Urolithin A Is a Dietary Microbiota-Derived Human Aryl Hydrocarbon Receptor Antagonist
Urolithins (e.g., UroA and B) are gut microbiota-derived metabolites of the natural polyphenol ellagic acid. Urolithins are associated with various health benefits, including attenuation of inflammatory signaling, anti-cancer effects and repression of lipid accumulation. The molecular mechanisms und...
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-11-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/8/4/86 |
| _version_ | 1817992619802755072 |
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| author | Gulsum E. Muku Iain A. Murray Juan C. Espín Gary H. Perdew |
| author_facet | Gulsum E. Muku Iain A. Murray Juan C. Espín Gary H. Perdew |
| author_sort | Gulsum E. Muku |
| collection | DOAJ |
| description | Urolithins (e.g., UroA and B) are gut microbiota-derived metabolites of the natural polyphenol ellagic acid. Urolithins are associated with various health benefits, including attenuation of inflammatory signaling, anti-cancer effects and repression of lipid accumulation. The molecular mechanisms underlying the beneficial effects of urolithins remain unclear. We hypothesize that some of the human health benefits of urolithins are mediated through the aryl hydrocarbon receptor (AHR). Utilizing a cell-based reporter system, we tested urolithins for the capacity to modulate AHR activity. Cytochrome P450 1A1 (<i>CYP1A1</i>) mRNA levels were assessed by real-time quantitative polymerase chain reaction. Competitive ligand binding assays were performed to determine whether UroA is a direct ligand for the AHR. Subcellular AHR protein levels were examined utilizing immunoblotting analysis. AHR expression was repressed in Caco-2 cells by siRNA transfection to investigate AHR-dependency. UroA and B were able to antagonize 2,3,7,8-tetrachlorodibenzo-<i>p</i>-dioxin (TCDD)-induced AHR-mediated transcriptional activity. Furthermore, UroA and B attenuated TCDD-mediated stimulation of <i>CYP1A1</i> mRNA levels. In addition, competitive ligand binding assays characterized UroA as a direct AHR ligand. Consistent with other AHR antagonists, UroA failed to induce AHR retention in the nucleus. AHR is necessary for UroA-mediated attenuation of cytokine-induced interleukin 6 (<i>IL6</i>) and prostaglandin-endoperoxide synthase 2 (<i>PTGS2</i>) expression in Caco-2 cells. Here we identified UroA as the first dietary-derived human selective AHR antagonist produced by the gut microbiota through multi-step metabolism. Furthermore, previously reported anti-inflammatory activity of UroA may at least in part be mediated through AHR. |
| first_indexed | 2024-04-14T01:28:28Z |
| format | Article |
| id | doaj.art-c060e7b4d15e4ceaaaf804b535c8597a |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-04-14T01:28:28Z |
| publishDate | 2018-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-c060e7b4d15e4ceaaaf804b535c8597a2022-12-22T02:20:18ZengMDPI AGMetabolites2218-19892018-11-01848610.3390/metabo8040086metabo8040086Urolithin A Is a Dietary Microbiota-Derived Human Aryl Hydrocarbon Receptor AntagonistGulsum E. Muku0Iain A. Murray1Juan C. Espín2Gary H. Perdew3Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USACenter for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USALaboratory of Food & Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, 30100 Murcia, SpainCenter for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USAUrolithins (e.g., UroA and B) are gut microbiota-derived metabolites of the natural polyphenol ellagic acid. Urolithins are associated with various health benefits, including attenuation of inflammatory signaling, anti-cancer effects and repression of lipid accumulation. The molecular mechanisms underlying the beneficial effects of urolithins remain unclear. We hypothesize that some of the human health benefits of urolithins are mediated through the aryl hydrocarbon receptor (AHR). Utilizing a cell-based reporter system, we tested urolithins for the capacity to modulate AHR activity. Cytochrome P450 1A1 (<i>CYP1A1</i>) mRNA levels were assessed by real-time quantitative polymerase chain reaction. Competitive ligand binding assays were performed to determine whether UroA is a direct ligand for the AHR. Subcellular AHR protein levels were examined utilizing immunoblotting analysis. AHR expression was repressed in Caco-2 cells by siRNA transfection to investigate AHR-dependency. UroA and B were able to antagonize 2,3,7,8-tetrachlorodibenzo-<i>p</i>-dioxin (TCDD)-induced AHR-mediated transcriptional activity. Furthermore, UroA and B attenuated TCDD-mediated stimulation of <i>CYP1A1</i> mRNA levels. In addition, competitive ligand binding assays characterized UroA as a direct AHR ligand. Consistent with other AHR antagonists, UroA failed to induce AHR retention in the nucleus. AHR is necessary for UroA-mediated attenuation of cytokine-induced interleukin 6 (<i>IL6</i>) and prostaglandin-endoperoxide synthase 2 (<i>PTGS2</i>) expression in Caco-2 cells. Here we identified UroA as the first dietary-derived human selective AHR antagonist produced by the gut microbiota through multi-step metabolism. Furthermore, previously reported anti-inflammatory activity of UroA may at least in part be mediated through AHR.https://www.mdpi.com/2218-1989/8/4/86aryl hydrocarbon receptorpolyphenolsinflammationurolithinAHR antagonist |
| spellingShingle | Gulsum E. Muku Iain A. Murray Juan C. Espín Gary H. Perdew Urolithin A Is a Dietary Microbiota-Derived Human Aryl Hydrocarbon Receptor Antagonist Metabolites aryl hydrocarbon receptor polyphenols inflammation urolithin AHR antagonist |
| title | Urolithin A Is a Dietary Microbiota-Derived Human Aryl Hydrocarbon Receptor Antagonist |
| title_full | Urolithin A Is a Dietary Microbiota-Derived Human Aryl Hydrocarbon Receptor Antagonist |
| title_fullStr | Urolithin A Is a Dietary Microbiota-Derived Human Aryl Hydrocarbon Receptor Antagonist |
| title_full_unstemmed | Urolithin A Is a Dietary Microbiota-Derived Human Aryl Hydrocarbon Receptor Antagonist |
| title_short | Urolithin A Is a Dietary Microbiota-Derived Human Aryl Hydrocarbon Receptor Antagonist |
| title_sort | urolithin a is a dietary microbiota derived human aryl hydrocarbon receptor antagonist |
| topic | aryl hydrocarbon receptor polyphenols inflammation urolithin AHR antagonist |
| url | https://www.mdpi.com/2218-1989/8/4/86 |
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