The neuropharmacology of butyrate: the bread and butter of the microbiota-gut-brain axis
Abstract
Several lines of evidence suggest that brain function and behaviour are influenced by microbial metabolites. Key products of the microbiota are short-chain fatty acids (SCFAs), including butyric acid. Butyrate is a functionally versatile molecule that is produced in the mammalian gut by fermentation of dietary fibre and is enriched in butter and other dairy products. Butyrate along with other fermentation-derived SCFAs (e.g. acetate, propionate) and the structurally related ketone bodies (e.g. acetoacetate and d-β-hydroxybutyrate) show promising effects in various diseases including obesity, diabetes, inflammatory (bowel) diseases, and colorectal cancer as well as neurological disorders. Indeed, it is clear that host energy metabolism and immune functions critically depend on butyrate as a potent regulator, highlighting butyrate as a key mediator of host-microbe crosstalk. In addition to specific receptors (GPR43/FFAR2; GPR41/FFAR3; GPR109a/HCAR2) and transporters (MCT1/SLC16A1; SMCT1/SLC5A8), its effects are mediated by utilisation as an energy source via the β-oxidation pathway and as an inhibitor of histone deacetylases (HDACs), promoting histone acetylation and stimulation of gene expression in host cells. The latter has also led to the use of butyrate as an experimental drug in models for neurological disorders ranging from depression to neurodegenerative diseases and cognitive impairment. Here we provide a critical review of the literature on butyrate and its effects on multiple aspects of host physiology with a focus on brain function and behaviour. We find fundamental differences in natural butyrate at physiological concentrations and its use as a neuropharmacological agent at rather high, supraphysiological doses in brain research. Finally, we hypothesise that butyrate and other volatile SCFAs produced by microbes may be involved in regulating the impact of the microbiome on behaviour including social communication.
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Growing evidence supports that short-chain fatty acids exert crucial physiological effects on several organs, including the brain.
“growing evidence supports the idea that SCFAs also exert crucial physiological effects on several organs, including the brain (17, 20, 21).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [20]
Short-chain fatty acids regulate systemic functions through inhibition of histone deacetylase activity, promoting acetylation of lysine residues in nucleosomal histones throughout various cell populations.
“Another mechanism by which SCFAs regulate systemic functions is through the inhibition of histone deacetylase (HDAC) activity, thus promoting the acetylation of lysine residues present in nucleosomal histones throughout various cell populations (20).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [20]
Histone deacetylase inhibition by short-chain fatty acids has been found in the gut and associated immune tissue, as well as in the peripheral nervous system and central nervous system.
“This intracellular signaling mechanism has been found in both the gut and associated immune tissue (86), as well as in the peripheral nervous system and CNS (20).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [20]
SCFAs can indirectly modulate the PNS through expression of FFA3 in the enteric neural plexus, portal nerve, and autonomic and sensory ganglia.
“SCFAs can indirectly modulate the PNS through expression of FFA3 in the enteric neural plexus, portal nerve, and autonomic and sensory ganglia (131).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [131]
Many microbial metabolites from dietary components, bodily secretions, or xenobiotics have been shown to influence brain structure and function in preclinical studies.
“Many of these metabolites have been shown to influence brain structure and function in preclinical studies [20, 21].”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [21]
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References 250 · Cited by 891
- Authors
- Stilling, R. M., van de Wouw, M., Clarke, G., Stanton, C., Dinan, T. G., & Cryan, J. F.
- Affiliations
- University College Cork (IE)
- Teagasc - The Irish Agriculture and Food Development Authority (IE)
- Corresponding author
- Stilling, Roman M.
- Cryan, John F.
- Venue
- Neurochemistry International
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 99
- Pages
- 110-132
- ISSN
- 0197-0186 (ISSN-L)
- OpenAlex
- W2460515486
- Semantic Scholar
- 737d3de77828809b98947d0df13bc8445601e054
- Cited by
- 891
- References
- 250
- Citations by year
- 2026: 96 · 2025: 113 · 2024: 125 · 2023: 100 · 2022: 114 · 2021: 99 · 2020: 77 · 2019: 62 · 2018: 60 · 2017: 35 · 2016: 10
- FWCI
- 4.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurochemistry International (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Science Foundation Ireland (12/RC/2273)
- Irish Research Council (GOIPD/2014/355)
- Government of Ireland Postdoctoral Fellowship
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- butyrate, short-chain fatty acids, microbiota-gut-brain axis, host-microbe crosstalk, histone deacetylase inhibition, histone acetylation, ketone bodies, dietary fiber fermentation, neurological disorders, depression, neurodegenerative diseases, cognitive impairment, social communication, gut microbiota, obesity, inflammatory bowel disease, colorectal cancer
- MeSH terms
- Gastrointestinal Microbiome, Animals, Brain, Butyrates, Dairy Products, Energy Metabolism, Humans, Gastrointestinal Tract
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