β-resorcylic acid released by Limosilactobacillus reuteri protects against cisplatin-induced ovarian toxicity and infertility

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作者：Yinglin Feng, Huimin Zheng, Chunhua Yin, Dong Liang, Siyou Zhang, Jingrui Chen, Feihong Mai, Zixin Lan, Menglin Zhu, Zhensheng Mai, Sj Shen, Thisun Jayawardana, Rong Wu, Wenli Tang, Renfang Zhang, Xiaoyun He, Shanshan Zheng, Qian Hu, Yubin Han, Yuanhao Yang, Shenhai Gong, Zhang Wang, Emad M. El-Omar, Wei Luo, Xueqin Chen, Guoqiang Chen, Pan Li, Xia Chen
期刊：Cell Reports Medicine
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Chemotherapy-induced premature ovarian insufficiency (CIPOI) triggers gonadotoxicity in women undergoing cancer treatment, leading to loss of ovarian reserves and subfertility, with no effective therapies available. In our study, fecal microbiota transplantation in a cisplatin-induced POI mouse model reveals that a dysbiotic gut microbiome negatively impacts ovarian health in CIPOI. Multi-omics analyses show a significant decrease in Limosilactobacillus reuteri and its catabolite, β-resorcylic acid, in the CIPOI group in comparison to healthy controls. Supplementation with L. reuteri or β-RA mitigates cisplatin-induced hormonal disruptions, morphological damages, and reductions in follicular reserve. Most importantly, β-RA pre-treatment effectively preserves oocyte function, embryonic development, and fetus health, thereby protecting against chemotherapy-induced subfertility. Our results provide evidence that β-RA suppresses the nuclear accumulation of sex-determining region Y-box 7, which in turn reduces Bcl-2-associated X activation and inhibits granulosa cell apoptosis. These findings highlight the therapeutic potential of targeting the gut-ovary axis for fertility preservation in CIPOI.