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  • Depressed survival rate body weight and colon

    2022-06-17

    Depressed survival rate, body weight, and colon length along with elevated clinical score comprise the essential characteristics of IBD (Hung et al., 2014; Shen et al., 2011; Sun et al., 2010). In the present study, we found that SB improved the survival rate, body weight, and colon length and decreased the clinical score in TNBS-induced WT mice, but had no effects on GPR109amice. We also found that supplementation with SB markedly inhibited the inflammatory response in TNBS-induced mice and LPS-induced macrophages. The results are consistent with previous reports that activation of the GPR109A receptor provides a protective effect on IBD (Macia et al., 2015; Singh et al., 2014).Dietary fiber exhibits multiple beneficial effects toward the maintenance of intestinal homeostasis, which are believed to be due to the fermentation of fibers by intestinal microbiota, resulting in the production of short-chain fatty acids such as acetate, propionate, and butyrate (Koh et al., 2016). Among the short-chain fatty acids, butyrate has attracted more attention, being shown to function as an energy source for coloncytes, to exhibit anti-inflammatory as well as immune modulatory effects, and to protect against intestinal cancer in a GPR109A-dependent manner (Koh et al., 2016; Leonel and Alvarez-Leite, 2012; Offermanns, 2017). Therefore, our results are consistent with those of previous studies wherein supplementation with fiber improves DSS- or TNBS-induced mouse colitis (Macia et al., 2015; Oppong et al., 2015), quite possibly in a GPR109A-dependent manner. The intestinal epithelium, among the most important interfaces between the body and the environment, not only plays a part in nutrient Aminoallyl-UTP but also acts as a barrier against the vast amount of commensal intestinal microorganisms and pathogenic microbes (Artis and Grencis, 2008; Peterson and Artis, 2014). Therefore, the integrity of the epithelial monolayer is critical for the health of the gut, and epithelial dysfunction is a hallmark of intestinal disorders such as IBDs (Citalan-Madrid et al., 2017; Worthington et al., 2017). In the TNBS-induced murine colitis model, ethanol is essential for providing access to intestinal epithelial cells, impairing barrier function, and allowing TNBS to penetrate the bowel wall. TNBS constitutes a covalently reactive compound that attaches to autologous proteins and stimulates a delayed-type hypersensitivity response to hapten-modified self antigens, a reaction that involves and is regulated by complex interactions among various functional subsets of CD4+ T cells (Elson et al., 1996; Miller and Butler, 1983), subsequently leading to the inflammatory response of innate immune cells and further damage of the intestinal epithelium barrier. In the present study, we found that SB reduced the permeability of the intestine and maintained proper tight junctions and MUC2 in the colon of TNBS-induced WT mice. To further confirm these results, we examined the effects of SB on the epithelium barrier in vitro and found that SB sharply reduced the effects of LPS-induced RAW246.7 macrophages on the resistance of the Caco-2 cell monolayer, as well as maintained proper tight junctions. Together, these results indicated that SB maintained a proper intestinal epithelium barrier by activating GPR109A. A previous study indicated that GPR109a mediates the anti-inflammatory effect by inhibiting the phosphorylation of the NF-κB p65 signaling pathway (Fu et al., 2015; Zandi-Nejad et al., 2013). In the present study, to investigate the definite mechanism Aminoallyl-UTP of SB on the inflammatory response, we examined the effects of SB on the classical inflammation pathways AKT, NF-κB, and MAPK and found that supplementation with SB markedly decreased the phosphorylation of AKT and NF-κB p65 in LPS-induced RAW246.7 cells and WT mouse primary peritoneal macrophages, but failed to suppress this phenomenon in GPR109a mouse primary peritoneal macrophages. Previous studies indicated that supplementation with SB improved the phosphorylation of the AKT signaling pathway in high-fat diet–induced insulin resistance (Gao et al., 2009; Zhang et al., 2017), elevated the phosphorylation of the AKT signaling pathway in the adipose tissue of obese mice (Guo et al., 2017), and inhibited platelet-derived growth factor-induced proliferation and migration in pulmonary artery smooth muscle cells through AKT inhibition (Cantoni et al., 2013). Therefore, the effects of SB on the AKT signaling pathway are not fixed; instead, they depend on the function of the AKT signaling pathway in different situations. Our results indicated that SB inhibited the phosphorylation of the AKT and NF-κB p65 signaling pathway in macrophages in a GPR109A-dependent manner.