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Microbiota-Derived Metabolites Suppress Arthritis by Amplifying Aryl-Hydrocarbon Receptor Activation in Regulatory B Cells
Open accessAbstract
The differentiation of IL-10-producing regulatory B cells (Bregs) in response to gut-microbiota-derived signals supports the maintenance of tolerance. However, whether microbiota-derived metabolites can modulate Breg suppressive function remains unknown. Here, we demonstrate that rheumatoid arthritis (RA) patients and arthritic mice have a reduction in microbial-derived short-chain fatty acids (SCFAs) compared to healthy controls and that in mice, supplementation with the SCFA butyrate reduces arthritis severity. Butyrate supplementation suppresses arthritis in a Breg-dependent manner by increasing the level of the serotonin-derived metabolite 5-Hydroxyindole-3-acetic acid (5-HIAA), which activates the aryl-hydrocarbon receptor (AhR), a newly discovered transcriptional marker for Breg function. Thus, butyrate supplementation via AhR activation controls a molecular program that supports Breg function while inhibiting germinal center (GC) B cell and plasmablast differentiation. Our study demonstrates that butyrate supplementation may serve as a viable therapy for the amelioration of systemic autoimmune disorders.
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“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 [706]
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“54 – 57 There is growing interest in developing targeted therapies that modulate AHR activity, potentially opening new avenues for medical intervention in autoimmune diseases such as rheumatoid arthritis, 58 chronic in fl ammatory skin disorders 59 and cardiovascular and pulmonary diseases.”
Modulating AHR function offers exciting therapeutic potential in gut immunity and inflammation
Chen, Y., Wang, Y., Fu, Y., Yin, Y., & Xu, K. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01046-y · Cited by 92
Gut-derived acetate promotes B10 cells with antiinflammatory effects
Daïen, C., Tan, J., Audo, R., Mielle, J., Quek, L., Krycer, J. R., Angelatos, A. S., Duraes, M., Pinget, G. V., Ni, D., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.144156 · Cited by 90
“Indeed, a previous report on the induction of splenic B10 cell by butyrate was shown to be an indirect effect by promoting the serotonin-derived metabolite 5-hydroxyindole-3-acetic acid (20).”
Wang, R., Li, B., Huang, B., Li, Y., Liu, Q., Lyu, Z., Chen, R., Qian, Q., Liang, X. S., Pu, X., et al. (2024) · Gastroenterology · doi:10.1053/j.gastro.2024.05.014 · Cited by 91
Bahman, F., Choudhry, K., Al‐Rashed, F., Al‐Mulla, F., Sindhu, S. T. A. K., & Ahmad, R. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1421346 · Cited by 106
“Butyrate supplements improved arthritis in mice by altering microbiota and favoring the production of 5-hydroxyindole-3-acetic acid (5-HIAA), a serotonin-derived metabolite that reduces the severity of arthritis (168).”
BackgroundLiu, Y., Zhou, Q., Ye, F., Yang, C., & Jiang, H. (2023) · Neoplasia · doi:10.1016/j.neo.2023.100928 · Cited by 89
Munteanu, C., & Schwartz, B. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25158250 · Cited by 93
“Furthermore, butyrate has been reported to promote regulatory B cells and inhibit the formation of germinal centers and plasmablasts, thereby reducing the severity of antigen-induced arthritis in mice [182].”
BackgroundThe bridge of the gut–joint axis: Gut microbial metabolites in rheumatoid arthritis
Xu, X., Wang, M., Wang, Z., Chen, Q., Chen, X., Xu, Y., Dai, M., Wu, B., & Li, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1007610 · Cited by 87
“Taken together, the findings show that SCFAs may regulate immune balance through the Treg/IL-10/ Th17 axis (131) or B cells (133).”
BackgroundInfluentialRannug, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165681 · Cited by 83
Gut microbiota and allergic diseases in children
Akagawa, S., & Kaneko, K. (2022) · Allergology International · doi:10.1016/j.alit.2022.02.004 · Cited by 92
The emerging role of microbiota-derived short-chain fatty acids in immunometabolism
Jasim, S. A., Opulencia, M. J. C., Ramírez‐Coronel, A. A., Abdelbasset, W. K., Abed, M. H., Markov, A. A., Al‐Awsi, G. R. L., Shamsiev, J. A., Hammid, A. T., Shalaby, M. N., et al. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.108983 · Cited by 90
Schiweck, C., Thanarajah, S. E., Aichholzer, M., Matura, S., Reif, A., Vrieze, E., Weigert, A., & Visekruna, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158272 · Cited by 80
“A recent study assessing levels of SCFAs in blood and stool of patients has shown reduced levels of SCFAs in patients with RA compared to controls, although diverging effects were detected for serum and stool concentrations and per study [62,63].”
