Treatments of Trimethylaminuria: Where We Are and Where We Might Be Heading

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Review Article

Treatments of trimethylaminuria: where we are and where we might be heading

Author(s): Schmidt, Aaron C.; Leroux, Jean-Christophe

Publication Date: 2020-09-09

Permanent Link: https://doi.org/10.3929/ethz-b-000423705

Originally published in: Drug discovery today 25(9), http://doi.org/10.1016/j.drudis.2020.06.026

Rights / License: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International

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Drug Discovery Today Volume 00, Number 00 June 2020 REVIEWS

Treatments of trimethylaminuria:

POST SCREEN

where we are and where we might be

heading Reviews

Aaron C. Schmidt and Jean-Christophe Leroux

Q1 Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland

Q3 Trimethylamine (TMA) is a volatile, foul-smelling, diet-derived amine, primarily generated in the colon

and metabolized in the liver to its odorless N-oxide (TMAO). In primary trimethylaminuria (TMAU), an

Q4 inherited deﬁciency in ﬂavin-containing monooxygenase 3 leads to elevated systemic TMA levels. The

excretion of elevated amounts of TMA in sweat, breath, urine and other bodily secretions gives

individuals affected by TMAU a smell resembling that of rotten ﬁsh. Although the disorder might not

seem an important health problem, its social and psychological burden can be devastating. To date, no

treatment modifying the disorder exists and only a few pharmacological therapies provide modest and

transient beneﬁts. This review provides an overview of investigated TMAU treatments and outlines

promising new research directions.

Introduction Although the ﬁrst case of TMAU was described in literature

Primary trimethylaminuria (TMAU) is a rare metabolic disorder around 1970 [3], to date, only a few hundred cases have been

where abnormally high levels of the aliphatic amine trimethyla- reported in the literature since [4,5]. A study on the incidence of

mine (TMA) are excreted through sweat, breath, urine and other TMAU revealed a rate of 1% of heterozygous carriers within the

bodily secretions, giving the patients a smell resembling that of white British population [6], whereas studies in other ethnic

rotting ﬁsh. TMAU has thus been referred to historically as ﬁsh groups, such as the New Guinean population, revealed a carrier

odor syndrome. TMA is a diet-derived amine that originates from rate of 11% [7]. Although passing one affected allele of the condi-

TMA N-oxide (TMAO) (which is present in marine ﬁsh), choline tion to the next generation, heterozygotes usually do not have any

and carnitine. Although at physiological pH most TMA is in its symptoms of TMAU, unless they are challenged with a TMA

protonated form (pKa 9.80) [1], it is in equilibrium with a small precursor overload [8].

fraction of the free base. The free base is highly volatile and readily TMAU usually manifests itself in childhood or early adult life

detected by the human olfactometric receptors in the ppb range but remains underdiagnosed. Online resources often attribute this

[2]. In unaffected individuals, the free base is metabolized in the to the fact that people having mild symptoms rarely tend to seek

liver to the odorless TMAO and excreted in the urine. Primary help. In addition, some physicians might be unaware of the

TMAU is a direct consequence of an impairment in this oxidation disorder, not recognizing the symptoms and potentially being

process. Secondary TMAU, however, is caused by an excess of unable to distinguish them from other conditions that result in

dietary precursors or other factors exacerbating the production an unpleasant body odor (http://rarediseases.org). In fact, a study

of TMA, therefore causing substrate overload for the enzyme, including 353 patients complaining of idiopathic malodor

which is unable to oxidize the elevated burden of TMA. In both revealed that approximately one-third of them suffered from

forms of the disorder, the metabolite accumulates in bodily secre- TMAU [9]. Although the disease is considered benign, its psycho-

tions and gives them the characteristic odor. logical burden can be devastating. Studies have mentioned various

psychosocial reactions of sufferers, such as strong feelings of

shame, embarrassment, social isolation and even suicidal tenden-

Corresponding author: Leroux, J.-C. ([email protected]) cies, among others [8,10,11]. To date, the disease has no cure and

