Intestinal Butyrate Ameliorates Rheumatoid Arthritis Through Promoting the Expression of Cortistatin in Ileum via HDAC3—Vitamin D Receptor Pathway

ABSTRACT Butyrate, administered orally or via drinking water, can effectively ameliorate experimental rheumatoid arthritis (RA) in mice despite its limited bioavailability. The discrepancy urges us to explore the involvement and role of intestinal anti‐RA factors in the action of butyrate. In this study, we found that substituting drinking water with butyrate (75 mM) could promote the expression of cortistatin (CST) in the ileal epithelium of mice with collagen‐induced arthritis (CIA), but butyrate did not alter the expression of other anti‐RA neuropeptides in the intestine and the expression of CST in the spleen and brain. The anti‐RA efficacy of butyrate was remarkably reduced following adeno‐associated virus (AAV)‐mediated knockdown of CST. Transcription factor screening revealed that butyrate upregulated CST expression via the vitamin D receptor (VDR). Notably, butyrate‐induced VDR and CST expression in intestinal epithelial cells was diminished by α‐cyano‐4‐hydroxycinnamic acid (CHC) rather than siRNA targeting G protein‐coupled receptors (GPCRs), suggesting that butyrate functions through an intracellular pathway. Furthermore, butyrate significantly reduced HDAC activity in intestinal epithelial cells and HDAC3 plasmid transfection attenuated the upregulation of butyrate against VDR and CST expression. Chromatin immunoprecipitation assay showed that butyrate selectively enhanced histone acetylation in the P3 and P4 regions of the VDR promoter. In summary, intestinal butyrate exerts an anti‐RA effect through selectively promoting the expression of CST in ileal epithelial cells via the HDAC3‐VDR pathway.