Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation
Open accessAbstract
Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T cells (Treg cells) expressing transcription factor Foxp3 have a key role in limiting inflammatory responses in the intestine. Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory T helper 17 (TH17) cells, the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we reasoned that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We tested this hypothesis by exploring the effect of microbial metabolites on the generation of anti-inflammatory Treg cells. We found that in mice a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg-cell numbers after provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells, as the observed phenomenon was dependent on intronic enhancer CNS1 (conserved non-coding sequence 1), essential for extrathymic but dispensable for thymic Treg-cell differentiation. In addition to butyrate, de novo Treg-cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of histone deacetylase (HDAC) inhibition, but not acetate, which lacks this HDAC-inhibitory activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.
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Butyrate is capable of inducing T regulatory cell differentiation and controlling inflammation.
“butyrate is capable of inducing Treg differentiation and controlling inflammation (17, 23, 24, 87).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [23]
The paper reports that butyrate promotes extrathymic Treg differentiation and that Tregs help limit intestinal inflammatory responses (Abstract; page unavailable). It also reports enhanced suppressor activity in Tregs from butyrate-treated mice, but does not show that butyrate itself controlled inflammation in an inflammatory condition. (LLM, conf=0.82)
Experimental — accuracy not yet measuredButyrate restricts inflammation by promoting the differentiation of Treg cells and supporting the functions of regulatory B cells.
“For instance, butyrate has been shown to restrict inflammation by promoting the differentiation of Treg cells and supporting the functions of regulatory B cells.706–708”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [707]
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 [10]
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 [133]
Pending further confirmation, short-chain fatty acids display context-dependent immune effects ranging from Treg cell differentiation to enhancement of effector T cell functions.
“Pending further confirmation, these results suggest that SCFAs display context-dependent immune effects that range from the differentiation of Treg cells to the enhancement of effector T cell functions.”
From Melanoma and microbiota: Current understanding and future directions (2024) · cites this paper as [58]
Both propionate and butyrate could act as histone deacetylase (HDAC) inhibitor, through which SCFA increased histone acetylation in the promoter and conserved non-coding sequence (CNS) regions of the Foxp3 locus.
“In addition, both propionate and butyrate could act as histone deacetylase (HDAC) inhibitor [74–76], through which SCFA increased histone acetylation in the promoter and conserved non-coding sequence (CNS) regions of the Foxp3 locus, the master transcription factor and specific marker of suppressive Tregs [75].”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [76]
Administration route and SCFA concentration are important for in vivo experiments.
“emphasizing the importance of administration route and SCFA concentration for in vivo experiments (Arpaia et al., 2013).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Arpaia et al., 2013
The expansion and de novo differentiation effects operate independently, as cTreg numbers in germ-free mice are reduced and can be rescued by separate provision of acetate, propionate, or butyrate.
“Each of these functions operates independently, as numbers of cTregs in germ-free mice, which are starkly reduced in the absence of treatment, can be rescued by separate provision of acetate, propionate or butyrate (Arpaia et al., 2013; Smith et al., 2013).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Arpaia et al., 2013
Direct application of 50 mM butyrate by enema elicited an increase in cTregs.
“Direct application of 50 mM butyrate by enema, however, did elicit an increase in cTregs”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Arpaia et al., 2013
De novo differentiation of cTregs relies on HDAC inhibition in dendritic cells and T cells, which acetate does not promote.
“Conversely, the de novo differentiation of cTregs relies on HDAC inhibition in both DCs and T cells, which acetate does not promote (Arpaia et al., 2013; Furusawa et al., 2013).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Arpaia et al., 2013
Acetate and propionate, but not butyrate, stimulate expansion of pre-existing colonic Tregs.
“acetate and propionate, but not butyrate, stimulate the expansion of pre-existing colonic Tregs (cTregs)”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Arpaia et al., 2013
Arpaia et al. detected no significant changes in cTregs at 36 mM butyrate.
“Arpaia et al. detected no significant changes at a concentration of 36 mM”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Arpaia et al., 2013
The lack of effect at 36 mM butyrate is likely because much of it was absorbed by the upper gastrointestinal tract before reaching the colon.
“likely because this lower quantity of butyrate was largely absorbed by the upper gastrointestinal tract before reaching the colon (Arpaia et al., 2013; Smith et al., 2013).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Arpaia et al., 2013
Propionate and butyrate, but not acetate, increase de novo differentiation of naive T cells into Tregs.
“whereas propionate and butyrate, but not acetate, increase the de novo differentiation of naive T cells into Tregs (Arpaia et al., 2013; Furusawa et al., 2013; Singh et al., 2014; Smith et al., 2013).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Arpaia et al., 2013
A subset of colonic regulatory CD4+ T cells lack differentiation in GF mice due to the absence of bacterial consortia capable of fermenting dietary fiber into SCFAs.
