Gut microbe-derived trimethylamine shapes circadian rhythms through the host receptor TAAR5
Year: 2026
Type: article
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. Graphical Abstract
Source: eLife
Authors: Kala K. Mahen, William J. Massey, Danny Orabi, Amanda L. Brown, Thomas C. Jaramillo, Amy C. Burrows, Anthony J. Horak, Sumita Dutta, Marko Mrdjen, Nour Mouannes, Venkateshwari Varadharajan, Lucas J. Osborn, Xiayan Ye, Dante M. Yarbrough, Treg Grubb, Natalie Zajczenko, Rachel Hohe, Rakhee Banerjee, Pranavi Linga, Dev Laungani, Adeline M. Hajjar, Naseer Sangwan, Mohammed Dwidar, Jennifer A. Buffa, Garth R. Swanson, Zeneng Wang, J. Mark Brown
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: G1892721040, G1952580428, G2091755577, Gut Microbiota and Cardiometabolic Diseases, G7047928173, Gut microbial N-acyl serinols regulate obesity-driven heart failure with preserved ejection fraction by GPR119 signaling, Dark GPCR signaling underlying the Microbiome-Gut-Brain Axis for Alzheimer's Disease and Related Dementia, G819535741, G87592374, Metaorganismal Endocrinology in Cardiometabolic Disease, G8848273994, G9000011841, G9000156126, Alcohol and tissue injury, from mechanisms to treatments
OpenAlex ID: W7126089331