Cited by 581Gut microbiota and healthT-cell and B-cell ImmunologyRheumatoid Arthritis Research and Therapies

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Microbiota-Derived Metabolites Suppress Arthritis by Amplifying Aryl-Hydrocarbon Receptor Activation in Regulatory B Cells

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Rosser, Elizabeth C., Piper, Christopher J.M., Matei, Diana E., Blair, Paul A., Rendeiro, André F., Orford, Michael, Alber, Dagmar G., Krausgruber, Thomas, Catalan, Diego, Klein, Nigel, Manson, Jessica J., Drozdov, Ignat, Bock, Christoph, Wedderburn, Lucy R., Eaton, Simon, Mauri, Claudia·2020·Cell Metabolism

DOI 10.1016/j.cmet.2020.03.003PMC PMC7156916

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Abstract

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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Graphical abstract CC BY · PubMed Central

Figure 1 Butyrate Levels Correlate with Immature B Cells in Patients with Inactive Rheumatoid Arthritis (A) Representative histograms show stool acetate, propionate, and butyrate levels in healthy controls (HC, n = 20) and RA patients (n = 19) as measured by high-performance liquid chromatography. (B–D) Scatterplots show correlation between stool (B) acetate, (C) propionate, and (D) butyrate levels and CD19+CD24hiCD38hiB cell frequency in the peripheral blood of RA patients (n = 19). (E–G) Scatterplots show correlation between stool (E) acetate, (F) propionate, and (G) butyrate levels and IL-10+B cell frequency in the peripheral blood of RA patients (n = 19). Data represent mean ± SE (A, Mann-Whitney test; B–G, Spearmen correlation). See also Figure S1.CC BY · PubMed Central

Figure 2 Butyrate Supplementation Suppresses Arthritis by Skewing the B Cell Compartment in Favor of a Regulatory Phenotype (A) Stool butyrate levels in WT mice pre-arthritis (n = 23), with acute arthritis (n = 8), and in remission from arthritis (n = 18) as measured by high-performance liquid chromatography (cumulative data are shown). (B) Mean clinical score of control (cumulative n = 25) and butyrate-supplemented B-WT chimeric mice or B-IL-10−/−chimeric mice (n = 8 per group) (one representative experiment of two experiments is shown); y axis shows percentage swelling in antigen-injected knee compared to control knee. (C) Mean clinical score of control (cumulative n = 15) and butyrate-supplemented IL-10eGFP reporter mice (cumulative n = 13); y axis shows percentage swelling in antigen-injected knee compared to control knee (one representative experiment of two experiments is shown). (D) Representative H&E staining of knee joints from control and butyrate-supplemented IL-10eGFP reporter mice (left) and blinded histology scores (right) of joint damage. (E) Representative flow cytometry plots (left) and bar charts (right) showing CD19+CD21hiCD24hiIL-10eGFP+Breg frequency and number in control (cumulative n = 15) and butyrate-supplemented mice (cumulative n = 13) (one representative experiment of three experiments is shown). (F) Representative flow cytometry plots (left) and bar charts (right) showing CD19+CD138+Blimp-1+plasmablast frequency and number in control and butyrate-supplemented mice (cumulative n = 11 per group, one representative experiment of two experiments is shown). (G) Bar charts show ratio of CD19+CD21hiCD24hiIL-10eGFP+Bregs to plasmablast in control and butyrate-supplemented mice (cumulative n = 11 per group, one representative experiment of two experiments is shown). (H) Representative flow cytometry plots (left) and bar chart (right) shows the percentage and number of CD19+CD95+GL7+ germinal center (GC) B cells in control and butyrate-supplemented mice (cumulative n = 11 per group, one representative experiment of three experiments is shown). (I) Bar chart shows ratio of CD19+CD21hiCD24hiIL-10eGFP+Bregs to GC B cells in control and butyrate-supplemented mice (cumulative n = 11, one representative experiment of two experiments is shown). (J) Representative immunofluorescence blinded histological analysis of the number and size of GC control and butyrate-supplemented mice (original magnification 20×, n = 3). (K) Mean clinical score following transfer of CD19+CD21hiCD24hiIL-10eGFP+Bregs from control (cumulative n = 6) or butyrate-supplemented mice (cumulative n = 6), a control group that did not receive a transfer; y axis shows percentage swelling in antigen-injected knee compared to control knee (cumulative n = 8) (one representative experiment of two experiments is shown). Cells were isolated at day 7 post-disease onset. Data represent mean ± SE (A, one-way ANOVA; B, C, and K, two-way ANOVA; D–J, Student’s t test). See also Figures S2–S4.CC BY · PubMed Central

