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. 2019 May 10;10(5):876–887. doi: 10.1093/advances/nmz012

Modulation of Circulating Trimethylamine N-Oxide Concentrations by Dietary Supplements and Pharmacological Agents: A Systematic Review

Nora A Kalagi 1,3, Kylie A Abbott 1, Khalid A Alburikan 3, Hadeel A Alkofide 3, Elizabeth Stojanovski 2, Manohar L Garg 1,✉
PMCID: PMC6743816  PMID: 31073588

ABSTRACT

Discovery of the association of plasma/serum trimethylamine N-oxide (TMAO) concentrations with atherosclerosis has sparked immense interest in exploring TMAO as a predictor of cardiovascular disease risk. A spectrum of antibiotics and other therapeutic strategies have been employed to test their potential to modulate TMAO concentrations, assuming the gut microbiome to be the key source of TMAO. The aim of this systematic review was to determine whether dietary supplements or pharmacological agents affect TMAO concentrations in adults. Six databases were searched (Medline, EMBASE, CINAHL, Scopus, ProQuest, and PubMed) for randomized and nonrandomized controlled trials. Searches were limited to the English language and to studies in adults. Thirteen eligible trials were identified, including 6 studies on dietary supplements and 7 on pharmacological agents. Whereas intervention studies involving dietary supplements were mostly randomized controlled trials, those involving pharmacological agents appeared opportunistic and varied greatly in study design and duration. Different interventional products were tested, and the studies lacked the consistency to reliably synthesize any evidence for the modifiability of TMAO concentrations by dietary supplements or pharmacological agents. Choline and l-carnitine are conditionally essential nutrients, and carefully designed placebo-controlled randomized trials specifically aimed at reducing the synthesis of microflora-dependent TMAO production from choline-containing precursors by pro- and/or prebiotics, antibiotics, or other pharmaceutical agents may be the way forward for future research.

Keywords: trimethylamine N-oxide, gut microbiota, dietary supplements, drugs, metabolic disease

Introduction

Trimethylamine N-oxide (TMAO) is a low-molecular-weight amine oxide derived by the microbial metabolism of choline-containing compounds (phosphatidylcholine, carnitine, and betaine) to trimethylamine (TMA) in the large bowel, followed by oxidation of TMA to TMAO in the liver by the flavin monooxygenase 3 (FMO3) enzyme (1) (Figure 1). TMAO is known to accumulate in the tissues of marine animals, in which it functions to protect against the adverse effects of temperature, salinity, and protein-destabilizing effects of high urea and hydrostatic pressure (2). Although known to marine biologists for a long time, TMAO has generated much research interest in recent years with the discovery of its association with cardiovascular disease (CVD) in humans (3). Foods rich in choline, lecithin, and l-carnitine, such as red meat, eggs, dairy products, and saltwater fish, serve as potential precursors of TMAO in humans. Consumption of diets rich in these foods has been reported to be associated with high TMAO concentrations in the circulation (3–5). A direct association between TMAO and CVD risk was first reported in a large clinical cohort in 2011 (1). The study independently confirmed the prognostic value of elevated concentrations of TMAO, choline, and betaine in the diet in healthy subjects undergoing elective cardiac evaluation, being associated with an increased risk of peripheral artery disease, coronary artery disease, and myocardial infarction. Furthermore, results were consistent with the findings in atherosclerosis-prone mice fed a chow diet enriched with either choline or TMAO, showing a clear dose-dependent relationship between TMAO concentrations and atherosclerotic plaque size (1). Two recently published meta-analyses suggested a strong association between increased TMAO concentrations and elevated risk of heart disease, including heart failure and stroke. An increase in all-cause mortality was also reported in patients with elevated TMAO concentrations (6, 7). Another robust association was found between higher TMAO concentrations (>6.18 µM) and an increased risk of thrombotic events, increased carotid intima media thickness, and atherosclerosis (8). The highest quartile of TMAO concentrations in the range of 6.18–318 µM was associated with a 1.64-fold increase in incident thrombosis risk compared with the lowest quartile (<2.43 µM) (8). Previous studies have proposed an adverse association between plasma TMAO concentrations and diabetes risk in animal models of diabetes (9). However, a direct association between plasma TMAO concentrations and type 2 diabetes mellitus in humans has not been reported. Pharmacokinetics studies in healthy subjects have suggested that TMAO is predominantly eliminated through the kidneys by glomerular filtration; therefore, a strong association of TMAO concentrations with renal function has been postulated (10). Elevated concentrations of TMAO have been associated with kidney damage and dysfunction, and they portend poor long-term survival in patients with chronic kidney disease (CKD) (11). In addition, elevated TMAO concentrations have been demonstrated in certain types of cancers, including colorectal cancer in postmenopausal women (12) and prostate cancer (13, 14). Wide inter- and intra-individual variations in circulating TMAO concentrations exist among human populations (15). Several factors determine TMAO concentrations and can thus confound the association between TMAO and disease etiology, including host gut microbiota, diet, kidney function, liver enzymes, age, and anthropometric measures including BMI (in kg/m2). However, there appears to be only a marginal role for genetics in determining TMAO concentrations (15, 16). A number of studies have measured fasting plasma concentrations of TMAO in healthy and diseased subjects following dietary interventions. Given the fact that numerous dietary precursors carry a trimethylamine moiety, they have the potential to influence TMAO concentrations and subsequent cardiovascular and metabolic disease risk (3, 17).

