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ORAL BIOLOGY The Mouth's Microbes Could Hold Clues to Early Cancer DetectionApart from our twice-daily brushings, we rarely pay attention to the fabulous world that lies inside the mouth's fleshy cavern. With its enamel gullies and peaks, glistening walls, undulating tongue and tonsils, the mouth is home to a universe of tiny life forms--strange and diverse enough to satisfy any Trekkie or Star Wars fan.
Mouth-dwelling microbes may provide a clue to diseases in other parts of the body. "In some systemic diseases, including HIV, your first opportunity to clinically diagnose is with the oral cavity," said Donna Mager, shown above with Sigmund Socransky. Forsyth colleagues Bruce Paster (left) and Floyd Dewhirst appear below. (Photos by Steve Gilbert)
For a start, the microbes populating the mouth, once thought to be a rather homogeneous lot, are enormously eclectic. Floyd Dewhirst and Bruce Paster, both associate professors in the Harvard-Forsyth Department of Oral Biology, and their colleagues have been conducting a genetic survey of the mouth's microbes and so far have accumulated evidence for 615 bacterial species. What is more, members of these different species--rather than forming a haphazard scatter of individuals, each eking out an existence--band together to form ecological communities. Perhaps most intriguing of all is how these communities appear to change with disease. Sigmund Socransky, HSDM associate clinical professor of oral medicine, infection, and immunity, and colleagues have been exploring these multispecies ecological dwellings in people with periodontal disease and have shown that, structurally, they have more in common with luxury highrises--complete with sturdy superstructure, vertical levels, room service, and communication lines--than tent camps perched precariously on the landscape. The Mouth Speaks, Doctors ListenDonna Mager has been studying the microbial makeup of people with oral cancer and has found changes not just at the site of the lesion--floor, roof, or tongue--but in far-flung, apparently healthy, corners of the mouth. It is not clear whether this shift is a cause or consequence of disease. But the observation that oral lesions are linked to microbial change holds promising clues to a method for early diagnosis."Historically, oral cancer has been one of the more deadly and difficult-to-diagnose cancers," said Mager, a fellow in periodontology at Forsyth and a graduate of the department of oral biology at HSDM. "If we can use a sample from an area of the mouth or a saliva sample at a six-month check-up that says--OK, this microbial profile is an indication that something is wrong, now we need to do a biopsy--we might get people into the proper hands early." Sampling the mouth's microbes could help diagnose a wider variety of patients. Diseases such as periodontitis--which also are associated with microbial change--have recently been linked with illnesses such as cardiovascular disease, stroke, and upper respiratory diseases such as pneumonia. "Many of the pathogenic organisms found in the mouth are likely to be found in infections elsewhere in the body, where they are not easily recoverable," said Dewhirst. Clues Right Under Our NoseThis ecumenical view contrasts sharply with the traditional view of the mouth as a medically secluded kingdom. "Dentistry was a cottage industry for many years," said Mager. "Things were looked at in isolation from the rest of the body." One of the first hints that the mouth might provide as rich and complex an area for microbiological investigation as, say, the gut, came in the 1960s. Socransky and other researchers found an idiosyncratic bacterial species burrowing into the gums of patients with acute necrotizing ulcerative gingivitis, or trench mouth (named for its high prevalence among World War I soldiers).The implication--that specific microbial species might be causing disease--was given a boost when Socransky's colleague Anne Haffajee, now a senior member of the Forsyth Institute staff, discovered that the microbial composition of the plaque in people with periodontitis changed when their disease was treated. To find out which species changed--and more specifically, which might be causing disease--Socransky and colleagues developed a method for assaying the presence or absence of specific bacteria. Using this method, checkerboard DNA-DNA hybridization, they discovered that in contrast to healthy teeth and gums, which display relatively simply structured bacterial communities, diseased tissues support a more complex, multitiered biological structure characteristic of biofilms. Suspecting that the tongue and the fleshy lining of the mouth might also display idiosyncratic patterns, Mager, who worked as a dental hygienist for 25 years before going to dental school, set out to characterize the bacteria of these tissues in healthy mouths and also in people with oral cancer. Are the differences in microbial communities that she observed in cancer patients the cause or consequence of disease? To answer that question, she plans to explore how human habits correlated with oral cancer, such as smoking and drinking alcohol, affect the microbial environment of the mouth. To get a firmer grasp on the question, Paster and Dewhirst have been engaged in a comprehensive census of the oral cavity using the 16 S technique, which targets a conserved patch of DNA found in all bacteria. Over the past 15 years, they have turned up a trove of species, some of which have never been seen. "The whole reason to get this list is because you need to figure out what organisms are there before you truly understand disease," said Paster. A complete list could hold a key not just to new methods of diagnosis but also to new treatments. For example, people with periodontal disease are often prescribed a series of antibiotics, which can lead to even worse disease. By pinpointing which organisms are actually the disease culprits, more effective antibiotic strategies might be designed--ones that will encourage repopulation by healthy species rather than drug-resistant ones. Still, there will be challenges, said Socransky: "The question here is how do you change a mixed microbial community to one you want. We need to find ways to set up microbiota that are healthy." --Misia Landau |
Over the past few decades, a group of Forsyth Institute researchers has been quietly exploring this realm, meticulously collecting and cataloguing its microbial inhabitants. Wielding high-tech equipment, they have made a series of surprising discoveries that could lead to new methods for diagnosing, and possibly treating, oral cancers and other diseases.