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The Role of Uncultivable Bacteria in the Oral Microbiota

Microbiology Program
Integrative Biology and Infectious Diseases Branch
Division of Extramural Research


To increase our knowledge of the role that uncultivable bacterial species play in the microbial ecology of the human oral microbiota.

Research projects under this initiative will address the following objectives:

  • To integrate and optimize recent technological advances (state-of-the-art molecular labeling, biofilm imaging and metabolomic analysis technologies) in biofilm modeling and culture systems to enable high through-put analysis of oral biofilm communities in vitro under long-term culture conditions that mimic conditions in the oral cavity. Several variables could be examined to include varying population complexity (using both cultivable and uncultivable species in multiple combinations and densities) and variations in nutrient availability.
  • To configure mock communities composed of various combinations of known cultivable species present during conditions of either general oral health or known pathological states together with newly identified uncultivable species in order to understand metabolic and molecular interactions (metabolic cooperation, cell-cell signaling, etc.) required for maintenance of the uncultivable species and to determine their overall role in the composition and resilience of the oral microbiota.
  • To foster collaborative team science. Since the objectives of this initiative cover a broad range of technologies (classical metagenomics, biofilm modeling and imaging, metabolomics, domestication and handling of fastidious organisms, etc.), applicants would be strongly encouraged to configure research teams capable of covering the breadth of required technologies and expertise.


It is estimated that the human oral microbiota consists of over 600 individual taxa with ~200 being formally named species and only ~100 representing laboratory-cultivable strains. This lack of cultivability of many members of the population represents an enormous diversity of organisms about which we still know very little,  This is particularly true with regard to the molecular and metabolic interactions that occur between species and their host or the role uncultivable species may play in disease initiation or progression. Although single bacterial species can be used to validate Koch’s postulates and replicate specific oral diseases in carefully controlled model systems (e.g., gnotobiotic rodent models of caries with Streptococcus mutans and a cariogenic diet), human oral diseases are more complex and generally are recognized as being polymicrobial in origin. Periodontitis is recognized as an ecological disease. The so-called “red complex” of organisms seen in destructive periodontitis presents as a “pathogenic consortium” comprised of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia growing as a complex biofilm. While these organisms produce a myriad of virulence factors and induce a destructive inflammatory host response, much remains to be determined with regard to their role in disease initiation, progression, or their potential role in the maintenance of dental health. For example, in addition to severe periodontitis, P. gingivalis often is present in subgingival plaque and can colonize the oral epithelium without harm. Today the microbial etiology of periodontal disease remains as an association and the argument could be made that many organisms are present in lesions as a result of a late inflammatory process initiated by other host and/or unknown microbial factors such as the commensal flora and complement. What role the uncultivable species play in these processes is equally enigmatic.

The NIDCR has a rich legacy of supporting research that has examined the composition of the oral microbiota and the role this diverse microbial community plays in the initiation and progression of caries and periodontitis. In addition, the NIDCR co-led the NIH Roadmap Human Microbiome Project (HMP) and the oral cavity was one of five anatomical sites examined for microbial content in healthy humans. Together with the Human Oral Microbiome Database (HOMD), we are poised to utilize these datasets and move to the next level of investigation; that is, examining the role of the uncultivable members of the oral microbiota in mock communities under long-term culture conditions in order to provide insights into polymicrobial interactions potentially leading to the development of novel strategies for the prevention, diagnosis and treatment of polymicrobial oral diseases.

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This page last updated: April 11, 2014