FIGURE 1.

FIGURE 1

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TMA–TMAO gut microbiota-dependent production. TMA, trimethylamine; TMAO, trimethylamine N-oxide.

Despite reports on the association of TMAO with metabolic diseases, its specific mechanism remains speculative. It is yet to be determined whether TMAO acts as a mediator in causing CVD or whether TMAO concentrations might be influenced by factors affecting clot formation and lipid metabolism. It has been suggested that TMAO exerts its pathological effect through multiple mechanisms, mainly through suppressing the net reverse cholesterol transport in the small intestine and decreasing cholesterol efflux, which will lead to cholesterol accumulation (4, 18, 19). In addition, TMAO may enhance platelet responsiveness (8) and promote foam cell formation by increasing cell surface expression of proatherogenic scavenger receptors on macrophages CD36 and SR-A1, both of which are involved in pathogenesis of atherosclerosis (4, 20). In contrast, a recent study suggested that TMAO may have a protective effect against atherosclerosis by decelerating aortic lesion formation (21). In addition, FMO3 is suggested to play a crucial role in the regulation of circulating TMAO concentrations and the promotion of CVD and atherosclerosis (18, 22, 23). The gastrointestinal microbiome plays an important role in host health and disease (24, 25). It is possible that alterations in the development or composition of gut microbiota (known as dysbiosis) by environmental factors, including host diet and genetics, disturb the partnership between the microbiota and the human immune system, thus generating a disease-prone state (26). The complexity of the interaction of the gut microbiome with such factors has impeded efforts to explore the possibility of modulating the gut microbiota and their metabolites using various therapeutic approaches for health benefits; however, the discovery of TMAO and its association with cardiovascular disease risk has excelled such efforts (15). A spectrum of antibiotics and other therapeutic strategies have been employed to test their potential to modulate TMAO concentrations, assuming the gut microbiome to be the key source of TMAO. In addition, a limited number of oral probiotics have been examined for their ability to exert an influence on TMAO concentrations and TMAO-producing species (25, 27). Therefore, the aim of our systematic review was to determine whether dietary supplements or pharmacological agents affect TMAO concentrations in adults, as measured in serum, plasma, or urine, in randomized and nonrandomized controlled trials.

Methods

This systematic review followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) (28). The protocol was published in the PROSPERO database (http://www.crd.york.ac.uk/PROSPERO) under registration number CRD42018084978.

