Dietary Rice Bran Phytochemicals and Microbial Metabolites for Colon Chemoprevent

描述（由申请人提供）：结直肠癌是所有癌症中死亡率第二高的癌症，最近的研究表明，在饮食中增加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，米糠可以预防结肠癌的发展，并促进人类结肠癌细胞的死亡，然而，关于米糠植物化学物质与肠道微生物之间的相互作用作为引发这些预防作用的机制，我们知之甚少。生物活性米糠成分可以减轻炎症，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，γ -米甲醇，阿魏酸和植物甾醇和酚类物质。肠道发酵和微生物代谢副产物的机制，由膳食米糠摄入导致的结肠化学预防以前没有研究过。在我们的知识中存在一个重大的差距，即在饮食中摄入米糠后产生的微生物代谢物。我们假设米糠植物化学物质会刺激结肠中有益微生物的种群，产生抗炎的短链脂肪酸和/或通过微生物阿魏酸酯酶的活性将米糠成分（如γ -米甲醇）代谢为其生物活性代谢物阿魏酸。

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. PUBLIC HEALTH RELEVANCE: Colorectal cancer has the second highest mortality rate of all cancers and dietary intervention with rice bran components represents a promising opportunity for chemoprevention in humans. Dietary rice bran inhibits colon tumorigenesis in animal studies, but little is known regarding the effects of dietary rice bran intake in humans for reducing coloni inflammation directly or through metabolic by-products resulting from gut fermentation. Rice bran is a readily available agricultural by-product that is not yet widely consumed by humans. Clinical investigations into anti-inflammatory activity of rice bran phytochemicals, their biotransformation products, and microbial metabolites whose production is stimulated by rice bran consumption can help to advance the inclusion of rice bran as an agent to inhibit colonic inflammation and for widespread colorectal cancer prevention.