Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease

May 19, 2016Drug metabolism and disposition: the biological fate of chemicals

How the Body and Gut Bacteria Work Together to Produce Trimethylamine and Its Related Compound, Influencing Health and Disease

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Abstract

Flavin-containing monooxygenase 3 (FMO3) is responsible for converting trimethylamine (TMA) into nonodorous TMA N-oxide (TMAO), which is excreted in urine.

Impaired FMO3 activity leads to primary trimethylaminuria (TMAU), resulting in excessive excretion of TMA.
Dysbiosis in gut bacteria can contribute to secondary TMAU by altering TMA production.
Dietary components significantly influence TMA levels through their interaction with gut bacteria.
TMAO, the product of FMO3 activity, may be linked to various health conditions, including cardiovascular disease and metabolic disorders.
The microbiome-host axis involving TMA and TMAO is critical for understanding health and disease management.

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Flavin-containing monooxygenase 3 (FMO3) is known primarily as an enzyme involved in the metabolism of therapeutic drugs. On a daily basis, however, we are exposed to one of the most abundant substrates of the enzyme trimethylamine (TMA), which is released from various dietary components by the action of gut bacteria. FMO3 converts the odorous TMA to nonodorous TMA N-oxide (TMAO), which is excreted in urine. Impaired FMO3 activity gives rise to the inherited disorder primary trimethylaminuria (TMAU). Affected individuals cannot produce TMAO and, consequently, excrete large amounts of TMA. A dysbiosis in gut bacteria can give rise to secondary TMAU. Recently, there has been much interest in FMO3 and its catalytic product, TMAO, because TMAO has been implicated in various conditions affecting health, including cardiovascular disease, reverse cholesterol transport, and glucose and lipid homeostasis. In this review, we consider the dietary components that can give rise to TMA, the gut bacteria involved in the production of TMA from dietary precursors, the metabolic reactions by which bacteria produce and use TMA, and the enzymes that catalyze the reactions. Also included is information on bacteria that produce TMA in the oral cavity and vagina, two key microbiome niches that can influence health. Finally, we discuss the importance of the TMA/TMAO microbiome-host axis in health and disease, considering factors that affect bacterial production and host metabolism of TMA, the involvement of TMAO and FMO3 in disease, and the implications of the host-microbiome axis for management of TMAU.

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Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease

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