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

描述（由申请人提供）：口腔粘膜损伤（“粘膜炎”）是细胞毒性癌症治疗的常见并发症，包括口腔粘膜中的疼痛、衰弱性病变，影响患者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生物体的全身性传播的发生率很高，但关于细胞毒性癌症治疗对口腔微生物群落的影响的信息很少。因此，该项目的总体目标是研究化疗对口腔微生物菌群的影响，并确定口腔微生物组与口腔粘膜炎的临床体征和分子特征之间可能存在的关联。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已知对口腔粘膜炎具有可变易感性的患者人群中化疗过程中的细菌和真菌口腔微生物组，并与健康对照组进行比较。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的多样性和结构的变化。第三，我们将通过基因表达微阵列研究口腔粘膜对化疗的反应，以确定表征口腔粘膜炎的主要上皮细胞途径，并评估它们与真菌和细菌微生物组的关系。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/或化疗诱导的口腔微生物组变化与口腔粘膜炎结局相关。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：在化疗过程中口腔微生物区系是否发生变化，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是否与粘膜炎的发病率和/或严重程度相关？微生物组多样性或结构的变化是否与口腔环境中中性粒细胞功能和可用性的降低有关？口腔粘膜炎是否有特定的粘膜基因表达特征？这些粘膜特征是否与特定的微生物组相关？通过回答这些问题，我们希望提高对口腔粘膜炎病理生物学的理解，这反过来又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。 公共卫生相关性：该项目将提高我们对肿瘤治疗的口服副作用的理解。研究结果将使我们能够制定全面的预防方法，以改善患者的福祉和癌症治疗结果。

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.