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.
Highlights
The cytochrome P450 (CYP) family of enzymes was initially thought to catalyze the metabolism of xenobiotics and thereby be involved in chemical carcinogenesis, it has since become clear that many of these enzymes play physiological roles in the metabolism of a variety of endogenous compounds [1]
I discuss new perspectives on the role of FICZ produced by the microbiota in gut immunity, with particular focus on the key role played by cytochrome P4501A1 (CYP1A1) in the dynamic regulation of FICZ-stimulated production of interleukin 22 (IL-22) and the temporal pattern of aryl hydrocarbon receptor (AHR) signaling in the gut
It is known that a wide range of phytochemicals—including flavonoids, alkaloids, stilbenes and curcuminoids—bind to this receptor with no or low affinity but still activate CYP1A1, and we have proposed that compounds that inhibit the expression and/or, activity of CYP1A1 may attenuate clearance of endogenous FICZ, leading to indirect activation of the AHR [38]
Summary
The cytochrome P450 (CYP) family of enzymes was initially thought to catalyze the metabolism of xenobiotics and thereby be involved in chemical carcinogenesis, it has since become clear that many of these enzymes play physiological roles in the metabolism of a variety of endogenous compounds [1]. One of these endogenous compounds is 6-formylindolo[3,2-b]carbazole (FICZ), which binds to the aryl hydrocarbon receptor with the highest affinity yet reported. I discuss new perspectives on the role of FICZ produced by the microbiota in gut immunity, with particular focus on the key role played by CYP1A1 in the dynamic regulation of FICZ-stimulated production of interleukin 22 (IL-22) and the temporal pattern of AHR signaling in the gut
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