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

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.