Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms.

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.

• Authors: 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
• Journal: eLife (Elife) Vol. 11 (01 24 2022) ISSN: 2050-084X [Electronic] England
• PMID: 35072627 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022, Schugar et al.

Chemical References

• Enzyme Inhibitors
• Leptin
• Methylamines
• methylcholine
• Lyases
• trimethyloxamine
• trimethylamine
• Choline

Topics

• Animals
• Choline (administration & dosage, analogs & derivatives, metabolism)
• Circadian Rhythm (drug effects)
• Diet, High-Fat
• Enzyme Inhibitors (pharmacology)
• Gastrointestinal Microbiome (drug effects)
• Leptin (deficiency)
• Lyases (drug effects)
• Male
• Methylamines (metabolism)
• Mice
• Mice, Inbred C57BL
• Obesity (genetics, metabolism, microbiology)