Literature search and study identification

A preliminary search for existing systematic reviews on this area and related literature was performed. The initial search in Web of Science was performed using TMAO, trimethylamine N-oxide, treatment, diet, and drug therapy as keywords. The nails project (Network Analysis Interface for Literature Studies; http://nailsproject.net) was used to identify the highly cited articles and keywords to explore this research scope. A comprehensive literature search was performed in the following electronic databases: 1) MEDLINE through Ovid, 2) EMBASE, 3) ProQuest, 4) Scopus, 5) PubMed, and 6) CINAHL.

We used the following Medical Subject Headings (MeSH) words and their combinations: (TMAO or trimethylamine N-oxide or trimethylamine-N-oxide) and (gut microbiota or gut microbial flora or intestinal bacteria or Microbiome) and (diet or (treatment or drug therapy or agents)) and (randomized controlled trial or intervention studies or clinical trial(s)) and (cardiovascular disease or CVD or atherosclerosis). Full searching in MEDLINE is available as supplementary material (Supplemental Table 1). In addition, we conducted a manual search of the reference lists of the eligible studies to identify any further pertinent articles. Authors of primary studies or reviews were contacted for further information when required. We also searched ClinicalTrials.gov to identify any ongoing trials. Google Scholar and ProQuest were used to identify more papers including patents, conference abstracts, dissertations, and theses. The search included all articles published until July 2018.

Eligibility criteria and selection process

Studies were included if they were in adult humans; were randomized or nonrandomized controlled trials; and investigated the effect of specific interventions, either dietary supplements or pharmacological agents, on TMAO concentrations in serum, plasma, or urine. Studies were excluded if they were in animals; in a pediatric population; published in a non-English language; and non-interventional trials including observational studies, reviews, study protocol, and editorials. Also excluded were studies in which TMAO was not a measurable outcome . All inclusion and exclusion criteria are summarized in Table 1.

TABLE 1.

Inclusion and Exclusion Criteria (PICOTSS)1

Criterion Inclusion Exclusion
Population Adult humans In vitro studies, animals, and pediatrics
Intervention Dietary supplements or pharmacological drugs Dietary patterns
Surgical procedures
Comparison Placebo, any treatment, or no treatment None
Outcome TMAO concentrations in plasma, serum, and urine Betaine, choline, and other biomarker levels
Timing Any study duration None
Study design and article type RCT or nonrandomized controlled trails Observational studies
Crossover and parallel trials Reviews
Original articles published in peer review journal or in the gray literature Experts opinions
Abstracts Editorials
Patents Protocols
Study setting Any setting, inpatients or outpatients None
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1

PICOTSS, population, intervention, comparison, outcome, timing, study design and study setting; RCT, randomized controlled trial; TMAO, trimethylamine N-oxide.

After the initial search, two independent reviewers (NK) and (KA) assessed titles and abstracts to determine whether they met the eligibility criteria for inclusion in the systematic review. Full texts were retrieved if identified as potentially relevant or if the title or abstract did not give sufficient information to make this determination. Discrepancies and conflicts were resolved by a third reviewer (MG). Identified studies were divided into 2 categories: dietary supplements and pharmacological agents.

Assessment of bias

Risk of bias within studies was assessed with the use of the Cochrane Collaboration's tool for randomized controlled trials (29). The Cochrane tool aided in critically appraising the quality constructs of each publication as well as in determining the relevance and validity of the selected publication. Biases were assessed as a judgment (high, low, or unclear) for individual elements from 6 domains (selection, performance, detection, attrition, reporting, and other bias). The studies were scored as positive (high risk of bias), negative (low risk of bias), or neutral (unclear risk of bias). The tool was used by 1 reviewer (NK) and checked by a second reviewer for accuracy and agreement.