“A subset of colonic regulatory CD4+ T cells lack differentiation in GF mice resulting from the absence of bacterial consortia capable of fermenting dietary fiber into short-chain fatty acids (SCFAs).105–107”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [105]
In mice, intake of dietary carbohydrates, certain probiotics, artificial sweeteners and emulsifiers can modulate host immunity and inflammation, in part mediated by compositional changes of the gut microbiome.
“In mice, intake of dietary carbohydrates,105 certain probiotics,140 artificial sweeteners141 and emulsifiers142 can modulate host immunity and inflammation, in part mediated by compositional changes of the gut microbiome.”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [105]
Oral administration of short-chain fatty acids protects mice from T cell-induced colitis by inducing immunosuppressive regulatory T cells.
“oral administration of SCFAs protected mice from T cell-induced colitis by inducing immunosuppressive Tregs [38-40].”
From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [38]
Short-chain fatty acids are present at reduced concentrations in fecal pellets of germ-free or antibiotic-treated mice.
“SCFAs were present at reduced concentrations in the fecal pellets of GF or antibiotic-treated mice”
From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [38]
Microbiota-derived short-chain fatty acids, particularly propionate and butyrate, are responsible for regulatory T cell differentiation or accumulation.
“three different laboratories have identified microbiota-derived SCFAs (particularly propionate and butyrate), to be responsible for Treg differentiation/accumulation [38-40].”
From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [38]
Short-chain fatty acids act on dendritic cells, increasing their capacity to drive naïve T cell differentiation into regulatory T cells.
“and on DCs, conferring a higher capacity to drive naïve T cell differentiation into Tregs [38-40].”
From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [38]
Short-chain fatty acids act directly on T cells via GPCR43, enhancing FoxP3 expression through DNA acetylation.
“SCFAs were found to act directly on T cells via the receptor GPCR43, thus enhancing FoxP3 expression through DNA acetylation”
From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [38]
New-onset Treg generation in the periphery was enhanced by propionate.
“In addition to butyrate, new-onset Treg generation in the periphery was enhanced by propionate (115).”
From Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy (2020) · cites this paper as [115]
The mucosal immune system profoundly impacts gut barrier functions both in health and disease conditions.
“Additionally, the mucosal immune system profoundly impacts gut barrier functions both in health and disease conditions, reviewed previously.48,179, 180, 181, 182, 183”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [179]
SCFAs promote the development of naive CD4+ T cells into regulatory T cells, induce "tolerogenic" dendritic cells in the intestinal mucosa, and limit autoimmunity.
“SCFAs promote the development of naive CD4+ T cells into regulatory T cells (31, 32), induce “tolerogenic” dendritic cells in the intestinal mucosa (33), and limit autoimmity (34, 35).”
From Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia. (2018) · cites this paper as [32]
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- Authors
- Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., deRoos, P., Liu, H., Cross, J. R., Pfeffer, K., Coffer, P. J., & Rudensky, A. Y.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Heinrich Heine University Düsseldorf (DE)
- Corresponding author
- Rudensky, Alexander Y.
- ORCID
- Venue
- Nature
- Published
- 2013-11-13
- Volume
- 504
- Issue
- 7480
- Pages
- 451-455
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3869884
- OpenAlex
- W2003342633
- Cited by
- 4,838
- References
- 25
- Citations by year
- 2026: 462 · 2025: 488 · 2024: 468 · 2023: 498 · 2022: 468 · 2021: 519 · 2020: 400 · 2019: 365 · 2018: 303 · 2017: 264 · 2016: 249 · 2015: 185 · 2014: 161 · 2013: 3 · 2012: 1
- FWCI
- 89.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Public Health Service (T32A1007621)
- National Cancer Institute (T32CA009149, P30CA008748)
- National Institute of General Medical Sciences (T32GM007739)
- National Institute of Allergy and Infectious Diseases (R37AI034206, T32AI007621)
- 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 › IL-33, ST2, and ILC Pathways
- Keywords
- short-chain fatty acids, regulatory T cells, Foxp3, commensal bacteria, gut microbiota, colitis, histone H3 acetylation, colonic mucosa, intestinal immune homeostasis, Clostridia, Th17 cells, microbial metabolites
- MeSH terms
- Acetylation, Animals, Butyrates, Cell Differentiation, Dendritic Cells, Enhancer Elements, Genetic, Fermentation, Histone Deacetylases, Intestinal Mucosa, Intestines, Introns, Male, Mice, Inbred C57BL, Starch, Symbiosis, Cytokines, Lymphocyte Count, Inflammation Mediators, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors
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