1359-6446/ã 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Please cite this article in press as: Schmidt, A.C., Leroux, J.C. Treatments of trimethylaminuria: where we are and where we might be heading, Drug Discov Today (2020), https://doi.org/ 10.1016/j.drudis.2020.06.026

DRUDIS 2726 1–8

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Diet

Choline TMAO Oxidation Reviews L-carnitine TMA OTSCREEN POST

Bacterial fermentation

TMAO Choline

TMA

Excretion L-carnitine

Drug Discovery Today

FIGURE 1

Dietary precursors and metabolism of TMA. The main precursors include choline, TMAO and L-carnitine, which are metabolized to TMA within the intestine. The

dietary breakdown of these precursors depends on a range of bacteria, among them: Actinobacteria, Firmicutes, Proteobacteria and Bacteroidetes [17]. TMA is

subsequently oxidized to TMAO by FMO3 in the liver and excreted through the kidneys.

only palliative measures exist, such as washing with acidic soap in broad spectrum of xenobiotics and dietary amines [20–22]. So far,

combination with dietary restriction of TMA precursors [12,13]. >40 variants of the gene have been associated with TMAU [23,24],

Other available pharmacological treatments aim to reduce the most of which are missense mutations. Some of these are inacti-

generation and absorption of TMA or focus on improving oxida- vating mutations whereas other less severe ones reduce the thresh-

tion to the odorless TMAO. old of TMA oxidation of FMO3 [25]. The resulting impairment in

N-oxidation capacity accounts for most cases of TMAU reported in

Trimethylaminuria the literature.

TMA is produced in the gastrointestinal tract from dietary pre-

cursors such as choline, which is present in eggs, liver and poultry, Secondary TMAU

among others [14]. In the colon, choline is metabolized to TMA by Often referred to as acquired or sometimes transient TMAU, people

anaerobic microorganisms carrying the enzyme choline TMA lyase becoming afﬂicted with secondary TMAU might show prolonged

(Fig. 1). TMAO and carnitine, which are mainly present in marine symptoms. This form of the disorder can occur in a variety of

ﬁsh [15] and in red meat [16], respectively, are additional TMA different scenarios. Treatment with choline in Huntington’s and

precursors that are metabolized in the gut [17]. However, in the Alzheimer’s diseases has been associated with the development of

case of TMAO, the exact mechanism of conversion to TMA in a strong ﬁshy body odor [26,27], and is a classic example of

humans remains unknown. TMA is readily absorbed by passive precursor overload where the enzyme is unable to completely

diffusion and enters enterohepatic circulation. It is subsequently oxidize the TMA burden. Liver failure and portosystemic shunting

oxidized in the liver to the non-odorous N-oxide form. The en- of the blood can also result in increased TMA levels, owing to

zyme, responsible for this oxidation process, is of the ﬂavin-con- interference with ﬁrst-pass metabolism [28,29]. Other factors that

taining monooxygenase (FMO) family [18,19]. The N-oxide is then have been reported to cause or exacerbate the condition (including

readily excreted in the urine. As mentioned previously, TMAU can primary TMAU) encompass menstruation [30,31], asymptomatic

be classiﬁed in two forms of the disorder, which are described viral hepatitis [32] and testosterone treatment [33], and have been

below. reviewed elsewhere [4].

Primary TMAU Diagnosis

Primary TMAU is caused by a mutation in the FMO3 gene, which is Diagnosis of TMAU is usually done by urinary analysis after oral

inherited in a Mendelian autosomal recessive fashion [18]. The precursor challenge using choline [9] or TMA [8,34]. TMAO has

affected enzyme has a widespread substrate speciﬁcity, including a also been indicated to drastically shift the total combined TMA

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(TTMA) content (TMA + TMAO) toward TMA species after oral where degradation of carnitine to TMAO could be demonstrated

administration in the past, in affected individuals as well as [57]. A recent report on the mechanism of carnitine transforma-

heterozygous carriers of the disease [35,36]. However, it is not a tion to TMA identiﬁed a Rieske-type protein (a two-component

recognized diagnostic tool for TMAU. Upon precursor challenge, Rieske-type oxygenase/reductase) as the main protagonist [58,59].

