Gastrointestinal transformation of Fuzi alkaloids and their modulatory effects on gut microbiota

Aconitum carmichaelii Debx (Fuzi), a widely used herbal medicine in Traditional Chinese Medicine, is rich in diterpenoid alkaloids with well-documented pharmacological activities. Despite its extensive clinical use, the metabolic fate of Fuzi alkaloids during gastrointestinal digestion and their interactions with gut microbiota remain poorly understood. This study investigated the digestive and colonic fermentation-associated transformations of Fuzi alkaloids and evaluated their modulatory effects on gut microbiota composition and metabolic activity. The abundance and transformation of diester diterpenoid alkaloids (DDAs) and monoester diterpenoid alkaloids (MDAs) were monitored throughout digestion. While amine diterpenoid alkaloids (ADAs) formed from hydrolysis of DDAs and MDAs were quantified using UPLC-MS. Short-chain fatty acids (SCFAs) and reducing sugars were measured at defined time points during digestion and fermentation, and changes in gut microbial composition were systematically assessed. DDAs declined markedly during the oral-gastric phase and were below the detection limit in the small intestinal phase, accompanied by a significant increase in ADA bioaccessibility. Reducing sugar levels peaked in the small intestinal phase but decreased during fermentation, whereas SCFA production increased substantially. Microbiota analysis revealed reduced relative abundances of Bacteroidota and Firmicutes, alongside an enrichment of Actinobacteriota, particularly Bifidobacterium. These findings provide critical insights into the metabolic transformations of Fuzi and its alkaloids during digestion, as well as their potential to modulate gut microbiota composition and activity, thereby highlighting the importance of further investigations into the clinical relevance and safety implications of Fuzi consumption.