Microbiota, Metabolites, and Colon Neoplasia

微生物群、代谢物和结肠肿瘤

• 批准号: 10212528
• 负责人: Daniel William Rosenberg
• 金额: $ 71.04万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10212528
• 关键词: Age; Anti-Inflammatory Agents; Antioxidants; Bacteria; Bile Acids; Biological Markers; Blood; Cancer Model; Colon; Colonic Neoplasms; Colonoscopy; Colorectal Cancer; Colorectal Neoplasms; Complex; Consumption; Cross-Over Studies; Cross-Over Trials; DNA sequencing; Development; Diet; Dietary History; Ellagi-Tannins; Ellagic Acid; Exhibits; Feces; Food; Generations; Goals; Health; Human; Incidence; Individual; Inflammation; Inflammatory; Juglans; Lead; Lesion; Malignant Neoplasms; Measures; Metabolic; Metabolism; Microbe; Mitogen-Activated Protein Kinases; Modification; Mucous Membrane; Mus; Oncogenic; Pathway interactions; Patients; Phase; Plants; Polyps; Preventive; Probiotics; Process; Production; Property; Protective Agents; Randomized; Risk; Risk Factors; Role; Sampling; Schedule; Serrated Adenoma; Signal Transduction; Source; Supplementation; Tamoxifen; Testing; Transplantation; Urine; Volatile Fatty Acids; adenoma; anti-cancer; arm; base; bile acid metabolism; cancer prevention; cancer risk; colorectal cancer prevention; colorectal cancer risk; dietary control; fecal transplantation; gut bacteria; gut microbiota; high risk; human study; improved; inflammatory marker; inter-individual variation; interest; microbial colonization; microbiome; microbiome composition; microbiota; microbiota metabolites; microbiota transplantation; mouse model; nutrition; polyphenol; pre-clinical; prebiotics; probiotic supplementation; protective effect; recruit; screening; stool sample; transcriptome sequencing; tumor; tumor initiation; tumorigenesis; urinary

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.

项目概要 人类饮食可以对癌症发病率产生积极或消极的影响，其中植物源性化合物，例如 多酚——通常具有抗氧化、预防癌症的特性。核桃是一种特殊的来源 多酚鞣花单宁 (ET)，通过肠道微生物群转化为鞣花酸和各种尿石素 冒号。尿石素 A (UroA) 因其有效的抗癌、抗炎和益生元作用而受到特别关注 活动。然而，个体中 UroA 的产生可能存在显着差异，这可能取决于肠道的差异 微生物群。我们将证实源自食用的益生元/益生菌复合物的抗癌功效 核桃并确定人类个体间 UroA 形成变异的基础。 我们的总体假设是，补充核桃可以改善结肠健康并降低结直肠癌的发生率 (CRC) 通过 UroA 形成的风险。这导致了指导我们目标的几个工作假设： 假设 1. UroA 产生者发生晚期结肠病变的风险较低；工作假设2。 补充核桃会增加尿尿尿A水平；和工作假设 3. CRC 预防 UroA 生产者的核桃产量将高于非生产者。在目标 1 中，我们提出了一种随机、受控的方法 对 69 名患者（45-75 岁）进行的交叉试验，旨在检查核桃对 CRC 危险因素的影响。我们将关联一个 个体产生具有炎症和结直肠癌风险生物标志物的 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 ET 的益生元作用 两种条件性小鼠结直肠癌模型中的核桃，重点关注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 小鼠粪便微生物群移植 (MT) 研究中人类产生 UroA 的微生物群的益生菌作用 证明特定微生物在 UroA 形成中的因果作用。这将使我们能够验证以下概念： 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群产生的 代谢物。这还将定义突出这些食品益处的生物标志物和益生菌。我们的 该方法结合了个性化营养，重点关注结肠中 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增加 用于预防 CRC 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）。高危患者有可能得到有效救治 通过服用益生菌转化为保护状态，以实现富含 ET 食物的全部益处。