Elusive microbe fingered as culprit in gum disease

Stanford Report, April 28, 2004

Elusive microbe fingered as culprit in gum disease
Though unfamiliar, archaea are just about everywhere

By MITZI BAKER

Even biology majors may not have heard much about archaea. Along with bacteria and eukarya (which encompass every organism from fungi to mammals), the elusive microbes make up one of the three domains of life. Now researchers at the School of Medicine have for the first time tied a specific disease to one of these unfamiliar organisms.

"It's not surprising that no one has really heard about them; archaea have still not even penetrated mainstream biology textbooks," said David Relman, MD, associate professor of medicine (infectious diseases) and of microbiology and immunology. There are, however, at least as many of them as there are bacteria, he said.

Archaea look a lot like bacteria, but appearances can be deceiving. Genetically and biochemically they are as different from bacteria as bacteria are from humans. The microbes live in many extreme environments -- from hot springs to salt lakes to submarine volcanoes -- but also within animals, including the human colon, vagina and mouth.

"To me it is one of those fundamental puzzles: They are everywhere and, given that we must be exposed to them somewhat frequently, if not all the time, why is it that we can't name one disease-causing member of this enormous domain?" Relman wondered.

He and his group at the Veterans Affairs Palo Alto Health Care System have shown a never-before-known connection between the abundance of archaea and the severity of a human gum disease called periodontitis.

Chronic periodontitis, which affects about one-third of Americans, may result in tooth loss and is thought to play a role in a range of conditions including atherosclerosis, stroke and early delivery of low birth-weight infants. It results when gingivitis, a milder form of inflammation and infection of the gums, progresses to the ligaments and bone that support the teeth. While there is a general consensus that bacteria play a role in these diseases, no single microbe has been implicated as the culprit.

Relman and members of his lab embarked on a comprehensive, controlled study of the archaea found in the subgingival crevice -- the deep gap between the gums and teeth -- where periodontitis begins.

They rigorously analyzed samples from 58 patients' mouths taken by their collaborator, Gary Armitage, DDS, at the UC-San Francisco School of Dentistry, and found that more than one-third of the periodontitis patients had archaea in their diseased subgingival spaces, but nowhere else in their mouths.

In addition, the relative abundance of archaea correlated with disease severity. Their findings were published in last week's issue of the Proceedings of the National Academy of Sciences.

"Of course we'd ultimately like to say archaea caused disease, but it's a horse-and-cart problem right now because we haven't shown that the archaea come before the disease," Relman said.

In the future, he noted, they will collect specimens repeatedly from the same spot in the subgingival pocket in hope of being able to pinpoint the moment when the archaea start to increase in number and then determine whether that predicts the later development of the disease.

The paper's first author, Paul Lepp, PhD, research associate in microbiology and immunology, explained that while a third of the periodontitis sufferers harbored archaea, many of the others had high levels of bacteria that -- like archaea -- consume hydrogen. Hydrogen consumption creates a more hospitable environment for bacteria long known to play a role in gum disease.

The group speculates that archaea may not directly cause periodontal disease. Rather, the microbes may indirectly contribute to it by helping other organisms -- in this case, gum-damaging bacteria -- grow more productively. Lepp said they are now looking for other hydrogen consumers to test their theory.
"In my mind, it's increasingly clear that the disease may be the result of a community disturbance rather than the presence or absence of a particular organism," Relman said.

Relman also sees a potentially broader side to this research. "Maybe we should look a little harder for evidence of archaea as promoting or causing other diseases. We certainly have them in our bodies and we are exposed to them, so the archaea have the opportunity to cause disease if they are capable of doing so. We haven't been looking for them so we wouldn't know."

Other Stanford researchers involved in this study include graduate student Mary Brinig and postdoctoral scholar Cleber Ouverney, PhD, in microbiology and immunology, and research assistant Katherine Palm in the division of infectious diseases and geographic medicine.

This study was funded by a grant from the National Institute of Dental and Craniofacial Research, one of the National Institutes of Health, along with grants from the Ellison Medical Foundation and the University Exploratory Research Program of Procter & Gamble.

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