The gut metabolite 3-hydroxyphenylacetic acid rejuvenates spermatogenic dysfunction in aged mice through GPX4-mediated ferroptosis

Microbiome

Research

Yuzhuo Yang¹  Jing Hang²  Qi Wen²  Qiancheng Zhao³  Jianxing Cheng³  Yalei Cao³  Jiaming Weng³  Yu Xi³  Kai Hong⁴  Zhe Zhang⁴  Zirun Jin⁵  Hui Jiang⁶ 

[1] Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China;Department of Obstetrics and Gynecology, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, 49 North Garden Road, Haidian District, 100191, Beijing, China;Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing, China;Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproduction, Beijing, China;National Clinical Research Center for Obstetrics and Gynecology, Beijing, China;Department of Urology, Center for Reproductive Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, 100191, Beijing, China;Department of Urology, Center for Reproductive Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, 100191, Beijing, China;Department of Obstetrics and Gynecology, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, 49 North Garden Road, Haidian District, 100191, Beijing, China;Department of Urology, Center for Reproductive Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, 100191, Beijing, China;Department of Urology, Peking University First Hospital, Xishiku Road, Xicheng District, 100034, Beijing, China;Institute of Urology, Peking University, Beijing, China;Department of Andrology, Peking University First Hospital, Beijing, China;Department of Urology, Peking University First Hospital, Xishiku Road, Xicheng District, 100034, Beijing, China;Institute of Urology, Peking University, Beijing, China;Department of Andrology, Peking University First Hospital, Beijing, China;

关键词: Aging;    Spermatogenic dysfunction;    Gut microbiota;    3-Hydroxyphenylacetic acid;    Ferroptosis;   

DOI  :  10.1186/s40168-023-01659-y

 received in 2023-05-02, accepted in 2023-08-28,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAging-related fertility decline is a prevalent concern globally. Male reproductive system aging is mainly characterized by a decrease in sperm quality and fertility. While it is known that intestinal physiology changes with age and that microbiota is shaped by physiology, the underlying mechanism of how the microbiota affects male reproductive aging is still largely unexplored.ResultsHere, we utilized fecal microbiota transplantation (FMT) to exchange the fecal microbiota between young and old mice. Cecal shotgun metagenomics and metabolomics were used to identify differences in gut microbiota composition and metabolic regulation during aging. Our results demonstrated that FMT from young to old mice alleviated aging-associated spermatogenic dysfunction through an unexpected mechanism mediated by a gut bacteria-derived metabolite, 3-hydroxyphenylacetic acid (3-HPAA). 3-HPAA treatment resulted in an improvement of spermatogenesis in old mice. RNA sequencing analysis, qRT-PCR and Western blot revealed that 3-HPAA induced an upregulation of GPX4, thereby restraining ferroptosis and restoring spermatogenesis. These findings were further confirmed by in vitro induction of ferroptosis and inhibition of GPX4 expression.ConclusionsOur results demonstrate that the microbiome-derived metabolite, 3-HPAA, facilitates spermatogenesis of old mice through a ferroptosis-mediated mechanism. Overall, these findings provide a novel mechanism of dysregulated spermatogenesis of old mice, and suggest that 3-HPAA could be a potential therapy for fertility decline of aging males in clinical practice.5pcYmaM61yMj7bgSVcSwU1Video Abstract

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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