the urinary samples are assayed for TMA as well as TMAO, and their L-carnitine is present in high levels in red meat, poultry and some

respective amounts are compared to the TTMA. Because neither dairy products, which is why TMAU sufferers are recommended to

TMA nor TMAO have a native chromophore, quantitative urine avoid these in their diet [60]. Interestingly, allicin, an organosulfur

analysis is performed using H NMR spectroscopy [37,38], head- compound obtained from garlic, lowered TMAO levels when

space MS [39,40] and electrospray ionization mass spectrometry supplemented in addition to L-carnitine in male mice [61], an

[41]. Affected individuals excrete 80% of TTMA in the form of animal model that is a natural knockout for FMO3, and in which

TMA, whereas heterozygous carriers as well as unaffected people FMO1 does not efﬁciently catalyze the transformation of TMA to

secrete roughly 4%. Interestingly, after oral challenge with TMA, TMAO [62]. The mechanism of allicin remains elusive but is POST SCREEN

this number increases to 25% in heterozygotes [42]. Genetic hypothesized to be connected to its potential role as a Rieske

analysis can be performed to conﬁrm the diagnosis [43], provided protein inhibitor, which would reduce carnitine transformation

urinalysis indicates primary TMAU. to TMA by bacteria. However, the ability of allicin to decrease TMA

Reviews

levels remains to be demonstrated.

Treatment options

Unlike other metabolic disorders, TMAU appears to generally Protonation of TMA

attract little biomedical interest [4]. Consequently, research efforts Reducing the volatility of excreted TMA is a validated strategy for

for TMAU treatments have been modest. Existing treatment strat- the management of the ﬁsh-like body odor because TMA excretion

egies can be classiﬁed into the following groups: precursor intake in sweat is a signiﬁcant source of it. Although only mentioned

limitation, protonation of TMA, targeting of the gut metabolism anecdotally in the scientiﬁc literature, frequent washing with low

and targeting of the enzyme FMO3. pH soaps in combination with dietary management constitutes

the state-of-the-art treatment for TMAU [13,63]. When applied on

Limiting precursor intake the skin on a regular basis, acidic body lotions and soaps fully

A common approach to lower systemic TMA levels is to limit TMA convert excreted TMA to the non-smelling conjugate acid, reduc-

precursor intake. Several food-derived compounds are metabo- ing the body odor. Recently, our group reported a topical odor-

lized to TMA in the colon by bacteria, a topic that has been quenching formulation based on polymeric vesicles of the diblock

discussed at length in the past [17]. Indeed, a study on dietary poly(isoprene)-b-poly(ethylene glycol). The acidic solution (pH 2)

precursors showed that a few of them could be linked to increased contained in the vesicles establishes a transmembrane pH gradient

levels in urinary TMA [44]. Speciﬁcally, choline, carnitine and across their bilayer membrane that constitutes the basis for the

TMAO have been shown to increase concentrations of urinary system’s mechanism. The TMA free base readily permeates

TMA and TMAO, whereas betaine, creatinine and lecithin have not through the vesicular bilayer membrane and becomes protonated

[44,45]. Metabolism of betaine to TMA has been reported in sheep once inside the acidic core. The positive charge traps the TMA in

rumen in the past [46] but other studies have failed to show a the vesicle core and prevents its diffusion (Fig. 2). In an in vitro

consistent effect in rats [47] or in humans [48,49]. setting, the polymeric vesicles readily sequestered TMA at skin pH

Choline is absorbed in the small intestine via carrier-mediated (pH 5.8) and successfully decreased the odor intensity of TMA

transport across the mucosal border. Ingestion of choline-rich perceived by human volunteers in an olfactory study [64]. The

food saturates this transport capacity, which is half saturated at system’s clinical efﬁcacy is yet to be conﬁrmed in clinical studies

concentrations of 200–300 mM [50,51], resulting in increased where the polymeric vesicles would be applied topically on TMAU

choline concentrations in the large bowel where intestinal bacteria patients.

metabolize it to TMA and dimethylamine, as was shown in rats Deodorizing TMA by masking it with another stronger smell has

