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Sodium butyrate ameliorates the impairment of synaptic plasticity by inhibiting the neuroinflammation in 5XFAD mice
Abstract
Current strategies for the treatment of Alzheimer's disease (AD) focus on the pathology in the later stages of disease progression. Early microglia abnormality and β-amyloid (Aβ) deposition trigger disease development before identical symptoms emerge, which leads to poor clinical treatment effects in the later stages. In the early stage of disease progression, microglia in brains of 5XFAD mice have been activated by Aβ plaques to secrete more pro-inflammatory cytokines. In the meantime, these cytokines up-regulate Aβ via increasing the APP processing. Sodium butyrate (NaB), as one of the short chain fatty acid (SCFA) generated by gut microbiota, is the inhibitor of histone deacetylase (HDAC), which reduces the secretion of pro-inflammatory cytokines. In our experiment, 8-week-old 5XFAD mice and their litter WT mice were treated with NaB or normal saline for 2 weeks (WT + Vehicle group, WT + NaB group, AD + Vehicle group and AD + NaB group). After treatment, behavioral tests were carried out. The novel object recognition (NOR) and Morris water maze (MWM) tests demonstrated that there was no significant difference between four groups of mice. The results of long-term potentiation (LTP) and depotentiation (DEP) illustrated that the synaptic plasticity was promoted in 5XFAD mice after treatment with NaB. Compared to the AD + Vehicle group, the dendritic spines were more abundant in other groups of mice. Furthermore, the synapse-associated proteins (PSD-95, SYP, NR2B) were reduced and the pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) were increased in the AD + Vehicle group. These phenomena were reversed after treatment with NaB. Moreover, our results suggested that NaB suppressed the over-activation of microglia and the accumulation of Aβ in AD mice. Altogether, all results illustrated that HDAC inhibitor NaB could ameliorate the synaptic plasticity by reducing neuroinflammation in 5XFAD mice in the early stage of the disease.
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“Studies have demonstrated the neuroprotective effects of sodium butyrate in 5xFAD mice by inhibiting microglial activation and promoting synaptic plasticity (Fig. 3a).299,300”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [300]
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Ullah, R., Ali, G., Subhan, F., Khan, A., Halim, S. A., Naveed, M., Kalsoom, S., & Al-Harrasi, A. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.108083 · Cited by 17
Sodium Butyrate Protects Against Ethanol-Induced Toxicity in SH-SY5Y Cell Line
Getachew, B., Csoka, A. B., Garden, A. R., Copeland, R., & Tizabi, Y. (2021) · Neurotoxicity Research · doi:10.1007/s12640-021-00418-x · Cited by 17
Kang, X., Cheng, E., Guo, P., Xi, L., Xiang, C., Xu, S., Zhang, Y., Yang, Y., Zhang, J. J., & Long, H. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.157009 · Cited by 17
A high‐salt diet induces synaptic loss and memory impairment via gut microbiota and butyrate in mice
Lei, C., Liu, C., Peng, Y., Zhan, Y., Zhang, X., Liu, T., & Liu, Z. (2023) · iMeta · doi:10.1002/imt2.97 · Cited by 15
“Moreover, Jiang et al. [16] found that butyrate supplementation elevated the levels of synapse ‐ associated proteins and behavioral performance in mice with AD.”
BackgroundLi, Y., Wang, Z., Li, J., Yu, Y., Wang, Y., Jin, X., Dong, Y., Liu, Q., Duan, X., & Yan, N. (2023) · Biological Trace Element Research · doi:10.1007/s12011-023-03583-6 · Cited by 15
Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases
Zhou, M., Zheng, M., Liang, S., Li, M., Ma, J., Zhang, S., Song, X., Hu, Y., Lyu, Y., Ou, X., et al. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-01507 · Cited by 18
The role of gut microbiota in diabetic peripheral neuropathy rats with cognitive dysfunction
Huang, W., Lin, Z., Sun, A., Deng, J.-M., Manyande, A., Xiang, H., Zhao, G. F., & Hong, Q. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1156591 · Cited by 15
“In our experiments, we determined that Ruminococcaceae, a member of Firmicutes, was also less abundant in CD group than in NCD group; both Ruminococcaceae and Clostridium are gut microbiota that are beneficial for cognitive function; Ruminococcaceae produces butyrate, inhibits histone deacetylase, attenuates the secre…”
MethodZhang, Y., Huang, H. M., Yao, C., Sun, X., He, Q., Choudharyc, M. I., Chen, S., Liu, X., & Jiang, N. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1173920 · Cited by 14
“Research has found that SYP decreased and pro-inflammatory factors increased in mice with Alzheimer’s disease, and increasing the expression of SYP can ameliorate the impairment of the synaptic transmission effect in cognitive impairment (Liu et al., 2020; Jiang et al., 2021).”
