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

Hubbard, Troy D.; Murray, Iain A.; Perdew, Gary H.

doi:10.1124/dmd.115.064246

Cited by 477 publications

(452 citation statements)

References 142 publications

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“…Results from a variety of laboratories over the past decade have revealed that the AHR has key roles in the development of cardiovascular, reproductive, and neural systems as well as in hematopoiesis and regulation of immune responses (Benedict, Lin, Loeffler, Peterson, & Flaws, 2000; Esser & Rannug, 2015; Gasiewicz, Singh, & Bennett, 2014; Kimura, Ding, & Tohyama, 2016; Lahvis et al., 2005; Quintana & Sherr, 2013; Singh et al., 2014; Stockinger, Di Meglio, Gialitakis, & Duarte, 2014). Some of these functions may involve natural or endogenous ligands such as metabolites generated by the microbiome, tryptophan metabolites, or lipid‐derived molecules (Bessede et al., 2014; Hubbard, Murray, & Perdew, 2015; McMillan & Bradfield, 2007; Moura‐Alves et al., 2014). The exact relationship between the AHR‐dependent toxicity of DLCs and PAHs and these physiological roles of AHR is not yet clear.…”

Section: Ahr Pathwaymentioning

confidence: 99%

When evolution is the solution to pollution: Key principles, and lessons from rapid repeated adaptation of killifish (Fundulus heteroclitus) populations

Whitehead

Clark

Reid

et al. 2017

Evolutionary Applications

120

102

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For most species, evolutionary adaptation is not expected to be sufficiently rapid to buffer the effects of human‐mediated environmental changes, including environmental pollution. Here we review how key features of populations, the characteristics of environmental pollution, and the genetic architecture underlying adaptive traits, may interact to shape the likelihood of evolutionary rescue from pollution. Large populations of Atlantic killifish (Fundulus heteroclitus) persist in some of the most contaminated estuaries of the United States, and killifish studies have provided some of the first insights into the types of genomic changes that enable rapid evolutionary rescue from complexly degraded environments. We describe how selection by industrial pollutants and other stressors has acted on multiple populations of killifish and posit that extreme nucleotide diversity uniquely positions this species for successful evolutionary adaptation. Mechanistic studies have identified some of the genetic underpinnings of adaptation to a well‐studied class of toxic pollutants; however, multiple genetic regions under selection in wild populations seem to reflect more complex responses to diverse native stressors and/or compensatory responses to primary adaptation. The discovery of these pollution‐adapted killifish populations suggests that the evolutionary influence of anthropogenic stressors as selective agents occurs widely. Yet adaptation to chemical pollution in terrestrial and aquatic vertebrate wildlife may rarely be a successful “solution to pollution” because potentially adaptive phenotypes may be complex and incur fitness costs, and therefore be unlikely to evolve quickly enough, especially in species with small population sizes.

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Section: Ahr Pathwaymentioning

confidence: 99%

When evolution is the solution to pollution: Key principles, and lessons from rapid repeated adaptation of killifish (Fundulus heteroclitus) populations

Whitehead

Clark

Reid

et al. 2017

Evolutionary Applications

120

102

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“…The ability of the AHR also to regulate immune function and intestinal homeostasis in a manner that appears to involve microbiota-generated metabolites is currently of high interest. With this in mind, Hubbard et al (2015) focused on our emerging understanding of the metabolic formation of endogenous AHR ligands from tryptophan and indole by both the host and gut microbiota. In addition, they speculated on how the absence or presence of these metabolites may impact gut homeostasis, barrier function, and the gut inflammatory response via their AHR modulating activities.…”

Section: Contribution Of the Gut Microbiota To Intestinal Immune Homementioning

confidence: 99%

Drug Metabolism by the Host and Gut Microbiota: A Partnership or Rivalry?

Swanson

2015

Drug Metab Dispos

140

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The importance of the gut microbiome in determining not only overall health, but also in the metabolism of drugs and xenobiotics, is rapidly emerging. It is becoming increasingly clear that the gut microbiota can act in concert with the host cells to maintain intestinal homeostasis, cometabolize drugs and xenobiotics, and alter the expression levels of drug-metabolizing enzymes and transporters and the expression and activity levels of nuclear receptors. In this myriad of activities, the impact of the microbiota may be beneficial or detrimental to the host. Given that the interplay between the gut microbiota and host cells is likely subject to high interindividual variability, this work has tremendous implications for our ability to predict accurately a particular drug's pharmacokinetics and a given patient population's response to drugs. In this issue of Drug Metabolism and Disposition, a series of articles is presented that illustrate the progress and challenges that lie ahead as we unravel the intricacies associated with drug and xenobiotic metabolism by the gut microbiota. These articles highlight the underlying mechanisms that are involved and the use of in vivo and in vitro approaches that are currently available for elucidating the role of the gut microbiota in drug and xenobiotic metabolism. These articles also shed light on exciting new avenues of research that may be pursued as we consider the role of the gut microbiota as an endocrine organ, a component of the brain-gut axis, and whether the gut microbiota is an appropriate and amenable target for new drugs.

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“…A variety of tryptophan metabolites (e.g., indole, indole-3-aldehyde, indole-3-acetic acid, and indole-3-propionic acid) are generated primarily by bacterial metabolism in the colon and are then absorbed and circulated systemically [59, 60]; thus, plasma levels of these bacterial products are substantially lower in germ-free mice compared to conventional mice [61]. The nuclear receptors AhR (aryl hydrocarbon receptor) and PXR (pregnane/xenobiotic responsive receptor or pregnane X receptor) are molecular targets of these bacteria-derived tryptophan metabolites [59, 60, 62].…”

Section: Tryptophan Metabolitesmentioning

confidence: 99%

Gut Microbiome and Colon Cancer: Role of Bacterial Metabolites and Their Molecular Targets in the Host

Bhutia

Ogura

Sivaprakasam

et al. 2017

Curr Colorectal Cancer Rep

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Purpose of review The relationship between colonic bacteria and the host is symbiotic, but how communication between the two partners occurs is just beginning to be understood at the molecular level. Here, we highlight specific products of bacterial metabolism that are present in the colonic lumen and their molecular targets in the host that facilitate this communication. Recent findings Colonic epithelial cells and mucosal immune cells express several cell-surface receptors and nuclear receptors that are activated by specific bacterial metabolites, which impact multiple signaling pathways and expression of many genes. In addition, some bacterial metabolites also possess the ability to cause epigenetic changes in these cells via inhibition of selective enzymes involved in the maintenance of histone acetylation and DNA methylation patterns. Summary Colonic bacteria communicate with their host with selective metabolites that interact with host molecular targets. This chemical communication underlies a broad range of the biology and function of colonic epithelial cells and mucosal immune cells, which protect against inflammation and carcinogenesis in the colon under normal physiological conditions.

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

Cited by 477 publications

References 142 publications

When evolution is the solution to pollution: Key principles, and lessons from rapid repeated adaptation of killifish (Fundulus heteroclitus) populations

When evolution is the solution to pollution: Key principles, and lessons from rapid repeated adaptation of killifish (Fundulus heteroclitus) populations

Drug Metabolism by the Host and Gut Microbiota: A Partnership or Rivalry?

Gut Microbiome and Colon Cancer: Role of Bacterial Metabolites and Their Molecular Targets in the Host

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