handful of microbial species were involved in the development of periodontitis, but the latest studies have revealed that many of the microbes responsible for gum diseasecome from “previously underappreciated species,” according to a 2015 report in Advances in Experimental Medicine and Biology. Because many bacteria resist growth in a laboratory, only a small portion of some 500 to 700 species of oral microbes have been well characterized.

One aggressive pathogen, an organism called Porphyromonas gingivalis, has antennae that stick out and can pry open the space between two cells, Borgnakke says. “This is a really, really nasty bug.” Within minutes of invading blood vessels, P. gingivalis and its gang of accomplices are ferried to distant sites, where they can set up outposts. “Bacteria that normally live in the mouth are found in every organ in the body, and even muscle cells,” she says.

The body doesn’t take this assault lying down. The immune system gets agitated and tends to stay in a state of slow simmer. But the bacteria that cause periodontal disease have a knack for turning the body’s defense on its head, according to a 2015 review in Nature Reviews Immunology. Case in point: Common white blood cells called neutrophils are deployed to the failing gums — where they not only fail to control the infection, but also end up releasing enzymes that further destroy tissue. The immune system also releases an avalanche of chemicals designed to help control the infection. For example, the liver starts producing C-reactive protein, a molecule that has such an important role in signaling the rise of heart disease that it is considered a risk factor by some researchers.

Smoking gums

Even after two decades of study, it has been hard to directly link periodontal dynamics to blocked arteries, despite hundreds of studies that have tried. There are seemingly smoking guns. Among them, P. gingivalis is commonly found lodged inside arteries, and the development of plaque in the arteries is driven by many of the same inflammatory chemicals triggered by periodontal disease. Many researchers also point to C-reactive protein, which is probably present long before atherosclerosis develops.

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But people with periodontitis also tend to share well-known risk factors for heart disease, such as high cholesterol, smoking and obesity. A sugar-sweetened diet that promotes oral decay is no friend to your arteries. The relationship is also hard to study because both atherosclerosis and periodontitis unfold slowly over time, so epidemiologists must rely on indirect measures of disease.

Experts line up on both sides. “If there is an association, it’s a very weak one,” says Peter Lockhart, former chairman of oral medicine at Carolinas HealthCare System in Charlotte, N.C. An expert on heart valve infections, Lockhart was one of the leaders of an American Heart Association panel that reviewed the evidence before releasing an official statement in 2012. “I think the question has been answered for now,” he says. For cardiologists, the threat from periodontal disease “pales by comparison to the known risk factors that need to be focused on.”

Others aren’t ready to abandon the hypothesis. In 2015 in the journal Atherosclerosis, a team of German researchers reviewed studies released since the AHA statement. They pointed out that a large body of work published in the previous three years, using more refined tools and study design, shows that a connection between the two “cannot be ruled out.” One study, published in PLOS ONE in 2014 from researchers at the University of Florida in Gainesville, Meharry Medical College in Nashville and elsewhere, claims to have found a causal relationship, at least in mice. A significant portion of animals that drank water containing P. gingivalis experienced inflammation and bacterial accumulation in their hearts and blood vessels. Very few unexposed animals did.

Into the brain

While the artery studies carry on, new research is finding oral bacteria in surprising places. The brain, for one. In 2013, a team of researchers from Florida and the United Kingdom compared brain tissue samples from 10 people who had died from Alzheimer’s disease with samples from 10 people who had died from other causes. Signs of P. gingivalis infection showed up in four Alzheimer’s patients but in none of the comparison patients, the researchers reported in the Journal of Alzheimer’s Disease. In a follow-up experiment published in the same journal, the researchers inoculated P. gingivalis into the mouths of 12 mice genetically protected from Alzheimer’s. Six months later, evidence of the same bacteria appeared in the brains of three-fourths of the animals.

Tissue from the brain of an 84-year-old woman who died of Alzheimer’s disease shows evidence of infection with an oral species of Trepemona (dark blue).

Another type of oral bacteria, spirochetes calledTreponema denticola, “are already known to enter the brain,” says neuroscientist Sim Singhrao of the University of Central Lancashire in England. Traveling along the nerves that connect to the jaw, “they are a bit like jellyfish, crawling up into neurological tissue.” Once nestled inside the brain, oral bacteria could trigger an inflammatory chain reaction that eventually destroys certain nerve cells and leads to Alzheimer’s disease, says StJohn Crean, Lancashire’s executive dean of the College of Clinical and Biomedical Sciences.

