Lee_2025_Behav.Brain.Res_499_115961

Chronic neuroinflammation is a key contributor to cognitive decline in neurodegenerative disorders, and improving gut health with probiotics has been proposed as a potential therapeutic strategy. This study investigated the neuroprotective efficacy of Lactobacillus gasseri MG4247 and Lacticaseibacillus rhamnosus MG4644 in a lipopolysaccharide (LPS)-induced mouse model of neuroinflammation-induced cognitive impairment. Compared to mice receiving LPS alone, mice cotreated with LPS and probiotics demonstrated significantly improved spatial memory as measured in the Morris water maze, working memory in the Y-maze, and associative fear learning in the passive avoidance test. These improvements were comparable to LPS model mice cotreated with the clinical acetylcholinesterase inhibitor donepezil. Enzyme-linked immunosorbent assays analysis revealed marked reductions in proinflammatory cytokines (TNF-alpha, IL-6) in both serum and hippocampus, while histological examination showed reduced neuronal degeneration in the hippocampal CA1 region of LPS model mice cotreated with probiotics. Both probiotics also enhanced gut production of the butyrate, which is known to improve the gut microbial profile and barrier function. Notably, both probiotics also significantly increased brain-derived neurotrophic factor (BDNF) expression and restored phosphorylation of protein kinase B (Akt) and cAMP-response element binding protein (CREB), components of signaling cascade essential for synaptic plasticity, memory formation, and neuronal survival under neuroinflammatory stress. These findings suggest that L. gasseri MG4247 and L. rhamnosus MG4644 mitigate LPS-induced cognitive deficits through anti-inflammatory effects and activation of the Akt/CREB/BDNF pathway. This study supports the potential of probiotics for suppressing neuroinflammation and enhancing cognitive function via neural, immune, and endocrine pathways of the gut-brain axis.