Aryl Hydrocarbon Receptor Research Articles

Aryl hydrocarbon receptor (AHR) and nuclear factor erythroid-derived 2-like 2 (NRF2): An important crosstalk in the gut-liver axis.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, mainly involved in detoxification. However, in the intestine, metabolites derived from the diet, which are converted by a wide range of bacteria can also activate the AHR. This intestinal AHR activation plays a key role in maintaining the gut barrier by, for example, upregulating antimicrobial peptides and anti-inflammatory cytokines. Since the gut barrier influences the gut-liver axis by regulating the leaking of metabolites, bacteria, and endotoxins into circulation and particularly into the liver, the AHR is a key factor in the gut-liver axis. Vice versa, certain liver pathologies also influence the gut microbiome, thereby altering bacteria-derived activation of the AHR. Additionally, bile acids can impact the gut via the liver and thereby also affect the AHR. The aryl hydrocarbon receptor (AHR) interacts with several molecular factors, one of which is the nuclear factor erythroid-derived 2-like 2 (NRF2), a transcription factor primarily associated with regulating antioxidant stress responses. The interplay between AHR and NRF2 has been investigated in the context of various diseases; this review highlights the significance of this interaction within the framework of the gut-liver axis.

AhR governs lipid metabolism: the role of gut microbiota

The Aryl Hydrocarbon Receptor (AhR) is widely present in mammalian bodies, showing high affinity for various exogenous substances such as polycyclic aromatic hydrocarbons (PAHs) and coumarin. Under physiological conditions, AhR mainly participates in regulating the body’s immune response, cell proliferation, and apoptosis among a series of processes. Recent studies have revealed a close connection between AhR and lipid metabolism. The gut microbiota plays a significant role in regulating host lipid metabolism. Growing evidence suggests an inseparable link between gut microbiota and AhR signaling. This review summarizes the relationship between AhR and lipid metabolism disorders, as well as the interaction between gut microbiota and AhR, exploring how this interaction modulates host lipid metabolism.

The Role of Aryl Hydrocarbon Receptor in Skin Homeostasis: Implications for Therapeutic Strategies in Skin Disorders.

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is extensively expressed in diverse human organs and plays a pivotal role in mediating the onset, progression, and severity of numerous diseases. Recent research has explored the substantial impact of AhR on skin homeostasis and related pathologies. As a multi-layered organ, the skin comprises multiple cell populations that express AhR. In this review, we introduce the role of AhR in various skin cells and its impact on skin barrier function. Furthermore, we explore the involvement of AhR in the development of various skin diseases, highlighting its potential as a therapeutic target for skin disorders. By targeting AhR, we may open new avenues for the development of novel and efficient skin disease treatments.

Evaluation of the expression of FLG, AHR and ARNT genes in the skin of patients with atopic dermatitis after phototherapy

Background: Ultraviolet irradiation of the skin can activate the cytoplasmic aryl hydrocarbon receptor AhR, which, in combination with its nuclear translocator ARNT binds to the promoter of the FLG gene encoding filaggrin, a protective skin barrier protein. This suggests that the therapeutic effect of phototherapy may be due not only to the immunosuppressive effect, but also to stimulation of filaggrin production. Aims: to evaluate the effect of ultraviolet irradiation used for various phototherapy methods on the expression levels of the FLG, AHR and ARNT genes in the skin of patients with atopic dermatitis. Materials and methods: The expression levels of the FLG, AHR and ARNT genes were determined using real-time PCR. To define the severity of the disease, the SCORAD index was calculated. Results: 76 patients with atopic dermatitis were included in the study. 37 patients underwent narrow-band phototherapy; 39 – UFA1 therapy. Both methods of phototherapy were effective. After narrow-band phototherapy, the level of expression of the FLG, AHR and ARNT genes significantly increased. After UFA1 therapy, the expression of the AHR and ARNT genes increased, and no changes in the expression of the FLG gene were observed. Conclusions: Data have been obtained indicating that the therapeutic effect of narrow-band phototherapy in atopic dermatitis may be due to stimulation of the expression of the FLG gene in the skin. The revealed changes in the expression of the AHR and ARNT genes indicate the possible involvement of their protein products AhR and ARNT in the pathogenesis of the disease.

