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

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

  • Microbiome. 2023 Sep 27;11(1):212. doi: 10.1186/s40168-023-01659-y.
Zirun Jin # 1 2 3 4,  Yuzhuo Yang # 5,  Yalei Cao # 1,  Qi Wen 6 7 8 9,  Yu Xi 1,  Jianxing Cheng 1,  Qiancheng Zhao 1,  Jiaming Weng 1,  Kai Hong 1 6,  Hui Jiang 10 11 12,  Jing Hang 13 14 15 16,  Zhe Zhang 17 18
Affiliations

Affiliations

  • 1 Department of Urology, Center for Reproductive Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China.
  • 2 Department of Urology, Peking University First Hospital, Xishiku Road, Xicheng District, Beijing, 100034, China.
  • 3 Institute of Urology, Peking University, Beijing, China.
  • 4 Department of Andrology, Peking University First Hospital, Beijing, China.
  • 5 Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China.
  • 6 Department of Obstetrics and Gynecology, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China.
  • 7 Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing, China.
  • 8 Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproduction, Beijing, China.
  • 9 National Clinical Research Center for Obstetrics and Gynecology, Beijing, China.
  • 10 Department of Urology, Peking University First Hospital, Xishiku Road, Xicheng District, Beijing, 100034, China. [email protected].
  • 11 Institute of Urology, Peking University, Beijing, China. [email protected].
  • 12 Department of Andrology, Peking University First Hospital, Beijing, China. [email protected].
  • 13 Department of Obstetrics and Gynecology, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China. [email protected].
  • 14 Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing, China. [email protected].
  • 15 Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproduction, Beijing, China. [email protected].
  • 16 National Clinical Research Center for Obstetrics and Gynecology, Beijing, China. [email protected].
  • 17 Department of Urology, Center for Reproductive Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China. [email protected].
  • 18 Department of Obstetrics and Gynecology, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China. [email protected].
  • # Contributed equally.
PMID: 37752615 DOI: 10.1186/s40168-023-01659-y
Abstract

Background: Aging-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.

Results: Here, 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.

Conclusions: Our 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. Video Abstract.

Keywords

3-Hydroxyphenylacetic acid; Aging; Ferroptosis; Gut microbiota; Spermatogenic dysfunction.

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