[52]. Because choline is required for the biosynthesis of essential also been explored as a potential approach [65]. It was reported

phospholipids and the neurotransmitter acetylcholine, it is not that (E,E)-2,4-undecadienal, a naturally derived product from

possible to completely eliminate it from the diet [53]. In fact, coriander leaves, deodorized TMA levels of up to 1 mM. Although

healthy individuals on a choline-deﬁcient diet develop signs of effective at extremely low levels (10 ppm), the compound was

incipient liver dysfunction after only 3 weeks. Consequently, shown to be toxic in human ﬁbroblasts at 25 mM [66], which

intake of this nutrient can only be limited to a certain extent could represent a challenge when formulating topical or oral

[12,14], and personalized adjustments by a clinician are recom- formulations.

mended to prevent liver dysfunction and other side effects.

TMAO is an osmolyte found in marine organisms that counter- Targeting gut metabolism

acts the protein-destabilizing effects of hydrostatic and osmotic Most interventions reported in the literature target the production

pressures [15,54]. Ingestion of a ﬁsh-based meal leads to an in- of TMA in the colon and/or lower its subsequent absorption.

crease in urinary TMAO and subsequently TMA levels [55], so it is Inhibition of TMA precursor, inhibition of TMA metabolism

recommended to eliminate all seafood from the diet. Reports of L- and TMA sequestration have been investigated through different

carnitine and its effect on TMA levels are rather scarce. In vivo approaches. One aspect heavily intertwined with the metabolic

experiments have shown an increase in urinary TMAO after car- fate of TMA, is that of its N-oxide – TMAO. In recent years, TMAO

nitine challenge [56]. This was conﬁrmed in healthy volunteers, has been the object of extensive research because it was identiﬁed

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Archaebiotic cell (d) OTSCREEN POST (c)

Choline

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FIGURE 2

Clinical and investigational TMAU treatments. Targeting excreted TMA on patient skin by sequestration of its non-odorous protonated species with a

transmembrane pH-gradient polymersome-based topical formulation (a); restricting dietary intake of known TMA precursors, such as choline, carnitine and

TMAO (b); controlling TMA production in the colon with probiotics, such as methanogenic Archae to reduce TMA to methane via methyltransferase (Mtt) (c); or

with choline TMA-lyase inhibitors, such as DMB, FMC or iodomethylcholine (IMC) (d).

as a disease marker in cardiovascular disease (CVD). Further, it has is no medical emergency. Their extensive consumption could

been suggested to promote atherosclerosis in mice [67] and, in contribute to the emergence of antibiotic resistance at the indi-

addition, elevated TMAO plasma levels were associated with an vidual level, potentially compromising the treatment of bacterial

increased risk of cardiovascular events in patients following elec- infections [79,80]. In addition, antimicrobial treatment disrupts

tive coronary angiography [68]. Several studies have supported the microbiota composition and could be linked to other diseases

these ﬁndings in various patient populations [69–72]. Yet, litera- such as obesity [81,82].

ture ﬁndings on the topic remain controversial to this date. Several Metronidazole. The antibiotic metronidazole is thought to

studies indeed failed to show an association of TMAO levels with decrease the load of bacterial ﬂora that produces TMA [83]. This

incident CVD [73]. However, because elevated plasma TMAO nitroimidazole that acts speciﬁcally on anaerobic bacteria is used

levels are a direct result of dietary breakdown of TMA precursors in the chronic treatment of methylmalonic and propionic

and their subsequent oxidation in the liver, treatments targeting acidemias to diminish toxic metabolites produced by anaerobes

the metabolic breakdown of these precursors are of growing inter- [84]. It has also been tested as a short-term treatment of HE but its

est as potential treatments in CVD, a strategy that could eventually ototoxicity, nephrotoxicity and neurotoxicity make it unsuitable

be applied to TMAU in the future. However, caution must be taken for prolonged use [85]. Reports of TMAU patients receiving the

while interpreting these data, because a change in TMAO levels antibiotic over a range of weeks showed variable results,

does not necessarily imply a change in TMA levels, wherefore decreasing urinary TMA by a factor of three in some patients

concrete experimental evidence needs to be provided in the un- but not showing any effect in others [83,86]. Improved outcomes

derlying experimental setup. Furthermore, studies suggest the were obtained when combining the treatment with dietary

involvement of TMAO in various important biological functions, restrictions [87] or with another antibiotic [43,55].