Figure 3 Suppression of Arthritis by Butyrate Supplementation Depends upon AhR Activation and IL-10 Expression in B Cells (A) Bar chart shows expression of Cyp1a1 relative to β-actin in splenic B cells isolated from control or butyrate-supplemented mice (cumulative n = 5, one representative experiment of two experiments is shown). (B) Mean clinical score of control and butyrate-supplemented Mb1cre/+ mice or Ahrfl/−Mb1cre/+ mice; y axis shows percentage swelling in antigen-injected knee compared to control knee (cumulative n = 15 per group, one representative experiment of five experiments is shown). (C) IL-10 production by splenic B cells isolated from control Mb1cre/+ mice, butyrate-supplemented Mb1cre/+ mice, control Ahrfl/−Mb1cre/+ mice, and butyrate-supplemented Ahrfl/−Mb1cre/+ mice at day 7 post-disease onset as measured by ELISA (cumulative n = 3 per group). (D) Representative flow cytometry plots and bar charts showing the frequency and number of CD19+CD21hiCD24hiB cells in control Mb1cre/+ mice (cumulative n = 8), butyrate-supplemented Mb1cre/+ mice (cumulative n = 5), control Ahrfl/−Mb1cre/+ mice (n = 7), and butyrate-supplemented Ahrfl/−Mb1cre/+ mice (cumulative n = 6) at day 7 post-disease onset (cumulative data are shown). (E) Representative flow cytometry plots and bar charts showing the frequency and number of CD19+CD138+Blimp-1+B cells in control Mb1cre/+ mice (cumulative n = 8), butyrate-supplemented Mb1cre/+ mice (cumulative n = 5), control Ahrfl/−Mb1cre/+ mice (cumulative n = 7), and butyrate-supplemented Ahrfl/−Mb1cre/+ mice (cumulative n = 6) (cumulative data are shown). (F) Representative flow cytometry plots and bar charts showing the frequency and number of CD19+CD95+GL7+B cells in control Mb1cre/+ mice (cumulative n = 8), butyrate-supplemented Mb1cre/+ mice (cumulative n = 5), control Ahrfl/−Mb1cre/+ mice (cumulative n = 7), and butyrate-supplemented Ahrfl/−Mb1cre/+ mice (cumulative n = 6) (cumulative data are shown). Cells were isolated at day 7 post-disease onset. Data represent mean ± SE (A, Student’s t test; C, E, and F, one-way ANOVA; B, two-way ANOVA). See also Figures S5 and S6.CC BY · PubMed Central

Figure 4 Butyrate Supplementation Modulates the Transcriptional and Epigenetic Landscape of CD19+CD21hiCD24hiB Cells in an AhR-Dependent Manner (A) Volcano plots shows log2 fold change (FC) in gene expression between CD19+CD21hiCD24hiB cells isolated from butyrate-supplemented Mb1cre/+ mice compared to control Mb1cre/+ mice (top plot) and between butyrate supplemented Ahrfl/−Mb1cre/+ compared to control Ahrfl/−Mb1cre/+ mice (bottom plot). Red dots represent significant DEGs, with the red line denoting a cut off p value of <0.05. (B) Signaling pathway impact analysis (SPIA) ranked on significance (pG) comparing the over-represented (red) and under-represented (blue) pathways in butyrate-supplemented compared to control CD19+CD21hiCD24hiB cells from Mb1cre/+ mice (top graph) and Ahrfl/−Mb1cre/+ mice (bottom graph). The total perturbation accumulation (tA) score is listed for the “protein processing in endoplasmic reticulum” pathway. (C) Heatmap shows the expression of B cell differentiation genes in CD19+CD21hiCD24hiB cells isolated from control Mb1cre/+ mice, butyrate-supplemented Mb1cre/+ mice, control Ahrfl/−Mb1cre/+ mice, and butyrate-supplemented Ahrfl/−Mb1cre/+ mice. Mean z scores were calculated from log CPM values. Samples highlighted in red are significantly differentially expressed between CD19+CD21hiCD24hiB cells isolated from butyrate-supplemented Mb1cre/+ mice compared to butyrate-supplemented Ahrfl/−Mb1cre/+ mice. Samples highlighted in bold are significantly differentially expressed between CD19+CD21hiCD24hiB cells isolated from butyrate-supplemented Mb1cre/+ mice compared to control Mb1cre/+ mice. (D) Representative ATAC-seq tracks for the Bcl6 and Gpr183 loci in CD19+CD21hiCD24hiB cells from butyrate-supplemented or control Mb1cre/+ and Ahrfl/−Mb1cre/+ mice (n = 3). Track heights between samples are normalized through group autoscaling. For RNA-seq data, n = 3 per condition and genotype. (E) Heatmap shows inferred transcription factor activity scores based on accessibility at transcription factor binding motifs in CD19+CD21hiCD24hiB cells isolated from control Mb1cre/+ mice, butyrate-supplemented Mb1cre/+ mice, control Ahrfl/−Mb1cre/+ mice, and butyrate-supplemented Ahrfl/−Mb1cre/+ mice as measured by ATAC-seq. AhR co-factors are highlighted in red. For ATAC-seq data, n = 3 for Mb1cre/+ mice and n = 2 for Ahrfl/−Mb1cre/+ mice. For RNA-seq data, n = 3 per group. Cells were isolated at day 7 post-disease onset. See also Figure S7.CC BY · PubMed Central

