Hong-Hua-Xiao-Yao Tablet improves premenstrual syndrome via multiple mechanisms: from blood-absorbed components to gut microbiota interaction

Premenstrual syndrome (PMS), affecting more than 80% women globally with 20-30% experiencing clinically significant symptoms, lacks optimal treatments. Hong-Hua-Xiao-Yao Tablet (HHXYT) demonstrated clinical efficacy against PMS but their pharmacological mechanism remains unclear. This study employed a multi-omics approach to elucidate the systemic mechanisms by which HHXYT improves PMS. Here, we found that HHXYT administration modulated both serum metabolite profiles and target organ transcriptional profiles in PMS rats. Notably, its blood-absorbed components, particularly glycyrrhiza-derived compounds, significantly reduced neuroinflammation. Based on evidence from ex vivo and pseudo germ-free mouse models, we suggest that the gut microbiota partially mediates the therapeutic effects of HHXYT on PMS. Finally, by studying the interaction between gut microbiota and HHXYT, we confirmed that HHXYT maintain gut microbiota homeostasis and its gut microbiota-metabolized components ameliorated inflammation, oxidative stress, and hormone level disruption. Our findings demonstrate HHXYT improves PMS through dual mechanisms, including blood-absorbed components, maintain gut microbiota homeostasis and its gut microbiota-metabolized components, highlighting the important role of gut microbes in the exertion of HHXYT in ameliorating the pharmacological effects of PMS, and also provide a methodological reference for the mechanistic study of TCM compounding.