Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR–S6K pathway
Open accessAbstract
Microbial metabolites, such as short-chain fatty acids (SCFAs), are highly produced in the intestine and potentially regulate the immune system. We studied the function of SCFAs in the regulation of T-cell differentiation into effector and regulatory T cells. We report that SCFAs can directly promote T-cell differentiation into T cells producing interleukin-17 (IL-17), interferon-γ, and/or IL-10 depending on cytokine milieu. This effect of SCFAs on T cells is independent of GPR41 or GPR43, but dependent on direct histone deacetylase (HDAC) inhibitor activity. Inhibition of HDACs in T cells by SCFAs increased the acetylation of p70 S6 kinase and phosphorylation rS6, regulating the mTOR pathway required for generation of Th17 (T helper type 17), Th1, and IL-10(+) T cells. Acetate (C2) administration enhanced the induction of Th1 and Th17 cells during Citrobacter rodentium infection, but decreased anti-CD3-induced inflammation in an IL-10-dependent manner. Our results indicate that SCFAs promote T-cell differentiation into both effector and regulatory T cells to promote either immunity or immune tolerance depending on immunological milieu.
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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 [13]
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 [13]
Only CD4+ T cells derived from intestinal lamina propria, but not from other tissues, express high levels of these SCFA receptors.
“Only CD4+ T cells derived from intestinal lamina propria, but not that from other tissues, have been demonstrate to express high levels of these SCFA-receptors13.”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [13]
The pan-HDAC inhibitor TSA increases mTOR activity in T cells.
“the pan-HDAC inhibitor TSA was shown to increase mTOR activity in T cells13”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [13]
SCFAs promote generation of both effector and regulatory T cells depending on immunological context.
“SCFAs have also been reported to promote generation of both effector and regulatory T cells, depending on the immunological context (Park et al., 2015).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Park et al., 2015
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“The regulation of T cell biology may be even more complex, however, as SCFAs have also been reported to promote generation of both effector and regulatory T cells, depending on the immunological context (Park et al., 2015).”
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BackgroundShort-term dietary changes can result in mucosal and systemic immune depression
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How does the gut microbiome influence immune checkpoint blockade therapy?
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- Authors
- Park, J., Kim, M., Kang, S. G., Jannasch, A. H., Cooper, B., Patterson, J., & Kim, C. H.
- Affiliations
- Purdue University West Lafayette (US)
- Corresponding author
- Kim, C.H.
- Venue
- Mucosal Immunology
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 8
- Issue
- 1
- Pages
- 80-93
- ISSN
- 1933-0219 (ISSN-L)
- PMC
- PMC4263689
- OpenAlex
- W2039907390
- Cited by
- 1,307
- References
- 49
- Citations by year
- 2026: 155 · 2025: 187 · 2024: 170 · 2023: 160 · 2022: 155 · 2021: 136 · 2020: 93 · 2019: 79 · 2018: 61 · 2017: 54 · 2016: 30 · 2015: 20 · 2014: 4
- FWCI
- 16.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Mucosal Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Multiple Sclerosis Society (R01AI074745, R01DK076616)
- Crohn's and Colitis Foundation of America
- Purdue University
- Crohn's and Colitis Foundation
- Multiple Sclerosis Society
- National Institutes of Health (1s10rr002829-01)
- National Institute of Allergy and Infectious Diseases (R01AI080769, R01AI074745)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK076616)
- National Center for Research Resources (1S10RR02829, S10RR028293)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- short-chain fatty acids, histone deacetylase inhibition, p70 S6 kinase, Th17 cells, Th1 cells, IL-10, regulatory T cells, T cell differentiation, microbial metabolites, acetate, Citrobacter rodentium infection, immune tolerance, GPR41, GPR43
- MeSH terms
- Acetates, Animals, Cell Differentiation, Enterobacteriaceae Infections, Fatty Acids, Volatile, Histone Deacetylases, Immune Tolerance, Immunity, Innate, Interferon-gamma, Mice, Inbred C57BL, Signal Transduction, Interleukin-10, Mice, Knockout, Th1 Cells, Ribosomal Protein S6 Kinases, 70-kDa, Citrobacter rodentium, T-Lymphocytes, Regulatory, Mice, Th17 Cells, TOR Serine-Threonine Kinases, Cellular Microenvironment
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