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Enteric Bacterial Metabolites Propionic and Butyric Acid Modulate Gene Expression, Including CREB-Dependent Catecholaminergic Neurotransmission, in PC12 Cells - Possible Relevance to Autism Spectrum Disorders
Open accessAbstract
Alterations in gut microbiome composition have an emerging role in health and disease including brain function and behavior. Short chain fatty acids (SCFA) like propionic (PPA), and butyric acid (BA), which are present in diet and are fermentation products of many gastrointestinal bacteria, are showing increasing importance in host health, but also may be environmental contributors in neurodevelopmental disorders including autism spectrum disorders (ASD). Further to this we have shown SCFA administration to rodents over a variety of routes (intracerebroventricular, subcutaneous, intraperitoneal) or developmental time periods can elicit behavioral, electrophysiological, neuropathological and biochemical effects consistent with findings in ASD patients. SCFA are capable of altering host gene expression, partly due to their histone deacetylase inhibitor activity. We have previously shown BA can regulate tyrosine hydroxylase (TH) mRNA levels in a PC12 cell model. Since monoamine concentration is known to be elevated in the brain and blood of ASD patients and in many ASD animal models, we hypothesized that SCFA may directly influence brain monoaminergic pathways. When PC12 cells were transiently transfected with plasmids having a luciferase reporter gene under the control of the TH promoter, PPA was found to induce reporter gene activity over a wide concentration range. CREB transcription factor(s) was necessary for the transcriptional activation of TH gene by PPA. At lower concentrations PPA also caused accumulation of TH mRNA and protein, indicative of increased cell capacity to produce catecholamines. PPA and BA induced broad alterations in gene expression including neurotransmitter systems, neuronal cell adhesion molecules, inflammation, oxidative stress, lipid metabolism and mitochondrial function, all of which have been implicated in ASD. In conclusion, our data are consistent with a molecular mechanism through which gut related environmental signals such as increased levels of SCFA's can epigenetically modulate cell function further supporting their role as environmental contributors to ASD.
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“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 [116]
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.
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“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 [116]
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“Other SCFA effects, especially of propionate and butyrate, are mediated through their HDAC inhibitory activity (108, 116).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [116]
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“Propionate and butyrate can influence the cell signaling system via modification of the intracellular potassium levels (104), and they regulate the expression levels of tryptophan 5-hydroxylase 1, involved in the synthesis of serotonin, and tyrosine hydroxylase, which is involved in the biosynthesis of dopamine, adrenaline, and noradrenaline (105).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [105]
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The role of short-chain fatty acids in microbiota–gut–brain communication
Dalile, B., Van Oudenhove, L., Vervliet, B., & Verbeke, K. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0157-3 · Cited by 3,357
The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication
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“In particular, 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 neurochemist…”
BackgroundPrebiotics: Definition, Types, Sources, Mechanisms, and Clinical Applications
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Short-Chain Fatty-Acid-Producing Bacteria: Key Components of the Human Gut Microbiota
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Metadata
- Authors
- Nankova, B. B., Agarwal, R., MacFabe, D. F., & La Gamma, E. F.
- Affiliations
- New York Medical College (US)
- Western University (CA)
- Corresponding author
- Nankova, Bistra B.
- ORCID
- Nankova, Bistra B.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-08-29
- Volume
- 9
- Issue
- 8
- Pages
- e103740
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4149359
- OpenAlex
- W2028901643
- Cited by
- 294
- References
- 136
- Citations by year
- 2026: 24 · 2025: 26 · 2024: 30 · 2023: 29 · 2022: 43 · 2021: 34 · 2020: 37 · 2019: 19 · 2018: 21 · 2017: 8 · 2016: 14 · 2015: 8 · 2014: 1
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Touro Scholar (Touro College) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Autism Research Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- propionic acid, butyrate, short-chain fatty acids, gut microbiota, autism spectrum disorder, catecholaminergic neurotransmission, tyrosine hydroxylase, CREB transcription factor, PC12 cells, histone deacetylase inhibition, epigenetic regulation, monoamines, neurodevelopmental disorders, gut-brain axis
- MeSH terms
- Animals, Child Development Disorders, Pervasive, Enterobacteriaceae, Gene Expression Regulation, Synaptic Transmission, Propionates, Tyrosine 3-Monooxygenase, Transcriptional Activation, PC12 Cells, Cyclic AMP Response Element-Binding Protein, Butyric Acid, Rats, Gene Regulatory Networks, Host-Pathogen Interactions
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