The aryl hydrocarbon receptor as a moderator of host-microbiota communication

Abstract

The aryl hydrocarbon receptor (AHR) is an important component of the host-microbiota communication network. Comparisons of wild-type and Ahr-null mice as well as from exposure studies with potent AHR ligands (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin) have provided compelling evidence that the AHR may be a master regulator of the host-microbiota interaction thus helping to shape the immune system and impact host metabolism. Metabolomics and sequenced-based microbial community profiling, two recent technological advances, have helped to solidify this host-microbiota signaling concept and identified not only how specific ligands generated by the host and by the microbiota can activate the AHR, but also how activation/disruption of the AHR can influence and shape the microbiota. We are just beginning to understand how the temporal nature and tissue- and microbiota-specific generation of AHR ligands contribute to many AHR-dependent processes. In this review, we focus on several recent advances where metabolomics and characterization of the microbiota structure and function have generated new perspectives by which to evaluate AHR activity.

Metatranscriptomic Analysis of the Mouse Gut Microbiome Response to the Persistent Organic Pollutant 2,3,7,8-Tetrachlorodibenzofuran

“…Bacterial population shifts seen in Figure 1 were significant after permutational multivariate ANOVA using distance matrices (R function Adonis in the vegan package) and are illustrated using Unifrac distances. The differential effects on the microbiome from either 5 µg/kg BW TCDF or 24 µg/kg BW TCDF exposures support the importance of balanced AHR activity to maintain the microbiome community [10]. Additionally, a heat map of z-scores created from all significantly different bacteria genera after 5 and 24 µg/kg BW TCDF is shown in Figure 2.…”

“…2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), along with 2,3,7,8-tetrachlorodibenzofuran (TCDF) and coplanar polychlorinated biphenyls (PCBs), are agonists of the aryl hydrocarbon receptor (AHR) and have been reported to modulate the intestinal microbiome [9][10][11][12]. The AHR plays important roles in both adaptive and innate immunity (pro-inflammatory and anti-inflammatory responses) and in gut barrier function [13,14].…”

The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression

“…The array of natural AhR ligands that are known to exist is increasing steadily in number and currently includes ligands provided by diet, commensal microbiota and tryptophan metabolism (Stockinger et al, 2014; Zhang et al, 2017). For example, during HIV-1 infection, CD4+ T cells are rapidly depleted, especially in gut associated lymphoid tissue (GALT).…”

The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression

“…While viruses are not thought to generate AhR ligands, AhR could nevertheless be activated in macrophages, other myeloid lineage cells or even other cell types, in virus infected individuals through a variety of mechanisms. The array of natural AhR ligands that are known to exist is increasing steadily in number and currently includes ligands provided by diet, commensal microbiota and tryptophan metabolism 13,14 . For example, during HIV-1 infection, CD4+ T cells are rapidly depleted, especially in gut associated lymphoid tissue (GALT).…”

“…In addition to cytokines, other endogenous and exogenous substances, modulate the immune responses to viruses. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that is activated by a range of organic molecules of endogenous and exogenous origin, including environmental toxins, tryptophan metabolites, and products of the microbiome 13,14 . In response to ligand activation, AhR translocates from the cytoplasm into the nucleus where it induces the transcription of numerous target genes including detoxifying monooxygenases CYP1A1 and CYP1B1, as well as its own negative regulator, the AhR repressor (AHRR) 13 .…”