Flavin-Containing Monooxygenase 3 (FMO3) Is Critical for Dioxin-Induced Reorganization of the Gut Microbiome and Host Insulin Sensitivity
Exposure to some environmental pollutants can have potent endocrine-disrupting effects, thereby promoting hormone imbalance and cardiometabolic diseases such as non-alcoholic fatty liver disease (NAFLD), diabetes, and cardiorenal diseases. Recent evidence also suggests that many environmental pollut...
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| Format: | Article |
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MDPI AG
2022-04-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/12/4/364 |
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| author | William Massey Lucas J. Osborn Rakhee Banerjee Anthony Horak Kevin K. Fung Danny Orabi E. Ricky Chan Naseer Sangwan Zeneng Wang J. Mark Brown |
| author_facet | William Massey Lucas J. Osborn Rakhee Banerjee Anthony Horak Kevin K. Fung Danny Orabi E. Ricky Chan Naseer Sangwan Zeneng Wang J. Mark Brown |
| author_sort | William Massey |
| collection | DOAJ |
| description | Exposure to some environmental pollutants can have potent endocrine-disrupting effects, thereby promoting hormone imbalance and cardiometabolic diseases such as non-alcoholic fatty liver disease (NAFLD), diabetes, and cardiorenal diseases. Recent evidence also suggests that many environmental pollutants can reorganize the gut microbiome to potentially impact these diverse human diseases. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is among the most potent endocrine-disrupting dioxin pollutants, yet our understanding of how TCDD impacts the gut microbiome and systemic metabolism is incompletely understood. Here, we show that TCDD exposure in mice profoundly stimulates the hepatic expression of flavin-containing monooxygenase 3 (<i>Fmo3</i>), which is a hepatic xenobiotic metabolizing enzyme that is also responsible for the production of the gut microbiome-associated metabolite trimethylamine N-oxide (TMAO). Interestingly, an enzymatic product of FMO3 (TMAO) has been associated with the same cardiometabolic diseases that these environmental pollutants promote. Therefore, here, we examined TCDD-induced alterations in the gut microbiome, host liver transcriptome, and glucose tolerance in <i>Fmo3</i><sup>+/+</sup> and <i>Fmo3</i><sup>−/−</sup> mice. Our results show that <i>Fmo3</i> is a critical component of the transcriptional response to TCDD, impacting the gut microbiome, host liver transcriptome, and systemic glucose tolerance. Collectively, this work uncovers a previously underappreciated role for <i>Fmo3</i> in integrating diet–pollutant–microbe–host interactions. |
| first_indexed | 2024-03-09T04:23:40Z |
| format | Article |
| id | doaj.art-271c68498b3a477498a649a2d9e4c506 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-09T04:23:40Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-271c68498b3a477498a649a2d9e4c5062023-12-03T13:43:10ZengMDPI AGMetabolites2218-19892022-04-0112436410.3390/metabo12040364Flavin-Containing Monooxygenase 3 (FMO3) Is Critical for Dioxin-Induced Reorganization of the Gut Microbiome and Host Insulin SensitivityWilliam Massey0Lucas J. Osborn1Rakhee Banerjee2Anthony Horak3Kevin K. Fung4Danny Orabi5E. Ricky Chan6Naseer Sangwan7Zeneng Wang8J. Mark Brown9Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Lerner Research Institute, Cleveland, OH 44195, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Lerner Research Institute, Cleveland, OH 44195, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Lerner Research Institute, Cleveland, OH 44195, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Lerner Research Institute, Cleveland, OH 44195, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Lerner Research Institute, Cleveland, OH 44195, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Lerner Research Institute, Cleveland, OH 44195, USAInstitute for Computational Biology, Case Western Reserve University, Cleveland, OH 44106, USACenter for Microbiome & Human Health, Cleveland Clinic, Lerner Research Institute, Cleveland, OH 44195, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Lerner Research Institute, Cleveland, OH 44195, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Lerner Research Institute, Cleveland, OH 44195, USAExposure to some environmental pollutants can have potent endocrine-disrupting effects, thereby promoting hormone imbalance and cardiometabolic diseases such as non-alcoholic fatty liver disease (NAFLD), diabetes, and cardiorenal diseases. Recent evidence also suggests that many environmental pollutants can reorganize the gut microbiome to potentially impact these diverse human diseases. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is among the most potent endocrine-disrupting dioxin pollutants, yet our understanding of how TCDD impacts the gut microbiome and systemic metabolism is incompletely understood. Here, we show that TCDD exposure in mice profoundly stimulates the hepatic expression of flavin-containing monooxygenase 3 (<i>Fmo3</i>), which is a hepatic xenobiotic metabolizing enzyme that is also responsible for the production of the gut microbiome-associated metabolite trimethylamine N-oxide (TMAO). Interestingly, an enzymatic product of FMO3 (TMAO) has been associated with the same cardiometabolic diseases that these environmental pollutants promote. Therefore, here, we examined TCDD-induced alterations in the gut microbiome, host liver transcriptome, and glucose tolerance in <i>Fmo3</i><sup>+/+</sup> and <i>Fmo3</i><sup>−/−</sup> mice. Our results show that <i>Fmo3</i> is a critical component of the transcriptional response to TCDD, impacting the gut microbiome, host liver transcriptome, and systemic glucose tolerance. Collectively, this work uncovers a previously underappreciated role for <i>Fmo3</i> in integrating diet–pollutant–microbe–host interactions.https://www.mdpi.com/2218-1989/12/4/364microbiomedietdiabetespollutantdioxin |
| spellingShingle | William Massey Lucas J. Osborn Rakhee Banerjee Anthony Horak Kevin K. Fung Danny Orabi E. Ricky Chan Naseer Sangwan Zeneng Wang J. Mark Brown Flavin-Containing Monooxygenase 3 (FMO3) Is Critical for Dioxin-Induced Reorganization of the Gut Microbiome and Host Insulin Sensitivity Metabolites microbiome diet diabetes pollutant dioxin |
| title | Flavin-Containing Monooxygenase 3 (FMO3) Is Critical for Dioxin-Induced Reorganization of the Gut Microbiome and Host Insulin Sensitivity |
| title_full | Flavin-Containing Monooxygenase 3 (FMO3) Is Critical for Dioxin-Induced Reorganization of the Gut Microbiome and Host Insulin Sensitivity |
| title_fullStr | Flavin-Containing Monooxygenase 3 (FMO3) Is Critical for Dioxin-Induced Reorganization of the Gut Microbiome and Host Insulin Sensitivity |
| title_full_unstemmed | Flavin-Containing Monooxygenase 3 (FMO3) Is Critical for Dioxin-Induced Reorganization of the Gut Microbiome and Host Insulin Sensitivity |
| title_short | Flavin-Containing Monooxygenase 3 (FMO3) Is Critical for Dioxin-Induced Reorganization of the Gut Microbiome and Host Insulin Sensitivity |
| title_sort | flavin containing monooxygenase 3 fmo3 is critical for dioxin induced reorganization of the gut microbiome and host insulin sensitivity |
| topic | microbiome diet diabetes pollutant dioxin |
| url | https://www.mdpi.com/2218-1989/12/4/364 |
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