Bifidobacterium pseudocatenulatum AL44 ameliorates D-galactose-induced cognitive impairment by modulating the gut-brain axis.

Age-related cognitive decline, particularly deficits in learning and memory, has become a major health challenge among older adults. Probiotics have emerged as potential dietary interventions for maintaining cognitive resilience. This study investigated the neuroprotective effects of Bifidobacterium pseudocatenulatum AL44 against cognitive dysfunction in D-galactose (D-gal)-treated mice and elucidated the underlying gut microbiota-brain mechanisms. AL44 intervention markedly improved spatial learning and memory, attenuated hippocampal neuronal damage, and suppressed neuroinflammation and oxidative stress. Furthermore, AL44 upregulated the expression of brain-derived neurotrophic factor (BDNF), neuronal nuclei (NeuN), and synaptic proteins, while attenuating apoptosis through modulation of the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein/cysteine-aspartic acid protease 3 signaling pathway. These neuroprotective effects were linked to gut microbiota remodeling, characterized by the enrichment of Bacteroides, preservation of intestinal barrier integrity, and reduced circulating endotoxin levels. Moreover, AL44 treatment reshaped systemic metabolic profiles, particularly amino acid metabolism, leading to increased levels of citrulline, betaine, and kynurenine. Fecal microbiota transplantation confirmed that these neuroprotective effects were transferable via AL44-modulated gut microbiota, supporting the hypothesis that microbiota remodeling contributes to the neuroprotective effects associated with AL44 treatment. These results position AL44 as a promising probiotic candidate for the dietary management of age-related cognitive decline via modulation of the gut-brain axis.