Contribution of Circulating Host and Microbial Tryptophan Metabolites Toward Ah Receptor Activation

Ethan W Morgan; Fangcong Dong; Andrew J Annalora; Iain A Murray; Trenton Wolfe; Reece Erickson; Krishne Gowda; Shantu G Amin; Kristina S Petersen; Penny M Kris-Etherton; Craig B Marcus; Seth T Walk; Andrew D Patterson; Gary H Perdew

doi:10.1177/11786469231182510

Contribution of Circulating Host and Microbial Tryptophan Metabolites Toward Ah Receptor Activation

Int J Tryptophan Res. 2023 Jul 7:16:11786469231182510. doi: 10.1177/11786469231182510. eCollection 2023.

Authors

Affiliations

¹ Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, USA.
² Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, USA.
³ Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, USA.
⁴ Department of Microbiology and Cell Biology, Montana State University, Bozeman, USA.
⁵ Department of Pharmacology Penn State College of Medicine, Hershey, USA.
⁶ Department of Nutritional Sciences, The Pennsylvania State University, University Park, USA.

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that plays an integral role in homeostatic maintenance by regulating cellular functions such as cellular differentiation, metabolism, barrier function, and immune response. An important but poorly understood class of AHR activators are compounds derived from host and bacterial metabolism of tryptophan. The commensal bacteria of the gut microbiome are major producers of tryptophan metabolites known to activate the AHR, while the host also produces AHR activators through tryptophan metabolism. We used targeted mass spectrometry-based metabolite profiling to determine the presence and metabolic source of these metabolites in the sera of conventional mice, germ-free mice, and humans. Surprisingly, sera concentrations of many tryptophan metabolites are comparable between germ-free and conventional mice. Therefore, many major AHR-activating tryptophan metabolites in mouse sera are produced by the host, despite their presence in feces and mouse cecal contents. Here we present an investigation of AHR activation using a complex mixture of tryptophan metabolites to examine the biological relevance of circulating tryptophan metabolites. AHR activation is rarely studied in the context of a mixture at relevant concentrations, as we present here. The AHR activation potentials of individual and pooled metabolites were explored using cell-based assays, while ligand binding competition assays and ligand docking simulations were used to assess the detected metabolites as AHR agonists. The physiological and biomedical relevance of the identified metabolites was investigated in the context of a cell-based model for rheumatoid arthritis. We present data that reframe AHR biology to include the presence of a mixture of ubiquitous tryptophan metabolites, improving our understanding of homeostatic AHR activity and models of AHR-linked diseases.

Keywords: Aryl hydrocarbon receptor; homeostasis; indole; kynurenine pathway; metabolomics; microbiome; tryptophan metabolism.

Abstract

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