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

Abstract

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.

Fig. 1.

Metabolic pathways for the production and metabolism of TMA by the human microbiota. TMA can be produced from TMAO in a reaction catalyzed by TMAO reductase. Choline, either in its free form or released from lecithin (phosphatidylcholine), contributes to the formation of TMA directly, via the action of choline-TMA lyase, encoded by the choline utilization cluster (cutC), or potentially indirectly, via conversion to betaine. Similarly, l-carnitine, present in red meat or derived from γ-butyrobetaine, contributes to TMA formation directly via the action of a Rieske-type carnitine reductase/oxidase (cntAB), or potentially indirectly, via conversion to betaine or to γ-butyrobetaine. Betaine can potentially contribute to TMA formation directly, via the action of a betaine reductase, or indirectly, via conversion to dimethylglycine, which could be metabolized to TMA via a hypothetical decarboxylation. TMA can be produced from ergothioneine via the action of ergothionase. TMA itself can be oxidized to TMAO, via the action of TMA monooxygenase. Asterisks represent multistep pathways. Bold text, TMA and its precursors and metabolites. Plain text, enzymes that catalyze reactions in the pathways. Based on Zeisel, 1990; Kleber, 1997; Serra et al., 2002; Wood et al., 2010; Craciun and Balskus, 2012; Caspi et al., 2014; Zhu et al., 2014.

Fig. 2.

Metabolism of TMA by gut bacteria. TMA can be metabolized to TMAO, which is subsequently converted to dimethylamine (DMA) and formaldehyde. TMA can be converted by direct N-demethylation to DMA and formaldehyde. In methylotrophs, DMA can be further converted to MA and then ammonia, each step producing formaldehyde. Reactions are catalyzed by 1, TMA monooxygenase; 2, trimethylamine-oxide aldolase; 3, trimethylamine dehydrogenase; 4, dimethylamine dehydrogenase and 5, methylamine dehydrogenase (amicyanin). Based on Colby and Zatman (1973). Names of enzymes are those currently recommended by the Enzyme Commission, and some differ from those given in the original papers.

Fig. 3.

The origin of TMA and TMAO and factors that influence their production. (A) The production and metabolic fate of TMA. TMA is produced from dietary precursors by the action of gut bacteria. TMA can be metabolized by gut bacteria to TMAO and dimethylamine (DMA) (see Fig. 2) or absorbed and converted in the liver to TMAO in a reaction catalyzed by FMO3. TMAO and any unmetabolized TMA will enter the plasma and subsequently will be excreted in urine. (B) Factors affecting the production of TMA in the gut. The amount of TMA produced is dependent on the nature and quantity of dietary precursors and the relative abundance of TMA-producing and TMA-metabolizing bacteria. (C) Factors influencing TMA metabolism in the host. The metabolism of TMA to TMAO in liver is dependent on the amount and activity of FMO3. The abundance and activity of FMO3 can be increased as a consequence of genetic variation, resulting in an increase in the ratio of TMAO:TMA. The amount and activity of FMO3 can be decreased by genetic variation, hormones, inhibitors, and disease, resulting in a decrease in the ratio of TMAO:TMA.