Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles

Hubbard, Troy D.; Murray, Iain A.; Bisson, William H.; Lahoti, Tejas S.; Gowda, Raghavendra; Amin, Shantu; Patterson, Andrew D.; Perdew, Gary H.

doi:10.1038/srep12689

Cited by 278 publications

(253 citation statements)

References 52 publications

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“…In recent competitive ligand-binding experiments indole was found to preferentially activate human AHR compared with mouse AHR (Miller, 1997;Hubbard et al, 2015). In addition, indole was able to induce DRE-dependent luciferase activity with EC 50 of ;3 mM, which is well within the range of relevant physiologic concentrations.…”

Section: Downloaded Frommentioning

confidence: 83%

“…The accommodation and interaction of small molecules within the ligand-binding domain of AHR is likely to differ from that observed with high-affinity ligands such as dioxin (Backlund and Ingelman-Sundberg, 2004). Indeed, recent studies provide evidence that human AHR has the capacity to bind two indole molecules per ligand-binding pocket to facilitate activation (Hubbard et al, 2015).…”

Section: Possible Mechanism Of Ahr Activation By Low-molecularweight mentioning

confidence: 99%

“…This difference in affinity for dioxin has been shown to be associated with a single amino acid substitution in the ligand-binding pocket (Ema et al, 1994;Ramadoss and Perdew, 2004). The human receptor has been shown to have increased affinity for indole-based derivatives such as indigoids, indole, indoxyl-sulfate, and KA DiNatale et al, 2010a;Schroeder et al, 2010;Hubbard et al, 2015). Enhanced affinity of the human receptor for particular compounds may indicate an evolutionary adaptation to respond to specific endogenous and exogenous regulators that mediate certain physiologic responses (e.g., during inflammation).…”

Section: Photo-oxidation Of Tryptophanmentioning

confidence: 99%

“…Tryptophan is converted to IAA via the enzymes tryptophan monooxygenase and indole-3-acetamide hydrolase, which constitute the indole-3-acetamide pathway (Tsavkelova et al, 2012). The common fecal metabolite 3-methyl indole (skatole), generated by decarboxylation of IAA, has been shown to facilitate transcription of AHR target genes in human bronchial and colonic epithelial cells (Weems and Yost, 2010;Hubbard et al, 2015). The physiologic implications of AHR activation by tryptamine, IAA, or skatole remain to be established.…”

Section: Microbiota-derived Ahr Ligandsmentioning

confidence: 99%

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Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

Hubbard¹,

Murray²,

Perdew³

2015

Drug Metab Dispos

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444

405

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor recognized for its role in xenobiotic metabolism. The physiologic function of AHR has expanded to include roles in immune regulation, organogenesis, mucosal barrier function, and the cell cycle. These functions are likely dependent upon ligandmediated activation of the receptor. High-affinity ligands of AHR have been classically defined as xenobiotics, such as polychlorinated biphenyls and dioxins. Identification of endogenous AHR ligands is key to understanding the physiologic functions of this enigmatic receptor. Metabolic pathways targeting the amino acid tryptophan and indole can lead to a myriad of metabolites, some of which are AHR ligands. Many of these ligands exhibit species selective preferential binding to AHR. The discovery of specific tryptophan metabolites as AHR ligands may provide insight concerning where AHR is activated in an organism, such as at the site of inflammation and within the intestinal tract.

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Section: Downloaded Frommentioning

confidence: 83%

Section: Possible Mechanism Of Ahr Activation By Low-molecularweight mentioning

confidence: 99%

Section: Photo-oxidation Of Tryptophanmentioning

confidence: 99%

Section: Microbiota-derived Ahr Ligandsmentioning

confidence: 99%

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Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

Hubbard¹,

Murray²,

Perdew³

2015

Drug Metab Dispos

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444

405

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“…As well as acting as paradigms, these studies offer the potential for meta-analysis and recycling of data to determine (Hubbard et al, 2015).…”

Section: Et Vous Excrétion?mentioning

confidence: 99%

How to Determine the Role of the Microbiome in Drug Disposition

et al. 2018

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With a paradigm shift occurring in health care towards personalized and precision medicine, understanding the numerous environmental factors that impact drug disposition is of paramount importance. The highly diverse and variant nature of the human microbiome is now recognized as a factor driving inter-individual variation in therapeutic outcomes. The purpose of this review is to provide a practical guide on methodology that can be applied to study the effects of microbes on the absorption, distribution, metabolism, and excretion of drugs. We also highlight recent examples of how these methods have been successfully applied to help build the basis for researching the intersection of microbiome and pharmacology. While in vitro and in vivo preclinical models are highlighted, these methods are also relevant in late-phase drug development or even as a part of routine after-market surveillance. These approaches will aid in filling major knowledge gaps for both current and upcoming therapeutics with the long-term goal of achieving a new type of knowledge-based medicine that integrates data on the host and the microbiome.

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Immunity: Regulation by the Indigenous Gastrointestinal Microbiota

Butler

2017

Encyclopedia of Life Sciences

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Human beings are colonised by a beneficial ecosystem of microorganisms collectively termed the commensal microbiota or microbiome. Predominantly found at mucosal surfaces, these organisms are most abundant in the lower gastrointestinal tract. While the majority cannot be cultured outside the body, the development of molecular biological techniques (e.g. 16S ribosomal RNA PCR and shotgun metagenomic sequencing) is now allowing investigators to explore the microbiota in unprecedented detail. Research has uncovered a complex interplay between the intestinal microbiome and the host immune system. Gnotobiotic and germ‐free animal systems have revealed an absolute requirement for commensal microbes during normal immune development, and these interactions continue to shape immunity throughout adult life. In man, alterations to the normal intestinal microbiota (termed ‘dysbiosis’) have been associated with inflammatory bowel diseases, systemic autoimmune, metabolic and even neurological disorders. Key Concepts A human being is a ‘metaorganism’ – all mucosal surfaces are colonised by commensal microorganisms, collectively termed the microbiome. Microbes are most abundant in the lower GI tract. The intestinal microbiota provides the host with vital nutrients and prevents colonisation by pathogens. Novel molecular biology techniques (e.g. 16S rRNA PCR and shotgun metagenomic sequencing) are opening up the microbiome for in‐depth study. The human microbiome project has identified >10 000 different species associated with humans with individuals carrying 200–400 species in the gut. Colonization begins in the womb, continues during birth and normally reaches equilibrium by 2–3 years of age. The microbiota regulates the intestinal immune system by stimulating the epithelial barrier, promoting release of secretory IgA by plasma B cells and inducing the development of homeostatic Th17/Treg populations in the gut mucosa. Intestinal microbes can also influence systemic immunity via the production of bioactive molecules, such as pattern recognition receptor agonists (e.g. LPS), short‐chain fatty acids, tryptophan and polyamines. Abnormal changes in the microbiota are associated with chronic inflammatory diseases, allergic inflammation, metabolic and neurological diseases.

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Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles

Cited by 278 publications

References 52 publications

Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

How to Determine the Role of the Microbiome in Drug Disposition

Immunity: Regulation by the Indigenous Gastrointestinal Microbiota

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