Microbial SCFAs as epigenetic mediators: fine-tuning the gut-brain axis in neurodegenerative disorders

Mar 9, 2026Current research in microbial sciences

Microbial Short-Chain Fatty Acids may Influence the Gut-Brain Connection in Neurodegenerative Diseases through Gene Regulation

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Abstract

Short-chain fatty acids (SCFAs) may play a critical role in neuroprotective processes related to neurodegenerative diseases.

SCFAs are produced through the fermentation of dietary fiber in the gut and communicate with the central nervous system.
They are associated with reducing neuroinflammation and promoting neurogenesis, which are vital for brain health.
SCFAs enhance synaptic plasticity and help maintain the integrity of the blood-brain barrier.
Butyrate, a type of SCFA, functions as a histone deacetylase inhibitor, influencing gene expression linked to neuronal health.
SCFAs may also affect DNA methylation through modulation of specific enzymes, suggesting a complex role in epigenetic regulation.

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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.

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Microbial SCFAs as epigenetic mediators: fine-tuning the gut-brain axis in neurodegenerative disorders

Abstract

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