Figure 5 CD45.2+CD19+CD21hiCD24hiB Cells from Butyrate-Supplemented WT but Not AhR−/− Mice Retain Their Phenotype and Differentiate in IL-10+Bregs upon Adoptive Transfer (A and B) Representative flow cytometry plots show (A) CD45.2+CD19+B cell and (B) CD45.2+CD19+CD21hiCD24hi B cell frequency in CD45.1 congenic WT mice that had received a transfer of CD19+CD21hiCD24hiB cells isolated from control or butyrate-supplemented WT or AhR−/− mice. (C) Bar chart shows number of CD45.2+CD19+CD21hiCD24hiB cells recovered post-transfer from CD45.1 congenic WT mice that had received a transfer of CD19+CD21hiCD24hiB cells isolated from control or butyrate-supplemented WT or AhR−/− mice. (D) Representative flow cytometry plots and bar charts show CD45.2+CD19+IL-10+B cell frequency in CD45.1 congenic WT mice that had received a transfer of CD19+CD21hiCD24hiB cells isolated from control or butyrate-supplemented WT or AhR−/− mice. (E) Bar chart shows number of CD45.2+CD19+IL-10+B cells recovered post-transfer from CD45.1 congenic WT mice that had received a transfer of control or butyrate-supplemented WT or AhR−/− mice. Cells were isolated at 48 h post-transfer (cumulative n = 3 per group, cumulative data are shown). Data represent mean ± SE (C and E, one-way ANOVA).CC BY · PubMed Central

Figure 6 Butyrate Supplementation Increases the Availability of AhR Ligands (A) Mean clinical score of control and butyrate-supplemented ABX-treated or untreated mice; y axis shows percentage swelling in antigen-injected knee compared to control knee (cumulative n = 8 per group, one representative experiment of two experiments is shown). (B) Bar chart shows expression of Il10 relative to β-actin in splenic B cells isolated from ABX-treated WT or untreated mice (cumulative n = 3 per group). (C) Bar chart shows relative abundance of bacterial phyla in the stool of naive, control arthritic, or butyrate-supplemented arthritic mice (n = 4 per group). (D) XY graph shows operational taxonomic units (OTUs) of bacterial genera in butyrate-supplemented and control arthritic mice (n = 4 per group). (E–G) Bar charts shows levels of tryptophan, tryptamine, indole (E), L-Kynurenine, Kynurenic Acid (KYNA) (F), and 5-HIAA (G) in the stool of control arthritic WT and butyrate-supplemented arthritic mice (cumulative n = 5 per group). Data represent mean ± SE (A, two-way ANOVA; B, one-way ANOVA; E–G, Student’s t test). See also Figure S7.CC BY · PubMed Central

Figure 7 5-Hydroxyindole-3-Acetic Acid Increases Il10 Transcription by B cells In Vivo and In Vitro by Acting as a Ligand for AhR (A) Relative expression of Cyp1a1 and Il10 in total splenic B cells following 6-h culture with 5-HIAA or kynurenic acid (KYNA) compared to vehicle alone (n = 3, one of two experiments is shown). (B) Mean clinical score of control, 5-HIAA-gavaged, or KYNA-gavaged mice; y axis shows percentage swelling in antigen-injected knee compared to control knee (cumulative n = 8 per group, one representative experiment of two experiments is shown). (C) Bar charts show expression of Cyp1a1 and Il10 relative to β-actin in splenic B cells isolated from control, 5-HIAA-gavaged, or KYNA-gavaged mice. (D) Mean clinical score of control or 5-HIAA-gavaged Mb1cre/+ mice or Ahrfl/−Mb1cre/+ mice; y axis shows percentage swelling in antigen-injected knee compared to control knee (cumulative n = 8 per group, one representative experiment of two experiments is shown). (E) Mean clinical score of control and butyrate-supplemented L-para-chlorophenylalanine (PCPA)-treated (tryptophanase inhibitor, TPH) or vehicle-treated mice; y axis shows percentage swelling in antigen-injected knee compared to control knee (cumulative n = 10 per group, one representative experiment of two experiments is shown). Data represent mean ± SE (A, Student’s t test; B, two-way ANOVA; C, one-way ANOVA; D and E, two-way ANOVA).CC BY · PubMed Central

