Dietary Fiber, Gut Microflora, & Epigenetic Events that Prevent Colorectal Cancer

膳食纤维、肠道微生物群、

基本信息

批准号：
8110470
负责人：
Scott J Bultman
金额：
$ 26.91万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8110470
关键词：
Aberrant crypt foci Affect Anaerobic Bacteria Azoxymethane Bacteria Biological Assay Butyrates Cancerous Candidate Disease Gene Cell Death Cell Proliferation Colon Colorectal Cancer Colorectal Neoplasms CpG Islands DNA Data Set Deoxyribonuclease I Diagnosis Diet Dietary Factors Dietary Fiber Environmental Risk Factor Epidemiologic Studies Epigenetic Process Epithelium Event Fermentation Fiber Gene Expression Genes Genetic Genome Goals Histone Acetylation Histone Deacetylase Inhibitor Homeostasis Human Hypermethylation Hypersensitivity Immune system Immunoprecipitation Inbred Mouse Incidence Inflammation Institutes Lead Link Malignant Neoplasms Measures Mediating Methylation Modeling Modification Molecular Molecular Profiling Mus Mutagenesis NIH Program Announcements Physiology Predisposition Process Production Research Research Personnel Risk Role Site Sodium Dextran Sulfate Structure Testing Tissues Transcript Tumor Suppressor Genes United States Work bioactive food component cancer gene expression cancer prevention cancer risk chromatin immunoprecipitation feeding genome-wide gut microflora mouse model prevent programs promoter protective effect response sodium bisulfite tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the third most diagnosed and deadly cancer in the United States. Numerous epidemiological studies have shown that a high-fiber diet is correlated with decreased incidence of CRC. Although the underlying mechanism is unknown, we hypothesize that dietary fiber has a protective effect because it is metabolized by anaerobic bacteria in the colon and fermented into butyrate. Butyrate is a potent histone deacetylase (HDAC) inhibitor that alters epigenetic events and gene expression and might maintain cell proliferation and cell death homeostasis to prevent CRC. The objective of this application is to investigate the mechanistic link between dietary fiber, gut microflora, butyrate, and epigenetic modifications which result in gene expression changes that alter cancer susceptibility. To tightly control experimental variables, the proposed experimental plan utilizes several mouse models of CRC. ApcMin/+, azoxymethane (AOM) treated, and AOM plus dextran sodium sulfate (DSS) treated mice will be maintained with defined gut microflora or germfree and be fed high- or low-fiber diets to determine whether gut microflora is required for a high-fiber diet to protect against CRC. To determine whether bacterial fermentation of fiber into butyrate is the mechanism of the fiber effect, germfree mice will be recolonized with bacteria that produce high or low levels of butyrate. CpG methylation and gene expression will be analyzed in a genome-wide manner using methylated DNA immunoprecipitation (MeDIP) combined with BAG and CpG island microarrays and transcript profiling. CpG methylation and gene expression profiles from mice fed a high- or low-fiber diet in the presence or absence of gut microflora will be compared. Superimposing these data sets will identify CpGs with altered methylation that are also associated with changes in gene expression and cancer susceptibility. These sites will be considered candidates for contributing to altered risk for CRC. To understand the role of dietary fiber and gut microflora at a molecular level, epigenetic events will be analyzed at several candidate genes before and after the onset of tumor formation using chromatin immunoprecipitation (ChIP) assays, sodium bisulfite mutagenesis followed by sequencing, and DNase I hypersensitivity assays. This work should elucidate the mechanisim of the fiber effect on CRC susceptibility and may lead to new preventative strategies for CRC.

描述（由申请人提供）：结直肠癌（CRC）是美国第三大诊断和致命的癌症。许多流行病学研究表明，高纤维饮食与CRC发病率降低相关。尽管基本机制尚不清楚，但我们假设饮食纤维具有保护作用，因为它是由结肠中的厌氧菌代谢并发酵成丁酸的。丁酸酯是一种有效的组蛋白脱乙酰基酶（HDAC）抑制剂，它会改变表观遗传事件和基因表达，并可能维持细胞增殖和细胞死亡稳态以防止CRC。该应用的目的是研究饮食纤维，肠道微生物，丁酸酯和表观遗传学修饰之间的机械联系，从而导致基因表达改变，从而改变了癌症的敏感性。为了严格控制实验变量，提出的实验计划利用了几种CRC的小鼠模型。 APCMIN/+，已处理的甲氧烷烷（AOM）和AOM加硫酸钠（DSS）处理的小鼠将使用定义的肠道微生物或饮食来维持高纤维饮食，以确定是否需要高纤维饮食以保护CRC，并确定是否需要高纤维饮食。为了确定纤维向丁酸酯的细菌发酵是否是纤维效应的机制，将用产生高或低水平丁酸酯的细菌将无毛虫小鼠重新殖民。 CpG甲基化和基因表达将使用甲基化的DNA免疫沉淀（MEDIP）与BAG和CPG岛微阵列和转录物分析一起分析。在存在或不存在肠道微生物的情况下，喂养高或低纤维饮食的小鼠的CpG甲基化和基因表达谱。叠加这些数据集将识别甲基化改变的CPG，这也与基因表达和癌症易感性的变化有关。这些站点将被视为候选人，导致CRC风险改变。为了了解饮食纤维和肠道菌群在分子水平上的作用，在肿瘤形成开始前后，使用染色质免疫沉淀（CHIP）测定，BISUIMFITE诱变之前和之后，将在几个候选基因上进行表观遗传事件，然后进行测序和DNase I HyperSenitivity Assante hypersenitivity Assays。这项工作应阐明纤维对CRC敏感性的影响，并可能导致CRC的新预防策略。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation.

DOI：
10.1016/j.molcel.2012.08.033
发表时间：
2012-11-30
期刊：
MOLECULAR CELL
影响因子：
16
作者：
Donohoe, Dallas R.;Collins, Leonard B.;Wali, Aminah;Bigler, Rebecca;Sun, Wei;Bultman, Scott J.
通讯作者：
Bultman, Scott J.

Combined gene dosage requirement for SWI/SNF catalytic subunits during early mammalian development.

DOI：
10.1007/s00335-012-9433-z
发表时间：
2013-02
期刊：
MAMMALIAN GENOME
影响因子：
2.5
作者：
Smith-Roe, Stephanie L.;Bultman, Scott J.
通讯作者：
Bultman, Scott J.

Metaboloepigenetics: interrelationships between energy metabolism and epigenetic control of gene expression.

DOI：
10.1002/jcp.24054
发表时间：
2012-09
期刊：
JOURNAL OF CELLULAR PHYSIOLOGY
影响因子：
5.6
作者：
Donohoe, Dallas R.;Bultman, Scott J.
通讯作者：
Bultman, Scott J.

BRG1 and BRM function antagonistically with c-MYC in adult cardiomyocytes to regulate conduction and contractility.

DOI：
10.1016/j.yjmcc.2017.02.003
发表时间：
2017-04
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Willis MS;Holley DW;Wang Z;Chen X;Quintana M;Jensen BC;Tannu M;Parker J;Jeyaraj D;Jain MK;Wolfram JA;Lee HG;Bultman SJ
通讯作者：
Bultman SJ

Microbial regulation of glucose metabolism and cell-cycle progression in mammalian colonocytes.