Gut Microbe-Derived Trimethylamine Shapes Circadian Rhythms Through the Host Receptor TAAR5

Abstract Elevated levels of the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) are associated with cardiometabolic disease risk. However, the mechanism(s) linking TMAO production to human disease are incompletely understood. Initiation of the metaorganismal TMAO pathway begins when dietary choline and related metabolites are converted to trimethylamine (TMA) by gut bacteria. Gut microbe-derived TMA can then be further oxidized by host flavin-containing monooxygenases to generate TMAO. Previously, we showed that drugs lowering both TMA and TMAO protect mice against obesity via rewiring of host circadian rhythms. Although most mechanistic studies in the literature have focused on the metabolic end product TMAO, here we have instead tested whether the primary metabolite TMA alters host metabolic homeostasis and circadian rhythms via trace amine-associated receptor 5 (TAAR5). Remarkably, mice lacking the host TMA receptor (Taar5-/-) have altered circadian rhythms in gene expression, metabolic hormones, gut microbiome composition, and diverse behaviors. Also, mice genetically lacking bacterial TMA production or host TMA oxidation have altered circadian rhythms. These results provide new insights into diet-microbe-host interactions relevant to cardiometabolic disease, and implicate gut bacterial production of TMA and the host receptor that senses TMA (TAAR5) in the physiologic regulation of circadian rhythms in mice. HIGHLIGHTS Mice lacking the host TMA receptor (Taar5-/-) have altered circadian rhythms. Taar5-/- mice have altered innate behaviors in a time of day dependent manner. The normal circadian oscillations in the gut microbiome are dysregulated in Taar5-/- mice. Genetic deletion of bacterial TMA production or host TMA oxidation shapes circadian rhythms. Competing Interest Statement Competing interests: Z.W. reports being named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. Z.W. also reports having received royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland Heart Lab, a fully owned subsidiary of Quest Diagnostics and Procter & Gamble. C.M.T. consults for Abbott Laboratories. J.M.B. reports being named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to choline trimethylamine lyase inhibitors as therapies for cardiometabolic disease including obesity and type 2 diabetes. All other authors: K.M., W.J.M., D.O., A.L.B., T.J., A.C.B., A.H., S.D., M.M., N.M., V.V., L.J.O., X.Y., D.M.Y., N.Z., R.H., R.B., P.L., D.L., N.S., T.G., M.D., J.A.B., and G.R.S. have no competing interests. Footnotes This version is submitted with new data and updates that reflect the concerns of peer reviewers from eLife. ABBREVIATIONS USED - Arntl - basic helix-loop-helix ARNT like 1 or Bmal1 - BAT - brown adipose tissue - CKD - chronic kidney disease - Cry1 - cryptochrome 1 - Cry2 - cryptochrome 2 - CVD - cardiovascular disease - EIF2AK3 - eukaryotic translation initiation factor 2-alpha kinase 3 - ER - endoplasmic reticulum - FMO3 - flavin containing monooxygenase 3 - GPCR - G protein-coupled receptor - IFNγ - interferon gamma - IL - interleukin - MCP-1 - monocyte chemoattractant protein-1 - NFκB - nuclear factor κB - NLRP3 - nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 - Nr1d1 - nuclear receptor subfamily 1 group D member 1 or REV-ERBalpha - Pemt - phosphatidylethanolamine N-methyltransferase - PERK - eukaryotic translation initiation factor 2-alpha kinase 3 - Per1 - period 1 - Per2 - period 2 - Taar5 - trace amine associated receptor 5 - TMA - trimethylamine - TMAO - trimethylamine oxide - WAT - white adipose tissue - ZT - zeitgeber time