Role of the xenobiotic receptor in inflammatory bowel disease

Abstract

Background Gene-environment interplay modulates Inflammatory Bowel Diseases [IBD]. Dioxin-like compounds can activate the Aryl Hydrocarbon Receptor [AhR] and alter macrophage function as well as T cell polarization. We hypothesized that attenuation of the AhR signaling pathway will ameliorate colitis in a murine model of IBD. Design DSS colitis was induced in C57BL/6 AhR null mice [AhR −/−], heterozygous mice [AhR−/+], and their wild type [WT] littermates. Clinical and morphopathological parameters were used to compare the groups. Patients: AhR pathway activation was analyzed in biopsy specimens from 25 IBD patients and 15 healthy controls. Results AhR −/− mice died before the end of the treatment. However, AhR −/+ mice exhibited decreased disease activity compared to WT mice. The AhR −/+ mice expressed less proinflammatory cytokines such as TNFα (6.1 versus 15.7 fold increase) and IL17 (23.7 versus 67.9 fold increase) and increased antiinflammatory IL-10 (2.3 fold increase) compared with the AhR+/+ mice in the colon. Colonic macrophage infiltration was attenuated in the AhR −/+ group. AhR and its downstream targets were significantly upregulated in IBD patients versus control (CYP1A1 – 19.9, and IL8-10 fold increase). Conclusion Attenuation of the AhR receptor expression resulted in a protective effect during DSS-induced colitis, while the absence of AhR exacerbated the disease. Abnormal AhR pathway activation in the intestinal mucosa of IBD patients may promote chronic inflammation. Modulation of AhR signaling pathway via the diet, cessation of smoking or administration of AhR antagonists could be viable strategies for the treatment of IBD.

Aryl Hydrocarbon Receptor Activity of Tryptophan Metabolites in Young Adult Mouse Colonocytes

“…The important functions of the AhR in maintaining intestinal function and health and protection against bacterial infections has been described in several reports showing that the AhR and its ligands also protect against intestinal damage/inflammation in experimental models of colitis and Crohn's disease (Arsenescu et al, 2011;Furumatsu et al, 2011;Monteleone et al, 2011;Singh et al, 2011). The severity of the effects of 2,4-trinitrobenzene sulfonic acid-induced colitis (which resembles Crohn's disease) in mice was significantly decreased by treatment with the AhR agonists FICZ and TCDD (Benson and Shepherd, 2011), and this was accompanied by suppression of several markers of inflammation.…”

“…The AhR is expressed in the gastrointestinal tract, and studies in animal models demonstrate that this receptor and its ligands play an important role in gut health and response to stressors and disease (Kawajiri et al, 2009;Arsenescu et al, 2011;Benson and Shepherd, 2011;Furumatsu et al, 2011;Kiss et al, 2011;Li et al, 2011;Monteleone et al, 2011;Singh et al, 2011;Lee et al, 2012). Loss of the AhR results in formation of colon tumors at the cecum, and this is accompanied by increased expression of b-catenin in the small intestine, whereas wild-type AhR +/+ mice do not develop tumors or overexpress b-catenin (Kawajiri et al, 2009).…”

“…The development of AhR 2/2 and tissue-specific AhR knockout mice has been instrumental in showing that this receptor plays an essential role in various tissues and is a critical regulator of inflammation, autoimmune and immune responses and is a potential drug target for treating multiple diseases including cancer (Kerkvliet, 2009;Stevens et al, 2009;Marshall and Kerkvliet, 2010;Busbee et al, 2013;Safe et al, 2013 vegetables play a protective role in mouse models of intestinal cancer and inflammation (Kawajiri et al, 2009;Arsenescu et al, 2011;Benson and Shepherd, 2011;Furumatsu et al, 2011;Kiss et al, 2011;Li et al, 2011;Monteleone et al, 2011;Singh et al, 2011;Lee et al, 2012). Several studies have reported that the gut microbiota produces metabolites that include AhR-active compounds that could potentially modulate AhR-mediated intestinal resiliency and responses to inflammatory stimuli (Li et al, 2009;Bansal et al, 2010;Zelante et al, 2013;Fukumoto et al, 2014;Venkatesh et al, 2014).…”

Microbiome-Derived Tryptophan Metabolites and Their Aryl Hydrocarbon Receptor-Dependent Agonist and Antagonist Activities

“…For example, in gastrointestinal tissues including lymphoid tissues, the receptor and its ligands modulate inflammatory responses, including those associated with induced colitis in animal models (Kawajiri et al, 2009;Arsenescu et al, 2011;Benson and Shepherd, 2011;Furumatsu et al, 2011;Kiss et al, 2011;Li et al, 2011;Singh et al, 2011). The AHR agonist b-naphthoflavone significantly suppresses dextran sodium sulfate-induced colitis in C57BL/6 mice (Furumatsu et al, 2011) and in the APC min model of colon cancer, the loss of AHR enhances colon carcinogenesis, and AHR ligands inhibit polyp formation in APC min /AHR 1/1 mice (Kawajiri et al, 2009).…”

“…However, other tryptophan-derived compounds, including tryptamine, indole-3-acetate, and 3-indoxyl sulfate, have previously been characterized as AHR agonists (Gillner et al, 1985;Heath-Pagliuso et al, 1998;Miller, 1997;Schroeder et al, 2010;Vikstrom Bergander et al, 2012). It has been well established that the gut microbiome and its metabolites have a direct effect on intestinal homeostasis (Villard et al, 2007;DiNatale et al, 2010;Maynard et al, 2012;Tremaroli and Backhed, 2012), and the AHR plays an important role in maintaining gut homeostasis (Kawajiri et al, 2009;Arsenescu et al, 2011;Benson and Shepherd, 2011;Furumatsu et al, 2011;Kiss et al, 2011;Li et al, 2011;Singh et al, 2011). Therefore, the major objectives of this research were to investigate the AHR agonist or antagonist activity of tryptophan-derived microbiota metabolites in CaCo-2 human epithelial colon cancer cells and other cell lines, and determine their role in modulating inflammation in CaCo-2 cells.…”