Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells
Open accessAbstract
Background Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder with a high prevalence, especially in industrialized countries. Dysbiosis of the intestinal microbiota has been observed in RA patients. For instance, new-onset untreated RA (NORA) is associated with the underrepresentation of the Clostridium cluster XIVa, including Lachnospiraceae, which are major butyrate producers, although the pathological relevance has remained obscure. Follicular regulatory T (T FR ) cells play critical regulatory roles in the pathogenesis of autoimmune diseases, including RA. Reduced number of circulating T FR cells has been associated with the elevation of autoantibodies and disease severity in RA. However, the contribution of commensal microbe-derived butyrate in controlling T FR cell differentiation remains unknown. Methods We examined the contribution of microbe-derived butyrate in controlling autoimmune arthritis using collagen-induced arthritis (CIA) and SKG arthritis models. We phenotyped autoimmune responses in the gut-associated lymphoid tissues (GALT) in the colon and joint-draining lymph nodes in the CIA model. We developed an in vitro CXCR5 + Bcl-6 + Foxp3 + T FR (iT FR ) cell culture system and examined whether butyrate promotes the differentiation of iT FR cells. Findings Microbe-derived butyrate suppressed the development of autoimmune arthritis. The immunization of type II collagen (CII) caused hypertrophy of the GALT in the colon by amplifying the GC reaction prior to the onset of the CIA. Butyrate mitigated these pathological events by promoting T FR cell differentiation. Butyrate directly induced the differentiation of functional T FR cells in vitro by enhancing histone acetylation in T FR cell marker genes. This effect was attributed to histone deacetylase (HDAC) inhibition by butyrate, leading to histone hyperacetylation in the promoter region of the T FR -cell marker genes. The adoptive transfer of the butyrate-treated iT FR cells reduced CII-specific autoantibody production and thus ameliorated the symptoms of arthritis. Interpretation Accordingly, microbiota-derived butyrate serves as an environmental cue to enhance T FR cells, which suppress autoantibody production in the systemic lymphoid tissue, eventually ameliorating RA. Our findings provide mechanistic insights into the link between the gut environment and RA risk. Funding This work was supported by AMED-Crest (16gm1010004h0101, 17gm1010004h0102, 18gm1010004h0103, and 19gm1010004s0104 to KH), the Japan Society for the Promotion of Science (JP17KT0055, JP16H01369, and JP18H04680 to KH; JP17K15734 to DT), Keio University Special Grant-in-Aid for Innovative Collaborative Research Projects (KH), Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research (DT), the SECOM Science and Technology Foundation (KH), the Cell Science Research Foundation (KH), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (DT), the Suzuken Memorial Foundation (KH and DT), the Takeda Science Foundation (KH and DT), The Science Research Promotion Fund, and The Promotion and Mutual Aid Corporation for Private Schools of Japan (KH).
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SCFAs, in particular propionate and butyrate, mediate anti-inflammatory and immunosuppressive effects via interaction with G protein-coupled receptor (GPR).
“It is increasingly appreciated that SCFAs, in particular propionate and butyrate, mediate anti-inflammatory and immunosuppressive effects via interaction with G protein-coupled receptor (GPR) [70–72].”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [72]
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Moschovakis, G. L., Bubke, A., Friedrichsen, M., Falk, C. S., Feederle, R., & Förster, R. (2017) · Scientific Reports · doi:10.1038/s41598-017-08935-6 · Cited by 59 · see citing works
Butyrylated starch protects colonocyte DNA against dietary protein-induced damage in rats
Bajka, B. H., Clarke, J. M., Cobiac, L., & Topping, D. L. (2008) · Carcinogenesis · doi:10.1093/carcin/bgn173 · Cited by 51 · see citing works
Self-citationKim, Y. U., Lim, H., Jung, H. E., Wetsel, R. A., & Chung, Y. (2015) · PLoS ONE · doi:10.1371/journal.pone.0120294 · Cited by 42 · see citing works
ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis
Panneton, V., Yazdchi, S. B., Witalis, M., Chang, J., & Suh, W. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1701305 · Cited by 29 · see citing works
Zhong, M., & Veillette, A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.473736 · Cited by 19 · see citing works
Direct measurements of reaction time for extractive processes
Gotfryd, L., Becker, K., Pietek, G., et al. (2016) · Prace Naukowe Uniwersytetu Ekonomicznego we Wrocławiu · doi:10.5277/ppmp160230 · Cited by 1 · see citing works
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Worby, C. J., Schreiber, H. L., Straub, T. J., van Dijk, L. R., Bronson, R. A., Olson, B. S., Pinkner, J. S., Obernuefemann, C. L. P., Muñoz, V. L., Paharik, A. E., et al. (2022) · Nature Microbiology · doi:10.1038/s41564-022-01107-x · Cited by 188 · see citing works
Gut microbiota-mediated immunomodulation in tumor
Liu, X., Chen, Y., Zhang, S., & Dong, L. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-01983-x · Cited by 112 · see citing works
- Authors
- Takahashi, D., Hoshina, N., Kabumoto, Y., Maeda, Y., Suzuki, A., Tanabe, H., Isobe, J., Yamada, T., Muroi, K., Yanagisawa, Y., Nakamura, A., Fujimura, Y., Saeki, A., Ueda, M., Matsumoto, R., Asaoka, H., Clarke, J. M., Harada, Y., Umemoto, E., Komatsu, N., Okada, T., Takayanagi, H., Takeda, K., Tomura, M., & Hase, K.
- Affiliations
- Keio University (JP)
- The University of Osaka (JP)
- RIKEN Center for Integrative Medical Sciences (JP)
- Osaka Ohtani University (JP)
- Commonwealth Scientific and Industrial Research Organisation (AU)
- Tokyo University of Science (JP)
- Immunology Frontier Research Center, The University of Osaka (JP)
- The University of Tokyo (JP)
- Corresponding author
- Hase, Koji
- ORCID
- Venue
- EBioMedicine
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 58
- Pages
- 102913
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC7387783
- OpenAlex
- W3044546705
- Cited by
- 205
- References
- 81
- Citations by year
- 2026: 42 · 2025: 48 · 2024: 48 · 2023: 28 · 2022: 24 · 2021: 13 · 2020: 2
- FWCI
- 5.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Cell Science Research Foundation
- Keio University
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Secom Science and Technology Foundation
- Suzuken Memorial Foundation
- Japan Society for the Promotion of Science London
- Japan Agency for Medical Research and Development
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- butyrate, rheumatoid arthritis, follicular regulatory T cells, gut microbiota, Clostridium cluster XIVa, Lachnospiraceae, histone deacetylase inhibition, histone acetylation, autoantibodies, collagen-induced arthritis, gut-associated lymphoid tissue, Treg differentiation
- MeSH terms
- Gastrointestinal Microbiome, Acetylation, Aged, Arthritis, Experimental, Arthritis, Rheumatoid, Bacteria, Butyrates, Cell Differentiation, Cells, Cultured, Histone Deacetylases, Histones, Humans, Lymphoid Tissue, Middle Aged, Autoimmunity, Adoptive Transfer, T-Lymphocytes, Regulatory, Histone Deacetylase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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