Blockade of dendritic cell development by bacterial fermentation products butyrate and propionate through a transporter (Slc5a8)-dependent inhibition of histone deacetylases
Open accessAbstract
Mammalian colon harbors trillions of bacteria, yet there is no undue inflammatory response by the host against these bacteria under normal conditions. The bacterial fermentation products acetate, propionate, and butyrate are believed, at least in part, to be responsible for these immunosuppressive effects. Dendritic cells play an essential role in presentation of antigens to T lymphocytes and initiation of adaptive immune responses. Here we report that butyrate and propionate block the generation of dendritic cells from bone marrow stem cells, without affecting the generation of granulocytes. This effect is dependent on the Na(+)-coupled monocarboxylate transporter Slc5a8, which transports butyrate and propionate into cells, and on the ability of these two bacterial metabolites to inhibit histone deacetylases. Acetate, which is also a substrate for Slc5a8 but not an inhibitor of histone deacetylases, does not affect dendritic cell development, indicating the essential role of histone deacetylase inhibition in the process. The blockade of dendritic cell development by butyrate and propionate is associated with decreased expression of the transcription factors PU.1 and RelB. Butyrate also elicits its biologic effects through its ability to activate the G-protein-coupled receptor Gpr109a, but this mechanism is not involved in butyrate-induced blockade of dendritic cell development. The participation of Slc5a8 and the non-involvement of Gpr109a in butyrate effects have been substantiated using bone marrow cells obtained from Slc5a8(-/-) and Gpr109a(-/-) mice. These findings uncover an important mechanism underlying the anti-inflammatory functions of the bacterial fermentation products butyrate and propionate.
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The inhibition of dendritic cell maturation by butyrate and propionate is primarily mediated by HDAC inhibition and depends on the SCFA transporter SLC5A8.
“This appears to be primarily mediated by HDAC inhibition, as the effect is dependent on the SCFA transporter SLC5A8 (Singh et al., 2010).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Singh et al., 2010
Butyrate and propionate inhibit dendritic cell maturation.
“Several studies have demonstrated that butyrate and propionate inhibit the maturation of dendritic cells (DCs), which form a central bridge between the innate and adaptive immune systems (Lu Liu et al., 2012; Millard et al., 2002; Singh et al., 2010; B. Wang et al., 2008).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Singh et al., 2010
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- Authors
- Singh, N., Thangaraju, M., Prasad, P. D., Martin, P. M., Lambert, N. A., Boettger, T., Offermanns, S., & Ganapathy, V.
- Affiliations
- Augusta University (US)
- Max Planck Institute for Heart and Lung Research (DE)
- Heidelberg University (DE)
- Corresponding author
- Ganapathy, Vadivel
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 285
- Issue
- 36
- Pages
- 27601-27608
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2934627
- OpenAlex
- W2016216215
- Cited by
- 293
- References
- 52
- Citations by year
- 2026: 15 · 2025: 22 · 2024: 29 · 2023: 30 · 2022: 27 · 2021: 31 · 2020: 27 · 2019: 24 · 2018: 9 · 2017: 25 · 2016: 14 · 2015: 5 · 2014: 10 · 2013: 6 · 2012: 6
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- dendritic cell development, butyrate, propionate, acetate, bacterial fermentation products, SLC5A8, monocarboxylate transporters, histone deacetylase inhibition, immunosuppression, PU.1, RelB, GPR109A, G protein-coupled receptors, bone marrow, gut microbiota, anti-inflammatory activity
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Bacteria, Bone Marrow Cells, Butyrates, Cell Differentiation, Dendritic Cells, Fermentation, Histone Deacetylases, Mice, Inbred C57BL, Propionates, Proto-Oncogene Proteins, Receptors, Nicotinic, Trans-Activators, Granulocyte-Macrophage Colony-Stimulating Factor, Monocarboxylic Acid Transporters, Cation Transport Proteins, Receptors, G-Protein-Coupled, Mice, Transcription Factor RelB, Histone Deacetylase Inhibitors
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