Abstract
Aryl hydrocarbon receptor (AhR) ligands are important for gastrointestinal health and play a role in gut inflammation and the induction of T regulatory cells, and the short chain fatty acids (SCFAs) butyrate, propionate and acetate also induce similar protective responses. Initial studies with butyrate demonstrated that this compound significantly increased expression of Ah-responsive genes such as Cyp1a1/CYP1A1 in YAMC mouse colonocytes and Caco-2 human colon cancer cell lines. Butyrate synergistically enhanced AhR ligand-induced Cyp1a1/CYP1A1 in these cells with comparable enhancement being observed for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and also microbiota-derived AhR ligands tryptamine, indole and 1,4-dihydroxy-2-naphthoic acid (DHNA). The effects of butyrate on enhancing induction of Cyp1b1/CYP1B1, AhR repressor (Ahrr/AhRR) and TCDD-inducible poly(ADP-ribose)polymerase (Tiparp/TiPARP) by AhR ligands were gene- and cell context-dependent with the Caco-2 cells being the most responsive cell line. Like butyrate and propionate, the prototypical hydroxyamic acid-derived histone deacetylase (HDAC) inhibitors Panobinostat and Vorinostat also enhanced AhR ligand-mediated induction and this was accompanied by enhanced histone acetylation. Acetate also enhanced basal and ligand-inducible Ah responsiveness and histone acetylation, demonstrating that acetate was an HDAC inhibitor. These results demonstrate SCFA-AhR ligand interactions in YAMC and Caco-2 cells where SCFAs synergistically enhance basal and ligand-induced expression of AhR-responsive genes.
Highlights
Synthetic and naturally occurring compounds as ligands for this receptor
The Aryl hydrocarbon receptor (AhR) plays a important role in maintaining gastrointestinal health and several studies show that AhR expression in subsets of gut epithelial cells are important for bacterial resistance, gut inflammation and integrity and this has been associated with induction of T regulatory (Treg) cells, FoxP3 and interleukin-2217–25
Sodium butyrate is a major microbiota-derived metabolite and potent histone deacetylase (HDAC) inhibitor and there are conflicting reports showing that butyrate enhances[31] or does not affect[32] basal or AhR ligand-induced CYP1A1/CYP1A1-promoter activity
Summary
Synthetic and naturally occurring compounds as ligands for this receptor. These include industrial by-products, phytochemicals including flavonoids, indole-3-carbinol and related indole compounds, diverse pharmaceuticals, and possible endogenous ligands including formylindolino[2,3]b-carbazol (FICZ) [rev. in refs 15 and 16]. The AhR plays a important role in maintaining gastrointestinal health and several studies show that AhR expression in subsets of gut epithelial cells are important for bacterial resistance, gut inflammation and integrity and this has been associated with induction of T regulatory (Treg) cells, FoxP3 and interleukin-2217–25. These same studies show that AhR-active microbiota-derived metabolites including tryptophan catabolites or exogenous AhR-active compounds play a role in maintaining intestinal integrity and bacterial resistance and inhibiting inflammation. Our data show for the first time that one of the most abundant SCFAs, acetate, is in HDAC inhibitor
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