GSE157925
Gut Microbe-Targeted Choline Trimethylamine Lyase Inhibitors Improves Obesity Via Rewiring of Host Circadian Rhythms.
The increasing prevalence of obesity and related metabolic disorders represents a growing  public health concern. Despite advances in other areas of medicine, a safe and effective drug  treatment for obesity has been elusive. Obesity has repeatedly been linked to reorganization of  the gut microbiome 1-4 , yet to this point obesity therapeutics have been targeted exclusively  toward the human host. Here we show that gut microbe-targeted inhibition of the  metaorganismal trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic  disturbances associated with diet-induced obesity (DIO) or leptin deficiency (ob/ob). Selective  small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not  significantly reduce food intake, but instead is associated with beneficial remodeling of the gut  microbiome, improvement in glucose tolerance, and enhanced energy expenditure. Leveraging  untargeted metabolomics we discovered that CutC inhibition is associated with reorganization  of host circadian control of both phosphatidylcholine and energy metabolism. Collectively, this  study underscores the close 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 can  have profound effects on host energy metabolism, and have untapped potential as anti-obesity  therapeutics. Overall design: All animals were on a 60% high fat diet leading into the study. One group (n=5) was maintained as vehicle cohort. The other group (n=6) was maintained on IMC (specific inhibitor of choline conversion to TMA). We analyzed n = 6 per Vehicle group, however one of the control samples did not meet QC standards and was dropped from the study.