Rice Bran Microbial Metabolism for Colon Chemoprevention

米糠微生物代谢用于结肠化学预防

• 批准号: 9303309
• 负责人: Komal Raina
• 金额: $ 35.23万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303309
• 关键词: Aberrant crypt foci; Address; Agriculture; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Area; Avena sativa; Award; Azoxymethane; Bifidobacterium; Blood; Cancer Cell Growth; Cancer Survivor; Carcinogens; Cell Survival; Cells; Cereals; Chemoprevention; Chemopreventive Agent; Clinical; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Communities; Complex; Consumption; Data; Diet; Dietary Component; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Feces; Germ-Free; Growth; Human; Immune; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Investigation; Knowledge; Lipids; Mediating; Mesentery; Metabolic; Metabolism; Microbe; Molecular Profiling; Mucosal Immune Responses; Mucosal Immunity; Mus; Neoplasms; Nutrient; Outcome; Phenols; Phenotype; Phytic Acid; Phytochemical; Plant Sources; Population; Prevention; Probiotics; Production; Property; Protein Isoforms; Regulator Genes; Rice; Role; Sampling; Signal Transduction Pathway; Spleen; Structure; Structure of aggregated lymphoid follicle of small intestine; Testing; Tissues; Tocopherols; Tocotrienols; Translations; Transplantation; Validation; Wheat; cancer chemoprevention; cancer stem cell; colon tumorigenesis; comparative efficacy; cytokine; differential expression; feeding; functional food; gamma-oryzanol; gut microbiota; humanized mouse; inflammatory marker; innovation; lymph nodes; metabolomics; microbial; microbiome; microbiota; mouse model; novel; pre-clinical; public health relevance; small molecule; tumor; tumor microenvironment; tumor progression

 DESCRIPTION (provided by applicant): Colorectal cancer (CRC) develops as a result of complex interactions between the host mucosal immune response, microbiota, diet components, colon cancer stem cells (CSC) and inflammatory mediators. Rice bran is a `wasted' agricultural byproduct of rice processing that has shown CRC chemopreventive efficacy in numerous animal studies. Our metabolomics investigations revealed novel probiotic metabolism of rice bran using an R03 award, and our completed human studies from a recent R21 award provide compelling support that rice bran is a promising, novel dietary agent to be metabolized by the gut microbiota in favor of reducing CRC. Rice bran is a unique source of plant lipids and contains distinct contents from wheat, oat and other cereal grains. Rice bran is distinguished by gamma oryzanol, a distinct ratio of tocotrienols and tocopherol isoforms, and essential nutrients. Notably, rice bran phenolics, phytic acid, and tricin possess CRC chemoprevention activity. Little, however, is known regarding the microbial byproducts of rice bran that our preliminary studies show may be increasing gut mucosal immunity, decreasing colonic inflammation, and reducing neoplastic growth. The major objective of this proposal is to fill a significant gap in our knowledge regarding the microbiome-mediated mechanisms of action for rice bran associated CRC chemopreventive efficacy. Pre-clinical mice studies and stool results from our pilot human clinical rice bran trial showed that dietary rice bran increases healthy native gut microflora and production of stool metabolites with anti-inflammatory activities, favoring reduced colon tumorigenesis. Human stool extracts collected post- rice bran consumption also showed stronger inhibitory effects on CRC cell viability compared to pre-rice bran consumption samples. These data provide compelling rationale for studying the role of these human microbial populations and the utilization of rice bran by these microbes for CRC growth inhibition. The feasibility of carcinogen-treated humanized mice is now established for CRC, and this approach merits testing of stool samples from CRC survivors before and after daily rice bran consumption. We hypothesize that the phytochemicals in rice bran serve as gut microbial substrates and are metabolized into bioactive microbial metabolites that impact the colonic microenvironment for enhanced efficacy against CRC. Our specific aims are: I) To study the influence of dietary rice bran on the human gut microbiota and the gut microbial metabolism of rice bran for effective CRC chemoprevention.; II) To examine and establish the role of dietary rice bran - human gut microbiota interactions on inflammatory/immune milieu and cancer stem cells in the colonic tumor microenvironment; and III) To identify and define the microbial metabolites of rice bran, and relate their specific metabolic/ molecular signatures with anti-CRC efficacy. The results from these studies will provide rice bran-mediated mechanisms associated with anti-CRC efficacy and promote inclusion of rice bran as a sustainable, global functional food for colon cancer chemoprevention.

 描述（由适用提供）：结直肠癌（CRC）是由于宿主粘膜免疫响应，微生物群，饮食成分，结肠癌干细胞（CSC）和炎症介体之间的复杂相互作用而发展的。大米麸皮是水稻加工的“浪费”农业副产品，在众多动物研究中表明CRC化学预防效率。我们的代谢组学研究表明，使用R03奖揭示了稻米麸皮的新型益生菌代谢，而我们从最近的R21奖中完成的人类研究为米麸是一种希望，是一种新颖的饮食剂，可以由肠道菌群代谢，以减少CRC。米麸是植物脂质的独特来源，包含与小麦，燕麦和其他谷物谷物的不同含量。米麸的区别是伽马奥甘醇，这是生育三烯酚和生育酚同工型的明显比率，以及必需的营养素。值得注意的是，米麸酚，植酸和三酸含CRC化学预防活性。然而，关于水稻麸皮的微生物副产品，我们的初步研究表明，肠道粘膜免疫，减少结肠炎症并减少肿瘤生长，几乎没有知之甚少。该提案的主要目的是填补有关米麸相关的CRC化学预防有效性的微生物组介导的作用机制的显着空白。临床前小鼠的研究和粪便的结果来自我们的临床水稻麸皮试验表明，饮食中的米麸可以增加健康的天然肠道微生物，并产生具有抗炎活性的粪便代谢物，有利于减少结肠肿瘤的发生。与预先使用的麸皮消耗样品相比，水稻麸皮消耗后收集的人粪提取物对CRC细胞活力的影响也有很强的抑制作用。这些数据为研究这些人类微生物种群的作用以及这些微生物对CRC生长抑制的利用提供了令人信服的理由。现已为CRC建立了经致癌的人源化小鼠的可行性，这种方法值得在每天米熟食之前和之后对CRC表面的粪便样品进行测试。我们假设水稻麸皮中的植物化学物质用作肠道微生物底物，并将代谢成生物活性微生物代谢产物，从而影响结肠微环境，以提高针对CRC的效率。我们的具体目的是：i）研究饮食中的水稻麸对人类肠道微生物群的影响以及水稻麸皮的肠道微生物代谢，以进行有效的CRC化学预防。 ii）检查并确定饮食中的水稻麸皮 - 人类肠道菌群相互作用在结肠肿瘤微环境中炎症/免疫环境和癌症干细胞上的作用； iii）识别和定义水稻麸皮的微生物代谢物，并将其特定的代谢/分子特征与抗CRC效率联系起来。这些研究的结果将提供与抗CRC效率相关的米麸介导的机制，并促进米麸列入结肠癌化学预防的可持续全球功能性食品。