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

• Published in: Cell reports. Medicine Vol. 5; no. 8; p. 101678
• Main Authors: Feng, Yinglin, Zheng, Huimin, Yin, Chunhua, Liang, Dong, Zhang, Siyou, Chen, Jingrui, Mai, Feihong, Lan, Zixin, Zhu, Menglin, Mai, Zhensheng, Shen, Sj, Jayawardana, Thisun, Wu, Rong, Tang, Wenli, Zhang, Renfang, He, Xiaoyun, Zheng, Shanshan, Hu, Qian, Han, Yubin, Yang, Yuanhao, Gong, Shenhai, Wang, Zhang, El-Omar, Emad M., Luo, Wei, Chen, Xueqin, Chen, Guoqiang, Li, Pan, Chen, Xia
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 20.08.2024; Elsevier
• Subjects: cisplatin-induced premature ovarian insufficiency; gut metabolome; gut microbiota; Limosilactobacillus reuteri; β-resorcylic acid; gut metabolome; cisplatin-induced premature ovarian insufficiency; β-resorcylic acid; Limosilactobacillus reuteri; gut microbiota
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101678

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. [Display omitted] •Gut bacteria and metabolite patterns are altered in premature ovarian insufficiency patients•Limosilactobacillus reuteri intake protects against chemotherapy-induced subfertility•β-resorcylic acid, a gut bacterial catabolite, also exerts protective effects•β-resorcylic acid inhibits granulosa cell apoptosis via reduction in nuclear SOX7 Subfertility is a significant adverse effect of chemotherapy in reproductive-age females. Feng et al. identify that Limosilactobacillus reuteri and its catabolite, β-resorcylic acid, protect against chemotherapy-induced subfertility by inhibiting granulosa cell apoptosis through the SOX7-BAX axis. These findings suggest promising approaches for preventing chemotherapy-induced subfertility via the “gut-ovary axis.”