Sodium Butyrate Inhibits Inflammation and Maintains Epithelium Barrier Integrity in a TNBS-induced Inflammatory Bowel Disease Mice Model

• Published in: EBioMedicine Vol. 30; pp. 317 - 325
• Main Authors: Chen, Guangxin, Ran, Xin, Li, Bai, Li, Yuhang, He, Dewei, Huang, Bingxu, Fu, Shoupeng, Liu, Juxiong, Wang, Wei
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2018; Elsevier
• Subjects: Animals; Butyric Acid - pharmacology; Butyric Acid - therapeutic use; Caco-2 Cells; Colon - drug effects; Colon - pathology; Cytokines - metabolism; Disease Models, Animal; Epithelium - drug effects; Epithelium - pathology; Epithelium barrier; GPR109A; Humans; IBD; Inflammation; Inflammation - drug therapy; Inflammation - pathology; Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - pathology; Lipopolysaccharides; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mucin-2 - metabolism; Permeability; Phosphorylation - drug effects; Proto-Oncogene Proteins c-akt - metabolism; RAW 264.7 Cells; Research Paper; Signal Transduction - drug effects; Survival Analysis; Tight Junctions - drug effects; Tight Junctions - metabolism; TNBS; Transcription Factor RelA - metabolism; Trinitrobenzenesulfonic Acid; Weight Loss - drug effects; PBS; DSS; GPR109A; IBD; Inflammation; TNBS; LPS; SB; FITC; MUC2; Epithelium barrier; Cldn1; WT
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2018.03.030

G Protein Coupled Receptor 109A (GPR109A), which belongs to the G protein coupled receptor family, can be activated by niacin, butyrate, and β-hydroxybutyric acid. Here, we assessed the anti-inflammatory activity of sodium butyrate (SB) on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis mice, an experimental model that resembles Crohn's disease, and explored the potential mechanism of SB in inflammatory bowel disease (IBD). In vivo, experimental GPR109a−/− and wild-type (WT) mice were administered SB (5g/L) in their drinking water for 6weeks. The mice were then administered TNBS via rectal perfusion to imitate colitis. In vitro, RAW246.7 macrophages, Caco-2 cells, and primary peritoneal macrophages were used to investigate the protective roles of SB on lipopolysaccharide (LPS)-induced inflammatory response and epithelium barrier dysfunction. In vivo, SB significantly ameliorated the inflammatory response and intestinal epithelium barrier dysfunction in TNBS-induced WT mice, but failed to provide a protective effect in TNBS-induced GPR109a−/− mice. In vitro, pre-treatment with SB dramatically inhibited the expression of TNF-α and IL-6 in LPS-induced RAW246.7 macrophages. SB inhibited the LPS-induced phosphorylation of the NF-κB p65 and AKT signaling pathways, but failed to inhibit the phosphorylation of the MAPK signaling pathway. Our data indicated that SB ameliorated the TNBS-induced inflammatory response and intestinal epithelium barrier dysfunction through activating GPR109A and inhibiting the AKT and NF-κB p65 signaling pathways. These findings therefore extend the understanding of GPR109A receptor function and provide a new theoretical basis for treatment of IBD. •Sodium butyrate maintains the gut epithelium barrier and protects against inflammation in TNBS-induced colitis-model mice•Targeting GPR109A anti-inflammatory and pro-intestinal epithelium barrier functions is a new strategy for IBD treatment Butyrate, produced by microbial fermentation in the bowel, has a protective effect toward maintaining the integrity of the gut epithelium barrier, which can decrease inflammatory responses in inflammatory bowel disease (IBD) such as Crohn's disease, although the underlying mechanism remains unknown. Here, we used cell and animal models of colitis to demonstrate that butyrate-mediated activation of the GPR109A receptor, which is known to suppress the inflammatory effects in various diseases, underlies its protective effects on colon health. Our results demonstrate that activating GPR109A thus may represent a novel approach to treat IBD, for which effective treatments are urgently required.