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

Abstract

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 (5 g/L) in their drinking water for 6 weeks. 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.

The Suppressive Effect of Butyrate and Bromopyruvate on Inflammatory Cytokine Production and Short Chain Fatty Acid Receptor Expression by Blood Mononuclear Cells in Patients with Behçet's Disease

“…Further study to analyze FFAR2 and FFAR3 protein expression is required. Also, GPR109a (another SCFA receptor) expression analysis in PBMCs of BD patients will be informative given that butyrate significantly ameliorated the inflammatory response in a GPR109a dependent manner through inhibiting AKT and NFκB p65 signaling in inflammatory bowel disease model mice 13 . Given the increase in TH17 cell frequency and decrease in regulatory T cell frequency in BD patients 14,15 , it is noteworthy that BrPA inhibits TH17 cell differentiation and promotes regulatory T cell differentiation 4 .…”

Exploring the role of the metabolite-sensing receptor GPR109a in diabetic nephropathy

“…In vitro, GPR109a knockdown inhibits butyrate-induced increases in the tight junction protein Claudin-3, suggesting that GPR109a may have a role in the integrity of the intestinal epithelial barrier [8]. However in vivo, whilst deletion of GPR109a was associated with a trend towards an increase in intestinal permeability in an induced food allergy model [59] there was no effect in otherwise healthy mice [7], indicating that deletion of the GPR109a receptor alone is insufficient to alter intestinal permeability. While GPR109a is expressed at a relatively low level in the kidney [60] it is unlikely that butyrate would reach sufficient concentrations in the renal blood flow to effectively induce a biological response as a result of ligation to the receptor.…”

“…Furthermore, during ESRD, there is an increase in intestinal permeability and subsequent inflammation [6]. SCFAs have been shown to act via local metabolite-sensing receptors to reduce intestinal permeability and inflammation [7,8].…”

“…Butyrate is produced by the gut microbiota and accumulates in high concentrations of up to 10-20 mM in the colonic lumen [14], with the majority of butyrate produced being metabolised by the colonic epithelium [17]. Activation of GPR109a in rodents via butyrate or a high fibre diet reduces the severity of experimental colitis, via the anti-inflammatory effect of GPR109adependent IL-18 production [7,15,18].…”

Butyrate Decreases ICAM-1 Expression in Human Oral Squamous Cell Carcinoma Cells

“…Similarly, butyrate suppressed the cytokine-induced expression of ICAM-1 in primary oral epithelial cells ( Figure 2). Then, and in order to validate these observations, we used another experimental setting using primary mouse macrophages [37][38][39]. Notably, butyrate was capable of inhibiting the LPS-and saliva-induced ICAM-1 expression in primary mouse macrophages ( Figure 3).…”