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

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 beneficial remodeling of 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. * BMAL1 : aryl hydrocarbon receptor nuclear translocator like Cry1 : cryptochrome 1 CutC : choline trimethylamine lyase CVD : cardiovascular disease DIO : diet-induced obesity Fmo3 : flavin containing monooxygenase 3 IMC : iodomethylcholine LPC : lysophosphatidylcholine Per2 : period 2 PC : phosphatidylcholine PCA : principal component analysis RevErb α : nuclear receptor subfamily 1 group D member 1 TMA : trimethylamine TMAO : trimethylamine N-oxide ZT : zeitgeber.