Rice Bran Microbial Metabolism for Colon Chemoprevention

 描述(申请人提供)：结直肠癌(CRC)是宿主黏膜免疫反应、微生物区系、饮食成分、结肠癌干细胞(CSC)和炎症介质之间复杂相互作用的结果。米皮是大米加工过程中的一种“浪费的”农业副产品，在许多动物研究中显示出了结直肠癌的化学预防效果。我们的代谢组学研究揭示了使用R03奖对米糠进行的新型益生菌代谢，我们最近在R21奖上完成的人类研究提供了令人信服的支持，即米糠是一种很有前途的新型饮食制剂，可以通过肠道微生物群进行代谢，有利于减少CRC。米皮是植物脂肪的独特来源，含有与小麦、燕麦和其他谷物不同的成分。米皮的特点是伽马谷维素，生育三烯醇和生育酚异构体的比例不同，以及必需的营养物质。值得注意的是，米糠酚、植酸和三黄素具有结直肠癌化学预防活性。然而，关于米皮的微生物副产物，我们的初步研究表明，它可能提高肠道粘膜免疫力，减少结肠炎症，并减少肿瘤生长，人们对此知之甚少。这项建议的主要目的是填补我们对米糠相关结直肠癌化学预防效果的微生物群介导的作用机制的认识上的一个重大空白。临床前的小鼠研究和我们的试点人类临床米糠试验的粪便结果表明，膳食米糠增加了健康的本地肠道微生物群和具有抗炎活性的粪便代谢物的产生，有利于减少结肠肿瘤的发生。与食用米糠前的样品相比，食用米糠后收集的人类粪便提取物对CRC细胞的活力也显示出更强的抑制作用。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利用米糠抑制CRC生长提供了令人信服的理论基础。致癌物处理的人源化小鼠现在为结直肠癌建立了可行性，这种方法值得对结直肠癌幸存者在每天食用米糠之前和之后的粪便样本进行测试。我们假设米糠中的植物化学物质作为肠道微生物底物，被代谢成具有生物活性的微生物代谢产物，从而影响结肠微环境，从而增强对结直肠癌的疗效。我们的具体目标是：i)研究日粮米糠对人肠道微生物区系和米糠肠道微生物代谢的影响，以便有效地进行结直肠癌的化学预防。ii)检测和建立日粮米糠与人肠道微生物区系相互作用对结肠癌微环境中炎症/免疫环境和肿瘤干细胞的作用；以及iii)鉴定和确定米糠的微生物代谢物，并将其特异性代谢/分子特征与抗结直肠癌疗效联系起来。这些研究的结果将提供米糠介导的与抗结直肠癌疗效相关的机制，并促进米糠作为一种可持续的全球功能食品用于结肠癌的化学预防。

 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.