br Introduction Inflammatory bowel diseases IBDs including C

Introduction Inflammatory bowel diseases (IBDs) including Crohn's disease and ulcerative colitis (Baumgart and Sandborn, 2012; Beaugerie et al., 2006) are typically characterized by chronic, progressive, and relapsing inflammation of the intestine. Although the exact pathogenesis of IBD is unknown, it is considered to generally result from multiple immune, genetic, and environmental factors, with only suboptimal medical and surgical therapies being available (Farrell and Peppercorn, 2002). Previous studies have suggested that although the pathogenesis of ulcerative colitis and Crohn's disease is similar, important differences do exist (Ungaro et al., 2017). Ulcerative colitis is characterized by relapsing and remitting mucosal inflammation, often initiating in the rectum and extending to proximal segments of the colon (Ungaro et al., 2017). However, Crohn's disease constitutes a chronic, relapsing, systemic inflammatory disease that mainly affects the gastrointestinal tract, along with extra-intestinal manifestations and associated immune disorders (Baumgart and Sandborn, 2012). GPR109A constitutes a Gi protein-coupled receptor that is activated by nicotinic Astemizole australia (Soga et al., 2003; Tunaru et al., 2003; Wise et al., 2003), butyrate (Thangaraju et al., 2009), and beta-hydroxybutyric acid (Taggart et al., 2005). Previous studies have shown that the activation of GPR109A suppresses mammary tumorigenesis by inducing apoptosis in breast cancer cells (Elangovan et al., 2014). GPR109A is also linked to a pro-apoptotic pathway in neutrophils, suggesting that nicotinic acid may mediate anti-inflammatory effects in addition to its inhibitory function on adipocyte lipolysis (Kostylina et al., 2008). Moreover, as the ligand of GPR109A, niacin acid has the ability to reduce inflammation in atherosclerosis (Lukasova et al., 2011), obesity (Wanders et al., 2013), sepsis (Kwon et al., 2011), diabetic retinopathy (Gambhir et al., 2012), renal disease (Cho et al., 2009), and Parkinson's disease (Fu et al., 2014; Fu et al., 2015). Together, these findings indicated that GPR109A has the ability to inhibit inflammation in various diseases. In particular, studies have reported that the GPR109A receptor mediates the protective effects of dietary fiber on gut homeostasis through regulation of the inflammasome in dextran sulfate sodium (DSS)-induced mice (Macia et al., 2015) and suppresses colonic inflammation and tumorigenesis in mice (Singh et al., 2014; Thangaraju et al., 2009). However, the mechanism underlying GPR109A mediation of the process by which butyric acid inhibits inflammation and maintains epithelial barrier integrity in inflammatory bowel disease has not yet been elucidated. Butyrate, which is produced by bowel microbial fermentation of dietary carbohydrates, fibers, proteins, and peptides (Guilloteau et al., 2010; Leonel and Alvarez-Leite, 2012; Macfarlane and Macfarlane, 2003), serves as the energy source of small intestinal epithelial cells (Chen et al., 2015), thus stimulating their growth (Guilloteau et al., 2010). In this study, mice (in vivo) and cells (in vitro) were pre-treated with sodium butyrate (SB), a ligand of GPR109A, to explore the anti-inflammatory effects and functional mechanism of the GPR109A receptor.
Materials and Methods
Results
Discussion A growing body of evidence suggests that the activation of GPR109A suppresses the inflammatory effects in various diseases (Rahman et al., 2014; Sivaprakasam et al., 2016; Xu et al., 2017; Yang et al., 2015). Additionally, previous studies showed that the activation of GPR109a inhibits the inflammation seen in IBD (Salem and Wadie, 2017; Singh et al., 2014). However, these reports all focused on the anti-inflammatory effects of GPR109a and ignored the potential protective effects of GPR109A on the impaired intestinal epithelium barrier. Butyrate is produced by the intestinal microbial fermentation of dietary carbohydrates, fiber, proteins, and peptides (Guilloteau et al., 2010; Leonel and Alvarez-Leite, 2012). SB has been reported to decrease post-weaning diarrhea by modulating intestinal permeability in weaned piglets (Huang et al., 2015), promoting the recovering of intestinal wound healing through its positive effect on the tight junctions (Ma et al., 2012) and butyrate-releasing derivatives maintain proper Zo1 and Ocln expression in the colons of patients with DSS-induced colitis (Simeoli et al., 2017). However, the effect of SB on impaired intestinal epithelium barriers is not clear. In the present study, we examined the anti-inflammatory property of SB; confirmed its potential protective roles on the impaired intestinal epithelium barrier in a TNBS-induced IBD mouse model; and explored its mechanism in RAW246.7 macrophages, Caco-2 cells, and primary peritoneal macrophages in vitro.