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Cannabidiol regulates L-carnitine and butyric acid metabolism by modulating the gut microbiota to ameliorate collagen-induced arthritis
Geng, Q., Wang, Z., Shi, T., Wen, C., Xu, J., Jiao, Y., Diao, W., Gu, J., Wang, Z., Zhao, L., et al. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.156270 · Cited by 13
High-fat diet stimulated butyric acid metabolism dysbiosis, altered microbiota, and aggravated inflammatory response in collagen-induced arthritis rats
Liu, Y., Zhang, Y., Zhang, J., Ren, S., Cao, Q., Kong, H., Xu, Q., & Liu, R. (2024) · Nutrition & Metabolism · doi:10.1186/s12986-024-00869-x · Cited by 13
“Furthermore, RA patients exhibited a dramatic increase in butyric acid consumption [72, 73].”
Tailoring gut microbiota with a combination of Vitamin K and probiotics as a possible adjuvant in the treatment of rheumatic arthritis: a systematic review
Pereira, L. J. R., & Monteiro, R. (2022) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2022.08.002 · Cited by 13
Impact of local human microbiota on the allergic diseases: Organ–organ interaction
Alhamwe, B. A., López, J.-F., Zhernov, Y. V., von Strandmann, E. P., Karaulov, A. V., Kolahian, S., Gessner, R. V., & Renz, H. E. (2023) · Pediatric Allergy and Immunology · doi:10.1111/pai.13976 · Cited by 14
A role for the microbiota in complex regional pain syndrome?
Crock, L. W., & Baldridge, M. T. (2020) · Neurobiology of Pain · doi:10.1016/j.ynpai.2020.100054 · Cited by 13
“L.W. Crock and M.T. Baldridge Neurobiology of Pain 8 (2020) 100054 Metabolites, specifically SCFAs, have been recently shown to play a role in the progression of painful conditions such as rheumatoid arthritis (RA) through a B-cell dependent mechanism (Rosser et al., 2020).”
Background
Intestinal aging-related immune dysfunction: mechanisms and interventions
Shen, X., Gao, X., & Wang, L. (2025) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2025157 · Cited by 13
“For example, SCFAs can inhibit NF - kB and TNF - α , stimulate IL - 8 secretion [92], promote neutrophil recruitment, induce Treg differentiation [93], enhance regulatory B - cell differentiation, and inhibit the differentiation of plasma cells [94] to regulate systemic immune responses.”
Human gut‐associated lymphoid tissue: A dynamic hub propagating modulators of inflammation
Jain, S., Bemark, M., & Spencer, J. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1417 · Cited by 12
The Role of Gut Microbiota in Neuromyelitis Optica Spectrum Disorder
Yao, S., Yang, X., Cen, L., & Tan, S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063179 · Cited by 12
“Studies have shown that butyrate administration increased tryptophan metabolism bacteria in mice in an AhR-dependent manner to promote IL-10-producing regulatory B cells [156].”
Background
Changes in M6A methylation: A key factor in the vicious cycle of flora -gut aging
Ding, M., Yan, J., Chen, Y., Liu, J., Chao, G., & Zhang, S. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102351 · Cited by 12
Huangqin Qingre Chubi Capsule inhibits rheumatoid arthritis by regulating intestinal flora and improving intestinal barrier
Peng, Y., Huang, Y., Li, H., Li, C., Wu, Y., Chen, Z., Wang, X., Liao, F., & Miao, C. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1422245 · Cited by 12
The Critical Role of Regulatory T Cells in Immune Tolerance and Rejection Following Liver Transplantation: Interactions With the Gut Microbiome
Lee, S. K., Kwon, J. H., Jang, J. W., Bae, S. H., Yoon, S. K., Jung, E. S., & Choi, J. Y. (2024) · Transplantation · doi:10.1097/tp.0000000000005220 · Cited by 13
“137 Meanwhile, several bile acid metabolites, represented as lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, can inhibit Th17 cell differentiation via blocking retinoid orphan receptor gamma t, a key transcription factor for Th17 cells.”
Short-chain fatty acids in Huntington's disease: Mechanisms of action and their therapeutic implications
Saadh, M. J., Ahmed, H. H., Kareem, R. A., Sanghvi, G. V., Ganesan, S., Agarwal, M., Kaur, P., Taher, W. M., Alwan, M., Jawad, M. J., et al. (2025) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2025.173972 · Cited by 12
The identification, development and therapeutic potential of IL-10-producing regulatory B cells in multiple sclerosis
Xiang, W., Xie, C., & Guan, Y. (2021) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2021.577520 · Cited by 12
A pilot study of possible anti-inflammatory effects of the specific carbohydrate diet in children with juvenile idiopathic arthritis
Berntson, L. (2021) · Pediatric Rheumatology · doi:10.1186/s12969-021-00577-3 · Cited by 12
The Aryl Hydrocarbon Receptor Suppresses Chronic Smoke-Induced Pulmonary Inflammation
Guerrina, N., Traboulsi, H., Eidelman, D. H., & Baglole, C. J. (2021) · Frontiers in Toxicology · doi:10.3389/ftox.2021.653569 · Cited by 13