Single-cell analyses of intestinal epithelium reveal the dysregulation of gut immune microenvironment in systemic lupus erythematosus

BackgroundThe small intestine harbors a rich array of intestinal intraepithelial lymphocytes (IELs) that interact with structural cells to collectively sustain gut immune homeostasis. Dysregulation of gut immune homeostasis was implicated in the pathogenesis of multiple autoimmune diseases, however, whether this homeostasis is disrupted in a lupus autoimmune background remains unclear.MethodsWe performed single-cell RNA sequencing (scRNA-seq) analyses to elucidate immune and structural milieu in the intestinal epithelium of MRL/Lpr lupus mice (Lpr mice) and MRL/Mpj control mice (Mpj mice). Comprehensive analyses including unsupervised clustering, trajectories, and cellular communication were performed. The primary findings from scRNA-seq were further validated by quantitative polymerase chain reaction (qPCR), flow cytometry, and in vivo experiments including selenium supplementation.ResultsWe observed a significant reduction in CD8αα + IELs, accompanied by a marked increase in CD8αβ + IELs in Lpr mice. Additionally, subsets of CD8 + IELs exhibiting significantly enhanced effector functions were found to be markedly enriched in Lpr mice. Intercellular communication patterns within intestinal epithelial immune and structural cells were found to be specifically altered in Lpr mice. Moreover, scRNA-seq revealed significantly decreased intestinal TCRγδ T cells (γδT) associated with reduced aryl-hydrocarbon receptor repressor (AHRR) expression and subsequent oxidative stress and ferroptosis in Lpr mice. Antioxidant selenium effectively reversed the loss of γδT in Lpr mice, improved the gut barrier, and alleviated lupus symptoms.ConclusionsOur high-resolution single-cell atlas enhances the understanding of the immune and structural milieu of intestinal epithelium in lupus and provides new insights into lupus pathogenesis mediated by intestinal immune dysregulation.

Path of differentiation defines human macrophage identity.

Macrophages play central roles in immunity, wound healing, and homeostasis - a functional diversity that is underpinned by varying developmental origins. The impact of ontogeny on properties of human macrophages is inadequately understood. We demonstrate that definitive human fetal liver (HFL) hematopoietic stem cells (HSCs) possess two divergent paths of macrophage specification that lead to distinct identities. The monocyte-dependent pathway exists in both prenatal and postnatal hematopoiesis and generates macrophages with adult-like responses properties. We now uncover a fetal-specific pathway of expedited differentiation that generates tissue resident-like macrophages (TRMs) that retain HSC-like self-renewal programs governed by the aryl hydrocarbon receptor (AHR). We show that AHR antagonism promotes TRM expansion and mitigates inflammation in models of atopic dermatitis (AD). Overall, we directly connect path of differentiation with functional properties of macrophages and identify an approach to promote selective expansion of TRMs with direct relevance to inflammation and diseases of macrophage dysfunction.

Diet-derived urolithin A is produced by a dehydroxylase encoded by human gut Enterocloster species

Urolithin A (uroA) is a polyphenol derived from the multi-step metabolism of dietary ellagitannins by the human gut microbiota. Once absorbed, uroA can trigger mitophagy and aryl hydrocarbon receptor signaling pathways, altering host immune function, mitochondrial health, and intestinal barrier integrity. Most individuals harbor a microbiota capable of uroA production; however, the mechanisms underlying the dehydroxylation of its catechol-containing precursor (uroC) are unknown. Here, we use a combination of untargeted bacterial transcriptomics, proteomics, and comparative genomics to uncover an inducible uroC dehydroxylase (ucd) operon in Enterocloster species. We show that the ucd operon encodes a predicted molybdopterin-dependent enzyme complex that dehydroxylates urolithins at a specific position (9-OH). By interrogating publicly available metagenomics datasets, we observed that uroC-metabolizing Enterocloster species and ucd operon genes are prevalent in human feces. In ex vivo experiments with human fecal samples, only samples actively transcribing ucd could produce uroA, possibly explaining differences in urolithin metabolism between individuals. Collectively, this work identifies Enterocloster species and the ucd operon as important contributors to uroA production and establishes a multi-omics framework to further our mechanistic understanding of polyphenol metabolism by the human gut microbiota.

Indoleamine 2,3-Dioxygenase 1/Aryl Hydrocarbon Receptor Feedback Loop Mediates Anti-inflammation in lipopolysaccharide-stimulated Astrocytes to Dampen Inflammatory Neurotoxicity.

