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Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells
Abstract
Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.
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In 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 [708]
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 [12]
In the citing paper
“Commensal-derived butyrate was shown to induce epigenetic reprogramming of Tregs by enhancing the acetylation of histone H3 in the promoter and conserved non-coding sequence regions of the Foxp3 locus12.”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [12]
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 [75]
In the citing paper
“Butyrate plays a crucial role in regulating anti-inflammatory responses by controlling the expression of forkhead box protein P3 (Foxp3), essential for suppressing excessive inflammation [57].”
From The Gut–Brain–Microbiota Connection and Its Role in Autism Spectrum Disorders (2025) · cites this paper as [57]
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 Furusawa 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 Furusawa 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 Furusawa et al., 2013
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 [39]
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 [39]
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 [39]
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 [39]
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 [39]
In the citing paper
“These receptors, which play crucial roles in host-microbiota interactions, are expressed at various levels in different cell types such as IECs, innate lymphoid cells, macrophages, T cells, and dendritic cells.184”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [184]
In the citing paper
“The pathophysiological consequences of this condition are predictable (epithelial cell death and dysregulated inflammation), but the clinical consequences are unknown.”
From The microbiome and critical illness (2016) · cites this paper as [76]
In the citing paper
“Treg cells are induced by a variety of bacterial groups67,68 and by the SCFA butyrate47, which is produced by bacterial fermentation.”
From The gut microbiota and the brain–gut–kidney axis in hypertension and chronic kidney disease (2018) · cites this paper as [47]
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Metadata
- Authors
- Furusawa, Y., Obata, Y., Fukuda, S., Endo, T. A., Nakato, G., Takahashi, D., Nakanishi, Y., Uetake, C., Kato, K., Kato, T., Takahashi, M., Fukuda, N. N., Murakami, S., Miyauchi, E., Hino, S., Atarashi, K., Onawa, S., Fujimura, Y., Lockett, T., Clarke, J. M., Topping, D. L., Tomita, M., Hori, S., Ohara, O., Morita, T., Koseki, H., Kikuchi, J., Honda, K., Hase, K., & Ohno, H.
- Affiliations
- RIKEN Center for Integrative Medical Sciences (JP)
- Chiba University (JP)
- Institute for Advanced Biosciences, Keio University (JP)
- Shizuoka University (JP)
- Japan Science and Technology Agency (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Commonwealth Scientific and Industrial Research Organisation (AU)
- RIKEN Center for Sustainable Resource Science (JP)
- Corresponding author
- Fukuda, Shinji
- Hase, Koji
- Ohno, Hiroshi
- ORCID
- Obata, Yuuki
- Fukuda, Shinji
- Endo, Takaho A.
- Takahashi, Daisuke
- Kato, Keiko
- Kato, Tamotsu
- Takahashi, Masumi
- Murakami, Shinnosuke
- Miyauchi, Eiji
- Hino, Shingo
- Atarashi, Koji
- Fujimura, Yumiko
- Lockett, Trevor
- Clarke, Julie M.
- Tomita, Masaru
- Hori, Shohei
- Ohara, Osamu
- Morita, Tatsuya
- Koseki, Haruhiko
- Kikuchi, Jun
- Honda, Kenya
- Hase, Koji
- Ohno, Hiroshi
- Venue
- Nature
- Published
- 2013-11-13
- Volume
- 504
- Issue
- 7480
- Pages
- 446-450
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1999906527
- Cited by
- 5,549
- References
- 50
- Citations by year
- 2026: 611 · 2025: 525 · 2024: 506 · 2023: 471 · 2022: 526 · 2021: 583 · 2020: 494 · 2019: 398 · 2018: 399 · 2017: 328 · 2016: 309 · 2015: 220 · 2014: 160 · 2013: 2
- FWCI
- 103.09
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-02-12)
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (23390123, 25660101, 25293114, 24249029, 24380072, 13J05482, 24117723, 23780131, 25513012, 13J02667)
- 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
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Keywords
- butyrate, regulatory T cells, colitis, short-chain fatty acids, Foxp3, histone H3 acetylation, gut microbiota, commensal microorganisms, microbial metabolites, colonic mucosa, Treg differentiation, host-microbe interactions, immune homeostasis, Clostridia
- MeSH terms
- Acetylation, Animals, Butyrates, Cell Differentiation, Colitis, Colon, Female, Fermentation, Germ-Free Life, Histones, Homeostasis, Intestinal Mucosa, Male, Magnetic Resonance Spectroscopy, Promoter Regions, Genetic, Symbiosis, Conserved Sequence, Lymphocyte Count, Adoptive Transfer, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Metabolome
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