BackgroundCorrelation between APOE4 gene and gut microbiota in Alzheimer’s disease
Chen, X.-X., Zeng, M.-X., Cai, D., Zhou, H.-H., Wang, Y., & Liu, Z. (2023) · Beneficial Microbes · doi:10.1163/18762891-20220116 · Cited by 14
Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism
Sciarretta, F., Zaccaria, F., Ninni, A., Ceci, V., Turchi, R., Apolloni, S., Milani, M., Valle, I. D., Tiberi, M., Chiurchiù, V., et al. (2024) · Life Science Alliance · doi:10.26508/lsa.202402609 · Cited by 13
“Dietary butyrate ameliorates microglia-mediated neuroin fl ammation in several in fl ammatory mouse models (Jiang et al, 2021; Wei et al, 2023) and improves cognitive decline following neuroin fl ammatory neurotoxin injection (Ge et al, 2023).”
Altered cognitive function in obese patients: relationship to gut flora
Deng, M., Tang, F., & Zhu, Z. (2025) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-024-05201-y · Cited by 14
“Ruminococcus spp. produce butyrate, which inhibits histone deacetylase, reduces the secretion of pro-inflammatory cytokines, and improves cognitive functions [70].”
Saadh, M. J., Ahmed, H. H., Kareem, R. A., Sanghvi, G. V., Ganesan, S., Agarwal, M., Kaur, P., Taher, W. M., Alwan, M., Jawad, M. J., et al. (2025) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2025.173972 · Cited by 12
Dong, J., Xie, T., Shi, C., Feng, G., Zhang, H., Xu, Z., & Dong, L. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s543912 · Cited by 12
“130 Other HDAC inhibitors such as valproic acid have shown similar anti-inflammatory effects, acting through the STAT3/NF-κB axis to suppress microglia-mediated neuroinflammation in SCI models.”
Zhang, Q., Li, H., Yin, S., Feng, X., Chen, G., Zhou, J., Liu, K., & Cheng, Y. (2024) · Translational Pediatrics · doi:10.21037/tp-24-128 · Cited by 13
Ameen, A. O., Nielsen, S. W., Kjær, M. W., Andersen, J. V., Westi, E. W., Freude, K., & Aldana, B. I. (2024) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x241270457 · Cited by 13
“16,17 Studies in Alzheimer’s disease (AD), wild-type (WT) and germ free (GF) mice have further demonstrated the transmission of AD pathogenesis and cognitive decline via microbiota.”
Ricciardi, N. R., Modarresi, F., Lohse, I., Andrade, N. S., Newman, I. A., Brown, J. M., Borja, C., Marples, B., Wahlestedt, C., & Volmar, C. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03373-0 · Cited by 11
Nohesara, S., Abdolmaleky, H. M., Thiagalingam, S., & Zhou, J. (2023) · Epigenomics · doi:10.2217/epi-2023-0342 · Cited by 20
Wen, J., Xu, Q., Li, J., Shen, X., Zhou, X., Huang, J., & Liu, S. (2024) · Scientific Reports · doi:10.1038/s41598-024-55198-z · Cited by 12
Zhang, C., Tan, R., Zhou, X., Wang, R., Wang, X., Ma, R., Chu, F., Li, Y., Yin, T., & Liu, Z. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094651 · Cited by 9
“The long-term potentiation (LTP) and long-term depotentiation (DEP) protocols were similar to those in prior studies [85,86].”
ResultFasina, O. B., Li, L., Chen, D., Yi, M., Xiang, L., & Qi, J. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252111719 · Cited by 9
From Obesity to Mitochondrial Dysfunction in Peripheral Tissues and in the Central Nervous System
Marino, F., Petrella, L., Cimmino, F., Pizzella, A., Monda, A., Allocca, S., Rotondo, R., D’Angelo, M., Musco, N., Iommelli, P., et al. (2025) · Biomolecules · doi:10.3390/biom15050638 · Cited by 11
“Thus, it may be involved in regulating neural plasticity and preventing the development of NDDs [200,201].”
