Key targets and mechanisms by which gut microbiota-derived metabolites regulate Alzheimer's disease through the immune - inflammatory pathway: Based on network pharmacology and molecular docking.

This study integrated network pharmacology, bioinformatics, and molecular docking to explore potential immune-inflammatory pathways associated with the relationship between gut microbiota-derived metabolites and Alzheimer's disease (AD). A total of 260 gut microbiota - derived metabolites were initially retrieved, and 196 common targets were identified by intersecting predicted metabolite-associated targets with AD-related targets. Further screening identified 14 key overlapping targets, including IL6, NFKB1, IL1B, PTGS2, TLR4, and PPARG. Protein-protein interaction (PPI) network analysis identified IL6, NFKB1, IL1B, CXCL8, PPARG, FOS, and JUN as central hub genes. Functional enrichment analyses indicated that these targets were mainly involved in immune-inflammatory responses, response to lipopolysaccharide, oxidative stress-related processes, and regulation of apoptosis. KEGG pathway analysis further suggested that the overlapping targets were associated with several inflammation-related signaling pathways, including the NOD-like receptor, TNF, NF-κB, and MAPK signaling pathways. In silico pharmacokinetic and toxicity evaluation showed that several representative metabolites exhibited heterogeneous but informative drug-likeness and pharmacokinetic/toxicity-related profiles relevant to gut-brain-axis hypothesis generation. Molecular docking was performed as an exploratory structural assessment and suggested that selected metabolites, including Enterodiol, Coumarin, and 3,9-dihydroxy-6H-benzo[c]chromen-6-one, showed top-ranked predicted docking poses in computationally identified surface-accessible pockets of representative hub proteins such as IL6 and NFKB1, with docking scores ranging from - 6.8 to - 8.1 kcal/mol. These docking scores were interpreted only as qualitative descriptors of predicted structural compatibility and were not used to infer quantitative biological activity, target inhibition, or therapeutic efficacy. Overall, this study prioritizes a potential multi-target immune-inflammatory network centered on IL6, NFKB1, and IL1B, providing a hypothesis-generating framework for understanding the possible role of gut microbiota-derived metabolites in AD-related neuroimmune regulation. Further experimental studies are required to validate the predicted metabolite-target associations and clarify their biological relevance.