The Microbial Metabolite Butyrate Induces Expression of Th1-Associated Factors in CD4+ T Cells
Open accessAbstract
Short-chain fatty acids (SCFAs), which are generated by the bacterial fermentation of dietary fibers, promote expansion of regulatory T cells (Tregs). Potential therapeutic value of SCFAs has been recently highlighted in the experimental models of T cell-mediated autoimmunity and allergic inflammation. These studies suggest that physiological intestinal concentrations of SCFAs within the millimolar range are crucial for dampening inflammation-mediated processes. Here, we describe opposing effects of SCFAs on T cell-mediated immune responses. In accordance with published data, lower butyrate concentrations facilitated differentiation of Tregs in vitro and in vivo under steady-state conditions. In contrast, higher concentrations of butyrate induced expression of the transcription factor T-bet in all investigated T cell subsets resulting in IFN-g-producing Tregs or conventional T cells. This effect was mediated by the inhibition of histone deacetylase (HDAC) activity and was independent of SCFA-receptors FFA2 and FFA3 as well as of Na+-coupled SCFA transporter Slc5a8. Importantly, while butyrate was not able to induce the generation of Tregs in the absence of TGF-b1, the expression of T-bet and IFN-g was triggered upon stimulation of CD4+ T cells with this SCFA alone. Moreover, the treatment of germ-free (GF) mice with butyrate enhanced the expression of T-bet and IFN-g during acute colitis. Our data reveal that, depending on its concentration and immunological milieu, butyrate may exert either beneficial or detrimental effects on the mucosal immune system.
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SCFAs promote the expansion of Tregs but also seem to improve the function of effector T cells.
“These were shown to promote the expansion of Tregs, but they also seem to improve the function of effector T cells10–15.”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [15]
SCFAs are capable of promoting the activity of CD4+ effector T cells, indicating that the influence of microbial metabolites on the immune system may be more complex than previously thought.
“On the other side, some reports suggest that SCFAs are also capable of promoting the activity of CD4+ effector T cells, indicating that the influence of microbial metabolites on the immune system may be more complex than previously thought13,15.”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [15]
SCFAs have context-dependent effects, promoting Treg expansion and also improving effector T cell functions.
“SCFAs have context-dependent functions: they can promote the expansion of Treg cells and also improve effector T cell functions133–136.”
From Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy (2023) · cites this paper as [136]
Butyrate could exert bidirectional effects, depending on its concentration and immunological milieu.
“However, Kespohl et al. described that butyrate could exert bidirectional effects, depending on its concentration and immunological milieu [77].”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [77]
Lower concentration of butyrate facilitated differentiation of Tregs, whereas high concentration without TGF-β could induce expression of the transcription factor T-bet in all investigated T cell subsets and promote IFN-γ production, contributing to polarization towards Th1 cells.
“In line with previous studies, lower concentration of butyrate facilitated differentiation of Tregs, whereas high concentration without TGF-β could induce expression of the transcription factor T-bet in all investigated T cell subsets and promote IFN-γ production, contributing to polarization towards Th1 cells [77].”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [77]
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- Authors
- Kespohl, M., Vachharajani, N., Luu, M., Harb, H., Pautz, S., Wolff, S., Sillner, N., Walker, A., Schmitt-Kopplin, P., Boettger, T., Renz, H., Offermanns, S., Steinhoff, U., & Visekruna, A.
- Affiliations
- Philipps University of Marburg (DE)
- Helmholtz Munich (DE)
- Max Planck Institute for Heart and Lung Research (DE)
- Corresponding author
- Visekruna, Alexander
- ORCID
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2017-08-28
- Volume
- 8
- Pages
- 1036-1036
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC5581317
- OpenAlex
- W2746788320
- Cited by
- 294
- References
- 31
- Citations by year
- 2026: 26 · 2025: 38 · 2024: 53 · 2023: 38 · 2022: 37 · 2021: 41 · 2020: 26 · 2019: 24 · 2018: 10 · 2016: 1
- FWCI
- 6.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Immunology (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, cc-by-sa)
- Site cant be reached (submittedVersion, cc-by)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- Fritz Thyssen Stiftung (Foundation grant by Alexander Visekruna)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- butyrate, short-chain fatty acids, CD4+ T cells, Th1 differentiation, T-bet, interferon-gamma, regulatory T cells, histone deacetylase inhibition, TGF-β1, germ-free mice, colitis, mucosal immunity, dietary fiber fermentation, gut microbiota
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