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates cell immune responses in a cell type-specific and ligand-dependent manner. In the central nervous system, astrocytic AhR plays important roles in regulating neuroinflammation by mediating responses to endogenous ligands generated from the inflammation-induced indoleamine 2,3-dioxygenase 1 (IDO1)/kynurenine (KYN) pathway. We previously demonstrated that reduction of AhR expression decreases lipopolysaccharide (LPS)-induced pro-inflammatory responses in microglia. However, the role of AhR in the astrocytic immune responses and its subsequent effects on microglial activation and neurotoxicity remain unclear. In this study, we used LPS-induced neuroinflammation in rat cortical glia-neuron (GN) mix cultures, which increased the expression of tumor necrosis factor-α and interleukin-6 and microglial activation. These proinflammatory responses were attenuated by a specific AhR agonist 6-formylindolo [3,2-b] carbazole (FICZ), but not by the AhR antagonist CH223191. CH223191, which inhibits LPS- and FICZ-induced AhR activation, enhanced neurotoxicity induced by LPS-glutamate co-treatment in GN mix cultures. Furthermore, inhibition of AhR expression and activation enhanced LPS-induced proinflammatory responses, and LPS-induced AhR activation was abrogated by the inhibition of IDO1 expression in astrocytes. Notably, AhR knockdown inhibited the anti-inflammatory effects of KYN while enhancing LPS-induced IDO1 expression in astrocytes, suggesting that AhR mediates the anti-inflammatory effect of KYN and the negative feedback regulation of IDO1 expression. Finally, we examined the role of astrocytic AhR in inflammatory astrogliosis-induced neurotoxicity by treating primary cortical neurons with LPS-treated astrocyte-conditioned medium (ACM). The results revealed that ACM derived from siAhR-transfected astrocytes increased neurotoxicity. In conclusion, inflammation-activated AhR mediates the anti-inflammatory effects and negative feedback regulation of the IDO1/KYN pathway in astrocytes, thereby dampening inflammatory astrogliosis-induced neurotoxicity.

Deciphering the phenotypic, inflammatory, and endocrine disrupting impacts of e-waste plastic-associated chemicals.

As the volume of plastic waste from electrical and electronic equipment (WEEE) continues to rise, a significant portion is disposed of in the environment, with only a small fraction being recycled. Both disposal and recycling pose unknown health risks that require immediate attention. Existing knowledge of WEEE plastic toxicity is limited and mostly relies on epidemiological data and association studies, with few insights into the underlying toxicity mechanisms. Therefore, this study aimed to perform comprehensive chemical screening and mechanistic toxicological assessment of WEEE plastic-associated chemicals. Chemical analysis, utilizing suspect screening based on high-resolution mass spectrometry, along with quantitative target chemical analysis, unveiled numerous hazardous compounds including polyaromatic compounds, organophosphate flame retardants, phthalates, benzotriazoles, etc. Toxicity endpoints included perturbation of morphological phenotypes using the Cell Painting approach, inflammatory response, oxidative stress, and endocrine disruption. Results demonstrated that WEEE plastic chemicals altered the phenotypes of the cytoskeleton, endoplasmic reticulum, and mitochondria in a dose-dependent manner. In addition, WEEE chemicals induced inflammatory responses in resting macrophages and altered inflammatory responses in lipopolysaccharide-primed macrophages. Furthermore, WEEE chemicals activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, indicating oxidative stress, and the aryl hydrocarbon receptor (AhR). Endocrine disruption was also observed through the activation of estrogenic receptor-α (ER-α) and the induction of anti-androgenic activity. The findings show that WEEE plastic-associated chemicals exert effects in multiple subcellular sites, via different receptors and mechanisms. Thus, an integrated approach employing both chemical and toxicological methods is essential for comprehensive assessment of the toxicity mechanisms and cumulative chemical burden of WEEE plastic-associated chemicals.

