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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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In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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 the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Self-citation
Metadata
- 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
- 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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