for instance acting as a protein stabilizer and as an osmotic agent Neomycin. One of the antibiotics that has been tested in

[74,75], which should be taken into account while aiming to lower combination with metronidazole is the poorly bioavailable

TMAO levels. aminoglycoside neomycin: This antimicrobial agent has been

Antibiotics used since the late 1960s when it was approved for treating

Because TMA production from dietary precursors is dependent on overt HE by the FDA [88]. Similarly to metronidazole, its major

its metabolism by intestinal microbiota [76,77], antibiotics have drawbacks are its ototoxicity and nephrotoxicity [89], the latter

been assessed as a treatment for TMAU. Antibiotics are used to affecting about one-third of the patient population [90]. Single

deplete intestinal bacteria in other diseases such as hepatic en- use of neomycin was reported to lower TMA levels in mice [76]

cephalopathy (HE) (a consequence of hyperammonemia), where and in small patient populations [91,92]. However, owing to a

they target urease-producing bacteria to decrease ammonia pro- non-permanent alteration of the microbiome, values quickly

duction [78]. Although antibiotics can alleviate the main symp- returned to baseline upon termination of the treatment and

tom of TMAU patients, their chronic use should be avoided if there subsequent proliferation of bacteria [92].

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Rifaximin. Another antibiotic that has been explored for the especially E. limosum and members of the Clostridial clade XV

treatment of TMAU is rifaximin. It has been reported to lower family, claiming that they demethylated quaternary amines

TMA levels [93] and to be generally tolerated rather well [94]. that would otherwise form TMA and TMAO [107]. However, so

This poorly absorbed semisynthetic rifamycin derivative has a far this has only been shown in vitro observing the growth of gut

broad spectrum of antibacterial activity, including aerobes and microbes in the presence and absence of quaternary amines.

anaerobes, Gram-positive and Gram-negative bacteria, and was The main drawback of probiotics remains the difﬁculty to

approved by the FDA in 2010 for the treatment of HE. Unlike achieve signiﬁcant shifts in the microbial community despite

systemically available antibiotics, rifaximin allows localized being administered continuously. The low survival of probiotics

targeting of enteric pathogens, which minimizes the risk of side in the GI tract presents a big hurdle to overcome, highlighting the

effects [95]. need for efﬁcient colonic formulations.

Probiotics Miscellaneous: small molecules

Probiotics have recently emerged as a therapeutic alternative to In 2012, Hazen et al. patented the small molecule 3,3-dimethyl-1-

POST SCREEN

antibiotics for indications such as Clostridium difﬁcile infection butanol (DMB) and similar compounds for their ability to lower

[96,97]. Probiotics are bacteria that can alter the microbial metab- intestinal TMA in the treatment of CVD [108]. After observing

olism by implantation or colonization and exert various health- decreased TMA production from choline in mouse cecum in vitro,

Reviews

promoting functions such as stimulating immunity when present DMB was administered to C57BL/6J mice in drinking water, result-

in sufﬁcient numbers [98]. Various mechanisms are associated ing in a reduction of urinary and plasma TMA levels. The proposed

with the beneﬁcial effects of probiotics; for instance, production mechanism of action was the inhibition of several TMA lyases,

of inhibitory substances such as bacteriocins, competition with including choline TMA lyase, as determined in vitro [109]. The

pathogenic bacteria for nutrients, blockage of adhesion sites for patent was further extended to acetylsalicylic acid (ASA) and its

pathogenic bacteria, degradation of toxins and blockage of toxin derivatives, because ASA showed inhibition of TMA lyase activity

receptors, among others [99]. of Proteus mirabilis – a microbe with abundant TMA lyase activity in

Methanogenic archaebiotics. Natural methanogenic Archaea of an in vitro setup [110]. Subsequent studies in C57BL/6J mice treated

the human gut have been shown to reduce TMA with hydrogen with ASA-supplemented drinking water, and in human volunteers,

for methanogenesis (Fig. 2) [100]. Although the underlying following daily administration of 81 mg ASA for 1 month, showed

chemistry was described >40 years ago in the rumen of cows signiﬁcant decreases in plasma TMAO levels but omitted to men-

