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Gut microbe-derived trimethylamine shapes circadian rhythms through the host receptor TAAR5

Kala K Mahen1,2,3, William J Massey2,4, Danny Orabi1

  • 1Department of Cancer Biology, Cleveland Clinic, Cleveland, United States.

Elife
|January 29, 2026
PubMed

Insights

Trimethylamine (TMA), a gut microbe metabolite, disrupts circadian rhythms and metabolic homeostasis by activating the host receptor TAAR5. This reveals a novel diet-microbe-host interaction influencing cardiometabolic disease risk.

Area of Science:

  • Microbiology
  • Metabolism
  • Chronobiology

Background:

  • Elevated trimethylamine N-oxide (TMAO) links gut microbes to cardiometabolic disease.
  • The mechanisms connecting TMAO production to human disease remain unclear.
  • Dietary choline is converted to trimethylamine (TMA) by gut bacteria, then oxidized to TMAO by the host.

Purpose of the Study:

  • Investigate if TMA, the precursor metabolite, impacts host metabolic homeostasis and circadian rhythms.
  • Determine the role of trace amine-associated receptor 5 (TAAR5) in mediating TMA's effects.
  • Explore the link between TMA production/oxidation and circadian rhythm regulation.

Main Methods:

  • Utilized knockout mice lacking the TAAR5 receptor (Taar5-/-).
  • Examined mice genetically deficient in bacterial TMA production or host TMA oxidation.
  • Assessed circadian rhythms in gene expression, metabolic hormones, gut microbiome, and behavior.

Main Results:

  • Mice lacking TAAR5 exhibited altered circadian rhythms in gene expression, hormones, microbiome, and behavior.
  • Genetic absence of bacterial TMA production or host TMA oxidation also led to altered circadian rhythms.
  • These findings implicate TMA and TAAR5 in the physiological regulation of circadian rhythms.

Conclusions:

  • Gut bacterial metabolite TMA, sensed by host receptor TAAR5, plays a significant role in regulating host circadian rhythms.
  • This pathway represents a novel diet-microbe-host interaction relevant to cardiometabolic health.
  • Understanding TMA's role offers new therapeutic targets for metabolic and circadian disorders.
Keywords:
biochemistrychemical biologycircadian rhythmmetabolismmicrobiomemouseolfaction

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