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.

Trace Amines and Their Receptors

“…Although trimethylamine levels have been associated with various disease conditions (Chhibber-Goel et al, 2016), are sexually dimorphic (Gavaghan McKee et al, 2006), and a proposed male pheromone in mice (males having a genetic deficiency in trimethylamine metabolism) , there is no known endogenous synthetic pathway. Rather, trimethylamine production is thought to occur as a by-product of prokaryotic degradation of 566 dietary choline, betaine, phosphatidylcholine, and Lcarnitine (Zhang et al, 1999;Craciun and Balskus, 2012;Zhu et al, 2014;Kalnins et al, 2015;Fennema et al, 2016). Such well documented production by the commensal microbiota, along with an established host receptor (TAAR5, see subsequent sections), makes trimethylamine an attractive candidate molecule for investigating the growing appreciation of the role of the microbiota in health and disease.…”

“…The main interest in trimethylamine thus far has been with respect to its degradation. This primarily occurs via the enzyme flavin monooxygenase 3 (FMO3; EC 1.14.13.8), which is prevalent in hepatic tissue, including in humans (Fennema et al, 2016). This generates trimethylamine-N-oxide (TMAO), a compound that has been increasingly implicated as playing a role in both cardiovascular and metabolic disorders (Fennema et al, 2016;Zhang and Davies, 2016).…”

“…This primarily occurs via the enzyme flavin monooxygenase 3 (FMO3; EC 1.14.13.8), which is prevalent in hepatic tissue, including in humans (Fennema et al, 2016). This generates trimethylamine-N-oxide (TMAO), a compound that has been increasingly implicated as playing a role in both cardiovascular and metabolic disorders (Fennema et al, 2016;Zhang and Davies, 2016). Interestingly, the K m for trimethylamine metabolism by FMO3 is rather high (28 mM; Lang et al, 1998) and is approximately 100-fold in excess of the EC 50 values of trimethylamine at TAAR5 from various species (Berry et al, 2017).…”

“…In humans, a genetic deficiency in FMO3 leads to the condition of trimethylaminuria (Humbert et al, 1970), in which large quantities of trimethylamine are excreted in sweat, urine, and exhaled air (Fennema et al, 2016). Kidney damage (Bain et al, 2006;Chhibber-Goel et al, 2016) and gut dysbiosis (Fennema et al, 2016) can also lead to trimethylaminuria, as can invasion by pathologic microflora associated with bacterial vaginosis or infections of the oral cavity (Fennema et al, 2016;Zhang and Davies, 2016). The increased trimethylamine urinary excretion associated with menstruation (Mitchell and Smith, 2010) may reflect regulation of FMO3 by female sex hormones (Coecke et al, 1998;Shimizu et al, 2007).…”

NMR-based pharmacometabonomics: A new paradigm for personalised or precision medicine

“…The association of high levels of TMAO with moderate necrosis may indicate an involvement of gut bacteria in determining the degree of toxicity, since TMAO is formed by oxidation of bacterially derived trimethylamine by mammalian flavin monoxygenase 3 (FMO3). [47] This paper [46] was a landmark in terms of demonstrating the ability of a metabolic profile to operate in a prognostic as opposed to diagnostic mode, but it was a pre-clinical study in rats.…”