Terminalia chebula decoction-processed Aconitum kusnezoffii preserves therapeutic effects through regulation of metabolism and intestinal microbiota

Background Aconitum kusnezoffii Reichb. is a commonly used medicinal herb in Mongolian medicine (a branch of traditional Chinese medicine). Processing A. kusnezoffii with a decoction of Terminalia chebula Retz. represents a characteristic and widely applied detoxification method in Mongolian medicine practice. This processing technique can reduce the toxicity of A. kusnezoffii . However, the underlying mechanisms remain insufficiently understood. Methods Normal Sprague–Dawley (SD) rats were randomly divided into the control (Ctrl), raw A. kusnezoffii (SCW), and Terminalia chebula decoction-processed A. kusnezoffii (HZZCW) groups. The metabolic profiles of rat feces and intestinal microbiota were detected. Hematoxylin and eosin (H&E) staining and enzyme-linked immunosorbent assay (ELISA) were performed to verify the toxicity of A. kusnezoffii . Western blot (WB) and RT-qPCR were used to assess the expression of the PI3K/AKT signaling pathway. In addition, a collagen-induced arthritis (CIA) model was established to evaluate the anti-inflammatory effect. Results Metabolomic analysis revealed that processing A. kusnezoffii with Terminalia chebula decoction significantly altered metabolic pathways, particularly those related to ubiquinone biosynthesis, porphyrin and pyrimidine metabolism. The results of 16S rDNA sequencing showed that the processed product markedly changed the α-diversity of the gut microbiota and reduced the relative abundance of Xanthomonas and Corynebacterium. Pharmacodynamic evaluation indicated that HZZCW reduced the toxicity of raw A. kusnezoffii by regulating the levels of malondialdehyde (MDA), lactate dehydrogenase (LDH), and superoxide dismutase (SOD), while activating the PI3K/AKT pathway to maintain its therapeutic efficacy. Furthermore, the CIA model confirmed its significant anti-inflammatory activity. Conclusion Terminalia chebula Decoction-processed A. kusnezoffii may exert its pharmacodynamic effects through multiple mechanisms, including modulation of ubiquinone biosynthesis, porphyrin metabolism, and pyrimidine metabolism, regulation of the intestinal microbiota, and activation of the PI3K/AKT signaling pathway.