Most cited article - PubMed ID 35895845
Butyrate acts through HDAC inhibition to enhance aryl hydrocarbon receptor activation by gut microbiota-derived ligands
Herbal extracts represent a wide spectrum of biologically active ingredients with potential medical applications. By screening minor constituents of jasmine essential oil towards aryl hydrocarbon receptor (AhR) activity using a gene reporter assay (GRA), we found the antagonist effects of jasmone (3-methyl-2-[(2Z)-pent-2-en-1-yl]cyclopent-2-en-1-one). It inhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-, benzo[a]pyrene (BaP)-, and 6-formylindolo[3,2-b]carbazole (FICZ)-triggered AhR-dependent luciferase activity in a concentration-dependent manner. However, the inhibition differed markedly between TCDD, BaP, and FICZ, with the latter being significantly less inhibited. The dose-response analysis confirmed an allosteric type of AhR antagonism. Furthermore, jasmone efficiently inhibited AhR activation by AhR agonists and microbial catabolites of tryptophan (MICTs). TCDD- and FICZ-inducible CYP1A1 expression in primary human hepatocytes was inhibited by jasmone, whereas in the human HepG2 and LS180 cells, jasmone antagonized only TCDD-activated AhR. Jasmone only partially displaced radiolabeled TCDD from its binding to mouse Ahr, suggesting it is not a typical orthosteric ligand of AhR. TCDD-elicited AhR nuclear translocation was not affected by jasmone, whereas downstream signaling events, including the formation of the AhR:ARNT complex and enrichment of the CYP1A1 promoter, were inhibited by jasmone. In conclusion, we show that jasmone is a potent allosteric antagonist of AhR. Such discovery may help to find and/or clarify the use of jasmone in pharmaco- and phytotherapy for conditions where AhR plays a key role.
- Keywords
- AhR, CYP1A1, ChIP, HepG2, LS180, jasmone,
- MeSH
- Cytochrome P-450 CYP1A1 genetics metabolism MeSH
- Humans MeSH
- Ligands MeSH
- Mice MeSH
- Polychlorinated Dibenzodioxins * adverse effects MeSH
- Receptors, Aryl Hydrocarbon * antagonists & inhibitors MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Cytochrome P-450 CYP1A1 MeSH
- jasmone MeSH Browser
- Ligands MeSH
- Polychlorinated Dibenzodioxins * MeSH
- Receptors, Aryl Hydrocarbon * MeSH
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 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 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, cellular metabolism, and immunity. Their presence in host intestines 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.
- MeSH
- Ligands MeSH
- Receptors, Steroid * metabolism MeSH
- Intestines MeSH
- Carrier Proteins MeSH
- Xenobiotics metabolism MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- Ligands MeSH
- Receptors, Steroid * MeSH
- Carrier Proteins MeSH
- Xenobiotics MeSH
Aryl hydrocarbon receptor (AHR) plays pivotal roles in intestinal physiology and pathophysiology. Intestinal AHR is activated by numerous dietary, endogenous, and microbial ligands. Whereas the effects of individual compounds on AHR are mostly known, the effects of real physiological mixtures occurring in the intestine have not been studied. Using reporter gene assays and RT-PCR, we evaluated the combinatorial effects (3520 combinations) of 11 microbial catabolites of tryptophan (MICTs) on AHR. We robustly (n = 30) determined the potencies and relative efficacies of single MICTs. Synergistic effects of MICT binary mixtures were observed between low- or medium-efficacy agonists, in particular for combinations of indole-3-propionate and indole-3-lactate. Combinations comprising highly efficacious agonists such as indole-3-pyruvate displayed rather antagonist effects, caused by saturation of the assay response. These synergistic effects were confirmed by RT-PCR as CYP1A1 mRNA expression. We also tested mimic multicomponent and binary mixtures of MICTs, prepared based on the metabolomic analyses of human feces and colonoscopy aspirates, respectively. In this case, AHR responsiveness did not correlate with type of diet or health status, and the indole concentrations in the mixtures were determinative of gross AHR activity. Future systematic research on the synergistic activation of AHR by microbial metabolites and other ligands is needed.
- Keywords
- aryl hydrocarbon receptor, indole derivatives, microbiome, mimic mixtures, tryptophan metabolites,
- MeSH
- Cytochrome P-450 CYP1A1 genetics metabolism MeSH
- Indoles metabolism pharmacology MeSH
- Humans MeSH
- Ligands MeSH
- RNA, Messenger metabolism MeSH
- Propionates MeSH
- Pyruvates MeSH
- Receptors, Aryl Hydrocarbon * metabolism MeSH
- Intestines MeSH
- Tryptophan * metabolism pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Cytochrome P-450 CYP1A1 MeSH
- Indoles MeSH
- Ligands MeSH
- RNA, Messenger MeSH
- Propionates MeSH
- Pyruvates MeSH
- Receptors, Aryl Hydrocarbon * MeSH
- Tryptophan * MeSH