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

The DOI matches its Crossref record; 75 of the 75 references it cites were found in a registry or an index.

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

Open access
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
Open this paper in CoChat — free accountOpen PDF

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.cmet.2020.03.003

Cites

75 of 75 references verified0 citation errors · 0 not checkable

Statistics

Figures

Graphical abstract
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.
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.
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.
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.
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).
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.
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).
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

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 75 references

Cited by

Sorted by citations

See all 581

Related

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)
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
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

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 ›

Are you an author, or do you see a problem with this page? Request a review