Ramulus mori (Sangzhi) alkaloids improve intestinal oxidative damage and inflammation in DHEA-induced polycystic ovary syndrome rats via gut microbiota and metabolite modulation.

Introduction: Intestinal dysbiosis, characterized by reduced diversity and enrichment of pro-inflammatory taxa, is implicated in the pathogenesis of polycystic ovary syndrome (PCOS). Ramulus mori (Sangzhi) alkaloids (SZ-A), approved in China for type 2 diabetes with broad metabolic effects, remain untested as a microbiota-targeted intervention for PCOS. Methods: In a dehydroepiandrosterone (DHEA)-induced rat model of PCOS, we evaluated the therapeutic efficacy of SZ-A and its underlying microbiota-metabolite interactions through integrated assessments of reproductive and endocrine-metabolic function, oxidative stress, inflammatory cytokines, and gut microbiota and serum metabolite profiles. Results: Relative to SD rats, PCOS rats showed approximately 10-fold higher cystic follicle burden and a one-third reduction in corpora lutea, with serum testosterone rising from 0.12 ± 0.08 to 0.27 ± 0.08 ng/mL, total bile acids falling from 34.22 ± 5.52 to 20.63 ± 4.94 μM, and HOMA-IR significantly increased (all p < 0.05). SZ-A treatment reduced cystic follicles, restored estrous cyclicity and luteal formation, and shifted testosterone, total bile acids, and HOMA-IR toward SD levels. At the molecular level, SZ-A appears to act by remodeling gut microbiota composition and serum metabolite profiles. SZ-A significantly shifted microbial β-diversity in PCOS rats while retaining a community dominated by Bacteroidetes and Firmicutes with Discussion: Collectively, these findings indicate that SZ-A alleviates PCOS by attenuating intestinal oxidative stress and normalizing gut microbiota-metabolite interactions, and highlight fenoldopam as a potential effector, supporting SZ-A as a promising therapeutic candidate for PCOS.