P0145 Role of PPARg on anti-inflammatory effects mediated by AhR ligands in a Caco-2/THP-1 in vitro “inflamed gut” model

Abstract Background Inflammatory Bowel Diseases (IBD) lack therapeutic options capable of inducing long-term remission in a cost-efficient manner. Repurposing strategies have allowed already established receptors and ligands to be tested as alternative pharmacotherapy for treatment of IBD. Agonists of the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor traditionally associated with xenobiotic toxicity, have been explored as potential anti-inflammatory drugs to treat IBD, but specific mechanisms have yet to be elucidated. Like AhR, the peroxisome proliferator-activated receptor gamma (PPARg), responsible for control of lipid metabolism, has been evidenced as a key player in control of inflammation. In this study, we have explored a hypothetical crosstalk between PPARg and AhR in attenuating intestinal inflammation. Methods Bioinformatics analyses of a GEO RNAseq dataset of gut macrophages from IBD patients were used to assess correlations between PPARg and AhR. In vitro, macrophage-differentiated THP-1 cells and Caco-2 gut epithelial cells were seeded in Transwell® inserts to generate a gut-like co-culture model. Cells were treated with 100 ng/mL lipopolysaccharide (LPS) for 24 h in order to mimic a phenotype of intestinal inflammation, and also with combinations of AhR/PPARg agonists and antagonists at concentrations of 10 µM each. Proprietary AhR agonists were also tested. AhR translocation and cytokine secretion in macrophages as well as monolayer integrity and expression of tight junction proteins (e.g., claudin-2) in epithelial cells were assessed. Results Principal component analysis and Pearson correlation tests of the RNAseq dataset revealed that PPARg and AhR correlate with each other during intestinal homeostasis, but their expression patterns diverge during gut inflammation. In our co-culture model, blocking PPARg in THP-1 macrophages with a specific antagonist (GW9662) prevented AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ) from inducing AhR nuclear translocation and secreting interleukin (IL)-6. In Caco-2 gut epithelial cells, GW9662 blocked the anti-inflammatory effects of FICZ on monolayer disruption and claudin-2 expression. These effects of FICZ were confirmed to be AhR-dependent, as they were prevented under treatment with the AhR antagonist CH223191. Proprietary AhR ligands also inhibited IL-6 secretion, which was shown to be the most dominant parameter in terms of converging anti-inflammatory effects of both PPARg and AhR. Conclusion Our data points to a pivotal cross-talk between AhR and PPARg, where PPARg is likely recruited downstream of AhR activation and contributes to the anti-inflammatory effects of FICZ, especially inhibition of IL-6 secretion.

Myricetin protects mice against colitis by activating aryl hydrocarbon receptor signaling pathway

Objective: Myricetin is a bioactive compound in many edible plants. We have previously demonstrated that myricetin could significantly protect mice against colitis by regulating Treg/Th17 balance, while underlying mechanism remains unclear. The current study aimed to unravel the potential regulating mechanism of myricetin. Methods: The concentrations of 22 amino acids in colon were determined using HPLC-MS/MS and principal component analysis (PCA) was performed on the data. MetaboAnalyst was used to detect potential biological pathway influenced by myricetin. The results were further verified using qPCR, molecular docking method, and AhR inhibitor. Results: Studies had found that the biosynthesis of phenylalanine, tyrosine, and tryptophan; phenylalanine metabolism; and histidine metabolism were the most important pathways related to myricetin. Therefore, the aryl hydrocarbon receptor (AhR), which is closely related to the metabolism of tryptophan, phenylalanine, and tyrosine, was postulated to be the underlying signaling pathways. Furthermore, administration of myricet in significantly increased the relative expressions of CYP1A1 and CYP1B1, whereas AhR inhibitor abolished the amelioration of myricetin on DSS-induced colitis. Moreover, AhR inhibitor weakened the regulatory effect of myricetin on Treg/Th17 balance. Furthermore, the results obtained by the molecular docking method speculated that myricetin could bind to AhR as a ligand and activate AhR. Conclusion: The results suggested that myricetin could exert its protection against dextran sulfate sodium (DSS)-induced colitis by activating AhR signaling pathway.

