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）癌症是美国第三大常见的癌症，其发病率正在增加。饮食是CRC的重要危险因素，饮食成分是通过肠道微生物作用来改变的。高纤维食品中饮食纤维和植物木质植物的微生物发酵产生生物活性最终产物，例如丁酸酯和肠肠酯。在某些流行病学研究中，肠肠杆菌，肠痛（ENL）和肠二醇（END）与较低的CRC相关。已显示木质杆和饮食纤维可减少动物模型中的结肠肿瘤，丁酸酯和结束和ENL影响对体外癌症风险重要的细胞途径。 我们在70名健康的男性和女性（20-45岁）中提出了3周期的随机，交叉干预，目的是测试与以下可表达的宿主基因在上皮和层状细胞中的宿主表达相比，测试亚麻籽木质补充剂的效果，并进行了亚麻籽补充剂的效果，并进行了defated子状的亚麻籽粉（包含Lignans +饮食纤维）的作用（含有Lignans +膳食纤维）。 2）肠道微生物群落组成，以及3）肠道微生物组，肠球菌暴露和结肠基因表达在高和低ENL排泄剂中的相互作用。结肠活检，粪便和尿液将在三个60天的时间结束时收集，以评估木质疗法的作用。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中的基因表达。肠道微生物组将使用16S rRNA基因的pyrosequencing和qPCR进行表征。 Lignans将通过GC-MS在尿液中测量。此外，使用来自低和高eNL排泄剂的一部分干预参与者的样品，我们将在体外测量肠道微生物组的功能性宏基因组学。 该提出的项目将是第一个通过独特的跨学科协作，木质蛋白暴露，肠道微生物生态学与基因表达之间的关系进行整合和表征的项目。这种安慰剂对照干预的结果将弥合临床前动物模型和流行病学研究的当前知识，并将有助于告知CRC预防方法。