Regulatory B (Breg) cells are important for maintaining immunological tolerance and for suppressing pathogenic responses in autoimmune diseases such as rheumatoid arthritis. New findings suggest that butyrate, a gut microbiota-derived short-chain fatty acid generated during fermentation of dietary fibres, can suppress arthritis by influencing the development and function of Breg cells.

“There have been many studies investigating how microbiota-derived metabolites affect T cell and myeloid cell function but little work has been carried out to investigate how these metabolites modulate B cell function,” explains Elizabeth Rosser, first author on the new study.

Credit: Science Photo Library/Alamy Stock Photo

In a mouse model of experimental arthritis, the researchers found that dietary supplementation with butyrate could reduce arthritis severity in a manner dependent on IL-10-producing B cells. Indeed, butyrate supplementation skewed the B cell population in these mice towards a regulatory phenotype.

Using knockout mice, adoptive transfer experiments and chimeric mouse models, Rosser and colleagues pinpointed the involvement of the aryl-hydrocarbon receptor (AhR) in butyrate-mediated suppression of arthritis, including in the promotion of Breg cell function and suppression of germinal centre B cell and plasmablast differentiation.

Further experiments showed that butyrate did not directly upregulate AhR activity in B cells but instead increased the levels of the metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) in the gut, potentially through shifting the gut microbiota profile towards an increased abundance of particular bacteria genera. 5-HIAA itself directly increased the activity of AhR in B cells. Notably, treatment with 5-HIAA suppressed arthritis development in wild-type mice, but not in mice with a B-cell specific deletion of AhR or in mice treated with a tryptophan hydroxylase inhibitor known to reduce 5-HIAA synthesis.

butyrate supplementation skewed the B cell population in these mice towards a regulatory phenotype

“Our data suggest that a high fibre diet and/or butyrate-supplementation might be anti-inflammatory in the context of arthritis,” says corresponding author Claudia Mauri. “Modulating the production of gut-derived metabolites with dietary changes, prebiotics or probiotics could be immune-suppressive in the context of arthritis.”