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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Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, cytometry by time of flight indicated that the frequencies of memory-like Th17 cells (CD45RA−CCR7+IL-17A+CD4+), memory-like CD8+ T cells (CD38+CXCR3−CCR7+Helios−CD127−CD8+) and pro-inflam Macs (CD206−CD163−CD38midCD107alowCD86midHLA-DRmidCD14+) were increased, while the frequencies of anti-inflam Macs (CD206+CD163−CD86midCD33+HLA-DR+CD14+) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b+CD15hiHLA-DRlow) were decreased in the placenta of PE compared with that of normal pregnancy (NP), but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8+ T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80+CD206− pro-inflam Macs with a Folr2+Ccl7+Ccl8+C1qa+C1qb+C1qc+ phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+ Th17 cells via IGF1–IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8+ T cells but inhibited the production of Ly6g+S100a8+S100a9+Retnlg+Wfdc21+ gMDSCs at the maternal–fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.
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Background: Several fields have described low reproducibility of scientific research and poor accessibility in research reporting practices. Although previous reports have investigated accessible reporting practices that lead to reproducible research in other fields, to date, no study has explored the extent of accessible and reproducible research practices in cardiovascular science literature.
Methods: To study accessibility and reproducibility in cardiovascular research reporting, we screened 639 randomly selected articles published in 2019 in three top cardiovascular science publications: Circulation, the European Heart Journal, and the Journal of the American College of Cardiology (JACC). Of those 639 articles, 393 were empirical research articles. We screened each paper for accessible and reproducible research practices using a set of accessibility criteria including protocol, materials, data, and analysis script availability, as well as accessibility of the publication itself. We also quantified the consistency of open research practices within and across cardiovascular study types and journal formats.
Results: We identified that fewer than 2% of cardiovascular research publications provide sufficient resources (materials, methods, data, and analysis scripts) to fully reproduce their studies. Of the 639 articles screened, 393 were empirical research studies for which reproducibility could be assessed using our protocol, as opposed to commentaries or reviews. After calculating an accessibility score as a measure of the extent to which an article makes its resources available, we also showed that the level of accessibility varies across study types with a score of 0.08 for Case Studies or Case Series and 0.39 for Clinical Trials (p = 5.500E-5) and across journals (0.19 through 0.34, p = 1.230E-2). We further showed that there are significant differences in which study types share which resources.
Conclusion: Although the degree to which reproducible reporting practices are present in publications varies significantly across journals and study types, current cardiovascular science reports frequently do not provide sufficient materials, protocols, data, or analysis information to reproduce a study. In the future, having higher standards of accessibility mandated by either journals or funding bodies will help increase the reproducibility of cardiovascular research.
Funding: Authors Gabriel Heckerman, Arely Campos-Melendez, and Chisomaga Ekwueme were supported by an NIH R25 grant from the National Heart, Lung and Blood Institute (R25HL147666). Eileen Tzng was supported by an AHA Institutional Training Award fellowship (18UFEL33960207).
