Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Saikosaponin A restores the IDO1-driven gut-testis kynurenine axis to alleviate oligozoospermia.
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Li Yaqiu, Zhang Boqi, He Guitian, Shen Caomeihui, Chang Fuqiang, Yang Junjun, Wang Sihui, Wang Yueying, Zong Jinxin, Luo Yuxin, Wang Nan, Sun Yanan, Sui Yue, Wu Mengting, Lu Dongjin, Li Chunjin, Zhou Xu
Аннотация
BACKGROUND: Busulfan (Bus)-induced oligozoospermia still lacks a disease-modifying therapy, and its pathogenesis has been largely attributed to germ-cell DNA damage. Emerging evidence indicates that microbiota-derived metabolites are key determinants of spermatogenic failure. Saikosaponin A (SSA), a major triterpenoid from Bupleurum, has never been evaluated in male infertility. Consequently, its regulatory role in the gut microbiota-metabolite axis and causal efficacy remain completely undefined.
PURPOSE: To determine whether SSA rescues Bus-induced oligozoospermia via the gut microbiota-metabolite axis, and to uncover a novel pathogenic mechanism of Bus, beyond the known germ-cell DNA damage pathway, revealing a gut microbiota-metabolite-mediated regulatory axis.
METHODS: Bus-induced oligozoospermia was established in male C57BL/6 J mice and followed by SSA treatment. Sperm count, testis index, and histology were assessed; spermatogenic proteins were quantified by Western blot. Microbiota and metabolites were profiled via 16S rDNA sequencing; serum metabolomics; and fecal microbiota transplantation (FMT) from SSA donors. Testicular transcriptome sequencing identified differentially expressed pathways. Indole-3-carboxaldehyde (ICA) administration and Kynurenine (Kyn) supplementation were performed in parallel. Indoleamine 2,3-dioxygenase 1 (IDO1) protein level and activity were measured by Western blot and ELISA. ICA-IDO1 interaction was verified by molecular docking and surface plasmon resonance (SPR). The l-tryptophan/L-kynurenine ratio was determined by targeted liquid chromatography-mass spectrometry (LC-MS/MS).
RESULTS: SSA restored sperm count, testis index, and tubular architecture while increasing DDX4, DAZL, and SYCP1/3. It reversed Bus-induced Lactobacillus expansion, decreased colonic ICA, relieved ICA-mediated IDO1 inhibition, thereby restoring colonic IDO1 activity, and elevated Kyn. FMT from SSA donors reproduced these protective effects. Transcriptomics showed up-regulation of AKT-mediated targets: pro-growth (CCND1), antioxidant (NRF2), and anti-apoptotic (Bcl-2), with down-regulation of pro-apoptotic genes. Mechanistically, SSA reshaped the gut microbiota, lowered colonic ICA, relieved ICA-mediated IDO1 inhibition, and restored Kyn-dependent testicular antioxidant and anti-apoptotic signaling.
CONCLUSION: By reshaping the gut microbiota, reducing colonic ICA and relieving ICA-mediated IDO1 inhibition, SSA restored Kyn-driven testicular antioxidant and anti-apoptotic signaling. This suggests a microbiota-directed, non-hormonal candidate preclinical approach for Bus-induced oligozoospermia; the gut microbiota-ICA-IDO1-Kyn axis offers a framework awaiting human validation.
PURPOSE: To determine whether SSA rescues Bus-induced oligozoospermia via the gut microbiota-metabolite axis, and to uncover a novel pathogenic mechanism of Bus, beyond the known germ-cell DNA damage pathway, revealing a gut microbiota-metabolite-mediated regulatory axis.
METHODS: Bus-induced oligozoospermia was established in male C57BL/6 J mice and followed by SSA treatment. Sperm count, testis index, and histology were assessed; spermatogenic proteins were quantified by Western blot. Microbiota and metabolites were profiled via 16S rDNA sequencing; serum metabolomics; and fecal microbiota transplantation (FMT) from SSA donors. Testicular transcriptome sequencing identified differentially expressed pathways. Indole-3-carboxaldehyde (ICA) administration and Kynurenine (Kyn) supplementation were performed in parallel. Indoleamine 2,3-dioxygenase 1 (IDO1) protein level and activity were measured by Western blot and ELISA. ICA-IDO1 interaction was verified by molecular docking and surface plasmon resonance (SPR). The l-tryptophan/L-kynurenine ratio was determined by targeted liquid chromatography-mass spectrometry (LC-MS/MS).
RESULTS: SSA restored sperm count, testis index, and tubular architecture while increasing DDX4, DAZL, and SYCP1/3. It reversed Bus-induced Lactobacillus expansion, decreased colonic ICA, relieved ICA-mediated IDO1 inhibition, thereby restoring colonic IDO1 activity, and elevated Kyn. FMT from SSA donors reproduced these protective effects. Transcriptomics showed up-regulation of AKT-mediated targets: pro-growth (CCND1), antioxidant (NRF2), and anti-apoptotic (Bcl-2), with down-regulation of pro-apoptotic genes. Mechanistically, SSA reshaped the gut microbiota, lowered colonic ICA, relieved ICA-mediated IDO1 inhibition, and restored Kyn-dependent testicular antioxidant and anti-apoptotic signaling.
CONCLUSION: By reshaping the gut microbiota, reducing colonic ICA and relieving ICA-mediated IDO1 inhibition, SSA restored Kyn-driven testicular antioxidant and anti-apoptotic signaling. This suggests a microbiota-directed, non-hormonal candidate preclinical approach for Bus-induced oligozoospermia; the gut microbiota-ICA-IDO1-Kyn axis offers a framework awaiting human validation.