“However, the AhR has emerged as a critical component of immunity, dampening the severity of diseases associated with chronic inflammation such as rheumatoid arthritis (Rosser et al., 2020; Nehmar et al., 2021), inflammatory bowel disease (Riemschneider et al.”
Background
Microbiota-assisted therapy for systemic inflammatory arthritis: advances and mechanistic insights
Li, B., Yang, B. K., Liu, X., Zhao, J., Ross, R. P., Stanton, C., Zhang, H., & Chen, W. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04498-6 · Cited by 12
“(2) An increase in the level of 5-hydroxy-indole-3-acetic acid (5-HIAA), a derivative of 5-HT, can activate the aromatic hydrocarbon receptor (AhR) and inhibit Breg-dependent arthritis [12].”
Background
Gut microbiota–host post-translational modification axis in immunometabolic diseases
Li, S., Guo, Y., An, S., Ge, L., You, J., & Ren, W. (2025) · Trends in Immunology · doi:10.1016/j.it.2025.06.006 · Cited by 11
Expanding Human Breg for Cellular Therapy in Transplantation: Time for Translation
McNee, A., Kannan, A., Jull, P., & Shankar, S. (2024) · Transplantation · doi:10.1097/tp.0000000000005243 · Cited by 11
“75,76 Transcriptome analyses demonstrated that loss of AhR in B cells reduced IL-10 expression by skewing the differentiation of CD19 + CD21 hi CD24 hi B cells into a proinflammatory program, under Breg-inducing conditions.”
Compromised anti-osteoclastogenic and immunomodulatory functions of regulatory B cells (Bregs) aggravate inflammatory bone loss in post-menopausal osteoporosis
Sapra, L., Saini, C., Mishra, P. K., Garg, B., Gupta, M., & Srivastava, R. K. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2025.167675 · Cited by 13
SIRT3 deficiency reduces PFKFB3-driven T-cell glycolysis and promotes arthritic inflammation
Wang, T., Han, T., Xiao, X., Guo, D., Sun, X., Liu, Y., Zhao, L., Xu, H., Li, R., Jiang, L., et al. (2025) · Science China Life Sciences · doi:10.1007/s11427-024-2823-2 · Cited by 12
“AIA was induced and assessed as previously described (Carter et al., 2011; Oleinika et al., 2018; Rosser et al., 2014; Rosser et al., 2020).”
Impact of immune cell metabolism on membranous nephropathy and prospective therapy
Duan, X., Lv, X., Wang, X., Zhang, Y., Hu, Y., Li, H., Zhou, Y., & Jing, Y. (2025) · Communications Biology · doi:10.1038/s42003-025-07816-3 · Cited by 11
“This process leads to an increase in the transcription of the anti-in ﬂ ammatory cytokine IL-10 in B cells 33 .”
Tryptophan metabolites at the service of neuroimmune sensing of microbes
Wang, Y., Li, J., Lian, Z., Hao, H., & Zheng, X. (2025) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2025.10.009 · Cited by 10
Bacillus subtilis KC1 prevents Mycoplasma gallisepticum-induced lung injury by enhancing intestinal Bifidobacterium animalis and regulating indole metabolism in chickens
Chen, X., Ishfaq, M., Hu, F., Zheng, Q., Hu, X., Jian, W., & Huo, N. (2023) · Poultry Science · doi:10.1016/j.psj.2023.102824 · Cited by 11
Decoding host-microbiome interactions through co-expression network analysis within the non-human primate intestine
Uehara, M., Inoue, T., Hase, S., Sasaki, E., Toyoda, A., & Sakakibara, Y. (2024) · mSystems · doi:10.1128/msystems.01405-23 · Cited by 10
“Tryptophan is an essential amino acid that, upon uptake by intestinal cells and subsequent metabolism, can activate the Aryl hydrocarbon receptor and influence B cell immune responses (38).”
Background
The influence of the gut microbiota on B cells in autoimmune diseases
He, L., Li, X., Jiang, S., Ou, Y., Wang, S., Shi, N., Yang, Z., Yuan, J., Silverman, G. J., & Niu, H. (2025) · Molecular Medicine · doi:10.1186/s10020-025-01195-5 · Cited by 11
“Among them, the monopolization of E. coli will promote the production of IL-10 by B10 cells, and it is believed that Bregs rely on bacteria to activate TLR2/TLR4, resulting in an immunosuppressive signaling effect (Maerz et al. 2019).”
Influential
Nanovaccines: Antigen selection, stabilization, adjuvantation, formulation, and evaluation
Lu, L., Yang, M., Deng, D., Shi, X., Lovell, J. F., & Jin, H. (2025) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2025.216806 · Cited by 10
NLRP6 deficiency expands a novel CD103+ B cell population that confers immune tolerance in NOD mice
Pearson, J. A., Peng, J., Huang, J., Yu, X.-Q., Tai, N., Hu, Y., Sha, S., Flavell, R. A., Zhao, H., Wong, F. S., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1147925 · Cited by 10
“Bregs are influenced by gut microbiota and gut microbiota-induced cytokines and AhR signaling (22, 38, 40), and here we have demonstrated that inflammasomes also modulate Breg development.”
Background
Development of yacon syrup fermented by Lactiplantibacillus plantarum NCU001043: Metabolite profiling, antioxidant and glycosidase inhibition activity
Peng, F., Huang, H., Lin, J., Yang, T., Xie, M., Xiong, T., & Peng, Z. (2022) · LWT · doi:10.1016/j.lwt.2022.114051 · Cited by 10
Autophagy activation within inflammatory microenvironment improved the therapeutic effect of MSC-Derived extracellular Vesicle in SLE
