Total glycosides of Cistanche deserticola ameliorate alcohol-induced oligoasthenozoospermia via the modulation of gut microbiota-mediated spermidine metabolism

  • Phytomedicine. 2026 Jun 23:159:158483. doi: 10.1016/j.phymed.2026.158483.
Shuo Yuan  1 ,  Jiaxin Hong  1 ,  Huanan Zhang  2 ,  Peng Gao  1 ,  Ping Yang  1 ,  Jun Lei  1 ,  Yan He  1 ,  Xinlan Fang  1 ,  Yingyuan Lu  1 ,  Bin Wang  2 ,  Pengfei Tu  3 ,  Xiao Zhang  4 ,  Yong Jiang  5
Affiliations
  • 1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, PR China.
  • 2. Dongzhimen Hospital, Beijing University of Chinese Medicine, PR China.
  • 3. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, PR China. Electronic address: [email protected].
  • 4. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, PR China. Electronic address: [email protected].
  • 5. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, PR China. Electronic address: [email protected].
PMID: 42372605 DOI: 10.1016/j.phymed.2026.158483
Abstract

Background: Oligoasthenozoospermia is a major cause of male infertility, with chronic excessive alcohol consumption being a prevalent etiology. Cistanche deserticola Ma., a traditional Chinese medicine historically employed for reproductive improvement. However, the role and mechanism in alcohol-induced reproductive dysfunction remains unexplored.

Purpose: This study aimed to elucidate the protective effect and underlying mechanism of total glycosides of C. deserticola (TGCD) against alcohol-induced oligoasthenozoospermia.

Methods: The effects of TGCD were evaluated using a NIAAA mouse model. Mechanisms were elucidated through multi-omics, fecal microbiota transplantation, Lactobacillus reuteri supplementation, spermidine supplementation, and so on. Translational relevance was assessed by patients with alcohol-induced sperm abnormalities and a public single-cell transcriptome dataset.

Results: TGCD administration significantly improved alcohol-impaired sperm quality, restored testosterone levels and testicular architecture. Mechanistically, TGCD selectively enriched L. reuteri, which enhanced spermidine production. Spermidine activated the Nrf2-mediated antioxidant pathway, thereby reducing ROS accumulation and reinstating the expression of key steroidogenic Enzymes. Critically, these findings are corroborated by clinical data showing reduced fecal L. reuteri abundance in patients with alcohol-related sperm abnormalities, as well as human testicular single-cell transcriptomic evidence of concurrent downregulation of spermidine and Nrf2 pathways in infertile patients.

Conclusion: TGCD alleviates alcohol-induced oligoasthenozoospermia via a gut microbiota-dependent mechanism involving L. reuteri-enhanced spermidine production and subsequent activation of the Nrf2 antioxidant pathway. This study not only highlights the therapeutic potential of TGCD for male infertility but also underscores the gut-testis axis as a promising target. Fecal abundance of L. reuteri emerges as a potential biomarker for clinical translation in this context.

Keywords
Gut-testis axis; Lactobacillus reuteri; Nrf2 pathway; Oligoasthenozoospermia; Spermidine; Total glycosides of Cistanche deserticola.
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