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Gut Microbe-Targeted Choline Trimethylamine Lyase Inhibition Improves Obesity Via Rewiring of Host Circadian Rhythms



Rebecca Schugar, Christy Gliniak, Lucas Osborn, William Massey, Naseer Sangwan, Anthony Horak, Rakhee Banerjee, Danny Orabi, Robert Helsley, Amanda Brown, Amy Burrows, Chelsea Finney, Kevin Fung, Frederick Allen, Daniel Ferguson, Anthony Gromovsky, Chase Neumann, Kendall Cook, Amy McMillan, Jennifer Buffa, James Anderson, Margarete Mehrabian, Maryam Goudarzi, Belinda Willard, Tytus Mak, Andrew Armstrong, Garth Swanson, Ali Keshavarzian, Jose Carlos Garcia-Garcia, Zeneng Wang, Aldons Lusis, Stanley Hazen, Mark Brown


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 (ob/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 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 untapped potential as anti-obesity therapeutics.


obesity, microbiome, insulin resistance, circadian, metabolomics


Schugar, R. , Gliniak, C. , Osborn, L. , Massey, W. , Sangwan, N. , Horak, A. , Banerjee, R. , Orabi, D. , Helsley, R. , Brown, A. , Burrows, A. , Finney, C. , Fung, K. , Allen, F. , Ferguson, D. , Gromovsky, A. , Neumann, C. , Cook, K. , McMillan, A. , Buffa, J. , Anderson, J. , Mehrabian, M. , Goudarzi, M. , Willard, B. , Mak, T. , Armstrong, A. , Swanson, G. , Keshavarzian, A. , Garcia-Garcia, J. , Wang, Z. , Lusis, A. , Hazen, S. and Brown, M. (2022), Gut Microbe-Targeted Choline Trimethylamine Lyase Inhibition Improves Obesity Via Rewiring of Host Circadian Rhythms, eLIFE, [online], (Accessed May 23, 2024)


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Created January 24, 2022, Updated November 29, 2022