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Role of Bile Acids and Gut Bacteria in GI Diseases

胆汁酸和肠道细菌在胃肠道疾病中的作用

基本信息

批准号：
8698288
负责人：
PHILLIP B HYLEMON
金额：
--
依托单位：
VA VETERANS ADMINISTRATION HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8698288
关键词：
Acids Active Sites Amino Acids Androgens Applications Grants Bacteria Bile Acids Bile fluid Binding Biochemical Pathway Biological Assay Blood Chemicals Chenodeoxycholic Acid Cholelithiasis Cholesterol Cholic Acids Clinical Research Clostridium Colon Colon Carcinoma DNA Data Deoxycholic Acid Detection Development Diet Disease Ecosystem Enterohepatic Circulation Enzyme Kinetics Enzymes Feces Future Gene Expression Profile Genes Glucocorticoids Goals Growth Health Hospitals Human Human Microbiome Hydro-Lyases Incidence Individual Intestines Laboratories Lithocholic Acid Liver Mammalian Cell Metabolic Biotransformation Metabolism Molecular Monitor Oxidoreductase Pathway interactions Patients Physiological Play Population Prostate Proteins RNA Reverse Transcriptase Polymerase Chain Reaction Risk Role Sampling Secondary to Site-Directed Mutagenesis Steroid 17-alpha-monooxygenase Steroids Sterols Substrate Specificity Techniques Time Tissues Virginia arm dehydroxylation disorder risk in vivo inhibitor/antagonist men millimeter mutant novel patient population steroid hormone three dimensional structure tool transcriptome sequencing tumor growth

项目摘要

DESCRIPTION (provided by applicant): The human colon harbors one of the most densely populated bacterial ecosystems known (>1011 bacteria/g feces). Cholic acid (CA) and chenodeoxycholic acid (CDCA) are primary bile acids synthesized from cholesterol in the liver. Bile acids undergo enterohepatic circulation several times each day. Primary bile acids entering the colon are deconjugated and free bile acids are biotransformed to more than 20 different metabolites by gut bacteria. The major biotransformation is 7¿-dehydroxylation (7¿- DeOH) of CA and CDCA yielding the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. Hydrophobic secondary bile acids are highly toxic to mammalian cells and can accumulate to high levels (>70%) in the bile acid pool of some individuals as the human liver cannot 7¿-hydroxylate secondary bile acids. High levels of DCA in blood, bile, and feces have been correlated with an increase risk of colon cancer and cholesterol gallstone disease, in some patients. The formation of secondary bile acids is carried out by a few species of the genus Clostridium and the level of these bacteria in feces is correlated with DCA levels in bile. The biochemical pathway of bile acid 7¿-DeOH has been elucidated by our group. However, many of the genes encoding enzymes in this pathway have not been isolated and characterized nor have the 3D structure of key enzymes in this pathway determined. Some strains of 7¿- dehydroxylating bacteria can convert glucocorticoids into C-19 androgenic compounds and the genes encoding these enzymes have not been isolated. Isolation of these genes is crucial for the development of molecular techniques (RT-PCR) to easily monitor intestinal bile acid and glucocorticoid metabolism and pharmacological or dietary ways to decrease formation of secondary bile acids and C-19 androgenic compounds. Subaim 1A. Identify CA, allo-CA, and glucocorticoid inducible genes from the human bile acid 7¿-dehydroxylating bacterium, Clostridium scindens ATCC 35704, via a wholetranscriptome approach (RNAseq). Subaim 1B. Develop quantitative PCR assays for key genes involved in allo-DCA and C-19 androgen formation. Aim 2. Characterize the allo-CA and glucocorticoid inducible enzymes from Clostridium scindens ATCC 35704 catalyzing the formation of allo-DCA acid and C-19 androgens, respectively. Aim 3: Determine the 3D structure of bile acid 7¿ and 7¿-dehydratases, the rate limiting enzymes in bile acid 7¿/7¿-DeOH, from Clostridium scindens. The results of these studies will give us the tools to carry out clinical studies to determine the most effective ways to decrease DCA in the bile acid pool with the aim of decreasing the risk of colon cancer and cholesterol gallstones, in some patients.

描述（由申请人提供）：