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The role of short-chain fatty acids in microbiota–gut–brain communication
Open accessAbstract
Short-chain fatty acids (SCFAs), the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract, are speculated to have a key role in microbiota-gut-brain crosstalk. However, the pathways through which SCFAs might influence psychological functioning, including affective and cognitive processes and their neural basis, have not been fully elucidated. Furthermore, research directly exploring the role of SCFAs as potential mediators of the effects of microbiota-targeted interventions on affective and cognitive functioning is sparse, especially in humans. This Review summarizes existing knowledge on the potential of SCFAs to directly or indirectly mediate microbiota-gut-brain interactions. The effects of SCFAs on cellular systems and their interaction with gut-brain signalling pathways including immune, endocrine, neural and humoral routes are described. The effects of microbiota-targeted interventions such as prebiotics, probiotics and diet on psychological functioning and the putative mediating role of SCFA signalling will also be discussed, as well as the relationship between SCFAs and psychobiological processes. Finally, future directions to facilitate direct investigation of the effect of SCFAs on psychological functioning are outlined.
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In the citing paper
“The gut microbiota influences gut barrier and produce neurotransmitters, amino acids and microbial metabolites61.”
From Association between attention-deficit/hyperactivity disorders and intestinal disorders: A systematic review and Meta-analysis (2025) · cites this paper as [61]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“gut microbiota dysbiosis has been implicated in behavioral and neurologic pathologies, such as depression, Alzheimer's (AD) and Parkinson's (PD) diseases and autism spectrum disorder (ASD) (9, 21, 25–27).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [21]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“brain to gut signaling can directly affect the microbiota, either via immune system or gut functions such as motility, release of neurotransmitters and intestinal immune tone (12, 17, 21, 31).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [21]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“the gut microbiota can interact with the CNS via gut modulation or directly via metabolites and endotoxin translocation from the lumen to the circulation (9, 17, 21).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [21]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“altered SCFA production has been demonstrated in a variety of neuropathologies (19, 21, 33–35).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [21]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“these SCFAs regulate the expression levels of tryptophan 5-hydroxylase 1, the enzyme involved in synthesis of serotonin, and tyrosine hydroxylase, which is involved in a rate-limiting step in the biosynthesis of dopamine, noradrenaline and adrenaline; therefore, producing an effect on brain neurochemistry (21, 55, 56, 116, 117).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [21]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Microbial metabolites such as short chain fatty acids (SCFAs) exert beneficial effects on psychiatric disorders via the microbiota–gut–brain axis through humoral, hormonal, and immune pathways [12].”
From Effect of Supplementation with Probiotics in Patients with Schizophrenia: Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials (2025) · cites this paper as [12]
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In the citing paper
“SCFAs exert their physiological activities by acting as endogenous ligands for G-protein-coupled receptors (GPCRs), and modulating gene expression by inhibiting histone deacetylases (HDACs).282”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [282]
The cited source says what the claim attributes to it.
In the citing paper
“SCFAs can modulate the levels of neurotransmitters and neurotrophic factors and regulate the expression of tryptophan 5-hydroxylase, the enzyme involved in the synthesis of serotonin, and tyrosine hydroxylase, the enzyme involved in the rate-limiting step in dopamine, noradrenaline, and adrenaline synthesis (18, 132, 164, 222).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [132]
The cited source says what the claim attributes to it.
In the citing paper
“Other pathways through which SCFAs can influence gutbrain communication and brain function include immune, endocrine, neuronal, vagal, and other humoral pathways (360).”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [360]
The cited source says what the claim attributes to it.
