Gut microbiota dysbiosis contributes to cognitive decline and is modifiable through dietary interventions. Black rice wine (BRW), a traditional Chinese fermented alcoholic beverage enriched with phenolics and containing ethanol, raises the question of whether its complex matrix confers neuroprotection. To address this, we investigated the effect of BRW on cognitive decline and microbiota-gut-brain axis (MGBA) mechanisms in a D-galactose-induced aging mouse model, using vitamin C (VC), aleurone-removed BRW (AR-BRW), and 12% ethanol as comparator groups. Metabolomic profiling revealed distinct flavonoid enrichment in BRW compared with AR-BRW. Following a 10-week treatment, BRW ameliorated gut dysbiosis, including suppression of lipopolysaccharide (LPS)-associated Desulfovibrio enrichment of acetate-producing Blautia, leading to increased SCFAs and reduced systemic LPS, which in turn restored intestinal barrier integrity. Notably, BRW preferentially enriched known flavonoid-metabolizing taxa, including Eubacterium_oxidoreducens_group and Lachnospiraceae_UCG-010, compared with AR-BRW. Concurrently, BRW attenuated microglial activation and astrocytic reactivity, preserved hippocampal neurons, and improved cognitive performance. Hierarchical clustering revealed a marked separation. For behavioral parameters, BRW and VC clustered with the control group, whereas AR-BRW and ethanol aligned with the D-galactose model. Importantly, for microbiota-metabolite-barrier indices, only BRW retained this alignment with the control group. In contrast, despite its behavioral efficacy, VC aligned with AR-BRW, whereas ethanol remained associated with the D-galactose model. Collectively, BRW exerted ethanol-independent neuroprotection superior to that of AR-BRW via an MGBA mechanism distinct from that of VC. This effect can be attributed to its unique phytochemical profile, highlighting its potential as a dietary strategy to attenuate age-related cognitive decline by targeting the MGBA.
