How the AHR Became Important in Intestinal Homeostasis—A Diurnal FICZ/AHR/CYP1A1 Feedback Controls Both Immunity and Immunopathology

Abstract

Ever since the 1970s, when profound immunosuppression caused by exogenous dioxin-like compounds was first observed, the involvement of the aryl hydrocarbon receptor (AHR) in immunomodulation has been the focus of considerable research interest. Today it is established that activation of this receptor by its high-affinity endogenous ligand, 6-formylindolo[3,2-b]carbazole (FICZ), plays important physiological roles in maintaining epithelial barriers. In the gut lumen, the small amounts of FICZ that are produced from L-tryptophan by microbes are normally degraded rapidly by the inducible cytochrome P4501A1 (CYP1A1) enzyme. This review describes how when the metabolic clearance of FICZ is attenuated by inhibition of CYP1A1, this compound passes through the intestinal epithelium to immune cells in the lamina propria. FICZ, the level of which is thus modulated by this autoregulatory loop involving FICZ itself, the AHR and CYP1A1, plays a central role in maintaining gut homeostasis by potently up-regulating the expression of interleukin 22 (IL-22) by group 3 innate lymphoid cells (ILC3s). IL-22 stimulates various epithelial cells to produce antimicrobial peptides and mucus, thereby both strengthening the epithelial barrier against pathogenic microbes and promoting colonization by beneficial bacteria. Dietary phytochemicals stimulate this process by inhibiting CYP1A1 and causing changes in the composition of the intestinal microbiota. The activity of CYP1A1 can be increased by other microbial products, including the short-chain fatty acids, thereby accelerating clearance of FICZ. In particular, butyrate enhances both the level of the AHR and CYP1A1 activity by stimulating histone acetylation, a process involved in the daily cycle of the FICZ/AHR/CYP1A1 feedback loop. It is now of key interest to examine the potential involvement of FICZ, a major physiological activator of the AHR, in inflammatory disorders and autoimmunity.

The Ability of AhR Ligands to Attenuate Delayed Type Hypersensitivity Reaction Is Associated With Alterations in the Gut Microbiota

“…Recently, several studies, including those from our laboratory, have shown that AhR plays a vital and important role in maintaining intestinal homeostasis, both when conditions are healthy and when not (58)(59)(60)(61)(62). In the current study, we noted that not only did the gut microbiota alter following DTH induction but also caused further changes in the microbiota in the administration of AhR ligands.…”

How Ah Receptor Ligand Specificity Became Important in Understanding Its Physiological Function

“…A principal contender as an endogenous AHR ligand was 6-formylindolo [3,2b] carbazole (FICZ), a photo-oxidation product of tryptophan [ 14 , 15 ]. FICZ fulfills the criteria, exhibiting high-affinity/specificity (similar to 2,3,7,8-tetrachlorodibenzo- p -dioxin, TCDD), high potency with regard to CYP1A1 induction and is detectable in vivo [ 16 , 17 , 18 , 19 ]. Additionally, FICZ activity has been revealed to be transient, by virtue of it being a metabolic substrate for CYP1A1, thus establishing a FICZ/AHR/CYP1A1 autoregulatory loop, consistent with an endogenous ligand [ 20 ].…”

“…However, it has become apparent that this criterion is insufficient to validate AHR ligand status. A number of endogenous AHR activators, including flavonoids, arachidonic acid metabolites and certain tryptophan metabolites have been demonstrated to be metabolized by CYP1A1 [ 16 , 20 , 69 , 70 , 71 ]. Thus, it can be envisioned that, in the context of these CYP1A1-labile AHR activators, any compound that may or may not itself bind AHR but presents as a competitive CYP1A1 substrate or inhibitor, will effectively increase AHR activator bioavailability and manifest as an AHR activator.…”

The Interplay between the Gut Microbiome and the Immune System in the Context of Infectious Diseases throughout Life and the Role of Nutrition in Optimizing Treatment Strategies

“…Tryptophan metabolites and especially indoles are derived from the commensal fermentation of dietary tryptophan and function as ligands for the aryl hydrocarbon receptor (AhR), a receptor important in the maintenance of intestinal homeostasis, and loss of these metabolites is associated with the occurrence of inflammatory bowel disease [ 31 , 32 ].…”