Postbiotics alleviate cognitive impairment and neuroinflammation via gut-brain axis and TLR4/MyD88/NLRP3 pathway

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cerebral amyloid-β deposition, neurofibrillary tangles of hyperphosphorylated tau, and chronic neuroinflammation. Growing evidence underscores the role of the gut-brain axis in mediating bidirectional communication between the gut and the central nervous system. Postbiotics, non-viable microorganisms and/or ingredients that are beneficial to the host's health, have emerged as promising modulators of brain function via this axis. Herein, we evaluated the neuroprotective effects of three postbiotics derived from Bifidobacterium animalis subsp. lactis IOBL07, Lactiplantibacillus plantarum IOB602 and Lactobacillus paracasei IOB413 in a D-galactose/AlCl₃-induced AD rats. These postbiotics ameliorated cognitive deficits and anxiety-like behaviors, reduced neuronal degeneration and Aβ accumulation, and suppressed microglial activation and neuroinflammation via the TLR4/MyD88/NLRP3 signaling pathway. 16S rDNA sequencing revealed that postbiotics intervention induced substantial gut microbiota remodeling, selectively enriching Lachnospiraceae, Ruminococcus and Lactobacillus, while depleting Muribaculaceae. Postbiotic administration also elevated fecal short-chain fatty acid levels. Metabolomics analysis identified 11 metabolites, including indole derivatives, cholinergics and niacinamides, that were uniquely enriched in the IOB602 group. These metabolites may underlie its anti-AD effects by attenuating oxidative stress, modulating neuroinflammation, and enhancing mitochondrial function. Together, these findings provide a foundation for developing postbiotic-based adjuvant therapies against AD pathogenesis.