50th Anniversary Celebration Collection Special Section on Xenobiotic Receptors-Minireview Microbial Metabolites as Ligands to Xenobiotic Receptors: Chemical Mimicry as Potential Drugs of the Future

Xenobiotic receptors, such as the pregnane X receptor, regulate multiple host physiologic 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 celltype 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 focuses on recent efforts to derive potentially nontoxic microbial metabolite chemical mimics that could one day be developed as drugs combating xenobiotic receptor-modifying pathophysiology. The review will include our perspective on the field and recommend certain directions for future research.SIGNIFICANCE STATEMENT Xenobiotic receptors (XRs) regulate host drug metabolism, cel-lular metabolism, and immunity. Their presence in host intes-tines allows them to function not only as xenosensors but also as a response 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 toward discovery of novel chemical mimics as potential drugs of the future for diseases such as inflammatory bowel disease.

Automated summary

Xenobiotic receptors play a crucial role in regulating host physiological pathways and have recently been explored for their interaction with microbial metabolites. This review focuses on the potential development of chemical mimics of microbial metabolites as therapeutic drugs for diseases such as inflammatory bowel disease.