Gut Microbiome Profiles and Risk of Colorectal Cancer

描述（由申请人提供）：我们的假设是肠道微生物组特征与结直肠癌风险相关。改变的肠道微生物组可能通过诱导慢性炎症促进结直肠癌发生。此外，肠道微生物群可能通过代谢食物成分（例如致癌杂环胺）与CRC风险有关。然而，过去对微生物植物群和结直肠癌的研究仅限于动物模型和小型人体研究，两者都只考虑了选定数量的可培养微生物物种。据我们所知，没有流行病学研究使用基于基因序列的方法全面评估人类肠道微生物组与结直肠癌风险的关系。我们提出了一项创新研究，以全面检查病例对照研究（69例病例和114例对照）中肠道微生物组谱与结直肠癌风险之间的关系，在NCI收集的研究样本中，在开始任何治疗之前获得先前收集和冻干的粪便生物标本，并提供相关的人口统计学和临床信息（Schiffman MH et al，Cancer Research，1989）。我们将通过16S rRNA微生物基因测序，全面调查粪便生物标本中常见的肠道微生物菌种（包括不可培养物）。我们将1）定义对照组中的正常肠道微生物组，2）检查结直肠癌病例和对照组之间的肠道微生物组是否不同。作为次要目的，我们将评估个体内变异性（在研究招募时和6个月后从对照组随机选择的20名个体的子集中收集的肠道微生物组谱的时间稳定性）。该项目是及时和高度相关的， NIH路线图和NIH人类微生物组项目（HMP）的目标。首次对肠道微生物组进行全面评估的结果将确定结直肠癌相关的肠道细菌谱，并提高我们对这种疾病病因的理解。了解R03拨款中微生物组概况的时间稳定性将为后续R01申请奠定基础，提出通过粪便生物标本采集进行大规模前瞻性评估。考虑到结直肠癌作为美国癌症死亡的第二大原因的重大公共卫生负担，以及微生物组在其因果关系中的潜在重要性，非常需要拟议的R03研究。

DESCRIPTION (provided by applicant): Our hypothesis is that gut microbiome profiles are associated with risk of colorectal cancer. Altered gut microbiome may promote colorectal carcinogenesis by inducing chronic inflammation. Also, gut microbiota may be related to CRC risk by metabolizing food components, such as carcinogenic heterocyclic amines. However, past studies of microbial flora and colorectal cancer are limited to animal models and small human studies, both considering only a selected number of culturable microbial species. To our knowledge, no epidemiologic study has comprehensively evaluated the relationship of the human gut microbiome to risk of colorectal cancer using gene sequence-based approach. We propose an innovative study to comprehensively examine the relationship between gut microbiome profile and colorectal cancer risk in a case-control study (69 cases and 114 controls), with previously collected and lyophilized fecal biospecimens obtained before initiation of any treatment, in study samples collected by NCI with associated demographic and clinical information (Schiffman MH et al, Cancer Research, 1989). We will comprehensively survey common gut microbial species (including non-culturables) from fecal biospecimens by sequencing of the 16S rRNA microbial genes. We will 1) define the normal gut microbiome in the control group, and 2) examine if the gut microbiome differs between colorectal cancer cases and controls. As a secondary aim, we will evaluate intra-individual variability (temporal stability of gut microbiome profile collected at study recruitment and after 6 months in a subset of 20 randomly selected individuals from the control group. This project is timely and highly relevant to the goals of the NIH Roadmap and the NIH Human Microbiome Project (HMP). Results from this first comprehensive evaluation of the gut microbiome will identify colorectal cancer-related gut bacterial profiles and improve our understanding of the etiology of this disease. Understanding the temporal stability of the microbiome profile in this R03 grant will lay the foundation for subsequent R01 applications, proposing large-scale prospective evaluation with fecal biospecimen collection. Considering the significant public health burden of colorectal cancer as the second leading cause of cancer death in the US, and the potential importance of the microbiome in its causation, there is great need for the proposed R03 study.