Ligand activation of the Ah receptor contributes to gastrointestinal homeostasis

Abstract

The Ah receptor (AHR) is capable of binding a structurally diverse group of compounds that can be found in the diet, produced by bacteria in the gut and through endogenous metabolism. The gastrointestinal tract is a rich source of AHR ligands, which have been shown to protect the gut upon challenge with either pathogenic bacteria or toxic chemicals. The human AHR can be activated by a broader range of ligands compared to the mouse AHR, suggesting that studies in mice may underestimate the impact of AHR ligands in the human gut. The protective effect of AHR activation appears to be due to modulating the immune system within the gut. While several mechanisms have been established, due to the increasingly pleotropic nature of the AHR, other mechanisms of action likely exist that remain to be identified. The major contributors to AHR function in the gut and the most appropriate level of receptor activation that maintains intestinal homeostasis warrants further investigation.

Keywords: AHR; Ah receptor; IL22; gastrointestinal; indole; intestine.

Figure 1

Sources and examples of known dietary, endogenous and microbiota-derived AHR ligands.

Figure 2. The kynurenine pathway as a source of endogenous AHR ligands

Host tryptophan metabolism through the activity of hepatic tryptophan 2, 3-dioxygenase (TDO) or peripheral indolamine 2, 3-dioxygenase (IDO) yields kynurenine, an AHR ligand. Subsequent metabolism of kynurenine by kynurenine monooxygenase (KMO), kynureninase (KYNU) and kynurenine aminotransferase (KAT) provides additional AHR ligands. These AHR ligands have the capacity to further enhance expression of IDO in an autocrine loop. Activation of the kynurenine pathway is associated with increased immune tolerance and may contribute to gastrointestinal homeostasis.

Figure 3. Tryptophan metabolism by the gastrointestinal microbiota represents a source of AHR ligands and ligand precursors

The uptake of luminal tryptophan by the resident gastrointestinal microbiota though amino acid transporters e.g. Mtr, TnaB and AroP provides the substrate for enzymatic conversion by bacterial monooxygenases (IaaM), acetimide hydrolases (IaaH), decarboxylases to generate AHR ligands. In addition, microbial tryptophanse (TnaA) activity can generate the AHR ligand indole. Efflux of bacterial indole by transporters e.g. AcrE and AcrF provides a substrate for host metabolism e.g. CYP2E1 and sulfotransferases (SULT) resulting in the generation of additional AHR ligands and ligand precursors. The repertoire of tryptophan-derived microbial AHR ligands has the capacity to influence host-microbe homeostasis through the AHR-dependent modulation of IL22 expression and immunosuppressive Treg differentiation.