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Role of Gut Bacterial Side-Chain Cleavage of Cortisol in Host 11Beta-Hydroxyandrostenedione Formation

肠道细菌皮质醇侧链裂解在宿主 11β-羟基雄烯二酮形成中的作用

基本信息

批准号：
10370361
负责人：
Jason Michael Ridlon
金额：
$ 30.25万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10370361
关键词：
Adaptive Immune System Adrenal Glands Affect Anabolism Androgen Receptor Androgens Androstenedione Androsterone Animals Bacteria Blood Circulation Bone Marrow CYP17A1 gene Carbohydrates Cells Chromosomes, Human, 16-18 Clinical Research Clostridium Colon Complex Corticosterone Dendritic Cells Disease Dose Endocrine system Endocrinology Engineering Enzymes Escherichia coli Etiology Excretory function Exhibits Family suidae Feces Flow Cytometry Future Gene Expression Gene Expression Profile Genes Germ-Free Glucocorticoids Gnotobiotic Goals Health Human Human Activities Hydrocortisone Hydroxylation Immune Immunohistochemistry In Vitro Infusion procedures Literature Lyase Lymphoid Tissue Metabolism Minor Mixed Function Oxygenases Modeling Mucous Membrane Mus Nuclear Oral Pathway interactions Patients Physiological Physiology Production Rattus Rodent Role Route Serum Side Site-Directed Mutagenesis Stable Isotope Labeling Steroids Surface Testing Tissues Urine Vitamins absorption base cytokine dehydroepiandrosterone experimental study gastrointestinal gene discovery gut bacteria gut colonization gut microbiome gut microbiota immune function immune system function improved in vivo in vivo Model innovation intravenous injection mesenteric lymph node metabolome metabolomics microbial microbiome mutant novel porcine model rectal response single-cell RNA sequencing stable isotope synthetic biology transcriptome transcriptome sequencing transcriptomics urinary

项目摘要

A major controversy exists in the endocrinology literature regarding the biosynthesis of the pro-androgen 11β- hydroxyandrostenedione (11β-OHAD). The synthesis of 11β-OHAD is thought mainly to be synthesized in the adrenal gland by 11β-hydroxylation of androstenedione (A4). Another route is through the side-chain cleavage of cortisol, although it is thought to be minor. Patients with 17-hydroxylase/C17,20-lyase (CYP17A1) deficiency fail to synthesize either cortisol or A4. When given cortisol exogenously, the urinary profile exhibits derivatives of 11β-OHAD. This suggests either a novel host enzyme, or a gut microbial enzyme responsible for side-chain cleavage of cortisol. We have identified genes in a highly active gut microbial pathway that may be responsible for the side-chain cleavage of cortisol. We hypothesize that gut microbiota are an important, and understudied component of the host endocrine system, which generate significant quantities of 11β-OHAD. This project will test this hypothesis by comparing stable isotope-labeled cortisol metabolism in germ-free pigs and pigs colonized with gut microbiomes of different complexity. We will determine effects on host colonic physiology through single- cell RNA-Seq, immunohistochemistry, and flow cytometry of immune cells. Understanding the physiological role of side-chain cleavage by gut bacteria is also important in determining future strategies to modulate pro- androgen formation. We will determine bacterial transcriptomic responses to cortisol and 11β-OHAD both in vitro and in vivo. Furthermore, to demonstrate causation between the genes responsible for cortisol side-chain cleavage (desAB) and host steroid metabolome profile, we will utilize a synthetic biology approach to engineer the desAB pathway (both wild type and inactive mutant) into E. coli and colonize the gnotobiotic pigs. These studies are expected to resolve an enigma that has existed for decades, and may result in a paradigm-shift if it can be shown that the gut microbiota contributes significantly to a quantitatively major host steroid and pro- androgen.

关于前雄激素11β-的生物合成，在内分泌学文献中存在着很大的争议