Search

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., Highlights • 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.

Epithelial regeneration is a key process for the recovery from ulcerative colitis (UC). Here we demonstrate that a disintegrin and metalloproteinase-17 (ADAM17), a main sheddase for tumor necrosis factor (TNF)-α, is essential for defensive epithelial properties against UC by promoting epithelial cell growth and goblet cell differentiation in mouse and human. Mice with systemic deletion of Adam17 developed severe dextran sulfate sodium-induced colitis when compared to mice with myeloid cell Adam17 deletion or control littermates. ADAM17 was predominantly expressed by regenerating epithelia in control mice, and its loss or inhibition attenuated epidermal growth factor receptor (EGFR) activation, epithelial proliferation, mucus production and barrier functions. Conversely, ectopic EGFR stimulation promoted epithelial regeneration thereby partially rescuing the severe colitis caused by ADAM17 deficiency. In UC patients, epithelial ADAM17 expression positively correlated with both cell proliferation and goblet cell number. These findings suggest that maintaining ADAM17–EGFR epithelial signaling is necessary for the recovery from UC and would be beneficial to therapeutic strategies targeting ADAM17-mediated TNF-α shedding., Graphical Abstract, Highlights • Mice with systemic deletion of ADAM17, but not with its myeloid cell-specific deficiency, are more sensitive to colitis. • ADAM17-EGFR axis promotes repair processes through epithelial cell proliferation and goblet cell differentiation. • Epithelial ADAM17 expression correlates with cell growth and mucus production in ulcerative colitis patients. Epithelial regeneration is a key process for the recovery from ulcerative colitis (UC). We now demonstrate that a disintegrin and metalloproteinase-17 (ADAM17) is essential for defensive epithelial properties against UC by driving repair processes in mouse and human. During colonic inflammation, ADAM17 is up-regulated in regenerating epithelia, and its loss or inhibition attenuated epidermal growth factor receptor (EGFR) activation, epithelial proliferation, mucus production and barrier functions. These findings suggest that maintaining ADAM17–EGFR epithelial signaling is necessary for the recovery from UC and would be beneficial to therapeutic strategies targeting ADAM17-mediated tumor necrosis factor-α shedding.