Lactobacillus johnsonii attenuates ovarian aging by remodeling the gut–ovary axis

Abstract

Reproductive aging, accompanied by abnormal levels of sex hormones, affects overall health and poses a particular threat to women. Gut microbiota plays a key role in regulating host aging and is promising for alleviating reproductive aging. Here, we found that gut commensal Lactobacillus johnsonii ( L. johnsonii ) declined in accordance with ovarian failure in female aging mice. Restoring L. johnsonii partially rescued hormone levels in age‐ or chemically‐ induced ovarian decline murine models, thereby reversing cognitive decline and extending lifespan. Indole‐3‐propionic acid (IPA), the bioactive metabolite of L. johnsonii , promoted granulosa cell proliferation to upregulate sex‐steroid output by activating the AhR‐YAP signaling pathway. L. johnsonii ‐derived LdhA was identified as the essential enzyme for indole‐3‐lactic acid (ILA) biosynthesis, thereby increasing downstream IPA. In addition, significant positive correlations were observed between ovarian function and fecal L. johnsonii , as well as IPA levels. These findings establish L. johnsonii as a promising probiotic strategy for alleviating ovarian aging through microbiota‐derived metabolite signaling along the gut–ovary axis.