Postbiotics and the gut-brain axis: A mechanistic review on modulating neuroinflammation and cognitive aging

Aging triggers gut microbiota dysbiosis that disrupts the gut-brain axis (GBA), promoting neuroinflammation and neurodegeneration. Elderly exhibit reduced microbial diversity, depleted beneficial bacteria, and expanded pathobionts, elevating neurotoxic metabolites-lipopolysaccharides (LPS), trimethylamine-N-oxide, kynurenine derivatives, and secondary bile acids. These drive "inflammaging," blood-brain barrier breakdown, microglial activation, mitochondrial impairment, and proteinopathies in Alzheimer's and Parkinson's disease. Conversely, neuroprotective metabolites from commensals-short-chain fatty acids, indole-3-propionic acid, and urolithins-preserve gut integrity, suppress inflammation, upregulate BDNF for synaptic plasticity, and enhance mitophagy. Postbiotics, stable probiotic-derived bioactives (butyrate, polyphenol metabolites, and lactate derivatives), surpass live probiotics in safety and precision. They modulate GBA via histone deacetylase inhibition, GPR41/43 signaling, NF-κB blockade, and microglial M2 shift, blocking LPS translocation and bolstering neuronal resilience. Preclinical rodent studies demonstrate robust neuroprotection, but human translation reveals challenges: inter-individual microbiota variability (diet/genetics/comorbidities), inconsistent metabolite absorption/brain penetration between species, methodological limitations (16S rRNA vs. functional metagenomics), postbiotic standardization barriers, and sparse Phase I/II trials showing biomarker benefits without cognitive endpoints. This review synthesizes gut dysbiosis-metabolite-brain aging mechanisms, positioning postbiotics as precision therapeutics. Multi-omics stratified controlled trials are essential to validate long-term efficacy for delaying neurodegeneration and extending cognitive health.