Elucidating Gut Microbiota and Microbial Metabolites as Intervention Targets for Alzheimer’s Disease

Alzheimer’s disease (AD) presents a severe global public health challenge. The gut microbiota influences the physiological and pathological processes of AD. Although extensive research has been conducted to elucidate these effects, the roles of gut microbiota and microbial metabolites in AD remain to be further explored. This study adopted an integrated network pharmacology approach coupled with multiple database mining to dissect the molecular associations among gut microbiota, microbial metabolites and AD. Gut microbiota and microbial metabolites regulate the AD mainly through the core targets MAOB, MAOA, APP, DRD2, HTR1A, SLC6A4 and IL-1β. KEGG pathway analysis revealed that neuroactive ligand–receptor interaction, Alzheimer’s disease, dopaminergic synapse and neuroactive ligand signaling were the key signaling pathways underlying the regulation of AD by gut microbiota metabolites. In addition, 33 gut microbial metabolites and numerous gut bacterial species that regulate AD were identified. Molecular docking verified the favorable binding affinity and stability between microbial metabolites and core targets. Strains from the genera Bifidobacterium, Eubacterium, Bacteroides, Clostridium, Roseburia, Enterococcus, Blautia and Escherichia sp. exhibited significant regulatory effects in AD. These findings offer scientific support for further research on the molecular mechanisms by which gut microbiota and microbial metabolites regulate AD, and also provide insights for the development of probiotics and metabolite-based interventions.