HDAC inhibitor sodium butyrate-mediated epigenetic regulation enhances neuroprotective function of microglia during ischemic stroke
Abstract
Cerebral ischemia leads to neuroinflammation and activation of microglia which further contribute to stroke pathology. Understanding regulation of microglial activation will aid in the development of therapeutic strategies that mitigate microglia-mediated neurotoxicity in neuropathologies, including ischemia. In this study, we investigated the epigenetic regulation of microglial activation by studying histone modification histone 3-lysine 9-acetylation (H3K9ac) and its regulation by histone deacetylase (HDAC) inhibitors. In vitro analysis of activated microglia showed that HDAC inhibitor, sodium butyrate (SB), alters H3K9ac enrichment and transcription at the promoters of pro-inflammatory (Tnf-α, Nos2, Stat1, Il6) and anti-inflammatory (Il10) genes while inducing the expression of genes downstream of the IL10/STAT3 anti-inflammatory pathway. In an experimental mouse (C57BL/6NTac) model of middle cerebral artery occlusion (MCAO), we observed that SB mediates neuroprotection by epigenetically regulating the microglial inflammatory response, via downregulating the expression of pro-inflammatory mediators, TNF-α and NOS2, and upregulating the expression of anti-inflammatory mediator IL10, in activated microglia. Interestingly, H3K9ac levels were found to be upregulated in activated microglia distributed in the cortex, striatum, and hippocampus of MCAO mice. A similar upregulation of H3K9ac was detected in lipopolysaccharide (LPS)-activated microglia in the Wistar rat brain, indicating that H3K9ac upregulation is consistently associated with microglial activation in vivo. Altogether, these results show evidence of HDAC inhibition being a promising molecular switch to epigenetically modify microglial behavior from pro-inflammatory to anti-inflammatory which could mitigate microglia-mediated neuroinflammation.
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Sodium butyrate is capable of decreasing microglial activation and pro-inflammatory cytokine secretion.
“sodium butyrate is capable of decreasing microglial activation and pro-inflammatory cytokines secretion (108–110).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [108]
Other SCFA effects, especially of propionate and butyrate, are mediated through their HDAC inhibitory activity.
“Other SCFA effects, especially of propionate and butyrate, are mediated through their HDAC inhibitory activity (108, 116).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [108]
Sodium butyrate decreases neuroinflammation.
“Sodium butyrate additionally decreases neuroinflammation [147,148].”
From Unraveling the Connections: Eating Issues, Microbiome, and Gastrointestinal Symptoms in Autism Spectrum Disorder (2025) · cites this paper as [148]
SCFAs can modify neuroinflammation by affecting the morphology and function of glial cells.
“SCFAs can modify neuroinflammation by affecting the morphology and function of glial cells (120, 286, 289, 290).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [289]
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- Authors
- Patnala, R., Arumugam, T. V., Gupta, N., & Dheen, S. T.
- Affiliations
- National University of Singapore (SG)
- Corresponding author
- Dheen, S Thameem
- Venue
- Molecular Neurobiology
- Published
- 2016-10-08
- Volume
- 54
- Issue
- 8
- Pages
- 6391-6411
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- OpenAlex
- W2529049144
- Cited by
- 278
- References
- 85
- Citations by year
- 2026: 36 · 2025: 36 · 2024: 39 · 2023: 28 · 2022: 46 · 2021: 26 · 2020: 36 · 2019: 15 · 2018: 13 · 2017: 3
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Funders
- National University Health System seed fund for basic science research (T1-BSRG 2014-02)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- sodium butyrate, histone deacetylase inhibitors, microglial activation, ischemic stroke, neuroinflammation, H3K9 acetylation, epigenetic regulation, TNF-α, nitric oxide, anti-inflammatory gene expression, middle cerebral artery occlusion, lipopolysaccharide, neuroprotection
- MeSH terms
- Animals, Brain, Cells, Cultured, Brain Ischemia, Gene Expression Regulation, Male, Rats, Wistar, Microglia, Neuroprotective Agents, Butyric Acid, Stroke, Epigenesis, Genetic, Mice, Rats, Histone Deacetylase Inhibitors
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