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

作者：Xiaocui Xu, Yiwen Cheng, Xia Liu, Wenwen Ding, Zhangcheng Zhu, Lingbin Wu, Zongxin Ling, Yongtao Gao, Yue Jing · 发表于：Current Research in Microbial Sciences · 年份：2026 · DOI：10.1016/j.crmicr.2026.100574 · 被引用次数：8 · 研究领域：Gut microbiota and health、Epigenetics and DNA Methylation、Diet and metabolism studies

● 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...