Data extraction

Parameters collected during data extraction were author or authors, year of publication, country, sample size of each group, participant characteristics (age, gender, BMI, and health status), characteristics of intervention and comparator, study duration, outcome of interest, and the dietary status among the study participants. The data extraction was entered into an Excel spreadsheet by 1 author (NK) and checked by a second author (KA) for accuracy and completeness. Any disagreements were resolved by discussion. Results are synthesized narratively.

Results

Overview of studies

Our literature searches in 6 databases initially resulted in n = 1031 articles. An overview of search results is presented in the PRISMA flow diagram in Figure 2. After excluding duplicates, the initial search identified n = 978 abstracts for screening. A total of 13 studies, including n = 6 studies using dietary supplements and n = 7 studies using pharmaceutical agents, met the inclusion criteria and were included in this review (3, 30–42). Included studies were published in the United States (n = 3), Brazil (n = 1), Asia (n = 2), and Europe (n = 7); no studies were found from the Middle East or Africa. Five studies were conducted in healthy populations, defined as follows: good health; no overt chronic diseases such as heart disease, renal disease, and metabolic diseases; no active infections; and not taking any medications that could influence the study variables. The other 8 studies included subjects with diabetes mellitus (n = 3), metabolic syndrome (n = 1), or CKD (n = 1) and those on hemodialysis (n = 2). BMI was reported in 8 studies. The BMI of participants across studies ranged from 21.9 to 35. Three studies reported mean BMI in the healthy category (BMI: 18.5–24.9), 3 studies reported mean BMI in the overweight category (BMI: 25–29.9), and 2 studies reported mean BMI in the obese category (BMI: >30). The mean age of participants among the 9 studies was 52 ± 10 y (range: 22–76 y).

FIGURE 2.

FIGURE 2

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PRISMA flow diagram depicting overview of study-selection process for inclusion in the systematic review. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; TMAO, trimethylamine N-oxide.

The study designs used in dietary supplements studies were quite homogeneous; all the studies included were randomized controlled trials except 1, which was an open-label interventional study. However, this was not the case with the pharmacological agents, for which different experiential designs were used. Pre-intervention concentrations of TMAO in serum, plasma, and urine were not reported in 3 studies. Changes in TMAO concentrations post-intervention were reported in only 10 studies: serum (n = 2), urine (n = 1), and plasma (n = 7). The risk of biased assessment results is provided in Figure 3. Major possible sources of bias among the 13 studies were selection bias and performance bias. Three studies detailed their randomization methods. Two studies mentioned the randomization but did not adequately describe the method of randomization. The remaining 8 studies did not use any randomization technique and hence were classified as having a high risk of bias. A low risk of reporting bias and attrition bias was seen in all studies in which all expected outcomes were reported, and all studies performed a complete analysis.

FIGURE 3.

FIGURE 3

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Risk of bias assessments for included studies on dietary supplements and pharmacological agents. Graphical display of the results of the methodological analysis of the quality of included studies using the Cochrane Collaboration tool for randomized controlled trials. Studies were scored as positive (high risk of bias), negative (low risk of bias), or neutral (unclear risk of bias).