Liao, S., Guo, F., Xiao, Z., Xiao, H., Pan, Q.-R., Guo, Y., Chen, J., Wang, X., Wang, X., Huang, H., et al. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.01.044 · Cited by 11
“Microbiota-derived metabolites suppress arthritis by amplifying AhR activation in regulatory B Cells [69].”
Inhibition of 5-hydroxyindoleacetic acid to reduce neutrophil extracellular trap production improves lung condition in chronic obstructive pulmonary disease mice
Zeng, Q., Xue, L., Li, W., Liang, C., Zhou, W., Xiong, W., & Dai, X. (2025) · Annals of Medicine · doi:10.1080/07853890.2025.2474734 · Cited by 11
“[27].”
Influential
Heterogeneity of regulatory B cells in autoimmune diseases: implications for immune equilibrium and therapeutic strategies
Yan, H., He, J., & Lin, X. (2024) · Immunotherapy Advances · doi:10.1093/immadv/ltaf020 · Cited by 9
“…AhR and enhancing Breg function while inhibiting the differentiation of germinal center (GC) B cells and plasma cells, and suppressing RA [52] Radix Rehmanniae : enhancing the function of both human and murine B10 cells, reducing Th17 and Tfh. [97] CpG: restoring IL-10 expression [100]…”
AhR in biological processes of adipocytes and lipid metabolism in obesity: Friend and foe
Li, X., Wang, S., Mao, X., Fang, M., Liu, X., Jiang, J., & Jin, W. L. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.123996 · Cited by 8
Communication between gut microbiota-derived metabolites and the tumor microenvironment
Hu, X., Li, B., Li, Y., Liang, Y., & Huang, T. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1649438 · Cited by 10
“Furthermore, butyrate can enhance the immunosuppressive capabilities of Bregs, important for maintaining immune tolerance (49).”
The role of microbiota derived metabolites in modulating diabetic inflammation: a systematic review
Karthick, V., Thamarai, R., Amalraj, S., Kalimuthu, N., & Manimegalai, G. (2026) · Journal of Molecular Histology · doi:10.1007/s10735-026-10775-6 · Cited by 10
Characterising Post-mortem Bacterial Translocation Under Clinical Conditions Using 16S rRNA Gene Sequencing in Two Animal Models
Gates, L., Klein, N. J., Sebire, N. J., & Alber, D. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.649312 · Cited by 9
“…implemented throughout forensic literature, with particular interest placed on the use of the PM microbiome, commonly referred to as the thanatomicrobiome, as a microbial clock to determine the postmortem interval (PMI) in advanced phases of decomposition (Javan et al., 2019; Roy et al., 2021).”
BackgroundSelf-citation
Regulatory B Cell Therapy in Kidney Transplantation
Garcia, S. G., Sandoval-Hellín, N., & Franquesa, M. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.791450 · Cited by 11
“, 2021) and also cytokines and metabolites derived from these microbes, such as short chain fatty acids (SCFAs) (Rosser et al., 2020; Daïen et al., 2021; Pacaud et al., 2021; Zou et al., 2021) expanding Breg subsets.”
Background
The causal impact of saturated fatty acids on rheumatoid arthritis: a bidirectional Mendelian randomisation study
Yao, X., Yang, Y., Jiang, Z. S., Ma, W., & Yao, X. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1337256 · Cited by 9
What do we know about covid-19’s effects on the gut?
Lang, K. (2024) · BMJ · doi:10.1136/bmj.q842 · Cited by 9
Glycogen Synthase Kinase 3 Beta Regulates the Human Aryl Hydrocarbon Receptor Cellular Content and Activity
Yang, Y., & Chan, W. K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22116097 · Cited by 9
Disease Differentiation and Monitoring of Anti-TNF Treatment in Rheumatoid Arthritis and Spondyloarthropathies
Bogunia‐Kubik, K., Wojtowicz, W., Świerkot, J., Mielko, K. A., Qasem, B., Wielińska, J., Sokolik, R., Pruss, Ł., & Młynarz, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147389 · Cited by 9
Modulatory effects of gut microbiota on innate and adaptive immune responses following spinal cord injury
Li, Z., Wang, F., xing, J.-J., Hu, X., Gou, X., Li, J., Pang, R., & Zhang, A. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114866 · Cited by 8
Microbiota-associated mechanisms in colorectal cancer
González, A., Fullaondo, A., & Odriozola, A. (2024) · Advances in genetics · doi:10.1016/bs.adgen.2024.05.002 · Cited by 8
Dynamic roles of tumor-infiltrating B lymphocytes in cancer immunotherapy
Song, S., Wang, C., Chen, Y., Zhou, X., Han, Y., & Zhang, H. (2025) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-024-03936-7 · Cited by 9
“Therefore, targeting the AhR to limit the trend of tumor immune suppression warrants further investigation [70].”
Contributions of Dietary Patterns and Factors to Regulation of Rheumatoid Disease
Zhang, J., Wang, X., Fang, J., Li, Y., Yu, Y., Wang, J., & Sun, B. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26062674 · Cited by 8
“The mechanism of this study involves butyric acid increasing the level of 5-hydroxyindole-3-acetic acid, activating aromatic hydrocarbon receptors, and altering the direction of B cell differentiation, thus alleviating arthritis and inhibiting the development of RA [123].”
