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

 描述（由申请人提供）：提出的是创新研究，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）发展风险增加的生物学基础。我们假设，初级胆汁盐牛磺胆酸（TCA）是一种关键的饮食控制代谢产物，其使用的细菌Bilophila wadsaccharia和Clostridium candidens产生致癌物质和肿瘤促进剂，分别。这项工作的动机是我们广泛收集已发表的数据，表明结肠细菌产生的H2S和次级胆汁酸是导致CRC风险的关键环境损害。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，以及结肠炎症之间的差异在风险AA和非西班牙裔白人（NHW）。我们有趣的观察提供了理论依据，即粘膜中细菌（B. wadssynia）使用富含红肉的含硫氨基酸牛磺酸，是AA受试者而不是NHW受试者中CRC的强预测因子。胆汁酸牛磺胆酸盐的细菌去缀合提供了牛磺酸的另一个来源，并且一旦去缀合，游离的初级胆汁酸被结肠细菌进一步代谢为遗传毒性和促炎性次级胆汁酸。然后，我们将检验以下假设：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，促进了高危AA中CRC的风险。将饮食干预集中在AA上的理由来自于对牛磺酸呼吸细菌的观察，该细菌将AA而不是NHW CRC患者与健康对照区分开来，以及我们先前在AA中的工作，该工作侧重于与食用西式饮食相关的CRC风险增加的潜在机制。我们将进行一项前瞻性随机交叉喂养试验，检查两种微生物机制，通过这两种机制，动物性饮食可能支持细菌生长，这些细菌通过TCA代谢产生遗传毒性和促炎性终产物H2S和二级胆汁酸。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。受试者将在交叉设计中接受两种饮食中的每一种，从而作为他们自己的对照。将使用中介模型来确定饮食[自变量]与CRC风险和DNA损伤的粘膜标志物[因变量]之间的关系在多大程度上由结肠细菌及其功能[中介变量]解释。这项研究将产生关于一种机械靶向营养素的新信息，旨在开发简单基于饮食的有效癌症预防干预措施，这可能有助于减少AA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.