The gut microbiota is increasingly recognized as an important contributor to Alzheimer's disease (AD), potentially influencing disease progression through the gut-brain axis. Lactobacillus murinus (L. murinus) is a Gram-positive bacterium with established anti-inflammatory and antibacterial properties; however, the neuroprotective potential of heat-killed L. murinus (H-K L. murinus) in AD models remains unclear. In the present study, we investigated the effects of H-K L. murinus in an Aβ25-35-induced rat model. H-K L. murinus treatment significantly improved behavioral and cognitive performance while attenuating neuronal damage in the hippocampus and cerebral cortex. Untargeted metabolomic analysis identified 6-phosphogluconic acid (6-PGA) as a markedly elevated hippocampal metabolite following H-K L. murinus administration. Exogenous 6-PGA supplementation largely recapitulated the protective effects of H-K L. murinus, improving cognitive performance and preserving neuronal integrity. Mechanistically, both H-K L. murinus and 6-PGA increased NADPH and glutathione (GSH) levels, suppressed reactive oxygen species (ROS) accumulation, down-regulated Bax expression, up-regulated Bcl-2 expression, and ultimately attenuated neuronal apoptosis in Aβ25-35-treated rats. Collectively, these findings demonstrate that H-K L. murinus mitigates Aβ25-35-induced neurotoxicity and highlight hippocampal 6-PGA-associated metabolism as a potential candidate contributor to its neuroprotective effects.