P1138 Curcumin-QingDai combination for patients with active Crohn’s disease: Initial real-world experience from a retrospective multi-center cohort study

Abstract Background A combination of Curcumin and QingDai (CurQD) was shown to exert aryl-hydrocarbon-receptor (AhR) pathway activation and to be effective in ulcerative colitis. However, its benefit in Crohn’s disease (CD) has not been studied Methods A retrospective cohort study of patients with active CD treated with CurQD at three academic centers. Active disease was defined by PRO-2 SF≥2 and AP ≥1. The primary endpoint was the rate of clinical remission at the end-of-induction (weeks 8-12), PRO2 SF≤1 and AP=0. Secondary endpoints included biomarker response (FCP drop ≥50% in a patient with FCP >250mcg/gr at baseline) and remission (FCP drop ≥50% and FCP<250mcg/gr at end-of-induction) and CurQD retention. Public-domain GTEx dataset was explored for mRNA expression of the target AhR in colon versus small intestinal mucosa Results Thirty patients were identified for the safety dataset, of whom 13/30 (43%) were bio-experienced, and 25 were eligible for inclusion in the efficacy analysis,. Clinical PRO2 remission at the end of induction was achieved in 12/25 (48%) of patients and clinical response in 19/25 (76%), with an overall reduction in median PRO2 score from 15 (95%CI 13-19.7) to 4 (95%CI 2-8.7, p<0.001). Biomarker remission and response were observed in 11/20 (55%) and 15/20 (75%), respectively, of patients with baseline FCP>250mcg/gr, with an overall reduction in median FCP from a baseline 639 mcg/gr (95%CI 128-5480) to 138mcg/gr (95%CI 5-1470, p=0.001). Biomarker remission was observed in 8/11 (73%) of patients with colonic-involving L2/L3 disease versus 3/9 (33%) L1 extent (OR 4.5, 95%CI 0.8- 24, p=0.08). After 8-months’ median follow-up (range 2-26 months), 16/19 (84%) of responding patients were still taking CurQD. Three patients experienced headaches and three had abdominal pain/diarrhea. Two of the six stopped CurQD due to these symptoms. One patient had elevated liver transaminases X3/normal, which resolved upon halving CurQD dose. To explore if the signal for a difference in efficacy in patients with or without colonic involvment relates to different expression of the target AhR in colon versus small bowel, an analysis of GTEx dataset was performed, which revealed comparable AhR mRNA expression levels in human colonic and terminal ileum segments. Conclusion In this first-reported real-world experience, the AhR-agonist CurQD was effective in inducing and maintaining clinical and biomarker remission in CD patients, including in biologic-experienced patients

RELMβ sets the threshold for microbiome-dependent oral tolerance.

Tolerance to dietary antigens is critical for avoiding deleterious type 2 immune responses resulting in food allergy (FA) and anaphylaxis1,2. However, the mechanisms resulting in both the maintenance and failure of tolerance to food antigens are poorly understood. Here we demonstrate that the goblet-cell-derived resistin-like molecule β (RELMβ)3,4 is a critical regulator of oral tolerance. RELMβ is abundant in the sera of both patients with FA and mouse models of FA. Deletion of RELMβ protects mice from FAand the development of food-antigen-specific IgE and anaphylaxis. RELMβ disrupts food tolerance through the modulation of the gut microbiome and depletion of indole-metabolite-producing Lactobacilli and Alistipes. Tolerance is maintained by the local production of indole derivatives driving FA protective RORγt+ regulatory T (Treg) cells5 through activation of the aryl hydrocarbon receptor. RELMβ antagonism in the peri-weaning period restores oral tolerance and protects genetically prone offspring from developing FA later in life. Together, we show that RELMβ mediates a gut immune-epithelial circuit regulating tolerance to food antigens-a novelmode of innate control of adaptive immunity through microbiome editing-and identify targetable candidates in this circuit for prevention and treatment of FA.

The Gut Microbiota-Xanthurenic Acid-Aromatic Hydrocarbon Receptor Axis Mediates the Anticolitic Effects of Trilobatin.

Current treatments for ulcerative colitis (UC) remain limited, highlighting the need for novel therapeutic strategies. Trilobatin (TLB), a naturally derived food additive, exhibits potential anti-inflammatory properties. In this study, a dextran sulfate sodium (DSS)-induced animal model is used to investigate the effects of TLB on UC. It is found TLB significantly alleviates DSS-induced UC in mice, as evidenced by a reduction in the disease activity index, an increase in colon length, improvement in histopathological lesions. Furthermore, TLB treatment results in a decrease in proinflammatory cytokines and an increase in anti-inflammatory cytokines. TLB mitigates UC by modulating the intestinal microbiota, particularly Akkermansia, which enhances tryptophan metabolism and upregulates the production of xanthurenic acid (XANA). To confirm the role of TLB-induced microbiota changes, experiments are performed with pseudogerm-free mice and fecal transplantation. It is also identified XANA as a key metabolite that mediates TLB's protective effects. Both TLB and XANA markedly activate the aromatic hydrocarbon receptor (AhR). Administration of an AhR antagonist abrogates their protective effects, thereby confirming the involvement of AhR in the underlying mechanism. In conclusion, the study reveals a novel mechanism through which TLB alleviates UC by correcting microbiota imbalances, regulating tryptophan metabolism, enhancing XANA production, and activating AhR.

