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Metagenomic Evaluation of Oral Polymicrobial Disease

Microbiology Program, and AIDS and Immunosuppression Program
Integrative Biology and Infectious Diseases Branch, DER


OBJECTIVE

This initiative seeks to stimulate innovative research that will increase our knowledge of the role that polymicrobial communities, those specifically composed of archaea, bacteria, and fungi, play in the initiation and progression of oral diseases through metagenomic technologies. Specific research areas will include studies to: (1) understand the role of uncultivable species in oral infections and inflammation as well as their potential contributions to oral health; (2) investigate the role of microbial consortia in the initiation and progression of diseases such as periodontitis, caries, or other oral conditions suspected of having a microbial etiology including endodontic and restoration failures; (3) examine secondary oral manifestations of microbial origin due to malignancy, acute and chronic HIV infection, and immunosuppressive states due to AIDS, transplantation, chemotherapy, radiotherapy, aging, or other chronic conditions affecting the oral cavity; and (4), examine the role of the oral microbiota in respiratory infections acquired during critical-care scenarios such as aspiration pneumonia or ventilator-associated infections particularly if those studies could provide diagnostic, predictive, or preventative options for the clinician. Studies will concentrate on investigating variations in microbial populations between individuals without disease, in the early stages of disease, with differing degrees of disease severity, both pre- and post treatment, and examine how these differences might be utilized for guiding treatment options, predicting clinical outcomes, or leading to the discovery and development of novel prophylactic strategies and treatment modalities.

Research projects will address the following objectives:

  • Identify an oral microbial study system suitable for examining the relationship between a specific microbiota and a specific disease state as well as a clearly defined state of health for control subjects in the study population. Particular attention will be directed to disease initiation events. Study systems will be limited to an examination of archaea, bacteria, and fungi only.
  • Use high-throughput and cost-effective sequencing and metagenomic analytic technologies to study the oral microbiome under the specified conditions. This will include deep rRNA gene sequencing and metagenomic shot-gun sequencing capable of characterizing the composition of the microbiota at the site of investigation and providing assessments of numbers and types of microorganisms and the physiological relevance of the uncultivable species to the disease state or state of normal health.
  • Develop a cohesive data analysis and management plan that will provide a robust assessment of the study data particularly with regard to determining disease heterogeneity among individuals and populations, strategies for guiding treatment options, predicting clinical outcomes, or advancing new treatments and/or diagnostic options.

Due to current technical constraints in metagenomic methodologies for viral genomes, this initiative will not consider the viral component of the oral microbiome at this time. Likewise, studies examining the role of oral microbes in extra-oral conditions outside of the oral/respiratory tract or the potential of oral microbes to contribute to inflammatory sequelae affecting other organ systems (e.g., pre-term birth, low birth weight deliveries, or various cardiovascular diseases) will not be included nor will animal models of oral infectious diseases, general microbial ecology, or metagenomic studies directed at examining the primate oral microbiota.

BACKGROUND

It is estimated that the human oral microbiota consists of over 700 individual taxa with ~200 being formally named species and only ~100 representing laboratory-cultivable strains. This represents an enormous diversity of organisms for which we still know very little particularly 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. Human periodontitis is recognized as an ecological disease. The so-called “red complex” of organisms seen in destructive periodontitis appears to be a “pathogenic consortium” of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia present 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 the role of microbes in disease initiation, progression, or their potential role in the maintenance of dental health. For example, P. gingivalis often is present in subgingival plaque and can colonize the oral epithelium without harm. Today the microbial etiology of periodontal disease in humans remains as an association and the argument could be made that many organisms are present in lesions as a result of an inflammatory process initiated by other host and/or unknown microbial factors.  More work is needed to address the factors affecting disease initiation and what role, if any, less well-characterized or uncultivable microbes may play in the process. 

Similarly, a limited number of studies have shown that the composition of the oral microbiota is dynamically altered during HIV infection.  It is well established that treatment of HIV/AIDS patients with antimicrobial agents leads to alterations in the type and number of microorganisms colonizing the host.  In addition, it has also been shown that widespread use of antiretroviral therapy (ART) results in a significant decrease in the incidence of opportunistic enteric pathogens, suggesting that ART influences the gut microbiome.  Yet, a critical gap exists regarding the oral microbiota in triggering oral disease in HIV/AIDS individuals.  Therefore, studies are necessary to better understand the potential role of the oral microflora and its variation in the exacerbation of AIDS-related oral manifestations and malignancies. 

The NIDCR has a rich legacy of supporting research that has examined the oral microbiota and the role this diverse microbial community plays in the initiation and progression of caries and periodontitis. NIDCR co-leads the NIH Roadmap Human Microbiome Project (HMP) of which the oral cavity is but one of five anatomical sites being examined for microbial content. In the jump-start phase of the project, the HMP is a survey exercise aimed at cataloging the site-specific microbiota of a small population of healthy individuals from two geographic locations in the US (Houston and St. Louis). NIDCR also has been directing the oral component of the HMP “Reference Set” of bacteria that will be an essential tool for any future metagenomic studies of the oral cavity. The secondary or “Demonstration Project” phase of the HMP is just beginning and involves investigator initiated projects examining changes in the microbiota associated with diseases at various body sites. None of the demonstration projects specifically address the oral microbiota.

Investigator-initiated metagenomic projects or those specifically submitted under a current NIDCR program announcement, PA-08-090 (Metagenomic Analyses of the Oral Microbiome [R01]), have been sporadic and have not comprehensively addressed disease outcomes or treatment stratification particularly for immunocompromised individuals. In order to expand the portfolio of metagenomic projects entering NIDCR programs, dedicated funding will be required to heighten attention to this institute priority and expand the pool of potential applicants.

Taken together, this initiative will complement effort seeded by the HMP, expand the NIDCR portfolio, and capture research opportunities to provide insights to polymicrobial interactions leading to the pathogenesis of oral diseases, and the development of novel strategies for the prevention, diagnosis and treatment of polymicrobial oral diseases.

 

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This page last updated: February 26, 2014