bioRxiv : the preprint server for biologyNov 24, 2025

Gut Microbe Chemical Trimethylamine May Influence Body Clock Through a Specific Host Receptor

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Updated Feb 26, 2026

Abstract

Mice lacking the host receptor for trimethylamine (TMA) show altered circadian rhythms and metabolic changes.

Elevated levels of the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) are linked to cardiometabolic disease risk.
Dietary choline is converted by gut bacteria into TMA, which is then oxidized by the host to produce TMAO.
Mice without the TMA receptor exhibit changes in gene expression related to circadian rhythms and metabolism.
Genetic alterations that prevent TMA production or its oxidation also lead to fluctuations in circadian rhythms.
These findings suggest a connection between gut bacteria, host metabolism, and circadian regulation.

Simplified

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 () 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. Taar5 -/-

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Competing interests

Declaration of interests 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.

PubMed

Gut Microbe Chemical Trimethylamine May Influence Body Clock Through a Specific Host Receptor

Abstract

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