Congming decoction alleviates Alzheimer's Disease induced by Aβ25-35 in rats via the microbiota-metabolism-inflammation axis, demonstrating its formulation advantages.
BACKGROUND: Congming decoction (CMD) is a traditional Chinese herbal formulation traditionally employed for enhancing memory. Despite its historical use, the specific mechanisms and advantages of CMD in the context of Alzheimer's disease (AD) remain inadequately understood. PURPOSE: This study seeks to elucidate the therapeutic effects of CMD on AD in rats induced by Aβ25-35 and to clarify its underlying process through a multi-perspective approach. STUDY DESIGN AND METHODS: Cognitive function and pathological alterations were assessed using behavioral tests, hematoxylin and eosin (HE) staining, and immunohistochemistry. Fecal metabolomics analysis, conducted via ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap mass spectrometry (UHPLC-Q-Orbitrap-MS), was utilized to investigate CMD's impact on metabolic disorders. The structure of the gut microbiota was analyzed through 16S rRNA sequencing. Short-chain fatty acids (SCFAs) and bile acids (BAs) in feces, serum, and brain tissue were quantified using gas chromatography-mass spectrometry (GC-MS) and ultra-high-performance liquid chromatography-tandem quadrupole mass spectrometry (UHPLC-TQ-MS). To establish causal relationships, experiments involving antibiotic-induced microbiota depletion (ABX) and fecal microbiota transplantation (FMT) were performed. Network pharmacology and molecular docking techniques were also employed to identify potential active components and targets. Inflammatory markers were evaluated using enzyme-linked immunosorbent assay (ELISA) kits, immunohistochemistry, and immunofluorescence in brain tissue. RESULTS: CMD markedly enhanced learning and memory, mitigated pathological changes in the brain and colon, and reestablished gut microbiota equilibrium. It regulated 45 endogenous metabolites involved in BAs, α-linolenic acid, and linoleic acid metabolism. CMD also modulated the levels of SCFAs and BAs in fecal matter, serum, and brain tissue. Strong correlations were identified among gut microbiota, metabolites, and AD-related indicators. Antibiotic treatment inhibited the neuroprotective benefits of CMD, whereas FMT from CMD-treated donors successfully replicated its therapeutic benefits. Network pharmacology analysis indicated that the active components of CMD might target inflammatory pathways. Additionally, CMD exhibited a significant restorative impact on markers associated with the AKT/NF-κB signaling pathway. CONCLUSION: CMD exerts anti-AD effects by modulating the microbiota-gut-brain axis through remodeling gut microbiota, regulating metabolic homeostasis, and reducing brain inflammation. Notably, CMD demonstrated superior efficacy compared to single herbs or herb pairs.