Paridis rhizoma total saponins ameliorate abnormal uterine bleeding via regulating Proteus mirabilis 2024-mediated estrogen metabolism in the gut-reproductive axis.

BACKGROUND AND PURPOSE: Abnormal uterine bleeding (AUB) is a highly prevalent gynecological disorder worldwide, for which first-line steroid hormone therapy is limited by well-documented adverse effects. Paridis rhizoma total saponins (PRS) are the core pharmacodynamic material basis of Gongxuening Capsules, a classic traditional Chinese medicine (TCM) formula with well-validated clinical hemostatic efficacy for AUB. However, its active ingredients and underlying therapeutic mechanisms remain largely unclear, especially the potential regulatory role of the gut-reproductive axis. This study aimed to systematically elucidate the anti-AUB mechanism of PRS.

METHODS

The therapeutic effect of PRS was evaluated in a rat model of AUB induced by incomplete abortion in early pregnancy. Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was used to characterize the chemical profile and in vivo distribution of PRS. Integrative analysis of uterine transcriptomics, fecal multi-omics, fecal microbiota transplantation, bacterial isolation, gene functional validation, and administration of individual monomeric compound was performed to decipher the mechanism.

RESULTS

PRS dose-dependently alleviated uterine and ovarian pathological damage, mitigated uterine inflammation and ovarian apoptosis, and restored systemic estrogen homeostasis in AUB rats, characterized by significantly reduced serum estradiol (E2) and elevated estrone (E1). Polyphyllin I (PI) and Paris saponin VII (PVII) were identified as the core active monomers of PRS. We first isolated and identified Proteus mirabilis 2024 (PM_2024) as the key bacterial strain driving the conversion of E2 to E1, and confirmed that the PM_2024_3180 gene was the core functional element encoding short-chain dehydrogenase/reductase (SDR) for estrogen metabolism. Mechanistically, PRS and its active monomers PI/PVII significantly enriched intestinal PM_2024, enhanced its E2 metabolic capacity, upregulated ovarian HSD17B2/HSD17B8 expression, and modulated FKBP5/PGR within the uterine estrogen signaling pathway to exert anti-AUB effects.

CONCLUSION

This study elucidates a novel estrogen-mediated gut-reproductive axis mechanism of PRS against AUB for the first time, deciphers the scientific connotation of the classic hemostatic TCM Paridis rhizoma, and provides a novel gut microbiota-targeted microecological therapeutic strategy for AUB and other hormone-related gynecological disorders.