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

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

项目成果

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Jason Michael Ridlon其他文献

Jason Michael Ridlon的其他文献

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{{ truncateString('Jason Michael Ridlon', 18)}}的其他基金

Gut bacterial metabolism of the side-chain of corticosteroids
皮质类固醇侧链的肠道细菌代谢
  • 批准号:
    10703384
  • 财政年份:
    2022
  • 资助金额:
    $ 30.25万
  • 项目类别:
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
  • 批准号:
    10726864
  • 财政年份:
    2020
  • 资助金额:
    $ 30.25万
  • 项目类别:
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
  • 批准号:
    10594989
  • 财政年份:
    2020
  • 资助金额:
    $ 30.25万
  • 项目类别:
Studies towards a pan-genome and genetic manipulation of Clostridium scindens
梭菌的全基因组和遗传操作研究
  • 批准号:
    10113519
  • 财政年份:
    2020
  • 资助金额:
    $ 30.25万
  • 项目类别:
Studies towards a pan-genome and genetic manipulation of Clostridium scindens
梭菌的全基因组和遗传操作研究
  • 批准号:
    9979542
  • 财政年份:
    2020
  • 资助金额:
    $ 30.25万
  • 项目类别:
Characterization of bacterial reductases acting on the A-ring of 11-oxy-androgens
作用于 11-氧雄激素 A 环的细菌还原酶的表征
  • 批准号:
    10653436
  • 财政年份:
    2020
  • 资助金额:
    $ 30.25万
  • 项目类别:

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