Attenuation of Rheumatoid Inflammation by Sodium Butyrate Through Reciprocal Targeting of HDAC2 in Osteoclasts and HDAC8 in T Cells

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.

Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells

“…The intraperitoneal administration of sodium butyrate at a high dose (100 mg/kg) suppresses the CIA by decreasing the T H 17/T REG ratio in DLNs [77] . In contrast, the T H 17/T REG ratio was not affected by the HAMSB diet in our study.…”

The gut-bone axis: how bacterial metabolites bridge the distance

“…Osteoclasts are multinucleated cells that are responsible for physiological and pathological bone resorption. SCFAs blunt osteoclast differentiation (97), and inhibition of HDAC activity is one mechanism whereby this occurs (98)(99)(100). For example, differentiation of primary bone marrow (BM) cells into osteoclasts is suppressed by butyrate and by trichostatin A, a known HDAC inhibitor (101).…”

The Role of the Microbiome in Driving RA-Related Autoimmunity

“…Elements known to influence the mucosal barrier integrity include bacteria, their by-products and diet ( Horta-Baas et al, 2017 ; Guerreiro et al, 2018 ). Microbial by-products particularly short chain fatty acids (SCFA), including acetate, propionate, and butyrate have been linked to amelioration of arthritis development in CIA models ( Mizuno et al, 2017 ; Kim et al, 2018 ). Mizuno et al (2017) showed that oral administration of SCFA was able to decrease disease severity by decreasing Th1 cells, and increasing Treg cells thereby damping the immune response.…”