肠道微生物调控颗粒细胞凋亡参与化疗损伤性卵巢早衰发病的机制研究

颗粒细胞凋亡是化疗损伤性卵巢早衰（CIPOF）的重要原因，严重影响绝经前化疗女性生育力和生活质量。前期实验发现：CIPOF患者肠道菌群组成和功能显著改变，肠道共生菌Lactobacillus、Butyricicoccus以及代谢物2,4-DHBA含量明显降低；CIPOF粪菌液加剧顺铂卵巢毒性；补充2,4-DHBA可改善颗粒细胞凋亡和POF症状，降低JNK磷酸化水平、FoxO3表达以及凋亡蛋白clv-Caspase-9和Bax表达水平。因此，肠道微生物或是化疗药物诱发POF的重要媒介，通过2,4-DHBA调控JNK/FoxO3通路介导颗粒细胞凋亡参与CIPOF发病。本研究拟以JNK/FoxO3通路为切入点，从人群队列、多组学分析、体内外实验等水平对CIPOF肠道菌群与宿主互作机制开展完备论证，阐明以2,4-DHBA为代表的菌群代谢物调控CIPOF发病分子机制，为CIPOF临床防治开辟新思路。

Chemotherapy-induced premature ovarian failure (CIPOF) damages female fertility and quality of life. Apoptosis of granulosa cells is one of the main causes of CIPOF. Our previous works showed significant alteration in gut microbiota in CIPOF patients, including the decrease of Lactobacillus, Butyricicoccus and 2,4-DHBA. Furthermore, CIPOF fecal content could aggravate the ovarian impairment of cisplatin. At the same time, we found that 2,4-DHBA could alleviate the cisplatin-induced apoptosis of ovarian granulosa cells and POF symptoms by reducing the level of JNK phosphorylation, FOXO3 expression, clv-Caspase-9 and Bax expression. This suggests that CIPOF could be regulated by intestinal bacteria, which potentially play a role through 2,4-DHBA in regulating the apoptosis of granulosa cells. Focusing on the JNK/FOXO3 signaling pathway, this study is to demonstrate the interaction of intestinal flora and host in CIPOF. By recruiting human cohort and performing multi-omics analysis, along with in vitro and in vivo experiments, we aim to clarify the mechanism of intestinal flora and 2,4-HDBA in clinical alleviating CIPOF.