Microbiota, Metabolites, and Colon Neoplasia

项目摘要 人类的饮食可以积极或消极地影响癌症的发病率，植物衍生的化合物-如 多酚--通常表现出抗氧化剂的抗癌特性。核桃是一种特殊的来源， 多酚鞣花单宁（多酚鞣花单宁，多酚鞣花单宁被消化道中的肠道微生物群转化为鞣花酸和各种尿石素， 结肠尿石素A（UroA）因其有效的抗癌、抗炎和益生元而特别令人感兴趣 活动然而，个体的UroA产量可能会有很大差异，可能是基于肠道的差异。 微生物群我们将证实从食用益生菌中提取的益生元/益生菌复合物的抗癌益处。 核桃，并确定UroA形成中人类个体间差异的基础。 我们的总体假设是，核桃补充剂改善结肠健康，降低结直肠癌 (CRC)通过UroA形成的风险。这导致了几个工作假设指导我们的目标：工作 假设1. UroA生产者患晚期结肠病变的风险较低;工作假设2。 核桃补充剂会增加尿UroA水平;和工作假设3。CRC预防， 核桃将是更大的UroA生产者比非生产者。在目标1中，我们提出了一种随机、对照 在69名患者（45-75岁）中进行交叉试验，以检查核桃对CRC危险因素的影响。我们将关联一个 个体产生具有炎症和CRC风险生物标志物的UroA的能力，并识别细菌 负责尿石素代谢的物种。在目标2中，我们将研究含有ET的益生元效应。 核桃在两种条件性小鼠CRC模型中的应用，重点关注CRC和炎症的重要过程， 包括胆汁酸代谢、炎症和短链脂肪酸产生。在目标3中，我们将测试 在小鼠粪便微生物群移植（MT）研究中，人产生UroA的微生物群的益生菌作用， 证明了特定微生物在UroA形成中的因果作用。这将使我们能够验证这样一个概念， 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来源的 代谢物。这也将定义生物标志物和益生菌，突出这些食物的好处。我们 方法结合个性化营养，重点关注结肠中的UroA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元和益生菌， 用于CRC预防的保护性尿石素。这些非常重要的研究将测试微生物群的能力， 产生结肠粘膜保护剂（例如，UroA）。高风险患者可以有效地 通过服用益生菌将其转化为保护状态，以实现富含ET的食物的全部益处。

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.