Mouth microbes have been implicated in a variety of ills, from arthritis to Alzheimer’s

Mouth microbes have been implicated in a variety of ills, from arthritis to Alzheimer’s

BY 

LAURA BEIL 

9:00AM, APRIL 6, 2016

COMMUNITY BUILDING  With inadequate brushing and flossing, bacteria caught between the tooth and gum coalesce into a biofilm. Eventually, oral tissue can deteriorate, allowing bacteria to infect other parts of the body.

NICOLLE RAGER FULLER

Magazine issue: Vol. 189, No. 8, April 16, 2016, p. 18

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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.

50

percent

U.S. adults over age 30 with periodontal disease

6

times faster

Cognitive decline among Alzheimer’s patients with gum disease versus those with healthy gums

2.5

times greater

Risk of several cancers among nonsmokers with advanced gum disease versus those with healthy gums

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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Here to there

While questions remain, researchers theorize that oral bacteria can travel and infect tissues throughout the body, triggering inflammation that affects various systems, as well as a developing fetus.

J. HIRSCHFELD

Source: G. Hajishengallis/Nat. Rev. Immuno. 2015

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).

G.R. RIVIERE, K.H. RIVIERE, K.S. SMITH/ORAL MICROBIOL. IMMUNOL. 2002

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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Troublemakers

Hundreds of species of bacteria live in the mouth. Here are four particularly bad actors linked to a variety of conditions.

Microbe	Evidence found in	Some related conditions	Additional traits
Porphyromonas gingivalis	Multiple locations	Atherosclerosis, arthritis, Alzheimer’s and more	Clings to cells and tissues using thin appendages called fimbriae
Treponema(various species)	Arteries, brain tissue	Atherosclerosis, Alzheimer’s	A cousin of Treponema pallidum, which causes syphilis
Fusobacterium nucleatum	Gastrointestinal system, amniotic fluid, colorectal tumors	Pregnancy complications, cancer	An instigator of acute appendicitis
Prevotella(several species)	Genital tract, joints	Vaginosis, pregnancy complications, arthritis	Major players in the gut microbiome; thrive on a high-carb, low-meat diet

SOURCES: J MYSEK ET AL/J. IMMUNOL. RES. 2014; S. POOLE ET AL/J. ALZ. DIS. 2015; M. HUSSAIN ET AL/FRONT. IN IMMUNOL. 2015; SS. CHUKKAPALLI ET AL/INFECTION AND IMMUNITY 2014; I. OLSEN AND SIM K. SINGHRAO/J. ORAL MICROBIO. 2015; A. BASHIR ET AL/EURO. J. CANCER PREV. 2015; M. CASTELLARIN ET AL/GENOME RES. 2012; O. SANU ET AL/J. MATERNAL-FETAL & NEONATAL MED. 2011; Y. KIMURA ET AL/RHEUMATOLOGY 2015; R. PERSSON ET AL/BMC INFECT. DIS.2009; K. MOEN ET AL/CLIN. EXP. RHEUMATOL. 2006; MARIAN GLICK-BAUER AND MING-CHIN YEH/NUTRIENTS 2014. 

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.

---

This article appears in the April 16, 2016, issue of Science News under the headline, "Down in the mouth."

Citations

W.S. Borgnakke. Does treatment of periodontal disease influence systemic disease? Dental Clinics of North America. Vol. 59, October 2015, p. 885. doi: 10.1016/j.cden.2015.06.007.

G. Aarabi et al. Interaction between periodontal disease and atherosclerotic vascular disease: Fact or fiction? Atherosclerosis. Vol. 241, August 2015, p. 555. doi: 10.1016/j.atherosclerosis.2015.04.819.

P. Lockart et al. Periodontal Disease and Atherosclerotic Vascular Disease: Does the Evidence Support an Independent Association?Circulation. Published online April 18, 2012. doi: 10.1161/CIR.0b013e31825719f.

G. Hajishengallis. Periodontitis: from microbial immune subversion to systemic inflammation. Nature Reviews Immunology. Vol. 15, January 2015, p. 30. doi: 10.1038/nri3785.

D.S. Michaud et al. Periodontal disease and risk of all cancers among male never smokers: an updated analysis of the Health Professionals Follow-up Study. Annals of Oncology. Published online January 24, 2016. doi: 10.1093/annonc/mdw028.

S. Poole et al. Active Invasion of Porphyromonas gingivalis and Infection-Induced Complement Activation in ApoE Mice Brains.Journal of Alzheimer’s Disease. Vol. 43, January 2015, p. 67. doi: 10.3233/JAD-140315.

W.S. Borgnakke et al. Effect of periodontal disease on diabetes: systematic review of epidemiologic observational evidence.Journal of Periodontal Disease. Vol 84, April 2013, p. S135. doi: 10.1902/jop.2013.1340013.