Therapeutic Potential of Sodium Butyrate in Neurological and Psychiatric Disorders
Rahmani, D., Chodari, L., Kakallahpour, M., & Niknam, Z. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05428-w · Cited by 11
“Sodium butyrate (NaB), which is a member of the SCFAs family and the sodium form of the endogenous butyrate generated by gut microbiota, is a type of HDACI with the ability to decrease pro-inflammatory cytokines [21, 28, 29].”
The complement cascade in Alzheimer’s disease: modern implications of an ancient immune protagonist
Papavergi, M.-T., Bathini, P., Singh, B. B., & Lemere, C. A. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00916-y · Cited by 12
“It has been shown that early intervention with sodium butyrate in 5xFAD mice inhibits Aβ deposition [401, 402].”
Activation of β2-adrenergic receptors prevents AD-type synaptotoxicity via epigenetic mechanisms
Jin, M., Wei, Z., Ramalingam, N., Xiao, M., Xu, A., Yu, X., Song, Q., Liu, W., Zhao, J., Zhang, D., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02145-5 · Cited by 8
Shi, W., Wu, X., Yuan, C., Kuang, T., Xie, X., Gong, W., Li, F., Shen, L., Zhang, Y., & Liang, X. (2024) · European journal of medical research · doi:10.1186/s40001-024-02142-6 · Cited by 9
“The MWM test is a classical method that can be adopted for evaluating spatial learning and long-term memory, and the specific process has been previously described [18].”
Natural products: Harnessing the power of gut microbiota for neurological health
Cheng, H., Liu, J., Zhang, D., Wu, J., Wu, J., Zhou, Y., Tan, Y., Feng, W., & Peng, C. Y. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.156019 · Cited by 7
Dissecting the immune response of CD4+ T cells in Alzheimer’s disease
Kostić, M. S., Živković, N., Cvetanović, A., Bašić, J., & Stojanović, I. R. (2024) · Reviews in the Neurosciences · doi:10.1515/revneuro-2024-0090 · Cited by 8
Bellitto, D., Bozzo, M., Ravera, S., Bertola, N., Rosamilia, F., Milia, J., Barboro, P., Vargas, G. C., Lisa, D. D., Pastorino, L., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103544 · Cited by 6
“Nevertheless, several studies reported the involvement of butyrate, a short-chain fatty acid from which butanoate is derived, in reducing pro-inflammatory cytokines and improving synaptic plasticity in animal models of AD and PD [99 – 101].”
Does the Maternal Gut Microbiome Influence the Outcome of Perinatal Asphyxia?
Morozan, V.-P., Ionescu, M.-I., Zahiu, C. D. M., Catrina, A. M., Racoviță, A., Chirilă, A.-T., Dogaru, I.-A., Ciotei, C., Pîrcălăbioru, G. G., & Zăgrean, A. (2025) · Antioxidants · doi:10.3390/antiox14091134 · Cited by 8
“…animal models (induced through high-fat diet), butyrate improves mitochondrial function in the cerebral cortex and the synaptic fraction [192], enhances neuroplasticity [193], and shows an impressive neuroprotective effect in ischemia [142,194], all increasing the neural functional reserve.”
Metadata
- Authors
- Jiang, Y., Li, K., Li, X., Xu, L., & Yang, Z.
- Affiliations
- Nankai University (CN)
- Corresponding author
- Yang, Zhuo
- Venue
- Chemico-Biological Interactions
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 341
- Pages
- 109452
- ISSN
- 0009-2797 (ISSN-L)
- OpenAlex
- W3146836254
- Cited by
- 154
- References
- 54
- Citations by year
- 2026: 24 · 2025: 33 · 2024: 29 · 2023: 39 · 2022: 23 · 2021: 6
- FWCI
- 15.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Chemico-Biological Interactions (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- sodium butyrate, Alzheimer's disease, synaptic plasticity, neuroinflammation, microglial activation, amyloid-beta, 5xFAD mice, histone deacetylase inhibition, short-chain fatty acids, inflammatory cytokines, long-term potentiation, dendritic spines, synaptic proteins, early Alzheimer's disease
- MeSH terms
- Disks Large Homolog 4 Protein, Morris Water Maze Test, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Inflammation, Mice, Transgenic, Neuronal Plasticity, Amyloid beta-Peptides, Synaptophysin, Microglia, Long-Term Potentiation, Butyric Acid, Cognitive Dysfunction
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