The aryl hydrocarbon receptor as a mediator of host-microbiota interplay

Abstract

Increasing evidence suggests a significant role for microbiota dependent metabolites and co-metabolites, acting as aryl hydrocarbon receptor (AHR) ligands, to facilitate bidirectional communication between the host and the microbiota and thus modulate physiology. Such communication is particularly evident within the gastrointestinal tract. Through binding to or activating the AHR, these metabolites play fundamental roles in various physiological processes and likely contribute to the maintenance of intestinal homeostasis. In recent years, tryptophan metabolites were screened to identify physiologically relevant AHR ligands or activators. The discovery of specific microbiota-derived indole-based metabolites as AHR ligands may provide insight concerning how these metabolites affect interactions between gut microbiota and host intestinal homeostasis and how this relates to chronic GI disease and overall health. A greater understanding of the mechanisms that modulate the production of such metabolites and associated AHR activity may be utilized to effectively treat inflammatory diseases and promote human health. Here, we review microbiota-derived AHR ligands generated from tryptophan that modulate host-gut microbiota interactions and discuss possible intervention strategies for potential therapies in the future.

Keywords: Aryl hydrocarbon receptor; gut microbiota; immune response; indole; inflammatory disease; intestinal homeostasis; tryptophan.

Figure 1.

Structures of AHR and ARNT. AHR and ARNT belong to the family of basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) proteins. AHR contains a bHLH, a PAS, and transactivation domain. The transactivation domain is divided into three modular transcriptional domains, namely, an acidic region enriched with glutamic and aspartic acid residues, a glutamine-rich region (Q-rich), and a P/S/T region rich in proline/serine/threonine residues. ARNT has the similar structure with AHR. The function of each domain is illustrated above

Figure 2.

Canonical AHR signaling pathway and alternative AHR/RelB pathway. I. Canonical signaling pathway of AHR. Inactive AHR is retained in the cytoplasm in a multi-protein complex containing chaperone proteins, such as HSP90 and XAP2. AHR translocates into the nucleus after ligand binding and interacts with ARNT to form an AHR/ARNT complex. The AHR/ARNT dimer binds promoter regions containing DRE that regulate expression of numerous target genes, such as Ahrr, Cyp1a1, Cyp1b1 and IL22. II. AHR can also interact with RelB to induce the expression of cytokines and chemokines. The alternative NF-κB pathway is induced by ligands of TNFR superfamily members and is an IKKα-dependent kinase cascade. Activation of this cascade mediates phosphorylation of NIK leading to phosphorylation of IKKα, and subsequent phosphorylation of the p100 NF-κB subunit. This subunit is then cleaved to p52 leading to the formation of the p52/RelB complex. Following translocation of p52/RelB complex to the nucleus, AHR can interact with RelB to form RelB/AhR response element (RelBAHRE) regulating the expression of cytokines and chemokines. AHRR, AHR repressor; ARNT, AHR nuclear translocator; Cyp1a1, cytochrome P450 1A1; Cyp1b1, cytochrome P450 1B1; DRE, dioxin response element; HSP90, heat shock protein 90; IL22, interleukin 22; XAP2, X-associated protein 2; NF-κB, nuclear factor-κB; LTβR, lymphotoxin β receptor; RANK, receptor activator of NF-κB; BAFFR, B-cell activating factor receptor; CD40, cluster of differentiation 40; NIK, NF-κB-inducing kinase; IKK, IKB kinase; IL8, interleukin 8; RelBAHRE, RelB/AHR response element

Figure 3.

Summary of tryptophan and indole metabolites generated by host and gut microbiota metabolism. Tryptophan is acquired from dietary protein digested in the small intestine and converted to various catabolites. The key metabolites (in blue) have been identified to be AHR ligands and enzymes involved in metabolism are represented in red. AAAD, aromatic amino acid decarboxylase; TDO, tryptophan 2,3-dioxygenase; IDO, indoleamine 2,3-dioxygenase; KA, kynurenic acid; KAT, kynurenine aminotransferase; MAO, monoamine oxidase; TPH, tryptophan hydroxylase; 5-HIAA, 5-hydroxyindole-3-acetic acid; 3-HK, 3-hydroxykynurenine; 5-HTP, 5-hydroxytryptophan; ArAT, aromatic amino acid transaminase; fldBC, phenyllactate dehydratase; IAA, indole acrylic acid; I3A, indole-3-acetic acid; IAld, indole-3-aldehyde; IAAld, indole-3-acetaldehyde; IAM, indole-3-acetamide; ILA, indole-3-lactic acid; IEt, indole-3-ethanol; IPyA, indole-3-pyruvate; IPA, indolic-3-propionic acid; TMO, tryptophan-2-monooxygenase; TnaA, tryptophanase; TrpD, tryptophan decarboxylase; IS, indoxyl sulfate; TrA, tryptamine; SULT, sulfotransferase

Figure 4.

AHR as a therapeutic target. Novel strategies such as oral administration of nanoparticle-mediated cell-type-specific delivery of AHR agonist, AHR ligands and specific probiotics may serve to influence autoimmune inflammatory response. DC, dendritic cell; IBD, inflammatory bowel disease; CNS, central nervous system; RA, rheumatoid arthritis