Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease caused by both genetic and environmental factors. Recently, investigators have focused on the gut microbiota, which is thought to be an environmental factor that affects the development of RA. Metabolites secreted by the gut microbiota maintain homeostasis in the gut through various mechanisms [e.g., butyrate, which is one of the major metabolites of gut microbiota, exerts an anti-inflammatory effect by activating G-protein-coupled receptors and inhibiting histone deacetylases (HDACs)]. Here, we focused on the inhibition of the HDACs by butyrate in RA. To this end, we evaluated the therapeutic effects of butyrate in an animal model of autoimmune arthritis. The arthritis score and incidence were lower in the butyrate-treated group compared to the control group. Also, butyrate inhibited HDAC2 in osteoclasts and HDAC8 in T cells, leading to the acetylation of glucocorticoid receptors and estrogen-related receptors α, respectively. Additionally, control of the TH17/Treg cell balance and inhibition of osteoclastogenesis were confirmed by the changes in target gene expression. Interleukin-10 (IL-10) produced by butyrate-induced expanded Treg cells was critical, as treatment with butyrate did not affect inflammatory arthritis in IL-10-knockout mice. This immune-cell regulation of butyrate was also detected in humans. These findings suggest that butyrate is a candidate agent for the treatment of RA.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology that involves joint destruction [1]
To identify the mechanism underlying its antiarthritic effect, we examined the effect of butyrate on effector T-cell differentiation and osteoclastogenesis
The arthritis scores and the incidence of arthritis were dramatically reduced by butyrate compared to vehicle treatment (Figure 1A)
Summary
Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology that involves joint destruction [1]. An intestinal imbalance is involved in RA development, and gut bacteria have various effects on RA [2, 3]. Butyrate may have a therapeutic effect in immune-mediated inflammatory diseases. The abundance of Faecalibacterium prausnitzii, a butyrate-producing bacterium, is reduced in enthesitis-related arthritis [17], the direct therapeutic effect of butyrate on RA is unclear. Both the therapeutic effect of butyrate in RA and the mechanism underlying this effect should be investigated.
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