[101], delivering sufﬁcient amounts of these oxygen-sensitive tion the impact on plasma/urinary TMA levels. Further, it is to note

microorganisms to the gut remains an important hurdle. The that the inﬂuence of ASA on CVD is still controversial at this point

technique was patented, but so far has not been tested in [111]. In another study, the choline analogs iodomethylcholine

humans [102]. and ﬂuoromethylcholine (FMC) were tested for their ability to

Fecal microbial transplantation (FMT). FMT refers to the inhibit choline TMA lyase in the above-mentioned in vitro setup,

transplantation of fecal matter from a healthy donor into the using Proteus mirabilis [112]. For both, a potency of about four

GI tract of a patient. It is used in the treatment of Clostridium orders of magnitude higher than that of DMB could be observed.

difﬁcile infection and has been tested in several other When given as a single oral dose in C57BL/6J mice, both com-

indications [103]. A recent study with two individuals affected pounds induced an almost complete reduction in urinary TMA

with TMAU, receiving FMT after pre-treatment with metroni- levels, lasting for 2 days post treatment in the case of FMC.

dazole, reported a decrease in ﬁsh odor during the ﬁrst 6 Inhibition of TMA production was shown to be dose-dependent,

months in one of the patients [104]. However, perceived odor whereas no signs of toxicity following chronic exposure could be

returned to baseline after one year, suggesting that recurrent observed [112].

treatment would be necessary. Similar ﬁndings were reported Besides TMA lyase inhibitors, a few other small molecules could

by Hazen et al. while studying FMT in the context of CVD [105]. prove useful in the treatment of TMAU. The anti-ischemic and

In this work, low and high TMAO-producing mouse strains antiatherosclerotic drug meldonium is known to work through an

were chosen as FMT donors for apolipoprotin E null mice in L-carnitine lowering effect [113] by competition for selected

which resident intestinal microbes had been suppressed by a 3- enzymes and transport proteins [114]. An in vivo study in rats

week course of antibiotics. Initially, plasma TMA and TMAO showed a decrease in microbiota-dependent TMA/TMAO from

levels were lower in the recipient mice transplanted with fecal carnitine, but not from choline [114]. In another study, the

matter from the low TMAO-producing strain. Yet, the naturally occurring phytoalexin resveratrol was shown to lower

differences with the mice that had the high TMAO strain as TMAO levels in mice by inhibition of commensal microbial TMA

the donor leveled out after 16–20 weeks. However, as production via gut microbiota remodeling [115]. Another small

mentioned, a reduction in TMAO levels might not necessarily molecule potentially providing therapeutic beneﬁt for TMAU

translate into reduction in TMA. sufferers might be the drug desmopressin [116]. Although desmo-

Other probiotic treatments. Several other probiotics have been pressin has been linked to a decrease in odor in a TMAU sufferer,

tested for their ability to lower TMA levels, some of them resveratrol is mainly used in CVD and its use in TMAU has yet to be

showing promising results. Although screening various isolates investigated, especially regarding its efﬁcacy to reduce TMA odor

of the Enterobacteriaceae family in healthy Chinese fecal and its risk:beneﬁt ratio upon chronic use.

samples, E. aerogens ZDY01 was found to signiﬁcantly decrease Miscellaneous: oral sequestering agents

serum TMAO and cecal TMA levels in choline-loaded mice Dietary charcoal has been used in gastrointestinal detoxiﬁcation

[106]. Ferguson et al. patented the use of Eubacterium strains, for a long time given its physical adsorptive mechanism [117].