Binding of ligands to the aryl hydrocarbon receptor: An overview of methods.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which plays numerous and pivotal roles in human physiology and pathophysiology. Therefore, pharmacotherapeutic targeting of the AhR is a highly pertinent issue. The identification of new AhR ligands and the characterization of the interactions between the AhR ligands and AhR protein requires appropriate methodology. In spite the AhR is monomeric intracellular soluble receptor, the full-length human AhR protein has not been crystallized so far, and its isolation in a form applicable in the binding assays is highly challenging. Recent advances, including crystallization of AhR fragments, recombinant protein technologies, and cryogenic electron microscopy, allowed for exploitation of diverse experimental techniques for studying interactions between ligands and the AhR. In the current paper, we review existing AhR ligand binding assays, including their description, applicability and limitations.

Gut microbial metabolite indole-3-propionic acid alleviates polycystic ovary syndrome in mice by regulating the AhR-NLRP3 axis.

Polycystic ovary syndrome (PCOS) is a complex disorder that significantly impacts female reproductive health and increases the risk of metabolic and reproductive diseases. Emerging evidence suggests that alterations in gut microbiota and their metabolic activities contribute to PCOS pathogenesis, although the underlying mechanisms remain elusive. In the current study, we found that patients with PCOS had altered metabolic profiles, particularly characterized by reduced levels of indole-3-propionic acid (IPA). Administration of IPA alleviated dehydroepiandrosterone (DHEA)-induced PCOS in mice, as demonstrated by improved estrus cycle, insulin sensitivity, ovarian morphology and hormone levels. Additionally, IPA treatment alleviated DHEA-induced oxidative stress in the ovaries and enhanced thermogenesis in brown adipose tissue. Furthermore, IPA attenuated DHEA-induced inflammation both in vivo and in vitro. Mechanistically, IPA treatment suppressed DHEA-induced inflammatory responses and inhibited NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation by activating the aryl hydrocarbon receptor (AhR). Collectively, our findings indicate that IPA ameliorates DHEA-induced PCOS through modulation of the AhR-NLRP3 pathway in mice, suggesting that regulating gut microbial tryptophan metabolism and AhR activation may represent a promising therapeutic strategy for PCOS prevention.

Commensal-derived tryptophan metabolites fortify the skin barrier: Insights from a 50-species gnotobiotic model of human skin microbiome.

The epidermal barrier defends the body against dehydration and harmful substances. The commensal microbiota is essential for proper differentiation and repair of the epidermal barrier, an effect mediated by the aryl hydrocarbon receptor (AHR). However, the microbial mechanisms of AHR activation in skin are less understood. Tryptophan metabolites are AHR ligands that can be products of microbial metabolism. To identify microbially regulated tryptophan metabolites invivo, we established a gnotobiotic model colonized with fifty human skin commensals and performed targeted mass spectrometry on murine skin. Indole-related metabolites were enriched in colonized skin compared to germ-free skin. In reconstructed human epidermis and in murine models of atopic-like barrier damage, these metabolites improved barrier repair and function individually and as a cocktail. These results provide a framework for the identification of microbial metabolites that mediate specific host functions, which can guide the development of microbe-based therapies for skin disorders.

Quantitative analysis of the polar cod (Boreogadus saida) hepatic proteome highlights interconnected responses in cellular adaptation and defence mechanisms after dietary benzo[a]pyrene exposure.

