Deciphering traditional Mongolian medicine Sugemule-3 decoction: Chemical profiling and therapeutic effect evaluation against myocardial fibrosis

BACKGROUND Sugemule-3 Decoction (SD3) is developed from 'Four Continuations of Medicine', one of the traditional Mongolian medical classics compiled in the late 8th century. SD3 consists of Baidoukou (Amomum kravanh Pierre ex Gagnep.), Xianghanqin (Cuminum cyminum L.) and Biba (Piper longum L.). It has been demonstrated with significant therapeutic efficacy against cardiovascular diseases in clinic, while its underlying chemical profiles and pharmacological mechanisms remain unclear. The purpose of this study is to investigate how SD3 counteracts Isoproterenol (ISO)-induced myocardial fibrosis via gut microbiota and metabolites. METHODS SD3 components were analyzed by LC-MS and GC-MS. In ISO-induced MF mice, SD3 (14-day oral gavage) improved cardiac function and fibrosis, remodeled gut microbiota and metabolites, and regulated GPR43/NF-κB signaling, as confirmed by exogenous SCFAs. RESULTS In this study, 79 hydrophilic and 85 hydrophobic compounds were identified in SD3 using HPLC-Q-Exactive MS and GC/Q-TOF MS. SD3 improved cardiac function, reduced cardiac fibrosis and intestinal injury in mice with MF, and downregulated α-SMA and collagen I expression. It also decreased the Firmicutes/Bacteroidetes ratio and pathogenic bacteria abundance, restored SCFAs and BAs, and reduced 3-hydroxybutyrate (3-HB). Mechanistically, SD3 activated GPR43 and suppressed the NF-κB/IL-6 axis. Exogenous acetate, propionate, and valerate alleviated MF, whereas 3-HB exacerbated it. CONCLUSIONS This study presents deciphered traditional Mongolian medicine SD3 from both chemical profile and pharmacological effect against MF. Additionally, it highlights the potential significance of restoring gut homeostasis in managing long-term cardiac diseases as MF.