Date Published: June 30, 2017
Publisher: Public Library of Science
Author(s): Christiane Hammerschmidt-Kamper, Daniel Biljes, Katja Merches, Irina Steiner, Thomas Daldrup, Marianne Bol-Schoenmakers, Raymond H. H. Pieters, Charlotte Esser, Hossam M Ashour.
In general, dietary antigens are tolerated by the gut associated immune system. Impairment of this so-called oral tolerance is a serious health risk. We have previously shown that activation of the ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) by the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects both oral tolerance and food allergy. In this study, we determine whether a common plant-derived, dietary AhR-ligand modulates oral tolerance as well. We therefore fed mice with indole-3-carbinole (I3C), an AhR ligand that is abundant in cruciferous plants. We show that several I3C metabolites were detectable in the serum after feeding, including the high-affinity ligand 3,3´-diindolylmethane (DIM). I3C feeding robustly induced the AhR-target gene CYP4501A1 in the intestine; I3C feeding also induced the aldh1 gene, whose product catalyzes the formation of retinoic acid (RA), an inducer of regulatory T cells. We then measured parameters indicating oral tolerance and severity of peanut-induced food allergy. In contrast to the tolerance-breaking effect of TCDD, feeding mice with chow containing 2 g/kg I3C lowered the serum anti-ovalbumin IgG1 response in an experimental oral tolerance protocol. Moreover, I3C feeding attenuated symptoms of peanut allergy. In conclusion, the dietary compound I3C can positively influence a vital immune function of the gut.
Oral tolerance (OT) is a vital and unique feature mediated by the mucosal immune system. OT denotes that the immune system remains unresponsive to food antigens encountered in the gut. OT was first described many decades ago, and models of inducing OT in the mouse have shown that the antigen dose is important for the mechanism underlying OT. Thus, it was proposed that high doses of antigen in the diet result in anergic T cells, while low doses result in an induction of regulatory T cells (Treg) by dendritic cells (DC) of the small-intestine-draining mesenteric lymph nodes [1–3]. This rigid difference is challenged, however, by the finding that high numbers of Treg develop in high-dose tolerizing protocols , and the difficulties of providing direct proof of T cell deletion and anergy.
The health benefits of plants of the Brassica family are well known. The focus in the respective research is mainly on the anti-tumorigenic properties, however, where studies demonstrated beneficial effects of broccoli on some (but not all) cancers . The phytochemicals mediating these effects are often glucosinolates, indoles, and their various derivatives, in particular their acid-derivatives. Indoles can bind to the AhR, leading to gene expression, e.g., of phase I and phase II enzymes , and eventually cellular and systemic responses. In the rat, increased CYP1A1 enzyme activity has been shown in the liver after feeding of 57 mg I3C/kg for 7 days . We extended this study to show that oral exposure leads to induction of the cyp1a1 along the murine small intestine, i.e., our site of immunological interest. Moreover, we found that induction did not subside upon long-term exposure of a comparatively moderate dose, indicating constantly high AhR-activity by the diet. I3C is converted to several metabolites in the acid environment of the stomach, most abundantly into DIM, as well as into other products [26, 41]. Both I3C and DIM are AhR ligands, with binding affinities of approximately 2×10-10 (ICZ) and 9×10-8 (DIM) [26, 41], compared to 10–12 M for TCDD. Of note, we detected I3C derivatives in serum, i.e., they can transfer systemically. This extends older studies, which analyzed I3C derivatives DIM and ICZ locally in the gut and feces within a day of I3C feeding .