Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms
- Cleveland Clinic Lerner College of Medicine, United States
- University of Texas Southwestern Medical Center, United States
- University of California, Los Angeles, United States
- National Institute of Standards and Technology (NIST), United States
- Rush University Medical Center, United States
- Procter and Gamble, United States
Abstract
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.
Data availability
RNA sequencing data has been deposited in GEO under accession code GSE157925Microbiome data were submitted to the European Nucleotide Archive under accession code PRJEB48232
Article and author information
Author details
Jonathan Mark Brown
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK120679)
- Jonathan Mark Brown
National Heart, Lung, and Blood Institute (R01 HL130819)
- Zeneng Wang
National Institute of Diabetes and Digestive and Kidney Diseases (F32 DK122623)
- Christy M Gliniak
National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK007307)
- Christy M Gliniak
Leducq Transatlantic Network of Excellence awar (No grant number)
- Stanley L Hazen
American Heart Association (17POST3285000)
- Robert N Helsley
American Heart Association (15POST2535000)
- Rebecca C Schugar
Clinical and Translational Science Collaborative of Cleveland, School of Medicine, Case Western Reserve University (4UL1TR000439)
- Belinda Willard
Case Comprehensive Cancer Center, Case Western Reserve University (P30 CA043703)
- Jonathan Mark Brown
National Heart, Lung, and Blood Institute (P01 HL146823)
- Stanley L Hazen
National Institute on Alcohol Abuse and Alcoholism (P50 AA024333)
- Jonathan Mark Brown
National Institute on Alcohol Abuse and Alcoholism (U01 AA026938)
- Jonathan Mark Brown
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK130227)
- Jonathan Mark Brown
National Cancer Institute (P50 CA150964)
- Jonathan Mark Brown
National Heart, Lung, and Blood Institute (R01 HL103866)
- Stanley L Hazen
National Heart, Lung, and Blood Institute (R01 HL147883)
- Aldons J Lusis
National Heart, Lung, and Blood Institute (R01 HL144651)
- Aldons J Lusis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mice were maintained in an Association for the Assessment and Accreditation of Laboratory Animal Care, International-approved animal facility, and all experimental protocols were approved by the Institutional Animal Care and use Committee of the Cleveland Clinic. (Approved IACUC protocol numbers 2015-1381, 2018-1941, and 00002499).
Copyright
© 2022, Schugar et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms
eLife 11:e63998.
https://doi.org/10.7554/eLife.63998
Further reading
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- Medicine
- Neuroscience
Background:
Alcohol use disorder (AUD) is a global health problem with limited therapeutic options. The biochemical mechanisms that lead to this disorder are not yet fully understood, and in this respect, metabolomics represents a promising approach to decipher metabolic events related to AUD. The plasma metabolome contains a plethora of bioactive molecules that reflects the functional changes in host metabolism but also the impact of the gut microbiome and nutritional habits.
Methods:
In this study, we investigated the impact of severe AUD (sAUD), and of a 3-week period of alcohol abstinence, on the blood metabolome (non-targeted LC-MS metabolomics analysis) in 96 sAUD patients hospitalized for alcohol withdrawal.
Results:
We found that the plasma levels of different lipids ((lyso)phosphatidylcholines, long-chain fatty acids), short-chain fatty acids (i.e. 3-hydroxyvaleric acid) and bile acids were altered in sAUD patients. In addition, several microbial metabolites, including indole-3-propionic acid, p-cresol sulfate, hippuric acid, pyrocatechol sulfate, and metabolites belonging to xanthine class (paraxanthine, theobromine and theophylline) were sensitive to alcohol exposure and alcohol withdrawal. 3-Hydroxyvaleric acid, caffeine metabolites (theobromine, paraxanthine, and theophylline) and microbial metabolites (hippuric acid and pyrocatechol sulfate) were correlated with anxiety, depression and alcohol craving. Metabolomics analysis in postmortem samples of frontal cortex and cerebrospinal fluid of those consuming a high level of alcohol revealed that those metabolites can be found also in brain tissue.
Conclusions:
Our data allow the identification of neuroactive metabolites, from interactions between food components and microbiota, which may represent new targets arising in the management of neuropsychiatric diseases such as sAUD.
Funding:
Gut2Behave project was initiated from ERA-NET NEURON network (Joint Transnational Call 2019) and was financed by Academy of Finland, French National Research Agency (ANR-19-NEUR-0003-03) and the Fonds de la Recherche Scientifique (FRS-FNRS; PINT-MULTI R.8013.19, Belgium). Metabolomics analysis of the TSDS samples was supported by grant from the Finnish Foundation for Alcohol Studies.
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