Mouth microbes have been implicated in a variety of ills, from arthritis to Alzheimer’s
BY
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.
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.
Story continues after graphic
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.
Trepemona
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.
Story continues after table
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.