Journal Article

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

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

2022

Overview

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 ( Lep 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 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.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Antibiotics / Atherosclerosis / Body fat / Choline / Choline - administration & dosage / Choline - analogs & derivatives / Choline - metabolism / Circadian rhythm / Circadian Rhythm - drug effects / Circadian rhythms / Comorbidity / Diabetes / Diet, High-Fat / Digestive system / drug delivery / Energy expenditure / Energy metabolism / Enzyme Inhibitors - pharmacology / Enzymes / Fatty acids / Food intake / Gastrointestinal Microbiome - drug effects / Gene expression / genetic diseases / Glucose / Glucose tolerance / gut microbiome / Insulin resistance / Intestinal microflora / Kidney diseases / Lecithin / Leptin / Leptin - deficiency / Liver / Lyases - drug effects / Male / Medicine / Metabolism / Metabolites / Methylamines - metabolism / Mice / Mice, Inbred C57BL / Microbiomes / Microbiota / Microorganisms / nutrition / Obesity / Obesity - genetics / Obesity - metabolism / Obesity - microbiology / Phosphatidylcholine / Thrombosis / Trimethylamine / Weight control