Oral mucosal injury ("mucositis") s a common complication of cytotoxic cancer therapies consisting of painful, debilitating lesions in the oral mucosa that impact patient well-being and cancer treatment outcomes. While the cancer treatment regimen is the triggering event for development of the lesions, it is likely that the complex microbiota associated with oral mucosal surfaces affects the course and/or severity of mucositis. Furthermore, little information is available on the effects of cytotoxic cancer therapy on the oral microflora despite the high incidence of bacterial and fungal oral infections and systemic dissemination of intraoral organisms during oncologic treatment. Thus, the overall aims of this project are to investigate the effects of chemotherapy on the oral microflora and to identify a possible association between the oral microbiome and the clinical signs and molecular signatures of oral mucositis. To accomplish these goals we will conduct a prospective clinical study in which we will first characterize via amplicon-based pyrosequencing the bacterial and fungal oral microbiomes during the course of chemotherapy in a population of patients known to present variable susceptibility to oral mucositis and in comparison to healthy controls. Secondly, we will evaluate oral neutrophil presence and function in order to determine whether suppression of the local innate immune response contributes to shifts in the diversity and structure of the oral microbiome during chemotherapy. Thirdly, we will investigate via gene expression microarrays the oral mucosa response to chemotherapy in order to identify the major epithelial cellular pathways that characterize oral mucositis and evaluate their relationship with the fungal and bacterial microbiome. Since microorganisms could be an important contributing factor in the inflammatory cascades that lead to tissue destruction, we hypothesize that subject variability and/or chemotherapy-induced changes in the oral microbiome are associated with oral mucositis outcomes. We also hypothesize that qualitative and/or quantitative changes in the microbiome during the course of chemotherapy are inversely related to neutrophil presence and activity in the oral environment. Thirdly, we hypothesize that specific microbial taxa are associated with shifts in epithelial gene expression during chemotherapy. We expect to answer the following questions: Does the oral microflora change during the course of chemotherapy, and do these changes precede or follow the occurrence of mucositis? Are inter-individual differences in the oral microbiome associated with the incidence and/or severity of mucositis? Are changes in the microbiome diversity or structure associated with diminished neutrophil function and availability in the oral environment? Are there specific mucosal gene expression signatures characteristic of oral mucositis? Are these mucosal signatures associated with a specific microbiome? By answering these questions we expect to improve the understanding of the pathobiology of oral mucositis, which could in turn lead to the development of multi- factorial models of risk assessment and provide the foundation for novel multi-pronged preventive strategies.

Public Health Relevance

This project will improve our understanding of the oral side effects of oncologic therapy. The results will allow us to develop comprehensive preventive approaches to improve the well-being of patients and cancer treatment outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE021578-03
Application #
8301490
Study Section
Special Emphasis Panel (ZDE1-RW (22))
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2010-09-13
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$803,123
Indirect Cost
$157,378
Name
University of Connecticut
Department
Dentistry
Type
Schools of Dentistry
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Jensen, Siri B; Peterson, Douglas E (2014) Oral mucosal injury caused by cancer therapies: current management and new frontiers in research. J Oral Pathol Med 43:81-90
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Diaz, Patricia I; Strausbaugh, Linda D; Dongari-Bagtzoglou, Anna (2014) Fungal-bacterial interactions and their relevance to oral health: linking the clinic and the bench. Front Cell Infect Microbiol 4:101
Diaz, Patricia I; Hong, Bo-Young; Frias-Lopez, Jorge et al. (2013) Transplantation-associated long-term immunosuppression promotes oral colonization by potentially opportunistic pathogens without impacting other members of the salivary bacteriome. Clin Vaccine Immunol 20:920-30
Diaz, P I; Dupuy, A K; Abusleme, L et al. (2012) Using high throughput sequencing to explore the biodiversity in oral bacterial communities. Mol Oral Microbiol 27:182-201