Bifidobacterium lactis B94

The Bifidobacterium lactis LAFTI B94 was identified as having strong probiotic potential during the 8 years of Co-operative Research Centre for Food Industry Innovation research at the University of New South Wales in collaboration with CSIRO Division of Dairy Research.  Several studies have since been conducted on the beneficial effects of this particular strain at effectively suppressing bad bacteria, copies of which can be found at the following links:

Beneficial effects of B94 on premature babies in reducing Necrotising Enterocolitis - Necrotising Entercolitis (NEC) is essentially the gut of pre-term babies dying from the inside out due to what is most likely infection with particularly bad strains of proteolytic bacteria (protein eating bacteria). Although this study is focussed on premature babies, it has implications for other similar gut disorders in adults.

Treatment Outcomes of Infants With Cyanotic Congenital Heart Disease Treated With Synbiotics - similar to the above link, this study was done in pre-term babies, but this study focussed on the link between NEC, congenital heart disease, and improved survivability when the B94 strain was used on premature babies.

The Comparition of the Efficacy of Two Different Probiotics in Rotavirus Gastroenteritis in Children - This study looked at how the B94 strain impacted on the severity and duration of gastro symptoms, specifically gastro caused by Rotavirus infection.

The role of Bifidobacterium lactis B94 plus inulin in the treatment of acute infectious diarrhea in children - another gastro study, this time not specific to Rotavirus infection.

Food Intolerance

A Food Intolerance is generally defined as an adverse, but non-acute and delayed reaction to a food or food component.  Wikipedia has a great entry on Food Intolerance.  It is different from a Food Allergy, which has an acute and rapid onset caused by an immediate immune response to an allergen.

Food intolerances can have many different causes, but a common cause may be linked to the types of bacteria that are found in the gut.  In many cases, providing (sometimes harmful) resident gut bacteria with certain sugars or other compounds that they feed on can cause growth of these harmful bacteria, increasing the levels of harmful substances that these bacteria produce.

In other cases, overgrowth of certain bad bacteria in the gut can cause the wall of the intestine to become overly permeable, allowing large molecules from food to pass through the intestinal wall into the bloodstream, where the immune system identifies them as foreign and mounts an inflammatory immune response against them.

Overuse of antibiotics is likely a large contributor to the Food Intolerance phenomenon, causing a reduction of bacterial diversity which often leads to a overgrowth of bad bacteria to occur. A good probiotic product may assist with the treatment of this condition, as it introduces good bacteria into the gut to work against any bad bacteria that may be resident.

The Herxheimer Reaction

According to Wikipedia, the Jarisch-Herxheimer Reaction (also known simply as the Herxheimer Reaction) is caused when a large number of harmful bacteria are killed inside the body, causing the release of toxic substances into the blood stream that were previously contained inside the walls of the living bacterial cells.  The immune system mounts an immune response to the toxins found mostly in the dead bacterial cell walls (being either endotoxins, lipoproteins, or lipopolysaccharides), and causes a systemic inflammatory reaction.

The person experiencing this reaction will feel terrible.  They may experience symptoms that are indistinguishable from an acute viral or bacterial infection, such as fever, aches, pains, chills, headache, muscle pain, and other such symptoms.

Normally, this reaction is associated with the use of antibiotics.  However, anything that causes harmful bacteria to die off can trigger such a reaction.

We have seen this reaction in some people who have taken a very effective probiotic product, where the individual taking the probiotic has stopped taking it, thinking it was the probiotic that was making them sick.  In fact, it was far more likely that the probiotic was doing the very job it was being taken for!  In such cases, it is recommended that the dose of the probiotic is reduced and gradually increased over a period of 1-2 weeks, to allow time for the body to clear the immuno-toxic products from the body, and for the numbers of the probiotic bacteria to gradually increase and stabilise.

Lactobacillus acidophilus L10

Lactobacillus acidophilus LAFTI strain L10

This strain was isolated in the 1980's from a Japanese food.  It was originally named LA1 and was subsequently also given the suffix "LAVRI strain L10" at one stage.  It has recently been reclassified as a Lactobacillus helveticus but still retains the suffix "LAFTI strain L10".  It appears in the literature under all these names in various research papers.

In the 1990's it was included in the screening of a range of probiotic cultures as part of the Probiotics and Prebiotics Programme in the Government-funded Cooperative Research Centre (CRC) for Food Industry Innovation sited at The University of New South Wales.  This CRC ran for eight years and included scientists from UNSW, CSIRO Division of Dairying and industry (Burns Philp & Co. Ltd and Goodman Fielder Pty Ltd).  It was selected as one of the very best strains at inhibiting pathogenic bacteria such as E. coli, Salmonella and others.

In parallel work carried out between the Department of Primary Industries and International Animal  Health  Products, L10 and Bifidobacterium lactis LAFTI strain B94 were shown to be amongst the very best at inhibiting pathogenic bacteria.  The chart below is used by permission from IAHP. The cultures are arranged in order of effectiveness and the interesting thing to note is that a little over one third of the cultures (those marked in green) actually stimulated the bad E. coli and many of those are named "Lactobacillus acidophilus"!