Gut–lung axis in allergic rhinitis: microbial dysbiosis and therapeutic strategies
Yang, W., Wu, H., Li, X., Wan, Z., Kong, W., & Huang, C. (2025) · Frontiers in Microbiology · doi:10.3389/fmicb.2025.1654997 · Cited by 10
Gut microbiota in early and established stages of rheumatoid arthritis: from pathogenesis to promising prevention and treatment
Chen, S., Hoàng, M. H., Hu, D., He, Q., & Gao, Y. (2026) · Annals of Medicine · doi:10.1080/07853890.2026.2613484 · Cited by 8
“In contrast, findings regarding circulating SCFA concentrations remain inconsistent across studies [79,80].”
Influential
Roles of immune cell metabolism in rheumatoid arthritis
Xie, R., Chen, Z., Deng, S., Jiang, X., Feng, Y., & Zhao, W. J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1763130 · Cited by 8
The intriguing possibility of using probiotics in allergen-specific immunotherapy
Furci, F., Caminati, M., Crisafulli, E., Senna, G., & Gangemi, S. (2023) · World Allergy Organization Journal · doi:10.1016/j.waojou.2023.100751 · Cited by 8
“In particular, butyrate can induce an increasing of the quantity of the serotonin-derived metabolite 5-hydroxyindole-3-acetic acid (5-HIAA), which binds to the Aryl Hydrocarbon receptor (AhR).(27) AhR acts a transcriptional regulator for Bregs, increasing the production of IL-10 and”
Background
Maternal supplementation with konjac glucomannan improves maternal microbiota for healthier offspring during lactation
Gao, F., Zhang, W., Cao, M., Liu, X., Han, T., He, W., Shi, B., & Gu, Z. (2024) · Journal of the Science of Food and Agriculture · doi:10.1002/jsfa.13258 · Cited by 8
The Role of Gut Microbiota and Associated Compounds in Cardiovascular Health and its Therapeutic Implications
Liu, L., Kaur, G. I. J., Kumar, A., Kanwal, A., & Singh, S. P. (2024) · Cardiovascular & Hematological Agents in Medicinal Chemistry · doi:10.2174/0118715257273506231208045308 · Cited by 8
Bioluminescence imaging of Cyp1a1-luciferase reporter mice demonstrates prolonged activation of the aryl hydrocarbon receptor in the lung
Veland, N., Gleneadie, H. J., Brown, K. E., Sardini, A., Pombo, J., Dimond, A., Burns, V., Sarkisyan, K. S., Schiering, C., Webster, Z., et al. (2024) · Communications Biology · doi:10.1038/s42003-024-06089-6 · Cited by 8
“Thisisbestillustratedinthe mammaliangastrointestinal tract whereconstantexposureto microbesand dietary ligands requires an epithelial barrier equipped with immune surveillance to protect and maintain health 27,28,37,66 .”
Human microbial metabolite mimicry as a strategy to expand the chemical space of potential drugs
Li, H., Ranhotra, H. S., Mani, S., Dvořák, Z., Sokol, H., & Müller, R. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.06.007 · Cited by 8
“Other metabolites, such as butyrate, which also ameliorate inflammatory disorders [32], have rapid systemic clearance, and either clinically cumbersome dosing schedules are required or there is a need to design stable butyrate analogs [33].”
Background
Metabolomic analysis in spondyloarthritis: A systematic review
Huang, T., Pu, Y., Wang, X., Li, Y., Yang, H., Luo, Y., & Liu, Y. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.965709 · Cited by 10
“Modulating immunity and inflammation by the oral supplementation of metabolites with levels that are reduced in disease states, especially microbial-derived metabolites such as SCFAs, is considered a promising treatment for autoimmune diseases, including SpA (Rosser et al., 2020).”
Background
Immunmodulation durch Ernährung bei kritisch kranken Patienten
Hirschberger, S., Schmid, A., & Kreth, S. (2023) · Die Anaesthesiologie · doi:10.1007/s00101-023-01258-4 · Cited by 8
Elucidating a fresh perspective on the interplay between exosomes and rheumatoid arthritis
Zhao, J., Zhang, B., Meng, W., & Hu, J. Y. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1177303 · Cited by 9
In vitro fermentation characteristics of different types of fiber‐rich ingredients by pig fecal inoculum
Luo, C., Duan, J., Zhong, R., Liu, L., Gao, Q., Liu, X., Chen, L., & Zhang, H. (2024) · Journal of the Science of Food and Agriculture · doi:10.1002/jsfa.13355 · Cited by 7
3,3-Dimethyl-1-Butanol and its Metabolite 3,3-Dimethylbutyrate Ameliorate Collagen-induced Arthritis Independent of Choline Trimethylamine Lyase Activity
Fechtner, S., Allen, B. E., Chriswell, M. E., Jubair, W. K., Robertson, C. E., Kofonow, J. M., Frank, D. N., Holers, V. M., & Kuhn, K. A. (2024) · Inflammation · doi:10.1007/s10753-024-02126-y · Cited by 7
Mendelian randomization identifies causal associations between GWAS-associated bacteria and their metabolites and rheumatoid arthritis
Zhou, D., Jiao, W., Shi, W., Wang, Q., & Chen, M. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2024.1431367 · Cited by 8
“For example, short-chain fatty acids (SCFAs) synthesized by gut microbiota are noted to engage with germinal center B cells, aﬀect the diﬀerentiation of plasmablastes, and play a role in the formation of RA (Rosser et al., 2020).”
Background
