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Human gut bacteria as potent class I histone deacetylase inhibitors in vitro through production of butyric acid and valeric acid
Open accessAbstract
Overexpression of histone deacetylase (HDAC) isoforms has been implicated in a variety of disease pathologies, from cancer and colitis to cardiovascular disease and neurodegeneration, thus HDAC inhibitors have a long history as therapeutic targets. The gut microbiota can influence HDAC activity via microbial-derived metabolites. While HDAC inhibition (HDI) by gut commensals has long been attributed to the short chain fatty acid (SCFA) butyrate, the potent metabolic reservoir provided by the gut microbiota and its role in host physiology warrants further investigation in a variety of diseases. Cell-free supernatants (CFS) of 79 phylogenetically diverse gut commensals isolated from healthy human donors were screened for their SCFA profile and their total HDAC inhibitory properties. The three most potent HDAC inhibiting strains were further evaluated and subjected to additional analysis of specific class I and class II HDAC inhibition. All three HDAC inhibitors are butyrate producing strains, and one of these also produced substantial levels of valeric acid and hexanoic acid. Valeric acid was identified as a potential contributor to the HDAC inhibitory effects. This bacterial strain, Megasphaera massiliensis MRx0029, was added to a model microbial consortium to assess its metabolic activity in interaction with a complex community. M. massiliensis MRx0029 successfully established in the consortium and enhanced the total and specific HDAC inhibitory function by increasing the capacity of the community to produce butyrate and valeric acid. We here show that single bacterial strains from the human gut microbiota have potential as novel HDI therapeutics for disease areas involving host epigenetic aberrations.
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“This SCFA is rather a rare bacterial metabolite generated by low-abundant commensals such as Megasphaera massiliensis, which we have classified as a pentanoate-producing bacterial species21.”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [21]
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“Our broad screening approach revealed that among the commensal strains tested, only a few bacterial species exhibited a strong pan-HDAC inhibitory capacity21.”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [21]
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Metadata
- Authors
- Yuille, S., Reichardt, N., Panda, S., Dunbar, H., & Mulder, I. E.
- Corresponding author
- Mulder, Imke E.
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2018-07-27
- Volume
- 13
- Issue
- 7
- Pages
- e0201073
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC6063406
- OpenAlex
- W2884838967
- Cited by
- 257
- References
- 48
- Citations by year
- 2026: 23 · 2025: 23 · 2024: 46 · 2023: 48 · 2022: 34 · 2021: 27 · 2020: 37 · 2019: 18 · 2018: 1
- FWCI
- 7.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Keywords
- histone deacetylase inhibitors, gut microbiota, class I HDACs, class II HDACs, short-chain fatty acids, butyrate, valeric acid, hexanoic acid, cell-free supernatant, microbial consortia, epigenetic regulation, host-microbe interactions
- MeSH terms
- Gastrointestinal Microbiome, Culture Media, Histone Deacetylases, Humans, Pentanoic Acids, Cell Culture Techniques, HT29 Cells, Butyric Acid, Megasphaera, Histone Deacetylase Inhibitors
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