Microbiota, Metabolites, and Colon Neoplasia

项目摘要 人类的饮食可以对癌症发病率产生积极或消极的影响，包括植物衍生化合物--例如 多酚--通常表现出抗氧化剂--预防癌症的特性。核桃是一种特殊的 多酚鞣胶(ETS)，可被肠道微生物群转化为鞣花酸和各种尿脂 冒号。尿素A(UroA)因其强大的抗癌、抗炎和益生菌而特别受关注 活动。然而，个体的尿酸产量可能有很大的差异，这可能是基于肠道的差异 微生物区系。我们将证实通过食用益生菌/益生菌复合体的抗癌益处。 并确定了人类在乌罗阿地层中个体间变异性的基础。 我们的总体假设是，补充核桃可以改善结肠健康，降低结直肠癌 (CRC)通过Uroa形成的风险。这导致了几个指导我们目标的工作假设：工作 假设1。尿酸产生者患晚期结肠损害的风险较低；工作假设2。 补充核桃将增加尿尿酸水平；和工作假设3。通过以下方式预防结直肠癌 Uroa生产国的核桃将比非生产国的核桃更大。在目标1中，我们提出了一种随机的、受控的 在69名患者(45-75岁)中进行交叉试验，以检验核桃对结直肠癌危险因素的影响。我们将关联一个 个体产生带有炎症和结直肠癌风险生物标记物的尿液的能力，并识别细菌 负责尿脂新陈代谢的物种。在目标2中，我们将研究含有ET的益生菌效应 核桃在两种条件性小鼠结直肠癌模型中的作用，重点研究结直肠癌和炎症的重要过程， 包括胆汁酸代谢、炎症和短链脂肪酸的产生。在目标3中，我们将测试 在小鼠粪便微生物区系移植(MT)研究中人产尿酸微生物区系的益生菌效应 证明特定微生物在尿液形成中的因果作用。这将使我们能够验证这一概念 核桃和其他富含ET的食物的重要保护作用是通过特定的微生物区系实现的 代谢物。这也将定义生物标记物和益生菌，以突出这些食品的好处。我们的 该方法结合了个性化营养，重点放在结肠的尿酸生产者和非生产者 健康。最终，我们的人类和临床前小鼠研究可能会导致益生菌和益生菌增加 用于预防结直肠癌的保护性尿路结石。这些非常有意义的研究将测试微生物区系的能力 产生结肠粘膜保护剂(例如，尿酸)。有可能高危患者可以有效地 通过服用益生菌转变为保护状态，以实现富含ET食物的全部好处。

Project Summary The human diet can positively or negatively impact cancer incidence, with plant-derived compounds – such as polyphenols – often exhibiting antioxidant cancer-preventive properties. Walnuts are an exceptional source of polyphenolic ellagitannins (ETs) that are converted to ellagic acid and various urolithins by gut microbiota in the colon. Urolithin A (UroA) is of particular interest for its potent anti-cancer, anti-inflammatory, and prebiotic activities. However, UroA production in individuals can vary significantly, likely based on differences in gut microbiota. We will substantiate the anti-cancer benefits of a prebiotic/probiotic complex derived from consuming walnuts and determine the basis of human inter-individual variability in UroA formation. Our overall hypothesis is that walnut supplementation improves colonic health and lowers colorectal cancer (CRC) risk through UroA formation. This leads to several working hypotheses guiding our Aims: Working Hypothesis 1. UroA producers are at a lower risk of having an advanced colonic lesion; Working Hypothesis 2. Walnut supplementation will increase urinary UroA levels; and Working Hypothesis 3. CRC prevention by walnuts will be greater in UroA-producers than in non-producers. In Aim 1, we propose a randomized, controlled crossover trial in 69 patients (45-75 y) to examine walnut effects on CRC risk factors. We will associate an individual's ability to produce UroA with biomarkers of inflammation and CRC risk, and identify the bacterial species responsible for urolithin metabolism. In Aim 2, we will investigate prebiotic effects of ET-containing walnuts in two conditional mouse CRC models, focusing on important processes in CRC and inflammation, including bile acid metabolism, inflammation, and short chain fatty acid production. In Aim 3, we will test the probiotic effects of human UroA-producing microbiota in a mouse fecal microbiota transplant (MT) study and demonstrate a causal role for specific microbes in UroA formation. This will enable us to validate the concept that important protective effects of walnuts and other ET-rich foods occur through specific microbiota-derived metabolites. This will also define biomarkers and probiotics that highlight the benefits of these foods. Our approach incorporates personalized nutrition with a focus on UroA producers and non-producers in colonic health. Ultimately, our human and pre-clinical mouse studies may lead to prebiotics and probiotics that increase protective urolithins for CRC prevention. These highly significant studies will test the ability of the microbiota to generate colonic mucosa-protective agents (e.g., UroA). It is possible that high-risk patients can be efficiently converted to a protective state by taking probiotics to realize the full benefits of ET-rich foods.