In the citing paper
“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 [21]
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In the citing paper
“Accumulating evidence suggests that SCFAs that cross into the CNS have neuroactive properties.”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [21]
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In the citing paper
“It was described that SCFAs may modulate the levels of neurotransmitters and neurotrophic factors.”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [21]
In the citing paper
“SCFAs are endogenous ligands for a subset of GPCRs, including GPR43 and GPR41, which were subsequently renamed as free fatty acid receptor 2 (FFAR2) and FFAR3, respectively.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [282]
In the citing paper
“Another important GPCR activated by SCFA is GPR109A, also known as hydroxycarboxylic acid receptor 2 (HCAR2), which is activated by butyrate and β-D-hydroxy butyrate.282”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [282]
In the citing paper
“and intracellular SCFAs can influence gene expression via histone deacetylation (HDAC) inhibition (Dalile et al., 2019)”
From The modulatory effects of gut microbes and metabolites on blood-brain barrier integrity and brain function in sepsis-associated encephalopathy (2023) · cites this paper as Dalile et al., 2019
In the citing paper
“Moreover, SCFAs are endogenous ligands of orphan G protein-coupled receptors (GPCRs)”
From The modulatory effects of gut microbes and metabolites on blood-brain barrier integrity and brain function in sepsis-associated encephalopathy (2023) · cites this paper as Dalile et al., 2019
In the citing paper
“Altered SCFA production has also been demonstrated in a variety of neuropathologies (42, 116, 127, 130, 132, 292–295).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [132]
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Citations
Cites
Diet rapidly and reproducibly alters the human gut microbiome
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Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation
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Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour
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The role of inflammation in depression: from evolutionary imperative to modern treatment target
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Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease
Sampson, T. R., Debelius, J. W., Thron, T., Janssen, S., Shastri, G. G., Ilhan, Z. E., Challis, C., Schretter, C. E., Rocha, S., Gradinaru, V., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.018 · Cited by 3,622
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Jia, X., Chen, Q., Zhang, Y., & Asakawa, T. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1296713 · Cited by 22
Guo, X., Tang, P., Hou, C., Chong, L., Zhang, X., Liu, P., Chen, L., Liu, Y., Zhang, L., & Li, R. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.875101 · Cited by 19
Leonard, W., Zhang, P., Ying, D., Nie, S., Liu, S., & Fang, Z. (2022) · Food Hydrocolloids · doi:10.1016/j.foodhyd.2022.107836 · Cited by 19
Chen, H., Cao, T., Zhang, B., & Cai, H. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1097284 · Cited by 18
Ng, R. W. Y., Chen, Z., Yang, L., Wong, O. W. H., Leung, A. S. Y., Tsui, K. W., Kwok, N. M. W., Tang, L. H. Y., Cheung, P. M. H., Chan, P. K. S., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-04303-x · Cited by 13
“The gut microbiota influences gut barrier and produce neurotransmitters, amino acids and microbial metabolites 61 .”
Flegiel, E., Piotrowska, M., Ptasznik, M., Baran, A., Lenart, J., Podrażka, M., Mazurek, J., Stachowicz, H., Bartos, W., & Adamczyk, M. (2024) · Prospects in Pharmaceutical Sciences · doi:10.56782/pps.229 · Cited by 8
Li, L., Du, F., Liu, X., Song, M., Grosso, G., Battino, M., Boesch, C., Li, H., & Liu, X. (2025) · Foods · doi:10.3390/foods14101773 · Cited by 8
“Microbial metabolites such as short chain fatty acids (SCFAs) exert beneficial effects on psychiatric disorders via the microbiota–gut–brain axis through humoral, hormonal, and immune pathways [12].”
Dumitru, C. N., Dumitru, A. O., Popa, G. V., Marcu, T., Ursu, M., Nechita, A., & Matei, N. M. (2026) · Dentistry Journal · doi:10.3390/dj14050289 · Cited by 6
“In the context of oral pathogen-induced intestinal dysbiosis, reduced butyrate and altered butyrate/total SCFA ratios have been documented and correlate with intestinal permeability, systemic inflammation, and, indirectly, neuroinflammatory status [63–65].”
Metadata
- Authors
- Dalile, B., Van Oudenhove, L., Vervliet, B., & Verbeke, K.
- Affiliations
- KU Leuven (BE)
- Corresponding author
- Verbeke, Kristin
- Venue
- Nature Reviews Gastroenterology & Hepatology
- Published
- 2019-05-23
- Volume
- 16
- Issue
- 8
- Pages
- 461-478
- ISSN
- 1759-5045 (ISSN-L)
- 1759-5053
- OpenAlex
- W2946372752
- Cited by
- 3,357
- References
- 289
- Citations by year
- 2026: 631 · 2025: 685 · 2024: 567 · 2023: 511 · 2022: 429 · 2021: 334 · 2020: 174 · 2019: 25
- FWCI
- 21.30
- Type
- journal article
- Language
- en
- Open access
- green
- lirias.kuleuven.be
- Licence
- Locations
- Nature Reviews Gastroenterology & Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Keywords
- short-chain fatty acids, microbiota-gut-brain axis, dietary fiber fermentation, gut microbiota, psychological functioning, emotional processing, cognitive processes, prebiotics, probiotics, microbiota-targeted interventions, immune signaling, hormone signaling, psychobiology
- MeSH terms
- Gastrointestinal Microbiome, Animals, Mental Disorders, Brain, Dietary Fiber, Disease Models, Animal, Fatty Acids, Volatile, Humans, Neural Pathways, Signal Transduction, Gastrointestinal Tract
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