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Induction of AHR Signaling in Response to the Indolimine Class of Microbial Stress Metabolites
oleh: 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
Format: | Article |
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Diterbitkan: | MDPI AG 2023-08-01 |
Deskripsi
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 <i>M. morganii</i> in the gastrointestinal tract. Here, we determined that indolimine-200, -214, and -248 are direct AHR ligands that can induce <i>Cyp1a1</i> transcription and subsequent CYP1A1 enzymatic activity capable of metabolizing the carcinogen benzo(a)pyrene in microsomal assays. In addition, indolimines enhance <i>IL6</i> 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.