Diet modulation of bacterial sulfur & bile acid metabolism and colon cancer risk

细菌硫的饮食调节

基本信息

批准号：
9751249
负责人：
Rex Gaskins
金额：
$ 30.67万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-24 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751249
关键词：
Adenomatous Polyps Affect African African American Anaerobic Bacteria Animal Model Animals Bacteria Bacterial Genes Bile Acids Bile fluid Biliary Bilophila Bilophila wadsworthia Biological Biological Markers Blood Circulation Cancer Burden Cancer Control Cancer Etiology Cancer Prevention Intervention Carcinogens Cessation of life Cholic Acids Clostridium Collection Colon Colon Carcinoma Colorectal Cancer Consumption Crossover Design DNA Damage DNA Repair Pathway Data Deoxycholic Acid Development Diet Dietary Intervention Dietary intake Diffusion Environment Epithelial Epithelial Cells Ethnic group Exhibits Fatty acid glycerol esters Feces Fiber Free Radicals Gallbladder Genomic Instability Glycine Growth Human Hydrogen Sulfide Hydrolase Incidence Inflammation Inflammatory Intervention Studies Intervention Trial Intestines Lipids Literature Liver Mammalian Cell Measures Meat Mediating Mediation Mediator of activation protein Membrane Metabolic Metabolism Modeling Mucous Membrane Mutagens Names Not Hispanic or Latino Nutrient Outcome Oxidative Stress Pathway interactions Plants Population Production Proteins Publishing Race Randomized Research Research Design Respiration Risk Role Serum Signal Pathway Small Intestines Source Study models Sulfides Sulfites Sulfur Sulfur Amino Acids Sulfuric Acids Taurine Taurine Cholate Taurocholic Acid Testing Tumor Promoters United States Water Woman Work absorption bacterial metabolism base bile salts cancer risk colon bacteria colon cancer patients colon cancer risk colon carcinogenesis colon microbiota colorectal cancer risk cytokine epidemiology study feeding genotoxicity gut bacteria human subject ileum innovation men microbial microbiome composition microbiota mortality novel prospective public health relevance racial and ethnic racial difference saturated fat

项目摘要

DESCRIPTION (provided by applicant): Proposed are innovative studies designed to investigate the biological basis of the increased risk for the development of colorectal cancer (CRC) independently associated with being African American (AA) or consuming a diet high in red meat and saturated fat. We hypothesize that the primary bile salt taurocholic acid (TCA) is a key diet-controlled metabolite whose use by the bacteria Bilophila wadsworthia and Clostridium scindens yields a carcinogen and tumor-promoter, respectively. The work is motivated by our extensive collection of published data indicating H2S and secondary bile acid production by colonic bacteria serve as key environment insults contributing to CRC risk. First we will examine differences between at-risk AAs and non-Hispanic whites (NHWs) in mucosal abundance of bacterial genes associated with sulfur and bile acid metabolism, markers of bile metabolism in serum and stool, and colonic inflammation. Rationale is provided by our intriguing observation that mucosal abundance of a bacterium (B. wadsworthia) that uses the sulfur amino acid taurine, which is abundant in red meat, is a strong predictor of CRC in AA but not NHW subjects. Bacterial deconjugation of the bile acid taurocholate provides another source of taurine, and once deconjugated, free primary bile acids are further metabolized by colonic bacteria to genotoxic and proinflammatory secondary bile acids. We will then test the hypothesis that a diet high in animal protein and saturated fat creates a metabolic milieu in the colon that promotes risk for CRC in at-risk AAs by increasing the abundance and activity of bacteria that generate genotoxic sulfide and secondary bile acids. Rationale for focusing the diet intervention on AAs comes from the observation regarding a taurine respiring bacterium distinguishing AA but not NHW CRC patients from healthy controls and our prior work in AAs that focused on mechanisms underlying the increased risk for CRC associated with consumption of a Western type diet. We will conduct a prospective randomized crossover feeding trial that examines two microbial mechanisms by which an animal-based diet may support the growth of bacteria that generate the genotoxic and proinflammatory end products, H2S and secondary bile acids, through the metabolism of TCA. An animal- based diet rich in taurine and saturated fat will be compared with a plant-based diet low in taurine and saturated fat. Subjects will receive each of the two diets in a crossover design thereby serving as their own control. A mediation model will be used to determine the extent to which the relationship between diet [independent variable] and mucosal markers of CRC risk and DNA damage [dependent variables] is explained by colonic bacteria and their functions [mediator variables]. This research will generate novel information on a mechanistically targeted nutrient aimed to develop effective cancer prevention interventions based simply on diet that may contribute to a reduction in the unequal CRC burden in AAs.

描述（由申请人提供）：拟议的是创新研究，旨在研究与非洲裔美国人（AA）独立相关的结直肠癌（CRC）风险增加的生物学基础，或消耗含红肉和饱和脂肪的饮食。我们假设原发性胆汁盐牛胆胆酸（TCA）是一种关键的饮食控制代谢产物，可分别由bilophila bilophila wadsworthia和梭状芽胞杆菌的使用，分别产生致癌物和肿瘤促进剂。这项工作是由我们广泛的已发表数据收集的，该数据表明H2S和结肠细菌的二级胆汁酸的产生是有助于CRC风险的关键环境。首先，我们将研究与硫和胆汁酸代谢相关的细菌基因的粘膜丰度，血清和粪便中胆汁代谢的标志物以及结肠炎的细菌基因的差异。我们有趣的观察结果提供了理由，即使用硫氨基酸牛磺酸的粘膜丰度（B. wadsworthia）（在红肉中丰富）是AA中CRC的强烈预测指标，但不是NHW受试者。胆汁牛胆酸盐的细菌解偶联提供了另一种牛磺酸来源，一旦被结肠细菌进行了解共轭，自由的原代胆汁酸，将其进一步代谢，以遗传毒性和促炎性胆汁酸。然后，我们将检验以下假设：含有动物蛋白和饱和脂肪的饮食在结肠中产生代谢环境，该饮食通过增加细菌的丰度和活性来促进CRC的风险，从而产生遗传毒性硫化物和继发性胆汁酸。将饮食干预集中在AAS上的基本原理来自于牛磺酸呼吸细菌区分AA的观察结果，而不是NHW CRC患者与健康对照组以及我们先前在AAS中的工作，该研究侧重于与西方饮食消耗相关的CRC风险增加的机制。我们将进行一项前瞻性随机跨疗法试验，该试验检查了两种微生物机制，基于动物的饮食可以支持通过TCA的代谢产生遗传毒性和促炎性最终产物，H2S和胆汁酸的细菌的生长。将富含牛磺酸和饱和脂肪的动物饮食与低牛磺酸和饱和脂肪的植物性饮食进行比较。受试者将在跨界设计中接受两种饮食中的每一种，从而作为自己的控制。将使用调解模型来确定CRC风险和DNA损伤的饮食[独立变量]与粘膜标记之间的关系的程度[因变量]由结肠细菌及其功能[介体变量]解释。这项研究将生成有关机械靶向养分的新信息，旨在仅基于饮食而开发有效的癌症预防干预措施，这可能会导致AAS中不平等的CRC负担减轻。