Activation of the aryl hydrocarbon receptor in inflammatory bowel disease: insights from gut microbiota

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disease that affects more than 3.5 million people, with rising prevalence. It deeply affects patients' daily life, increasing the burden on patients, families, and society. Presently, the etiology of IBD remains incompletely clarified, while emerging evidence has demonstrated that altered gut microbiota and decreased aryl hydrocarbon receptor (AHR) activity are closely associated with IBD. Furthermore, microbial metabolites are capable of AHR activation as AHR ligands, while the AHR, in turn, affects the microbiota through various pathways. In light of the complex connection among gut microbiota, the AHR, and IBD, it is urgent to review the latest research progress in this field. In this review, we describe the role of gut microbiota and AHR activation in IBD and discussed the crosstalk between gut microbiota and the AHR in the context of IBD. Taken as a whole, we propose new therapeutic strategies targeting the AHR-microbiota axis for IBD, even for other related diseases caused by AHR-microbiota dysbiosis.

Keywords: aryl hydrocarbon receptor; gut microbiota; inflammatory bowel disease; interplay; therapy.

Figure 1

Structures of the AHR. The AHR contains three major domains, the bHLH, the PAS, and the TAD. The bHLH domain located at the N-terminus is involved in interaction with chaperones, HSP90, and XAP2, dimerization with ARNT, and binding to DNA. The PAS domain includes the PAS-A and PAS-B, among which, the PAS-A is involved in dimerization with ARNT and interaction with HSP90 and XAP2, while the PAS-B mediates AHR interaction with ligands. The C-terminal located TAD consists of three subdomains, an acidic residue (glutamate/aspartate) rich subdomain, a glutamate-rich subdomain (Q-rich), and a P/S/T region rich in proline/serine/threonine residues that are responsible for interaction with cofactors and mediating transcriptional activation. Abbreviation: AHR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; bHLH, basic helix-loop-helix; TAD, transactivation domain; PAS, period circadian protein (PER) Aryl Hydrocarbon Receptor Nuclear Translocator | single-minded protein (SIM); HSP90, heat shock protein 90; XAP2, X-associated protein 2.

Figure 2

Summary of the possible mechanism of AHR activation in the onset of IBD under the context of dysbiosis. The AHR is expressed by epithelial cells, endothelial cells, immune cells, and neurons of the gut. Upon microbial AHR ligand triggering, AHR activity maintains intestinal homeostasis involving multi-factors, including modulation of intestinal barrier integrity, immune and inflammatory responses, intestinal peristalsis and vascular function, and gut microbiota. Once the intestinal microecology is disturbed, the deficient AHR activation will be triggered, which may lead to increased microbial translocation, bacterial overgrowth, pro-inflammatory cytokines production, IELs activation, vascular leakage, collagen synthesis, and fibrosis, and decreased production of anti-inflammatory cytokines, anti-microbial peptides, Treg cells, goblet cells and mucus, and intestinal barrier damage, along with restriction of IEC proliferation and T cell differentiation and migration. These explain the role of AHR activation in the pathogenesis of IBD. Abbreviation: AHR, aryl hydrocarbon receptor; ARNT; aryl hydrocarbon receptor nuclear translocator; ENS, enteric nervous system; HSP90, heat shock protein 90; IBD, Inflammatory bowel disease; IECs, intestinal epithelial cells; IELs, intraepithelial lymphocytes; ILCs, innate lymphoid cells; XAP2, X-associated protein 2; XRE, xenobiotic response element.

Figure 3

Prospects in IBD therapy targeting the AHR–gut microbiota axis. Due to the altered AHR activity and microbiome in IBD, the detection of AHR activity and the microbiome may become a new method for the diagnosis of IBD in addition to endoscopy. Further, the dysbiosis of IBD patients can be reconstituted by diet, probiotics, FMT, and herbal medicine. Notably, the microbiome produced the tryptophan metabolites, short-chain fatty acids, and other metabolites that act as AHR agonists or inhibitors to regulate AHR activity. Thus, a restored healthy intestinal microbiome may upregulate the AHR activity based on the AHR–gut microbiota axis, thus alleviating IBD. Abbreviation: AHR, aryl hydrocarbon receptor; IBD, Inflammatory bowel disease; FMT, fecal microbiota transplantation.