SUMMARY
Highlights
We identified Clostridium innocuum as a key player in gut progesterone metabolism.
Progesterone is converted into epipregnanolone with negligible progestogenic activity.
We identified the enzyme and mechanisms of microbial epipregnanolone production.
C. innocuum caused decreased serum progesterone and follicular arrest in female mice.
C. innocuum is a causal factor of progesterone resistance in women taking progesterone.
In brief Chen et al. identified Clostridium innocuum as a major species involved in gut progesterone metabolism, with epipregnanolone as the main product, and elucidated the molecular mechanisms. C. innocuum inactivates gut progesterone in female mice, leading to decreased circulating progesterone levels. C. innocuum is also a causal factor of follicular arrest.
Levels of progesterone, an endogenous female hormone, increase after ovulation; progesterone is crucial in the luteal phase to maintain successful pregnancy and prevent early miscarriage. Both endogenous and exogenous progesterone are recycled between the liver and gut; thus, the gut microbiota regulate host progesterone levels by inhibiting enterohepatic progesterone circulation. Our data indicated Clostridium innocuum as a major species involved in gut progesterone metabolism in women with infertility. C. innocuum converts progesterone into the neurosteroid epipregnanolone (with negligible progestogenic activity). We purified and characterized the corresponding enzyme, namely NADPH-dependent 5β-dihydroprogesterone reductase, which is highly oxygen sensitive and whose corresponding genes are prevalent in C. innocuum. Moreover, C. innocuum–administered female C57BL/6 mice (aged 7 weeks) exhibited decreased serum progesterone levels (∼35%). Clostridium-specific antibiotics (metronidazole) restored low serum progesterone levels in these mice. Furthermore, prolonged C. innocuum administration (12 weeks) arrested ovarian follicular development in female mice. Cytological and histological analyses indicated that C. innocuum may cause luteal phase insufficiency and affect menstrual regularity. Our findings suggest C. innocuum as a causal factor of progesterone resistance in women taking progesterone.
Competing Interest Statement
The authors have declared no competing interest.