He points out that Chinese researchers, writing last year in the Journal of Periodontal Research, found that people carrying certain versions of APOE, a gene linked to Alzheimer’s, were also more likely to suffer aggressive periodontal infection. Finally, a study published in March in PLOS ONE found that among 59 people with hallmarks of Alzheimer’s disease followed for six months, those with periodontitisexperienced cognitive decline at more than six times the rate as those without gum disease.

“We’ve moved on from that ‘this-can’t-be-right’ feeling,” Crean says. He is hoping to get funding for a study that would compare progression of Alzheimer’s among people who receive intensive oral hygiene, such as frequent dental-office–style cleanings, compared with those who brush and floss regularly. But he also notes that the arrow connecting gum disease and Alzheimer’s could point in both directions. “When your memory goes, you’re not going to remember to brush your teeth.”

Teeth and tumors

Providing still more reason to invest in dental floss, new research is raising questions about cancer’s link to gum health. Aside from oral cancers, the cancer connection was barely on the scientific radar before 2008, when a study appeared in Lancet Oncology. Some research had suggested that gum disease is associated with higher cancer mortality, but questions remained about the influence of smoking. In the study in Lancet Oncology, researchers from Imperial College London, Harvard Medical School and elsewhere reviewed data for almost 50,000 men enrolled in the Harvard Health Professionals Follow-Up Study. That study found a small increased risk of cancer mortality in men with periodontal disease.

A second study, published in February in Annals of Oncology, found that men with advanced periodontal disease who had never smoked nonetheless had a 2.5 times higher risk of cancers associated with smoking, such as lung, bladder and esophageal tumors. The researchers hypothesize that gum disease might trigger the same sort of immune response that tobacco does. Another study examined data from more than 73,000 participants of the Women’s Health Initiative, which gathered health information from volunteers over 15 years. Participants diagnosed with periodontal disease had a 14 percent increased risk of breast cancer compared with women with healthy gums. “It’s a modest increase, but when 50 percent of adults are diagnosed with periodontal disease, you could see this becoming a very important factor for prevention,” says Buffalo’s Wactawski-Wende, who led the study, published in January’s Cancer Epidemiology, Biomarkers & Prevention.

Laboratory studies are also offering compelling evidence of associations with certain cancers. Almost a dozen studies conducted over the last five years have found one particular species of mouth bacteria,Fusobacterium nucleatum, living in seeming abundance in colorectal tumors. Like P. gingivalis, F. nucleatumthrives in diseased gums and in low-oxygen areas. Wactawski-Wende is studying samples of various tumors to look for oral organisms.

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Burning questions

Given that periodontal disease causes the immune system to remain in a state of irritation, other lines of research have tried to tie diseased gums to inflammatory diseases like rheumatoid arthritis and diabetes. Writing last year in the journal Mediators of Inflammation, researchers from the University of Ceará in Brazil reviewed published studies on rheumatoid arthritis, concluding that “the majority of the articles have confirmed that there is a correlation,” especially among women. Both gum disease and arthritis, they wrote, could even feed off one another, amplifying a hyperactive immune system that makes both conditions worse.

A long line of research has also examined the relationship between diabetes and periodontal disease. In 2013, Borgnakke and an international team reviewed the evidence in the Journal of Clinical Periodontology. Of the 17 studies they found to have sufficient quality, the evidence suggests that people with poor periodontal health have a greater chance of developing early symptoms of diabetes and having greater complications from the disease once it develops. But she acknowledges that diabetes, and in fact all conditions under study, have multiple causes, making the role of any one culprit difficult to determine.

It’s also hard to account for the role of genetics. “You could have two patients with the same amount of plaque. One patient will have really deep pockets [between teeth and gums], and the other one will have no consequences,” she says. “That’s why it’s so hard to say anything in general.”

Even as research continues, those involved concede that they may never satisfy skeptics, given the slim chance of ever having a long-term prospective study. That research would need to monitor the cardiac health of a large population over an extended time, half with gum disease and half without, to determine if those with periodontal problems experienced worse cardiac health. But given the length of time it takes for both gum disease and systemic disease to reveal themselves, a study would need to involve thousands of participants over many years to be definitive, Amar says. “It would be financially prohibitive.” And he points out that pharmaceutical companies, which often help fund large clinical trials, would not back a study that has no product for them to eventually sell.

“Causality may not ever be demonstrated,” he says. To most doctors, the mouth will probably remain unconnected to the body. Amar and others will nonetheless continue, in hopes their work may one day give health professionals a little more to chew on.