TY - JOUR
T1 - Butyrate suppresses mucosal inflammation in inflammatory bowel disease primarily through HDAC3 inhibition in monocytes and macrophages
AU - Parada-Venegas, Daniela
AU - De la Fuente López, Marjorie
AU - Dubois-Camacho, Karen
AU - Landskron, Glauben
AU - Blokzijl, Tjasso
AU - Molina, Héctor
AU - Casanova, María Celeste
AU - Cui, Yingying
AU - Liu, Moting
AU - Da Costa De Pina, Antonio M.
AU - Simian, Daniela
AU - González, María Julieta
AU - Weersma, Rinse K.
AU - Quera, Rodrigo
AU - Dijkstra, Gerard
AU - Faber, Klaas Nico
AU - Hermoso, Marcela A.
N1 - Publisher Copyright:
© 2025 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
PY - 2025
Y1 - 2025
N2 - 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 inhibitor SAHA. Contrary, specific GPR109A inhibition and gene G-protein-coupled receptor inhibition did not alter butyrate's effects. Butyrate restores MCT1 and IL-18 gene expression in inflamed epithelial cells, showing limited anti-inflammatory effects. Instead, butyrate targets HDAC3 in mononuclear cells, suppressing inflammation in IBD gut mucosa. The cell-type-specific effects of butyrate offer mechanistic insights that support its therapeutic relevance in IBDs.
AB - 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 inhibitor SAHA. Contrary, specific GPR109A inhibition and gene G-protein-coupled receptor inhibition did not alter butyrate's effects. Butyrate restores MCT1 and IL-18 gene expression in inflamed epithelial cells, showing limited anti-inflammatory effects. Instead, butyrate targets HDAC3 in mononuclear cells, suppressing inflammation in IBD gut mucosa. The cell-type-specific effects of butyrate offer mechanistic insights that support its therapeutic relevance in IBDs.
KW - butyrate
KW - epithelial SLC16A1/MCT1
KW - histone deacetylase (HDAC) inhibition
KW - inflammatory bowel diseases (IBD)
KW - monocytes/macrophages
UR - https://www.scopus.com/pages/publications/105019339045
U2 - 10.1111/febs.70289
DO - 10.1111/febs.70289
M3 - Article
C2 - 41110099
AN - SCOPUS:105019339045
SN - 1742-464X
JO - FEBS Journal
JF - FEBS Journal
ER -