Increased industrial offshore activities in northern waters raise the question of impact of polycyclic aromatic hydrocarbons (PAHs) on key Arctic marine species. One of these is the ecologically important polar cod (Boreogadus saida), which is the primary food source for Arctic marine mammals and seabirds. In the present work, we have conducted the first comprehensive proteomics study with this species by exploring the effects of dietary PAH exposure on the hepatic proteome, using benzo[a]pyrene (BaP) as a PAH model-compound. Functional annotation and pathway analyses of the proteins affected by BaP revealed a concerted cellular response for handling and adopting to its exposure, involving numerous interconnected signalling pathways and metabolic processes. In accordance with BaP being a strong aryl hydrocarbon receptor (Ahr) agonist, a prominent activation of the canonical Ahr signalling pathway was observed, including upregulation of Ahr target proteins like cytochrome P450 enzymes and microsomal glutathione transferase. Furthermore, cellular pathways for handling oxidative stress, protein misfolding and degradation, as well as endoplasmic reticulum stress and calcium homeostasis, were also activated by BaP, possibly as a result of the formation of harmful and redox reactive BaP metabolites via phase I metabolism. Activation of proteins that participate in the acute-phase response was also observed, suggesting prevalent tissue- and cellular damage that triggers the immune system and inflammatory responses. Our results at the protein level aligns well with previous analyses on the effects of BaP on the polar cod liver transcriptome and support that exposure to BaP and structural similar PAHs can cause adverse effects on polar cod physiology. Although more data is required for demonstrating how these molecular responses propagate to higher levels of biological organisation, increased knowledge about the initial cellular and molecular mechanisms that induce toxicity is a key-step towards a mechanistically informed impact assessment of PAH pollutants in the Arctic.

Using the Key Characteristics Framework to Unlock the Mysteries of Aryl Hydrocarbon Receptor-Mediated Effects on the Immune System.

Initially discovered for its role mediating the deleterious effects of environmental contaminants, the aryl hydrocarbon receptor (AHR) is now known to be a crucial regulator of the immune system. The expanding list of AHR ligands includes synthetic and naturally derived molecules spanning pollutants, phytochemicals, pharmaceuticals, and substances derived from amino acids and microorganisms. The consequences of engaging AHR vary, depending on factors such as the AHR ligand, cell type, immune challenge, developmental state, dose, and timing of exposure relative to the immune stimulus. This review frames this complexity using the recently identified key characteristics of agents that affect immune system function (altered cell signaling, proliferation, differentiation, effector function, communication, trafficking, death, antigen presentation and processing, and tolerance). The use of these key characteristics provides a scaffold for continued discovery of how AHR and its myriad ligands influence the immune system, which will help harness the power of this enigmatic receptor to prevent or treat disease.

Aryl Hydrocarbon Receptor Establishes a Delicate Balance between the Level of the Trace Amine Tryptamine and Monoamine Oxidase Activity in the Brain and Periphery in Health and Conditions such as Neurodegenerative, Neurodevelopmental, and Psychiatric Disorders.

The purpose of this review was to analyse the literature regarding the correlation between the level of tryptamine, aryl hydrocarbon receptor (AHR) signalling pathway activation, and monoamine oxidase (MAO)-A and MAO-B activity in health and conditions such as neurodegenerative, neurodevelopmental, and psychiatric disorders. Tryptamine is generated through the decarboxylation of tryptophan by aromatic amino acid decarboxylase (AADC) in the central nervous system (CNS), peripheral nervous system (PNS), endocrine system, and gut bacteria. Organ-specific metabolism of tryptamine, which is mediated by different MAO isoforms, causes this trace amine to have different pharmacokinetics between the brain and periphery. Reactive oxygen species (ROS) generated by MAO can influence miRNA-CYP enzyme regulatory network and affect mitochondrial function. Tryptamine regulates AHR function by acting as an endogenous ligand for AHR, initiating AHR activation and inhibiting the expression of the CYP1A1 and CYP1A2 genes. The dysregulation of AHR signalling, triggered by endogenous tryptamine binding, can disrupt the regulation of prolactin levels. Depending on the tryptamine concentration and context, tryptamine can be beneficial or harmful. By acting as an agonist of inhibitory serotonin receptors and trace-amine associated receptor 1 (TAAR1) and an antagonist of excitatory serotonin receptors, it can engage in diverse physiological interactions with serotonin. Increased tryptamine production is observed under hypoxic conditions and is associated with hypoxia-inducible factor 1α (HIF-1α) activation, leading to AHR activation. Dysregulation of the association between tryptamine levels, AHR signalling pathway activation, and MAO activity are observed in Alzheimer's disease (AD), Parkinson's Disease (PD), Autism Spectrum Disorder (ASD) and schizophrenia.