● SCFAs function as gut-derived epigenetic regulators, bridging dietary fiber metabolism to brain-wide chromatin remodeling in neurodegenerative diseases. ● Butyrate acts as a potent HDAC inhibitor, enhancing histone acetylation to suppress neuroinflammation and promote synaptic plasticity in AD and PD models. ● SCFAs modulate DNA methylation dynamics via TET-DNMT balance, correcting aberrant gene expression linked to Aβ and α-synuclein pathologies. ● Emerging evidence positions histone lactylation as a novel SCFA-sensitive mechanism linking microglial metabolism to neuroinflammatory loops in neurodegeneration. The gut-brain axis is a bidirectional communication system linking the gastrointestinal tract and the central nervous system (CNS). Short-chain fatty acids (SCFAs) are microbial metabolites produced through the anaerobic fermentation of dietary fiber. Growing evidence positions SCFAs as critical signaling molecules within this axis, capable of modulating key neurobiological processes relevant to neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). SCFAs exert neuroprotective effects by mitigating neuroinflammation, promoting neurogenesis, enhancing synaptic plasticity, and preserving blood–brain barrier integrity. These actions are largely mediated through epigenetic mechanisms. Butyrate functions as a histone deacetylase inhibitor to alter gene expression related to neuronal survival, inflammation, and metabolism. SCFAs also influence DNA methylation dynamics via modulation of DNA methyltransferases and ten-eleven translocation (TET) enzymes. Emerging findings suggest their involvement in novel histone modifications, such as lactylation. This review synthesizes current understanding of SCFA production, metabolic fate, and their multifaceted epigenetic actions in the brain, while evaluating their translational and therapeutic potential. Gut-derived SCFAs represent promising modulators of the brain’s epigenetic landscape. Elucidating their mechanisms offers a foundation for developing novel interventions, including dietary, probiotic, and epigenetics-based strategies, for the prevention and treatment of NDs.
Xu et al. (Sun,) studied this question.