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Supplementation with 750 mg of activated charcoal twice daily approach is only mentioned in perspective articles [128] and

over the course of 10 days has been reported to reduce urinary free patents [129] for which scientiﬁc data is lacking. Therefore, TMAU

TMA in TMAU patients and shift the TMA:TMAO ratio to values sufferers must adhere to simpler approaches, all of which are

similar to those found in healthy patients during the administra- thought to inﬂuence residual enzyme activity. Dietary supplemen-

tion period [118]. This observation was conﬁrmed in another case tation with riboﬂavin was reported to have a decreasing effect on

[119], although after termination of the treatment the values odor intensity as well as on TMA and TMAO levels in one patient

quickly returned to baseline. When using copper chlorophyllin [130], presumably owing to increasing FMO3 activity by acting as a

instead, the decrease in free urinary TMA could be extended to cofactor. However, additional studies are lacking at this point.

Reviews

several weeks post treatment [118]. Mechanistically, the decrease is Furthermore, affected individuals are advised to avoid drugs that

linked to complexation of TMA with copper chlorophyllin, which are metabolized by FMOs [21], such as clozapine, deprenyl and

OTSCREEN POST might open avenues for the exploration of similar compounds by ranitidine, among others [121], because these might exacerbate

chemical modiﬁcation (i.e., screening of various heterocyclic Cu the condition by competing for residual FMO3 activity. Tannins

complexes and their ability to complex TMA) [120]. Activated and especially brussels sprouts have shown pronounced inhibition

charcoal and copper chlorophyllin are recommended dietary sup- of human FMO3 activity when being administered over longer

plements for TMAU sufferers [121]. Recently, Kellermann et al. periods and should therefore be avoided [131,132].

patented a technology based on zeolites, claiming their ability to

decrease TMA levels in therapeutically effective amounts [122]. Concluding remarks

However, data supporting their claims were not provided and the Owing to the low prevalence and medical awareness of TMAU,

patent application status was abandoned. One of the major draw- research efforts on its treatment remain scarce. Diagnosis is the

backs of sequestering agents is their non-speciﬁc mechanism of ﬁrst step to helping affected individuals to manage the condition

action, which could result in the capture of other metabolites in and its social and psychological burden. Currently, the main

addition to the target [123]. treatment is dietary restriction of TMA precursors in combination

Miscellaneous: laxatives with frequent washing using acidic soaps. This approach might

The administration of the oligosaccharide lactulose, an osmotic prove sufﬁcient for patients showing minor and/or temporary

laxative, has been reported in the treatment of TMAU [124]. By symptoms (i.e., those suffering from secondary TMAU) but pro-

altering the intraluminal pH, lactulose can modify the gut’s ﬂora vide limited beneﬁt for those with primary TMAU. Although

[125]. After oral treatment in two individuals suffering from TMAU numerous treatment strategies have been described in the litera-

for 14 days, no alteration in basal TMA excretion could be ob- ture, a limited number of clinical studies have been performed,

served. However, the treatment abolished rises in urinary TMA most of them with very few patients. Antibiotics that deplete TMA-

excretion after dietary provocation as well as the accompanying producing bacteria have been shown to decrease TMA levels in

increase in odor, probably caused by the laxative effect, making it several studies but their beneﬁt:risk ratio might not be acceptable

convenient for occasional use but not long-term given the dehy- for chronic use given the potential side effects and risk of antibiotic

drating effects [124]. resistance promotion on an individual level, especially because

TMAU does not affect vital functions. Research into TMAO as a

Targeting FMO3 disease marker in CVD has drawn the attention of the scientiﬁc

TMAU is a genetic disorder related to variants of the enzyme community toward TMA and its metabolism, sparking novel

FMO3, which is responsible for the metabolism of TMA to the research directions such as the development of choline TMA lyase

non-smelling TMAO in the liver. Restoring FMO3 activity or inhibitors. The promising results that these novel molecules have

boosting its residual activity in cases of milder forms of TMAU, is shown in various in vivo models as well as in a limited number of

an interesting approach. Enzyme replacement therapy has pro- patients bring hope to those affected by TMAU, because they could

vided treatments for previously untreatable metabolic condi- potentially lead to an effective treatment for them in the near

tions [126] but so far there are no reports of its use in TMAU, future. Q5Q6

only publications naming it as a potential treatment option

[127]. Acknowledgments

Gene therapy aimed at restoring the oxidative function of The authors gratefully acknowledge funding from the Swiss

FMO3 might one day suppress TMAU, although at present this National Science Foundation (2-77082-16).

References

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