The role of aryl hydrocarbon receptor in the occurrence and development of periodontitis
Wu, L., Li, X., Li, J., Wang, Y., Yang, C., Zhao, C., & Gao, L. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1494570 · Cited by 7
Microbiota and immune dynamics in rheumatoid arthritis: Mechanisms and therapeutic potential
Jin, J., Cai, X., Rao, P., Xu, J. Q., & Li, J. (2025) · Best Practice & Research Clinical Rheumatology · doi:10.1016/j.berh.2025.102035 · Cited by 8
Intestinal Butyrate Ameliorates Rheumatoid Arthritis Through Promoting the Expression of Cortistatin in Ileum via HDAC3 —Vitamin D Receptor Pathway
Liao, M., Zhu, Y., Cui, Q., Yue, M., Li, J., Gao, L., He, Y., Guo, Y., Zhang, W., Wei, Z., et al. (2025) · Immunology · doi:10.1111/imm.13939 · Cited by 7
“Altering the diet to elevate the intestinal butyrate levels or administering butyrate via gavage can improve the symptoms of adjuvant-induced arthritis and CIA in mice [2–4, 37, 39].”
Influential
Enhancing immunotherapy efficacy in NSCLC through the combined use of phenelzine and Akkermansia muciniphila to regulate gut microbial metabolite 5-HIAA
Sun, S., Wang, L., Cui, K., Ding, Y., Wei, Y., Zheng, Y., Shen, Z., Zhu, L., Yang, Y., Pu, Y., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-011831 · Cited by 9
“18 The above studies suggest that gut microbiota can also serve as a target for regulating 5-HIAA synthesis.”
Modulating the gut-immune axis to alleviate rheumatoid arthritis: mechanistic insights and therapeutic potential of traditional Chinese medicine
Zhan, J., Fu, Y., Liu, Z., Zhang, S., & Wu, C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1637942 · Cited by 7
Free lipoproteins from Bifidobacterium longum alleviate osteoarthritis through modulation of the gut microbiome
Sané, F., Piva, F., & Romond, M. (2023) · Microbiome Research Reports · doi:10.20517/mrr.2023.12 · Cited by 7
Contribution of HLA DRB1, PTPN22, and CTLA4, to RA dysbiosis
Berthelot, J., Darrieutort‐Laffite, C., & Goff, B. L. (2022) · Joint Bone Spine · doi:10.1016/j.jbspin.2022.105446 · Cited by 7
Potential for TCDD to induce regulatory functions in B cells as part of the mechanism for T cell suppression in EAE
McDonald, A., Nicaise, A. J., Sears, E. R., Bell, A., Kummari, E., & Kaplan, B. L. F. (2022) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2022.116259 · Cited by 7
Correlating the Gut Microbiome to Health and Disease
Marques, T. M., Mall, J. G., Forsgård, R. A., Wall, R., Brummer, R. J., & de Vos, W. M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-99971-7.00010-2 · Cited by 9
Cordyceps militaris extract and cordycepin ameliorate LPS-challenged colonic damage in piglets by modulating the microbiota and metabolite profiles
Xiong, S., Wan, F., Jiang, J., Liu, Y., Hang, Y., Xue, H., Yang, L., & Su, Y. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1530098 · Cited by 6
Short‐Chain Fatty Acid Sodium Butyrate Suppresses Protective Humoral Immunity by Inhibiting Follicular T Helper Cell Differentiation
Nikam, B., Jha, S. N., Thakare, Y., Coshic, P., & Gupta, N. (2025) · European Journal of Immunology · doi:10.1002/eji.70076 · Cited by 6
Dietary modulation of the gut–immune–brain axis: nutritional immunoepigenomics for immune regulation in autoimmunity, cancer, and infection
Mukherjee, D. A. (2026) · Clinical Immunology Communications · doi:10.1016/j.clicom.2026.01.004 · Cited by 6
Targeting “Immunoporosis” as a novel concept of Immunotherapy in the management and treatment of Osteoporosis
Pol, V., Kaur, T., Bhardwaj, A., Sapra, L., Yadav, S., & Srivastava, R. K. (2023) · IntechOpen eBooks · doi:10.5772/intechopen.1003712 · Cited by 6
Association between Circulating T Cells and the Gut Microbiome in Healthy Individuals: Findings from a Pilot Study
Vivek, S., Shen, Y. S., Guan, W., Onyeaghala, G. C., Oyenuga, M., Staley, C. M., Karger, A. B., Prizment, A. E., & Thyagarajan, B. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25136831 · Cited by 6
“The gut microbiome can influence the differentiation and activation of immune cells, such as T cells and B cells [1–3], and also the production of immune molecules, such as antibodies and cytokines [4,5].”
Background

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: Rosser, Elizabeth C.
Piper, Christopher J.M.
Matei, Diana E.
Blair, Paul A.
Rendeiro, André F.
Orford, Michael
Krausgruber, Thomas
Klein, Nigel
Manson, Jessica J.
Drozdov, Ignat
Bock, Christoph
Wedderburn, Lucy R.
Eaton, Simon
Mauri, Claudia
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2020-04
Volume: 31
Issue: 4
Pages: 837-851.e10
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2020.03.003
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor)
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-UniversitÃ¤t 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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Microbiota-Derived Metabolites Suppress Arthritis by Amplifying Aryl-Hydrocarbon Receptor Activation in Regulatory B Cells

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