BackgroundProbiotics ameliorate alveolar bone loss by regulating gut microbiota
Jia, L., Tu, Y., Jia, X., Du, Q., Zheng, X. M., Yuan, Q., Zheng, L., Zhou, X., & Xu, X. (2021) · Cell Proliferation · doi:10.1111/cpr.13075 · Cited by 81
“Promoting gut-derived SCFAs generation has shown protective effects in multiple diseases including IBS, cardiovascular diseases, Alzheimer’s disease and rheumatoid arthritis[58, 64-66].”
BackgroundYang, Y., Zhang, Y., Song, J., Li, Y., Zhou, L., Xu, H., Wu, K., Gao, J., Zhao, M., & Zheng, Y. (2023) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2023.127335 · Cited by 77
Osteoimmunology: The Crosstalk between T Cells, B Cells, and Osteoclasts in Rheumatoid Arthritis
Yang, M., & Zhu, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052688 · Cited by 83
“Previous reports have indicated an inverse correlation between the frequency of CD19 + CD24 hi CD38 hi B cells, which harbor the highest proportion of IL-10 + Bregs, and the clinical severity of RA [83].”
BackgroundResultTrend, S., Leffler, J., Jones, A. P., Cha, L., Gorman, S., Brown, D. A., Breit, S. N., Kermode, A. G., French, M. A., Ward, N. C., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-84881-8 · Cited by 75
Circadian Host-Microbiome Interactions in Immunity
Butler, T. D., & Gibbs, J. E. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01783 · Cited by 75
“Recent work has uncovered a mechanism whereby bacteria derived butyrate enhances production of 5-HIAA which acts via AhR to support regulatory B cell function (70).”
BackgroundCrossing the barriers: Revisiting the gut feeling in rheumatoid arthritis
Brandl, C., Bucci, L., Schett, G. A., & Zaiss, M. M. (2021) · European Journal of Immunology · doi:10.1002/eji.202048876 · Cited by 77
Du, W., Jiang, S., Yin, S., Wang, R., Zhang, C., Yin, B., Li, J., Li, L., Qi, N., Zhou, Y. Q., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2400385121 · Cited by 80
“Since 5 - HIAA was recently suggested to activate the AhR signaling in regulatory B cells ( 28 ), we sought to examine whether 5 - HIAA acts as a ligand to activate hepatic AhR and the downstream signaling.”
Rheumatoid arthritis and oxidative stress, a review of a decade
Zamudio-Cuevas, Y. E., Martínez‐Flores, K., Martínez‐Nava, G. A., Clavijo‐Cornejo, D., Fernández‐Torres, J., & Sánchez‐Sánchez, R. (2022) · Cellular and Molecular Biology · doi:10.14715/cmb/2022.68.6.28 · Cited by 74
“In this regard, studies in mice have shown that supplementation with short-chain fatty acids, and in particular butyrate, has an immunosuppressive effect on RA (64).”
BackgroundInfluentialThe emerging field of regulatory B cell immunometabolism
Rosser, E. C., & Mauri, C. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.05.008 · Cited by 75
Self-citationOsteometabolism: Metabolic Alterations in Bone Pathologies
Srivastava, R. K., Sapra, L., & Mishra, P. K. (2022) · Cells · doi:10.3390/cells11233943 · Cited by 79
Intestinal Dysbiosis and Tryptophan Metabolism in Autoimmunity
Brown, J., Robusto, B. A., & Morel, L. M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01741 · Cited by 68
“In support of this hypothesis, the short chain fatty acid butyrate has been shown to increase the production of 5-HIAA from serotonin, which promotes Breg cell function through AhR and ameliorates murine autoimmune arthritis (85).”
BackgroundModulation of Immune Responses by Nutritional Ligands of Aryl Hydrocarbon Receptor
de Juan, A., & Segura, É. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.645168 · Cited by 71
“Gavage with 5-HIAA increases the expression of Il10 in spleen B cells and reduces the severity of joint swelling in a model of antigen-induced arthritis (13).”
