Gut Microbiota and colonic gene expression: A ligran trial in humans

肠道微生物群和结肠基因表达：人体 ligran 试验

• 批准号: 8726945
• 负责人: Robert Stephen Chapkin
• 金额: $ 60.79万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-09 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726945
• 关键词: Accounting; Affect; Age; Animal Model; Animals; Antioxidants; Bacteria; Biological; Biopsy; Butyrates; Cancer Etiology; Cells; Cereals; Cessation of life; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal; Colorectal Cancer; Consumption; Cross-Over Studies; Development; Diet; Dietary Factors; Dietary Fiber; Dietary Intervention; Dietary Lignans; Dimerization; Disease; Dose; Drug Kinetics; Eating; Ecology; Edible Plants; Enzyme Inhibition; Epidemiologic Studies; Epithelial; Epithelial Cells; Epithelium; Evaluation; Excretory function; Feces; Fermentation; Fiber; Flax; Food; Gastrointestinal Transit; Gender; Gene Expression; Genes; Genetic Crossing Over; Goals; Human; In Vitro; Incidence; Individual; Ingestion; Instruction; Intake; Intervention; Intervention Studies; Intestines; Knowledge; Life Style; Lignans; Lignin; Malignant Neoplasms; Measures; Metabolic Biotransformation; Metabolism; Metagenomics; Modification; Molecular Profiling; Mucous Membrane; Participant; Pathway interactions; Phytochemical; Placebo Control; Placebos; Plants; Population; Prevention; Production; Property; Randomized; Reporting; Risk; Risk Factors; Role; Sampling; Seeds; Sex Characteristics; Signal Pathway; Signal Transduction; Source; Stromal Cells; Structure; Supplementation; System; Testing; Time; United States; Urine; Variant; Woman; bioactive food component; cancer risk; cinnamic acid; colon carcinogenesis; dietary constituent; enterodiol; enterolactone; feeding; flaxseed lignan; gut microbiota; hormone metabolism; in vitro Model; in vivo; innovation; interdisciplinary collaboration; mRNA Expression; men; metagenome; microbial; microbial community; microbiome; pre-clinical; prevent; protective effect; pyrosequencing; rRNA Genes; response; secoisolariciresinol; transcriptome sequencing; tumor; urinary

DESCRIPTION (provided by applicant): Colorectal (CRC) cancer is the third most common cancer in the United States and its incidence is rising in younger populations. Diet is an important risk factor for CRC and dietary constituents are modified by gut microbial action. Microbial fermentation of dietary fiber and plant lignans in high-fiber foods produces bioactive endproducts, such as butyrate and enterolignans. The enterolignans, enterolactone (ENL) and enterodiol (END) have been associated with lower CRC in some epidemiologic studies. Lignans and dietary fiber have been shown to reduce colon tumors in animal models and butyrate and END and ENL influence cellular pathways important to cancer risk in vitro. We propose a 3-period randomized, cross-over intervention in 70 healthy men and women (ages 20-45) with the goal to test the effect of a flaxseed lignan supplement and defatted flaxseed meal (containing lignans + dietary fiber) as compared to placebo on: 1) host gene expression in epithelial and stromal cells from colon biopsies and exfoliated colonocytes extracted from feces; 2) gut microbial community composition, and 3) the interaction of the gut microbiome, enterolignan exposure, and colonic gene expression in high- and low-ENL excreters. Colon biopsies, stool, and urine will be collected at the end of each of the three 60-day periods to evaluate effects of the lignan treatments. We will use an innovative application of RNA-seq to measure gene expression in human colon cells from biopsy and stool. The gut microbiome will be characterized using pyrosequencing and QPCR of the 16S rRNA gene. Lignans will be measured in urine by GC-MS. Further, using samples from a subset of intervention participants who are low-and high-ENL excreters, we will measure the functional metagenomics of the gut microbiome in vitro. This proposed project will be the first to integrate and characterize, through a unique interdisciplinary collaboration, the relationships between lignan exposure, gut microbial ecology, and gene expression in cell- signaling pathways. Results of this placebo-controlled intervention will bridge the current knowledge from pre-clinical animal models and epidemiologic studies and will help to inform approaches for CRC prevention.

描述（由申请人提供）：结直肠癌 (CRC) 是美国第三大常见癌症，其发病率在年轻人口中呈上升趋势。饮食是结直肠癌的一个重要危险因素，膳食成分会受到肠道微生物作用的影响。高纤维食品中膳食纤维和植物木脂素的微生物发酵产生生物活性最终产品，例如丁酸盐和肠木脂素。在一些流行病学研究中，肠木脂素、肠内酯 (ENL) 和肠二醇 (END) 与较低的 CRC 相关。木脂素和膳食纤维已被证明可以减少动物模型中的结肠肿瘤，丁酸盐、END 和 ENL 会影响对体外癌症风险很重要的细胞途径。 我们建议对 70 名健康男性和女性（20-45 岁）进行 3 个周期的随机交叉干预，目的是测试亚麻籽木脂素补充剂和脱脂亚麻籽粉（含有木脂素 + 膳食纤维）与安慰剂：1）来自结肠活检和从粪便中提取的脱落结肠细胞的上皮细胞和基质细胞中的宿主基因表达； 2) 肠道微生物群落组成，3) 高和低 ENL 排泄物中肠道微生物组、肠木脂素暴露和结肠基因表达的相互作用。将在三个 60 天周期的每个周期结束时收集结肠活检、粪便和尿液，以评估木酚素治疗的效果。我们将使用 RNA-seq 的创新应用来测量活检和粪便中人类结肠细胞的基因表达。将使用 16S rRNA 基因的焦磷酸测序和 QPCR 来表征肠道微生物组。将通过 GC-MS 测量尿液中的木脂素。此外，利用来自低和高 ENL 排泄者的干预参与者子集的样本，我们将在体外测量肠道微生物组的功能宏基因组。 该拟议项目将是第一个通过独特的跨学科合作来整合和表征木脂素暴露、肠道微生物生态和细胞信号通路中基因表达之间关系的项目。这种安慰剂对照干预的结果将连接临床前动物模型和流行病学研究的当前知识，并将有助于为结直肠癌预防方法提供信息。