Microbiota, Metabolites, and Colon Neoplasia

微生物群、代谢物和结肠肿瘤

基本信息

批准号：
10616669
负责人：
Christian Jobin
金额：
$ 63.19万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
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/10616669
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 Eligibility Determination Ellagi-Tannins Ellagic Acid Exhibits Fatty Acids Feces Food Generations Goals Health Human Incidence Individual Inflammation Inflammatory Juglans Lesion Malignant Neoplasms Measures Metabolic Metabolism Microbe Mitogen-Activated Protein Kinases Modification Mucous Membrane Mus Oncogenic Pathway interactions Patients Phase Phytochemical 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 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

项目摘要

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.

项目摘要人类饮食可能会带来积极或负面影响癌症事件，并具有植物来源的化合物 - 例如多酚 - 经常表现出抗氧化剂预防性的特性。核桃是一个特殊的来源肠道酸性乙醇（ETS）通过肠道菌酸转化为椭圆酸和各种尿素冒号。尿石A（UROA）对于其潜在的抗癌，抗炎和益生元而特别感兴趣活动。但是，个体的UROA产生可能会有很大差异，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形成中人类间变异的基础。我们的总体假设是补充核桃可改善结肠健康并降低结直肠癌（CRC）通过UROA形成风险。这导致了一些有效的假设指导我们的目标：工作假设1。UROA生产者患有晚期结肠病变的风险较低。工作假设2。核桃补充剂将增加尿尿液水平；和工作假设3。预防CRC UROA生产者中的核桃将比非生产者更大。在AIM 1中，我们提出了一个随机，受控的在69名患者（45-75岁）中进行的跨界试验检查了对CRC危险因素的核桃影响。我们将使个人具有感染和CRC风险生物标志物的UROA的能力，并识别细菌负责尿石代谢的物种。在AIM 2中，我们将研究含有ET的益生元作用在两个条件小鼠CRC模型中的核桃，重点是CRC和注射中的重要过程，包括胆汁酸代谢，感染和短链脂肪酸的产生。在AIM 3中，我们将测试人类Uroa产生微生物群在小鼠粪便菌群移植（MT）研究中的益生菌作用和展示了特定微生物在UROA形成中的因果作用。这将使我们能够验证一个概念核桃和其他富裕食品的重要保护作用是通过特定的微生物衍生的代谢物。这还将定义生物标志物和益生菌，以突出这些食物的好处。我们的方法结合了个性化的营养，重点是结肠中的Uroa生产商和非生产者健康。最终，我们的人类和临床前的小鼠研究可能导致益生元和益生菌增加防止CRC预防的保护性尿石。这些非常重要的研究将测试菌群的能力产生结肠粘膜保护剂（例如UROA）。高危患者可能有效通过服用益生菌来实现ET-RICH食品的全部好处，转化为受保护状态。