Prospective Study of Human Oral Microbiome and Pancreatic Cancer Risk

描述（由申请人提供）：我们发现口腔健康状况不佳与胰腺癌风险增加有关。由于口腔细菌生态失调是口腔健康状况不佳的原因，我们推测口腔微生物群可能会促进胰腺癌的发生。支持这一点，最近的队列研究报告说，对多种口腔细菌的循环抗体较高的个体患胰腺癌的风险更高。在我们最近的病例对照研究中，通过对口腔样本的高通量基因组测序直接评估口腔微生物组，我们发现特异性革兰氏阴性口腔细菌与胰腺癌风险增加3倍相关。我们还证明了这些细菌存在于人类胰管中，并在动物实验中表明，口腔微生物群进入胰腺并通过器官部位的炎症产生致癌作用。由于病例对照研究在因果推理方面受到限制，目前一个关键的研究空白是缺乏对诊断前口腔微生物组与胰腺癌风险之间联系的前瞻性确认。第二个研究缺口是对微生物群和人类宿主反应的综合功能作用的有限理解。本研究的总体目标是确定与胰腺癌后续风险相关的口腔微生物群，并提高我们对微生物群在可能与胰腺肿瘤发生相关的宿主反应中的作用的理解。我们的具体目标是：1)在巢式病例对照研究中测试口腔微生物组是否与随后的胰腺癌风险相关；2)确定人类胰腺中代谢活跃的细菌功能，并将这些细菌活动与人类炎症信号通路的表达联系起来。本研究的优势包括大型前瞻性研究设计，在癌症发展之前收集口腔样本，以及用于评估口腔和胰腺微生物群及其相关功能的最先进的基因组微生物组和转录组分析。这项研究是首次对口腔和胰腺微生物组与胰腺癌风险的研究。胰腺癌是一种高度致命的疾病，人们对这种疾病的检测和预防方法知之甚少。我们希望鉴定与胰腺癌风险相关的特定口腔细菌，并鉴定胰腺代谢活性细菌功能和相关宿主胰腺炎症反应。这些结果将扩大我们目前对胰腺癌病因的有限了解，将有助于确定胰腺癌的高危人群，并可能导致基于微生物的胰腺癌预防性预防。因此，这些发现可能有助于迅速提高我们减轻这种高度致命疾病负担的能力。

DESCRIPTION (provided by applicant): We found that poor oral health status is associated with increased risk of pancreatic cancer. Because poor oral health status is due to oral bacterial dysbiosis, we hypothesize that oral microbiota potentiate pancreas carcinogenesis. Supporting this, recent cohort studies reported that individuals with greater circulating antibodies to multipe oral bacteria have a greater risk of pancreatic cancer. Directly assessing oral microbiome from high-throughput genomic sequencing of oral samples in our recent case-control study, we found that specific gram-negative oral bacteria are associated with 3-fold increased risk of pancreatic cancer. We also showed that these bacteria are present in the human pancreatic duct and showed in animal experiments that oral microbiota access the pancreas and have oncogenic effects via inflammation at the organ site. Because case-control studies are limited for causal inference, a current critical research gap is the lack of prospective confirmation of the link between pre-diagnostic oral microbiome and pancreatic cancer risk. A second research gap is the limited understanding of the comprehensive functional roles of the microbiota and the human host response. The overarching goals of this study are to identify oral microbiota associated with subsequent risk of pancreas cancer and to improve our understanding of the role of the microbiome in host responses potentially related to pancreatic tumorigenesis. Our specific aims are: 1) to test whether oral microbiome is associated with subsequent risk of pancreatic cancer in a nested case-control study and 2) to identify metabolically active bacterial function in the human pancreas and correlate these bacterial activities with expression of human inflammatory signaling pathways. Strengths of this study include a large prospective study design, with oral samples collected prior to cancer development, and state-of-art genomic microbiome and transcriptome assays for assessing oral and pancreas microbiota and related functions. This study is the first study of oral and pancreas microbiome and pancreatic cancer risk. Pancreatic cancer is highly lethal and little is known about ways to detect and prevent this disease. We expect to identify specific oral bacteria associated with risk of pancreas cancer and to identify metabolically active bacterial functions in the pancreas and related host pancreatic inflammatory responses. These outcomes will expand our current limited knowledge on the causes of pancreatic cancer, will help to identify people at high risk for this disease, and may lead to microbial-based prophylactic preventions for pancreatic cancer. Thus, findings may help to rapidly advance our ability to reduce the burden of this highly fatal disease.