Induction of AHR Signaling in Response to the Indolimine Class of Microbial Stress Metabolites
Dhwani Patel,
Iain A. Murray,
Fangcong Dong,
Andrew J. Annalora,
Krishne Gowda,
Denise M. Coslo,
Jacek Krzeminski,
Imhoi Koo,
Fuhua Hao,
Shantu G. Amin,
Craig B. Marcus,
Andrew D. Patterson,
Gary H. Perdew
Affiliations
Dhwani Patel
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA
Iain A. Murray
Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA
Fangcong Dong
Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA
Andrew J. Annalora
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA
Krishne Gowda
Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA
Denise M. Coslo
Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA
Jacek Krzeminski
Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA
Imhoi Koo
Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA
Fuhua Hao
Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA
Shantu G. Amin
Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA
Craig B. Marcus
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA
Andrew D. Patterson
Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA
Gary H. Perdew
Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that plays an important role in gastrointestinal barrier function, tumorigenesis, and is an emerging drug target. The resident microbiota is capable of metabolizing tryptophan to metabolites that are AHR ligands (e.g., indole-3-acetate). Recently, a novel set of mutagenic tryptophan metabolites named indolimines have been identified that are produced by M. morganii in the gastrointestinal tract. Here, we determined that indolimine-200, -214, and -248 are direct AHR ligands that can induce Cyp1a1 transcription and subsequent CYP1A1 enzymatic activity capable of metabolizing the carcinogen benzo(a)pyrene in microsomal assays. In addition, indolimines enhance IL6 expression in a colonic tumor cell line in combination with cytokine treatment. The concentration of indolimine-248 that induces AHR transcriptional activity failed to increase DNA damage. These observations reveal an additional aspect of how indolimines may alter colonic tumorigenesis beyond mutagenic activity.
