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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZDE1-RW (22))
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Rodriguez-Chavez, Isaac R
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University of Connecticut
Schools of Dentistry
United States
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Abusleme, Loreto; Diaz, Patricia I; Freeman, Alexandra F et al. (2018) Human defects in STAT3 promote oral mucosal fungal and bacterial dysbiosis. JCI Insight 3:
Van Dyke, T E; Diaz, P I; Moutsopoulos, N et al. (2018) Task Force on Design and Analysis in Oral Health Research: Host-Microbiome Interactions in Dysbiosis. JDR Clin Trans Res 3:6-9
Abusleme, Loreto; Hong, Bo-Young; Hoare, Anilei et al. (2017) Oral Microbiome Characterization in Murine Models. Bio Protoc 7:
Diaz, Patricia I; Hong, Bo-Young; Dupuy, Amanda K et al. (2017) Mining the oral mycobiome: Methods, components, and meaning. Virulence 8:313-323
Hoare, Anilei; Marsh, Philip D; Diaz, Patricia I (2017) Ecological Therapeutic Opportunities for Oral Diseases. Microbiol Spectr 5:
Diaz, Patricia I; Hoare, Anilei; Hong, Bo-Young (2016) Subgingival Microbiome Shifts and Community Dynamics in Periodontal Diseases. J Calif Dent Assoc 44:421-35
Peterson, D E; Srivastava, R; Lalla, R V (2015) Oral mucosal injury in oncology patients: perspectives on maturation of a field. Oral Dis 21:133-41
Abusleme, Loreto; Hong, Bo-Young; Dupuy, Amanda K et al. (2014) Influence of DNA extraction on oral microbial profiles obtained via 16S rRNA gene sequencing. J Oral Microbiol 6:
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
Dupuy, Amanda K; David, Marika S; Li, Lu et al. (2014) Redefining the human oral mycobiome with improved practices in amplicon-based taxonomy: discovery of Malassezia as a prominent commensal. PLoS One 9:e90899

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