TY - JOUR T1 - <strong>Microbial Metabolites as Ligands to Xenobiotic Receptors: Chemical Mimicry as Potential Drugs of the Future</strong> JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.122.000860 SP - DMD-MR-2022-000860 AU - Zdenek Dvorak AU - Hao Li AU - Sridhar Mani Y1 - 2022/01/01 UR - http://dmd.aspetjournals.org/content/early/2022/10/02/dmd.122.000860.abstract N2 - Xenobiotic receptors, for example like the pregnane X receptor, regulate multiple host physiological pathways including xenobiotic metabolism, certain aspects of cellular metabolism, and innate immunity. These ligand-dependent nuclear factors regulate gene expression via genomic recognition of specific promoters and transcriptional activation of the gene. Natural or endogenous ligands are not commonly associated with this class of receptors; however, since these receptors are expressed in a cell-type specific manner in the liver and intestines, there has been significant recent effort to characterize microbially derived metabolites as ligands for these receptors. In general, these metabolites are thought to be weak micromolar affinity ligands. This journal anniversary minireview will focus on recent efforts to derive potentially non-toxic microbial metabolite chemical mimics that could one day be developed as drugs combating xenobiotic-receptor modifying pathophysiology. The review will include our perspective of the field and recommend certain directions for future research. Significance Statement The xenobiotic receptors (XR) regulate host drug metabolism, cellular metabolism, and immunity. Their presence in host intestines allows them to function not only as xenosensors, but also to respond to the complex metabolic environment present in the intestines. Specifically, this review focuses on describing microbial metabolite-XR interactions and the translation of these findings towards discovery of novel chemical mimics as potential drugs of the future for diseases such as inflammatory bowel disease. ER -