Sodium Butyrate Abolishes Lipopolysaccharide-Induced Depression-like Behaviors and Hippocampal Microglial Activation in Mice
Abstract
Patients with major depressive disorder have elevated peripheral inflammation; the degree of this increase correlates with the severity of the disorder. Chronic psychological stress increases pro-inflammatory cytokines and promotes microglial activation, leading to stress vulnerability. Epigenetics, including DNA methylation and histone modification, are also related to the pathophysiology of major depressive disorder. Sodium butyrate (SB), a histone deacetylase inhibitor, exerts an antidepressant effect by altering gene expression in the hippocampus. In this study, we investigated whether lipopolysaccharide (LPS)-induced depressive-like behaviors in mice are affected by the repeated treatment with SB. Intraperitoneal injection of LPS (5 mg/kg) induced cytokines and ionized calcium-binding adaptor molecule 1(Iba1), a marker of microglial activation, in the hippocampus. It also increased the immobility time in a forced swim test, without changing locomotion. Repeated treatment with SB reduced LPS-induced alterations. These findings suggested that epigenetic regulation exist in hippocampal microglial activation, and is involved in depressive-like behaviors associated with neuro-inflammation. Further, using cDNA microarray analyses, we examined whether LPS and SB treatment affected the microglial gene profiles. Our results indicated 64 overlapping genes, between LPS-increased genes and SB-decreased genes. Among these genes, EF hand calcium binding domain 1 was a particularly distinct candidate gene. Altogether, our findings indicated that microglial activation mediated through epigenetic regulation may be involved in depressive-like behaviors. In addition, we demonstrated the effect of SB on gene information in hippocampal microglia under neuroinflammatory conditions.
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Butyrate treatment in vitro and in vivo induces morphological and functional changes in microglia toward a homeostatic profile and inhibits lipopolysaccharide-induced pro-inflammatory modifications and depression-like behavior.
“butyrate treatment in vitro and in vivo induces morphological and functional changes in the microglia toward a homeostatic profile and inhibits LPS-induced pro-inflammatory modifications (109) and depression-like behavior (110).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [110]
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 [110]
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 [147]
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- Authors
- Yamawaki, Y., Yoshioka, N., Nozaki, K., Ito, H., Oda, K., Harada, K., Shirawachi, S., Asano, S., Aizawa, H., Yamawaki, S., Kanematsu, T., & Akagi, H.
- Affiliations
- Hiroshima University (JP)
- Hiroshima International University (JP)
- Corresponding author
- Yamawaki, Yosuke
- ORCID
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 1680
- Pages
- 13-38
- ISSN
- 0006-8993 (ISSN-L)
- OpenAlex
- W2774466845
- Cited by
- 204
- References
- 53
- Citations by year
- 2026: 13 · 2025: 25 · 2024: 28 · 2023: 35 · 2022: 25 · 2021: 30 · 2020: 25 · 2019: 17 · 2018: 6
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- JSPS KAKENHI (25861036, 15K19731, 17K11670)
- Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development, AMED (16dm0107093h0001)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- sodium butyrate, lipopolysaccharide, depression-like behavior, neuroinflammation, histone deacetylase inhibition, epigenetic regulation, Iba1, inflammatory cytokines, major depressive disorder, microglial gene expression
- MeSH terms
- Animals, Antidepressive Agents, Calcium-Binding Proteins, Depression, Disease Models, Animal, Dose-Response Relationship, Drug, Exploratory Behavior, Hippocampus, Histones, Lipopolysaccharides, Mice, Inbred C57BL, Microfilament Proteins, RNA, Messenger, Swimming, Gene Expression, Cytokines, Microglia, Butyric Acid, Oligonucleotide Array Sequence Analysis, Mice
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