BackgroundInfluentialGut Microbiota and Chemical-Induced Acute Liver Injury
Chen, T., Li, R., & Chen, P. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.688780 · Cited by 71
“Studies have demonstrated that SCFAs can affect the differentiation of B cells and maintain the homeostasis of intestinal T cells (Scott et al., 2018; Rosser et al., 2020).”
BackgroundMicrobiome-immune interactions in tuberculosis
Mori, G., Morrison, M., & Blumenthal, A. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009377 · Cited by 80
Xie, R., & Zhang, Y. (2022) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2022.102530 · Cited by 66
Cao, S., Budina, E., Raczy, M. M., Solanki, A., Nguyen, M., Beckman, T. N., Reda, J. W., Hultgren, K., Ang, P. S., Slezak, A. J., et al. (2024) · Nature Biomedical Engineering · doi:10.1038/s41551-024-01190-x · Cited by 77
“Furthermore, studies have demonstrated that butyrate supplementation effectively reduces arthritis severity in animal models by modulation of regulatory B cells 42 .”
Ding, T., Su, R. J., Wu, R., Xue, H., Wang, Y., Su, R., Gao, C., Li, X., & Wang, C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.641013 · Cited by 67
“Butyrate activates transcriptional marker aryl-hydrocarbon receptor (AhR) in a manner dependent on 5-Hydroxyindole-3acetic acid (5-HIAA) and therethrough indirectly supports CD19CD21CD24Breg cell function (77).”
BackgroundAryl hydrocarbon receptor: The master regulator of immune responses in allergic diseases
Riaz, F., Pan, F., & Wei, P. Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1057555 · Cited by 73
“Additionally, the activation of the Ahr is activated by microbiota-derived butyrate, which helps in the accumulation of Il-10-secreting regulatory B cells (Bregs) (174, 175).”
BackgroundA new paradigm for a new simple chemical: butyrate & immune regulation
Dang, G., Wu, W., Zhang, H., & Everaert, N. (2021) · Food & Function · doi:10.1039/d1fo02116h · Cited by 66
Metadata
- Authors
- Rosser, E. C., Piper, C. J. M., Matei, D. E., Blair, P. A., Rendeiro, A. F., Orford, M., Alber, D. G., Krausgruber, T., Catalan, D., Klein, N., Manson, J. J., Drozdov, I., Bock, C., Wedderburn, L. R., Eaton, S., & Mauri, C.
- Affiliations
- Great Ormond Street Hospital (GB)
- University College London (GB)
- Austrian Academy of Sciences (AT)
- University College Hospital (GB)
- Corresponding author
- Rosser, Elizabeth C.
- Mauri, Claudia
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2020-04
- Volume
- 31
- Issue
- 4
- Pages
- 837-851.e10
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC7156916
- OpenAlex
- W3013317600
- Cited by
- 579
- References
- 75
- Citations by year
- 2026: 73 · 2025: 103 · 2024: 112 · 2023: 104 · 2022: 88 · 2021: 70 · 2020: 27
- FWCI
- 23.50
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Universidad de Chile (submittedVersion, cc-by-nc-nd)
- Funders
- Weizmann Institute of Science
- Albert-Ludwigs-Universität Freiburg
- Bill and Melinda Gates Foundation
- Versus Arthritis (21140, 21141, 21593)
- Manchester Biomedical Research Centre
- Rosetrees Trust (M536)
- NIHR Bristol Biomedical Research Centre
- 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 › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- rheumatoid arthritis, regulatory B cells, gut microbiota, short-chain fatty acids, butyrate, aryl hydrocarbon receptor, 5-hydroxyindoleacetic acid, serotonin metabolism, germinal center B cells, plasmablast differentiation, IL-10, autoimmune disease therapy, dietary supplementation
- MeSH terms
- Gastrointestinal Microbiome, Animals, Arthritis, Rheumatoid, Butyrates, Cells, Cultured, Fatty Acids, Volatile, Female, Humans, Hydroxyindoleacetic Acid, Male, Mice, Inbred C57BL, Middle Aged, Receptors, Aryl Hydrocarbon, Mice, Basic Helix-Loop-Helix Proteins, B-Lymphocytes, Regulatory
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