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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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“Lower butyrate (SCFA) levels in the blood of RA patients and arthritic mice have been reported [80].”
BackgroundImmunometabolism shapes B cell fate and functions
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“In RA models, SCFAs supplementation significantly ameliorates pathological joint changes, reduces joint swelling and pain, and restores joint immune balance by increasing the proportion of Treg cells and suppressing Th17 cell activity [76] (Fig.”
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Advances in the Study of Probiotics for Immunomodulation and Intervention in Food Allergy
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Gut Microbiota and Aging: Traditional Chinese Medicine and Modern Medicine
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“Recent studies have also revealed its positive role in enhancing regulatory B-cell differentiation.(175) Indeed, gut microorganisms can decompose bile acids into secondary bile acids, such as deoxycholic acid (DCA) and lithocholic acid (LCA).”
The gut-lung axis: effects and mechanisms of gut microbiota on pulmonary diseases
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B cells: The many facets of B cells in allergic diseases
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Gut microbiota shape B cell in health and disease settings
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Gut Dysbiosis in Pancreatic Diseases: A Causative Factor and a Novel Therapeutic Target
Zhang, T., Gao, G., Sakandar, H. A., Kwok, L., & Sun, Z. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.814269 · Cited by 39
Aryl hydrocarbon receptor: From pathogenesis to therapeutic targets in aging-related tissue fibrosis
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Modification of Gut Microbiota in Inflammatory Arthritis: Highlights and Future Challenges
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“Butyrate supplementation suppresses the CIA in a B reg-dependent manner by increasing the serotonin-derived metabolite 5-hydroxy-indole-3acetic acid [77].”
BackgroundHost Genetics and Gut Microbiome: Perspectives for Multiple Sclerosis
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Translating Microbiome Research From and To the Clinic
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Mechanisms of gut homeostasis regulating Th17/Treg cell balance in PMOP
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Gut Microbiota Regulation of AHR Signaling in Liver Disease
Wang, B., Zhou, Z., & Li, L. (2022) · Biomolecules · doi:10.3390/biom12091244 · Cited by 35
“found that a new AHR ligand, the serotonin-derived metabolite 5-hydroxyindole-3-acetic acid (5-HIAA), was increased by butyrate supplementation [58].”
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Gut microbiota: A double-edged sword in immune checkpoint blockade immunotherapy against tumors
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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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