The oral microbiome during cancer chemotherapy and its role in oral mucositis

口腔黏膜损伤（“粘膜炎”）是细胞毒性癌症治疗的常见并发症，包括口腔黏膜疼痛，使人衰弱的病变，影响患者的健康和癌症治疗结果。虽然癌症治疗方案是病变发展的触发事件，但与口腔粘膜表面相关的复杂微生物群可能影响粘膜炎的病程和/或严重程度。此外，尽管在肿瘤治疗期间细菌和真菌口腔感染以及口腔内有机体的全身传播的发生率很高，但关于细胞毒性癌症治疗对口腔微生物群的影响的信息很少。因此，该项目的总体目标是研究化疗对口腔微生物群的影响，并确定口腔微生物群与口腔黏膜炎的临床体征和分子特征之间可能存在的联系。为了实现这些目标，我们将进行一项前瞻性临床研究，在该研究中，我们将首先通过基于扩增子的焦磷酸测序来表征化疗过程中已知对口腔黏膜炎具有可变易感性的患者群体中的细菌和真菌口腔微生物组，并与健康对照进行比较。其次，我们将评估口腔中性粒细胞的存在和功能，以确定局部先天免疫反应的抑制是否有助于化疗期间口腔微生物组多样性和结构的改变。第三，我们将通过基因表达微阵列研究口腔黏膜对化疗的反应，以确定表征口腔黏膜炎的主要上皮细胞通路，并评估它们与真菌和细菌微生物群的关系。由于微生物可能是导致组织破坏的炎症级联反应的重要促成因素，我们假设受试者变异性和/或化疗引起的口腔微生物组变化与口腔黏膜炎的结果有关。我们还假设化疗过程中微生物组的定性和/或定量变化与口腔环境中中性粒细胞的存在和活性呈负相关。第三，我们假设特定的微生物分类群与化疗期间上皮基因表达的变化有关。我们希望回答以下问题：口腔菌群在化疗过程中是否发生变化，这些变化是在粘膜炎发生之前还是之后？口腔微生物组的个体间差异与粘膜炎的发生率和/或严重程度有关吗？口腔环境中微生物群多样性或结构的变化是否与中性粒细胞功能和可利用性的降低有关？口腔黏膜炎是否存在特异性的粘膜基因表达特征？这些粘膜特征是否与特定的微生物群有关？通过回答这些问题，我们期望提高对口腔粘膜炎病理生物学的理解，这反过来可能导致风险评估的多因素模型的发展，并为新的多管齐下的预防策略提供基础。

DESCRIPTION (provided by applicant): 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.