Short-chain fatty acid-producing commensals: Key modulators of AD neuroinflammation via the microbiota-gut-brain axis

Alzheimer’s disease (AD) lacks effective disease-modifying therapies. Neuroinflammation has emerged as a central driver of AD pathogenesis, and the gut-brain axis represents a key modulator of neuroimmune responses. Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are microbial metabolites that bridge gut homeostasis with brain function. This review synthesizes current evidence on the functional depletion of SCFA-producing gut bacteria in AD, the journey of SCFAs from the gut to the brain, and their pleiotropic actions on neuroinflammatory cell states. SCFAs regulate microglial and astrocytic phenotypes, suppress NLRP3 inflammasome activation, and promote peripheral immune tolerance via GPCR signaling, HDAC inhibition, and metabolic reprogramming. They also modulate amyloid-β deposition, tau pathology, and synaptic integrity. Translational strategies, including dietary interventions, next-generation probiotics, postbiotics, and fecal microbiota transplantation, are critically evaluated. We further discuss challenges such as causal evidence gaps, host heterogeneity, and stage-dependent therapeutic windows, and propose a pharmacomicrobiomics framework for biomarker-guided trial design. Restoring SCFA-mediated regulatory networks holds promise as a first-line disease-modifying strategy for AD, but clinical translation will require rigorous mechanistic dissection and personalized approaches.