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

Cell Metab. 2020 Apr 7;31(4):837-851.e10. doi: 10.1016/j.cmet.2020.03.003. Epub 2020 Mar 25.


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.

Keywords: 5-Hydroxyindole-3-acetic acid; B cells; aryl-hydrocarbon receptor; autoimmunity; butyrate; regulatory B cells; rheumatoid arthritis; serotonin; short chain fatty acid; tryptophan metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / metabolism*
  • B-Lymphocytes, Regulatory / cytology
  • B-Lymphocytes, Regulatory / metabolism*
  • Basic Helix-Loop-Helix Transcription Factors* / metabolism
  • Butyrates / pharmacology*
  • Cells, Cultured
  • Fatty Acids, Volatile / metabolism*
  • Female
  • Gastrointestinal Microbiome
  • Humans
  • Hydroxyindoleacetic Acid / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Receptors, Aryl Hydrocarbon* / metabolism


  • Ahr protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Butyrates
  • Fatty Acids, Volatile
  • Receptors, Aryl Hydrocarbon
  • Hydroxyindoleacetic Acid