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The discrepancy urges us to explore the involvement and role of intestinal anti\u2010RA factors in the action of butyrate. In this study, we found that substituting drinking water with butyrate (75\u2009mM) could promote the expression of cortistatin (CST) in the ileal epithelium of mice with collagen\u2010induced arthritis (CIA), but butyrate did not alter the expression of other anti\u2010RA neuropeptides in the intestine and the expression of CST in the spleen and brain. The anti\u2010RA efficacy of butyrate was remarkably reduced following adeno\u2010associated virus (AAV)\u2010mediated knockdown of CST. Transcription factor screening revealed that butyrate upregulated CST expression via the vitamin D receptor (VDR). Notably, butyrate\u2010induced VDR and CST expression in intestinal epithelial cells was diminished by \u03b1\u2010cyano\u20104\u2010hydroxycinnamic acid (CHC) rather than siRNA targeting G protein\u2010coupled 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\u2010RA effect through selectively promoting the expression of CST in ileal epithelial cells via the HDAC3\u2010VDR pathway.<\/jats:p>","DOI":"10.1111\/imm.13939","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T01:51:17Z","timestamp":1746064277000},"page":"373-390","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Intestinal Butyrate Ameliorates Rheumatoid Arthritis Through Promoting the Expression of Cortistatin in Ileum via <scp>HDAC3<\/scp>\u2014Vitamin D Receptor Pathway"],"prefix":"10.1111","volume":"175","author":[{"given":"Minghui","family":"Liao","sequence":"first","affiliation":[{"name":"Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy China Pharmaceutical University  Nanjing 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