Bazi Bushen Capsule Modulates Akkermansia muciniphila and Spermidine Metabolism to Attenuate Brain Aging in SAMP8 Mice

Ethnopharmacological relevance Bazi Bushen Capsule (BZBS), a traditional Chinese medicine formulation composed of multiple bioactive herbal components, has been validated in multicenter randomized double-blind controlled trials for its potent anti-aging properties. Previous studies from our group have demonstrated that BZBS effectively restores gut microbiota homeostasis and attenuates the impairment of intestinal barrier function, thereby ameliorating age-related cognitive decline. However, the specific molecular mechanisms by which BZBS modulates key microbial-metabolite networks to delay brain aging remain poorly understood and warrant further investigation. Aim of the study This study aims to elucidate the key microbiota-metabolite networks through which BZBS improves cognitive function and delays brain aging in senescence-accelerated mouse-prone 8 (SAMP8) mice. Materials and methods Eight-week-old male SAMP8 mice were used as experimental models, randomly divided into Model, BZ-low (0.5 g/kg/d BZBS), BZ-high (1 g/kg/d BZBS), and RAPA (2 mg/kg/d rapamycin) groups. Senescence-accelerated mouse resistant 1 (SAMR1) mice served as the control group. Cognitive function was assessed using the Barnes Maze test and the three-chamber social test. The structural damage and pathological changes in the brain tissue were evaluated through transcranial Doppler, micro-computed tomography, Nissl staining, and Western blot analysis. Next, the intestinal barrier function was detected by hematoxylin-eosin (HE) staining, periodic acid-Schiff (PAS) staining, and immunofluorescence (IF) staining. Characteristic bacteria were identified by 16S rRNA sequencing, and metabolomic profiling was performed using non-targeted metabolomics. Akkermansia muciniphila (Akk) was cultured, and fecal microbiota transplantation (FMT) was employed to evaluate its contribution to intestinal barrier function. Results The study revealed that BZBS therapy not only enhances cognitive capabilities but also restores the intestinal barrier function. Akk was identified as a key regulatory agent mediating the therapeutic effects of BZBS. BZBS administration significantly increased the abundance of Akk and modulated its metabolite profile, particularly components associated with spermidine, thereby reinforcing the intestinal barrier and mitigating age-related cognitive decline. Furthermore, this study demonstrated that Akk, administered via fecal microbiota transplantation, alleviated dextran sulfate sodium (DSS)-induced colitis.. Conclusion The results showed that BZBS capsule, a traditional Chinese medicine, may delay brain aging in SAMP8 mice by modulating Akk and its spermidine production.