Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms
Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here, we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/63998 |
| _version_ | 1811203061258911744 |
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| author | Rebecca C Schugar Christy M Gliniak Lucas J Osborn William Massey Naseer Sangwan Anthony Horak Rakhee Banerjee Danny Orabi Robert N Helsley Amanda L Brown Amy Burrows Chelsea Finney Kevin K Fung Frederick M Allen Daniel Ferguson Anthony D Gromovsky Chase Neumann Kendall Cook Amy McMillan Jennifer A Buffa James T Anderson Margarete Mehrabian Maryam Goudarzi Belinda Willard Tytus D Mak Andrew R Armstrong Garth Swanson Ali Keshavarzian Jose Carlos Garcia-Garcia Zeneng Wang Aldons J Lusis Stanley L Hazen Jonathan Mark Brown |
| author_facet | Rebecca C Schugar Christy M Gliniak Lucas J Osborn William Massey Naseer Sangwan Anthony Horak Rakhee Banerjee Danny Orabi Robert N Helsley Amanda L Brown Amy Burrows Chelsea Finney Kevin K Fung Frederick M Allen Daniel Ferguson Anthony D Gromovsky Chase Neumann Kendall Cook Amy McMillan Jennifer A Buffa James T Anderson Margarete Mehrabian Maryam Goudarzi Belinda Willard Tytus D Mak Andrew R Armstrong Garth Swanson Ali Keshavarzian Jose Carlos Garcia-Garcia Zeneng Wang Aldons J Lusis Stanley L Hazen Jonathan Mark Brown |
| author_sort | Rebecca C Schugar |
| collection | DOAJ |
| description | Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here, we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (Lepob/ob). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake but is instead associated with alterations in the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that gut microbial CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have potential as anti-obesity therapeutics. |
| first_indexed | 2024-04-12T02:48:18Z |
| format | Article |
| id | doaj.art-1bf775b855894d52aa435ffcd48a01d8 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:48:18Z |
| publishDate | 2022-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-1bf775b855894d52aa435ffcd48a01d82022-12-22T03:51:04ZengeLife Sciences Publications LtdeLife2050-084X2022-01-011110.7554/eLife.63998Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythmsRebecca C Schugar0https://orcid.org/0000-0001-5908-2213Christy M Gliniak1https://orcid.org/0000-0003-3806-6112Lucas J Osborn2https://orcid.org/0000-0003-0077-9192William Massey3https://orcid.org/0000-0002-2087-6048Naseer Sangwan4Anthony Horak5Rakhee Banerjee6Danny Orabi7Robert N Helsley8https://orcid.org/0000-0001-5000-3187Amanda L Brown9Amy Burrows10Chelsea Finney11Kevin K Fung12Frederick M Allen13Daniel Ferguson14Anthony D Gromovsky15Chase Neumann16Kendall Cook17Amy McMillan18Jennifer A Buffa19James T Anderson20Margarete Mehrabian21Maryam Goudarzi22Belinda Willard23Tytus D Mak24Andrew R Armstrong25Garth Swanson26Ali Keshavarzian27https://orcid.org/0000-0002-7969-3369Jose Carlos Garcia-Garcia28Zeneng Wang29Aldons J Lusis30Stanley L Hazen31Jonathan Mark Brown32https://orcid.org/0000-0003-2708-7487Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartments of Medicine, Microbiology, and Human Genetics, University of California, Los Angeles, Los Angeles, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Proteomics and Metabolomics Core, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Proteomics and Metabolomics Core, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesMass Spectrometry Data Center, National Institute of Standards and Technology (NIST), Gaithersburg, United StatesDepartment of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, United StatesDepartments of Medicine, Microbiology, and Human Genetics, University of California, Los Angeles, Los Angeles, United StatesDepartment of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, United StatesLife Sciences Transformative Platform Technologies, Procter & Gamble, Cincinnati, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartments of Medicine, Microbiology, and Human Genetics, University of California, Los Angeles, Los Angeles, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Department of Cardiovascular Medicine, Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesObesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here, we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (Lepob/ob). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake but is instead associated with alterations in the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that gut microbial CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have potential as anti-obesity therapeutics.https://elifesciences.org/articles/63998nutritiondrug deliverygenetic diseasesgut microbiome |
| spellingShingle | Rebecca C Schugar Christy M Gliniak Lucas J Osborn William Massey Naseer Sangwan Anthony Horak Rakhee Banerjee Danny Orabi Robert N Helsley Amanda L Brown Amy Burrows Chelsea Finney Kevin K Fung Frederick M Allen Daniel Ferguson Anthony D Gromovsky Chase Neumann Kendall Cook Amy McMillan Jennifer A Buffa James T Anderson Margarete Mehrabian Maryam Goudarzi Belinda Willard Tytus D Mak Andrew R Armstrong Garth Swanson Ali Keshavarzian Jose Carlos Garcia-Garcia Zeneng Wang Aldons J Lusis Stanley L Hazen Jonathan Mark Brown Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms eLife nutrition drug delivery genetic diseases gut microbiome |
| title | Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms |
| title_full | Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms |
| title_fullStr | Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms |
| title_full_unstemmed | Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms |
| title_short | Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms |
| title_sort | gut microbe targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms |
| topic | nutrition drug delivery genetic diseases gut microbiome |
| url | https://elifesciences.org/articles/63998 |
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