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

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2021 · $293,589

## Abstract

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.

## Key facts

- **NIH application ID:** 10127672
- **Project number:** 5R01GM134423-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Jason Michael Ridlon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $293,589
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127672

## Citation

> US National Institutes of Health, RePORTER application 10127672, Role of Gut Bacterial Side-Chain Cleavage of Cortisol in Host 11Beta-Hydroxyandrostenedione Formation (5R01GM134423-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10127672. Licensed CC0.

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