Dietary Rice Bran Phytochemicals and Microbial Metabolites for Colon Chemoprevent

描述(申请人提供)：结直肠癌的死亡率是所有癌症中第二高的，最近的研究表明，增加饮食中植物性食物的数量可以预防70%的结直肠癌。在致癌物诱导的结肠癌模型中，米皮可以阻止结肠癌的发展，并促进人结肠癌细胞的死亡，但关于米皮植物化学物质与肠道微生物之间的相互作用是否具有这些预防作用的机制还知之甚少。生物活性米糠成分可能会减少炎症，因为它们是产生短链脂肪酸(SCFA)和其他抗炎代谢物的结肠微生物的新底物。化学预防米糠化学物质包括但不限于植酸盐、伽马谷维素、阿魏酸盐、植物甾醇和酚类化合物。肠道发酵的机制和饮食米糠所产生的微生物代谢副产物以前还没有被研究过用于结肠化学预防。我们对膳食米糠摄入后产生的微生物代谢物的认识存在着很大的差距。我们假设米糠植物化学物质将刺激结肠中产生抗炎单链脂肪酸的有益微生物群和/或通过微生物阿魏酸酯酶活性将米糠组分(如伽马谷维素)代谢为其生物活性代谢物阿魏酸。 拟议的研究项目将使用454焦磷酸测序、定量聚合酶链式反应和代谢组学技术来确定粪便中发现的微生物和代谢物的变化。检测细菌菌群的变化，改变米糠组分的新陈代谢，将促进我们对食用米糠来降低结肠癌风险的饮食潜力的理解。高通量DNA测序和特定微生物数据分析工具的进步使不同人类排泄物样本之间能够进行独立于培养的比较，并确定了来自许多属的微生物的变化。将这些信息与粪便代谢组的变化结合起来，是确定米糠化学物质如何减轻和/或预防结肠炎的一种创新方法。在目标1中，我们提出了在结肠癌幸存者增加米糠摄入量(每天30克，持续28天)或安慰剂对照摄入量后收集粪便样本，我们将在目标2中确定每天米糠摄入量如何调节粪便微生物群落结构。目标3将检测米糠摄入量与对照水平的粪便代谢物，并评估粪便代谢物提取物对结肠癌生存能力的影响。这项研究的主要成果将是确定特定的肠道微生物和代谢物，这些微生物和代谢物受膳食米糠摄入量的调节。这些发现将作为米糠介导的微生物代谢变化的关键先导数据，用于使用R01机制进行明确的、基于机理的米糠-微生物-代谢物化学预防研究。

DESCRIPTION (provided by applicant): Colorectal cancer has the second highest mortality rate of all cancers and recent studies indicate that increasing the amount of plant-based foods in the diet could prevent 70% of colorectal cancers. Rice bran can prevent colonic tumor development in carcinogen-induced colon cancer models and promote cell death of human colon cancer cells, however little is known regarding the interactions between rice bran phytochemicals and intestinal microbes as a mechanism to elicit these preventive effects. Bioactive rice bran components may reduce inflammation as they are novel substrates for colonic microorganisms that produce short chain fatty acids (SCFA) and other anti-inflammatory metabolites. Chemopreventive rice bran chemicals include, but are not limited to phytate, gamma-oryzanol, ferulate and phytosterols and phenolics. The mechanisms of gut fermentation and microbial metabolic by-products resulting from dietary rice bran intake have not been previously examined for colonic chemoprevention. A significant gap in our knowledge exists regarding the microbial metabolites produced following dietary rice bran intake. We hypothesize that rice bran phytochemicals will stimulate populations of beneficial microbes in the colon that produce anti-inflammatory SCFA and/or metabolize rice bran components, such as gamma-oryzanol to its bioactive metabolite ferulic acid via the activity of microbial ferulate esterases. The proposed research project will identify the change in microbes and metabolites found in stool using 454 pyrosequencing, qPCR, and metabolomics techniques. Examination of changes in bacterial flora that alter metabolism of rice bran components will advance our understanding of the dietary potential for rice bran consumption to reduce colon cancer risk. Advances in high-throughput DNA sequencing and microbe-specific data analysis tools allows for culture-independent comparisons between diverse human fecal samples and for defining changes in microbes from numerous genera. Integrating this information with changes in the fecal metabolome represents an innovative approach for determining how rice bran chemicals mitigate and/or prevent colonic inflammation. The collection of stool samples following increased rice bran intake (30 g/day for 28 days) or placebo control intake in colon cancer survivors is proposed in Aim 1, and we will determine how daily rice bran intake modulates fecal microbial community structure in Aim 2. Aim 3 will examine fecal metabolites from rice bran intake compared to control levels and will assess the effects of fecal metabolite extracts on colon cancer viability. Major outcomes from this study will be the identification of specific gut microbes and metabolites modulated by dietary rice bran intake. These findings will serve as critical, pilot data on rice bran-mediated changes in microbial metabolism for a definitive, mechanism based chemopreventive rice bran-microbe- metabolite investigation using a R01 mechanism.