Fiber Intake, Gut Bacteria Metabolites and Risk of Colorectal Cancer

描述(申请人提供)：背景：结直肠癌(CRC)是一个世界性的问题，每年有120万新病例。长期以来，膳食纤维一直被认为在结直肠癌中起到保护作用；然而，纤维预防结直肠癌的机制仍然知之甚少。我们最近发现，人类肠道细菌梭状芽胞杆菌的低丰度与结直肠癌风险的增加有关。梭状芽孢杆菌将难消化的纤维发酵成丁酸盐和其他抗癌的短链脂肪酸代谢物。目前的研究空白是缺乏将这些肠道微生物及其代谢物与结直肠癌联系起来的数据。假设/目的：这项流行病学研究的目标是确定纤维摄入、这些肠道细菌及其代谢产物与结直肠癌风险的相互关系。我们的假设是，梭状芽胞杆菌和其他肠道细菌对特定短链脂肪酸代谢物的纤维发酵可以预防CRC。我们的具体目标是：1)重建人类微生物组和结直肠癌(HMAC)研究人群；2)确定粪便短链脂肪酸代谢物与结直肠癌风险的关系；以及3)确定梭状芽胞杆菌和其他细菌丰度和纤维摄入量与粪便短链脂肪酸代谢物水平的关系。方法：我们将在纽约大学朗格尼医学中心完成300名受试者的招募(150例结直肠癌病例和150例无肿瘤对照)。将收集粪便生物检疫，并使用有效的问卷对纤维摄入量和人口统计信息进行评估。将使用细菌基因测序和LC/MS/GC/MS平台分别在一组样本(50例患者和50名对照)中分析肠道微生物组及其短链脂肪酸代谢物。数据分析将采用多元Logistic和线性回归，并对混杂因素进行控制。意义：在飓风桑迪之前，我们在HMAC研究中最初招募了300名参与者中的100名；然而，由于风暴，我们经历了人员招募人类受试者的时间损失、飞行员数据丢失以及PI实验室的物理搬迁。这个拟议的项目对于重建研究人口基础设施和重建被桑迪破坏的初步数据至关重要。创新：这是第一项以人为基础的研究，检查纤维摄入、特定的肠道微生物区系及其代谢产物与结直肠癌风险的关系。预期结果：我们希望发现高水平的粪便短链脂肪酸与降低结直肠癌的风险相关，并发现与低水平的梭菌携带者相比，高携带者的纤维摄入量和短链脂肪酸水平的关系更强。影响：这项研究将阐明纤维与结直肠癌关系的病因学基础，并为为肠道微生物相关结直肠癌预防提供量身定制的饮食指导提供直接适用的信息。

DESCRIPTION (provided by applicant): Background: Colorectal cancer (CRC) is a worldwide problem, with 1.2 million new cases annually. Dietary fiber has long been thought to play a protective role in CRC; yet the mechanisms by which fiber protects against CRC remain poorly understood. We recently found that low abundance of the human gut bacteria Clostridia is associated with increased risk of CRC. Clostridia ferments indigestible fiber to butyrate and other anti-carcinogenic short chain fatty acid metabolites. The current research gap is a lack of data linking these gut microbes and their metabolites to CRC. Hypothesis/Aims: The goal of this epidemiologic study is to identify inter-relationships of fiber intake, these gut bacteria and thei metabolites with risk of CRC. Our hypothesis is that fiber fermentation to specific short- chain fatty acid metabolites by Clostridia and other gut bacteria prevents CRC. Our specific aims are to 1) reestablish the Human Microbiome and Colorectal Tumor (HMAC) study population; 2) determine the relationship of fecal short chain fatty acid metabolites with risk of CRC; and 3) determine the relationship of Clostridia and other bacterial abundances and fiber intake with fecal short chain fatty acid metabolite levels. Approach: We will complete recruitment of 300 human subjects (150 CRC cases and 150 tumor free controls) at the NYU Langone Medical Center. Fecal biospecimens will be collected and fiber intake and demographic information will be assessed using validated questionnaires. Gut microbiome and their short chain fatty acid metabolites from fecal samples will be assayed using bacterial gene sequencing and LC/MS//GC/MS platforms, respectively, in a subset of samples (50 cases and 50 controls). Data analysis will be by multivariate logistic and linear regression, with control for confounding factors. Significance: Before Hurricane Sandy, we had recruited an initial 100 of 300 planned participants in the HMAC study, however; due to the storm we have experienced loss of staff time for human subject recruitment, loss of pilot data, and physical relocation of the PI's laboratory. This proposed project is critical in reestablishing research population infrastructure and rebuilding preliminary data damaged from Sandy. Innovation: This is the first human based study to examine fiber intake, specific gut microbiota and their metabolites in relation to CRC risk. Expected results: We expect to find that high levels of fecal short chain fatty acids are associated with decreased risk of CRC, and to find that the relationship of fiber intake and short chain fatty acid levels are stronger in high Clostridia carriers, compared to low Clostridia carriers. Impact: This study will clarify the etiologic basis of the fiber-CRC relationship and provide directly applicable information for tailored dietary guidance for gut microbiome-related CRC prevention.