Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease
Open accessAbstract
As tissue macrophages of the central nervous system (CNS), microglia constitute the pivotal immune cells of this organ. Microglial features are strongly dependent on environmental cues such as commensal microbiota. Gut bacteria are known to continuously modulate microglia maturation and function by the production of short-chain fatty acids (SCFAs). However, the precise mechanism of this crosstalk is unknown. Here we determined that the immature phenotype of microglia from germ-free (GF) mice is epigenetically imprinted by H3K4me3 and H3K9ac on metabolic genes associated with substantial functional alterations including increased mitochondrial mass and specific respiratory chain dysfunctions. We identified acetate as the essential microbiome-derived SCFA driving microglia maturation and regulating the homeostatic metabolic state, and further showed that it is able to modulate microglial phagocytosis and disease progression during neurodegeneration. These findings indicate that acetate is an essential bacteria-derived molecule driving metabolic pathways and functions of microglia during health and perturbation.
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Under homeostatic conditions, the gut microbiome is responsible for regulating microglial maturation and activation via short-chain fatty acids (SCFAs) release.
“Under homeostatic conditions, the gut microbiome is responsible for regulating microglial maturation and activation via short-chain fatty acids (SCFAs) release.190,191”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [190]
The host microbiota regulates microglia mitochondrial functions and acetate is the major SCFA-rescuing microglial homeostasis in GF mice.
“In a subsequent study, Erny et al. discovered that the host microbiota regulates microglia mitochondrial functions and identified acetate as the major SCFA-rescuing microglial homeostasis in GF mice.190”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [190]
In GF 5xFAD mice, administration of acetate aggravates hippocampal Aβ deposition by disrupting microglial phagocytosis of Aβ.
“In GF 5xFAD mice, the administration of acetate aggravates hippocampal Aβ deposition by disrupting microglial phagocytosis of Aβ.190”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [190]
The majority of studies reporting detrimental effects of SCFAs were conducted using GF mice, which are functionally and structurally abnormal across various physiological functions.
“Moreover, the majority of studies that reported the detrimental effects of SCFAs were conducted using GF mice,56,190,196,199 which are functionally and structurally abnormal across various physiological functions.313”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [190]
Acetate restores microglial homeostasis in GF mice, while propionate and butyrate do not have the same restorative effect.
“In particular, acetate has been found to restore microglial homeostasis in GF mice, while propionate and butyrate do not have the same restorative effect.190”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [190]
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Li, N., Tan, S., Wang, Y., Deng, J., Wang, N., Zhu, S., Tian, W., Xu, J., & Wang, Q. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2252764 · Cited by 117 · see citing works
Matsudaira, T., Nakano, S., Konishi, Y., Kawamoto, S., Uemura, K., Kondo, T., Sakurai, K., Ozawa, T., Hikida, T., Komine, O., et al. (2023) · Communications Biology · doi:10.1038/s42003-023-05027-2 · Cited by 98 · see citing works
A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice
Abdel-Haq, R., Schlachetzki, J. C., Boktor, J. C., Cantu-Jungles, T. M., Thron, T., Zhang, M., Bostick, J. W., Khazaei, T., Chilakala, S., Morais, L. H., et al. (2022) · eLife · doi:10.7554/elife.81453 · Cited by 82 · see citing works
Early changes of fecal short‐chain fatty acid levels in patients with mild cognitive impairments
Gao, C., Li, B., He, Y., Huang, P., Du, J., He, G., Zhang, P., Tang, H., & Chen, S. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14252 · Cited by 50 · see citing works
Mechanisms of myeloid cell entry to the healthy and diseased central nervous system
Amann, L., Masuda, T., & Prinz, M. (2023) · Nature Immunology · doi:10.1038/s41590-022-01415-8 · Cited by 50 · see citing works
Self-citationRegulation of microglial physiology by the microbiota
Cook, J., & Prinz, M. (2022) · Gut Microbes · doi:10.1080/19490976.2022.2125739 · Cited by 49 · see citing works
Self-citationBetween Dysbiosis, Maternal Immune Activation and Autism: Is There a Common Pathway?
Suprunowicz, M., Tomaszek, N., Urbaniak, A., Zackiewicz, K., Modzelewski, S., & Waszkiewicz, N. (2024) · Nutrients · doi:10.3390/nu16040549 · Cited by 44 · see citing works
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Analysis of gut microbiota and depression and anxiety: Mendelian randomization from three datasets
Lai, Y., & Xiong, P. (2025) · General Hospital Psychiatry · doi:10.1016/j.genhosppsych.2025.03.012 · Cited by 20 · see citing works
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- Authors
- Erny, D., Dokalis, N., Mezö, C., Castoldi, A., Mossad, O., Staszewski, O., Frosch, M., Villa, M., Fuchs, V., Mayer, A., Neuber, J., Sosat, J., Tholen, S., Schilling, O., Vlachos, A., Blank, T., Gomez de Agüero, M., Macpherson, A. J., Pearce, E. J., & Prinz, M.
- Affiliations
- University of Freiburg (DE)
- Max Planck Institute of Immunobiology and Epigenetics (DE)
- University of Bern (CH)
- Corresponding author
- Prinz, Marco
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2021-11
- Volume
- 33
- Issue
- 11
- Pages
- 2260-2276.e7
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W3209951581
- Cited by
- 478
- References
- 70
- Citations by year
- 2026: 82 · 2025: 111 · 2024: 130 · 2023: 86 · 2022: 66 · 2021: 3
- FWCI
- 28.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 366 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (A07, ID259373024, SFB/TRR167)
- Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg
- Max-Planck-Gesellschaft
- Novo Nordisk Fonden (SFB 1479, SFB 992)
- Roman, Marga und Mareille Sobek Stiftung
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (PZ00P3_168012)
- Fritz Thyssen Stiftung
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- acetate, short-chain fatty acids, microglia, gut microbiota, germ-free mice, microglial maturation, epigenetic regulation, H3K4me3, H3K9ac, mitochondrial dysfunction, electron transport chain, phagocytosis, neurodegeneration, innate immunity
- MeSH terms
- Acetates, Animals, Brain, Fatty Acids, Volatile, Immune System, Mice, Microbiota
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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