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

 描述(申请人提供)：拟议的创新性研究旨在调查与非裔美国人(AA)或食用高红肉和饱和脂肪饮食独立相关的结直肠癌(CRC)风险增加的生物学基础。我们推测，初级胆盐牛磺胆酸(TCA)是一种关键的饮食控制代谢物，它被华氏毕氏杆菌和华氏梭菌使用，分别产生致癌物质和促癌物质。这项工作的动机是我们广泛收集了已发表的数据，表明结肠菌产生的硫化氢和二次胆汁酸是导致结直肠癌风险的关键环境侮辱。首先，我们将检查高危AA和非西班牙裔白人(NHW)在粘膜中与硫和胆汁酸代谢相关的细菌基因、血清和粪便中胆汁代谢标志物以及结肠炎方面的差异。我们有趣的观察提供了理论基础，即一种使用硫磺氨基酸牛磺酸的细菌(B.wadsworth ia)的粘膜丰度是AA而不是NHW受试者CRC的强烈预测因子，这种氨基酸在红肉中大量存在。胆汁酸牛磺胆酸盐的细菌去结合作用提供了牛磺酸的另一种来源，一旦去结合，结肠细菌进一步将游离的初级胆汁酸代谢成具有遗传毒性和促炎作用的次级胆汁酸。然后，我们将测试这一假设，即高动物蛋白和饱和脂肪的饮食在结肠中创造了一个代谢环境，通过增加产生遗传毒性硫化物和次级胆汁酸的细菌的丰度和活性，提高了高危腹主动脉粥样硬化症的风险。将饮食干预的重点放在AAS上的理由来自于观察到一种牛磺酸呼吸细菌将AA而不是NHW CRC患者与健康对照组区分开来，以及我们先前在AAS中的工作集中在与食用西式饮食相关的CRC风险增加的潜在机制上。我们将进行一项前瞻性的随机交叉喂养试验，研究动物性饮食可能通过TCA的新陈代谢支持细菌生长的两种微生物机制，这些细菌产生遗传毒性和促炎最终产物硫化氢和次级胆汁酸。富含牛磺酸和饱和脂肪的动物性饮食将与低牛磺酸和饱和脂肪的植物性饮食进行比较。受试者将以交叉设计接受两种饮食中的每一种，从而充当他们自己的对照。一个中介模型将被用来确定饮食[自变量]和结肠癌风险的粘膜标记物和DNA损伤[应变量]之间的关系在多大程度上受到结肠菌及其功能[中介变量]的解释。这项研究将产生关于一种机械定向营养素的新信息，该营养素旨在仅基于饮食开发有效的癌症预防干预措施，可能有助于减轻AAS中不平等的CRC负担。

 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.