<i>Clostridium innocuum</i> , an opportunistic gut pathogen, inactivates host gut progesterone and arrests ovarian follicular development

\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 <i>Clostridium innocuum</i> as a major species involved in gut progesterone metabolism in women with infertility. <i>C. innocuum</i> 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 <i>C. innocuum</i>. Moreover, <i>C. innocuum</i>-administered female C57BL/6 mice (aged 7 weeks) exhibited decreased plasma progesterone levels (~35%). <i>Clostridium</i>-specific antibiotics (metronidazole) restored low plasma progesterone levels in these mice. Furthermore, prolonged <i>C. innocuum</i> administration (12 weeks) arrested ovarian follicular development in female mice. Cytological and histological analyses indicated that <i>C. innocuum</i> may cause luteal phase insufficiency and affect menstrual regularity. Our findings suggest <i>C. innocuum</i> as a causal factor of progesterone resistance in women taking progesterone.