Butyrate suppresses mucosal inflammation in inflammatory bowel disease primarily through HDAC3 inhibition in monocytes and macrophages

作者：Daniela Parada‐Venegas, Marjorie De la Fuente, Karen Dubois‐Camacho, Glauben Landskron, Tjasso Blokzijl, Héctor Molina, María José Casanova, Yingying Cui, Moting Liu, Antonio Pina, Daniela Simian, María‐Julieta González, Rinse K. Weersma, Rodrigo Quera, Gerard Dijkstra, Klaas Nico Faber, Marcela A. Hermoso · 发表于：FEBS Journal · 年份：2025 · DOI：10.1111/febs.70289 · 被引用次数：19 · 研究领域：Inflammatory Bowel Disease、Gut microbiota and health、Immune cells in cancer

Butyrate-producing gut bacteria and luminal butyrate levels are reduced in Inflammatory Bowel Diseases (IBDs). Butyrate has anti-inflammatory properties through mechanisms not well-characterized in IBDs. Here, we determined the butyrate anti-inflammatory effect on primary IBD tissues and intestinal cell models to identify key target cells and pathway(s) involved. Cytokines, monocarboxylate transporter-1 (MCT1), G-protein-coupled receptor-109A (GPR109A), and histone deacetylase-3 (HDAC3) levels were analyzed in IBD and healthy tissues using cytometric bead arrays, RNA-seq analysis and immunofluorescence. Inflammatory markers and phagocytosis in butyrate-treated colonic organoids, primary monocytes or THP-1 macrophages, were assessed by qPCR, flow cytometry and amikacin protection assays, when relevant combined with GPR109A or HDAC3 antagonists. Butyrate suppressed TNF and IL-6 secretion by > 50% in ex vivo-cultured inflamed IBD biopsies. MCT1 expression was reduced in inflamed epithelium and cytokine-exposed organoids, while IL-18 was reduced 0.5-fold in organoids, and both were restored by butyrate, without suppressing pro-inflammatory gene expression. GPR109A and HDAC3 were elevated in IBD tissues and upregulated by butyrate in cultured mucosa. Butyrate also suppressed IL-6, TNF-α, CD40, and CD80 by > 50% and enhanced adherent-invasive Escherichia coli (AIEC) phagocytosis by 62% in monocytes/macrophages. Histone acetylation (H3K9ac) increased > 5-fold, mimicking the HDAC inh...