Dietary supplements

Six studies on dietary supplements involving probiotics, prebiotics, l-carnitine, and vitamin combinations met the inclusion criteria (30, 36–38, 41, 42). A summary of study characteristics is shown in Table 2. The following three different types of probiotic supplementation were included in the review: Lactobacillus casei strain Shirota (LcS); VSL#3; and the strain-specific probiotic formulation known as RenadylTM, which includes Streptococcus thermophiles (KB19), Lactobacillus acidophilus (KB27), and Bifidobacteria longum (KB31). The prebiotic supplement included arabinoxylan oligosaccharide (AXOS); vitamin combinations included cholecalciferol (vitamin D-3) and B vitamins such as folic acid, pyridoxine (B-6), and cyanocobalamin (B-12). l-carnitine was provided as an oral dietary supplement in 1 study. Four studies on dietary supplements used a parallel design, 1 was a crossover study, and 1 was an open-label interventional trial. Four studies provided the interventions in a random order, whereas 1 study provided them in sequential order. Comparators included cornstarch (n = 1), maltodextrin (n = 1), wheat germ (n = 1), and standard therapy (n = 2). Trials on pre- and probiotics ranged from 4 to 12 wk in duration, whereas the study on vitamins lasted 12 mo. Subjects with l-carnitine deficiency were followed up after 6 mo of l-carnitine supplementation. In the crossover design study, the washout period was 4 wk. Studies included n = 219 participants, both males and females, except for 1 study, which included males only. Pre-intervention concentrations of TMAO were reported in all studies, but not with VSL#3 probiotic supplement. Dietary consumption of foods rich in seafood, fish, choline, l-carnitine, and betaine by the study participants was not controlled among the studies, except in 1 study, in which subjects were on a eucaloric control diet (55% carbohydrate, 30% fat, and 15% protein) for two weeks before the intervention and continued on a hypercaloric (+1000 kcal d−1) and high-fat diet (55% fat, 30% carbohydrate, and 15% protein) simultaneously with the interventional dietary supplement. The change in serum and plasma concentrations of TMAO after the administration of dietary supplements was considered the study endpoint. Among the 3 oral probiotics used (30, 38, 42), there was no significant change in the TMAO concentrations in the LcS, VSL#3, and Renadyl intervention groups compared with the control groups. AXOS prebiotic treatment resulted in a minor reduction in TMAO concentration compared with placebo. After 12 mo of treatment with vitamin D-3 and B vitamins, serum TMAO concentrations did not differ between the treatment groups and control groups. However, the amount of reduction in TMAO concentrations from baseline was highly significant in the treatment groups compared with the control groups (36). Plasma TMAO concentrations in hemodialysis (HD) patients were markedly higher at baseline compared with those in healthy subjects. After oral administration of l-carnitine in HD patients, plasma TMAO concentrations were significantly increased.

TABLE 2.

Characteristics and outcomes from studies that reported the effect of dietary supplements on TMAO concentrations1

Reference and country Participant characteristics Study design Intervention compared with control2 Duration and follow-up Baseline TMAO concentration (μM)3 Outcome4 Dietary status5
Tripolt et al. (38) Austria n = 13:156 Female: 4% Age: 51 ± 112 y BMI: 35 ± 5 Subjects with metabolic syndrome Open-label, randomized controlled, parallel study LcS milk probiotic (3 bottles/d, 65 mL of 108/mL LcS) Compared with no milk 12 wk Plasma I: 4.7 ± 2.7 C: 4.6 ± 2.8 NC* Uncontrolled7
Boutagy et al. (30) United States n = 9:106 Female: 0% Age: 22.4 ± 1.1 y BMI: 24.5 ± 1.1 Healthy subjects on hypercaloric HFD Randomized, placebo-controlled, double-blind, parallel study VSL#3 probiotic (2 packets, 900 billion live bacteria) Compared with placebo (2 packets, cornstarch) 4 wk Plasma NR NC* Controlled
Fukami et al. (41) Japan n = 31:476 Female: 56% Age: 55.9 ± 5.2 y 64.6 ± 10.8 y BMI: 21.2 ± 1.9 Healthy subjects compared to subjects on HD Open label, nonrandomized, interventional study Oral l-carnitine supplementation (900 mg OD) to both groups 6 mo Plasma I: 222.5 ± 111.7 C: 174.3 ± 99.7 ↑*** Uncontrolled
Poesen et al. (37) Belgium n = 40 Female: 30% Age: 70 ± 6.0 y BMI: 28.7 ± 5.0 Subjects with CKD Randomized, placebo-controlled, double-blind, crossover study AXOS prebiotic (10 g bid) Compared with placebo (maltodextrin 6.7 g bid) 12 wk Serum I: 8.9 IQR: (7.1–12.3)8 ↓** Uncontrolled
Obeid et al. (36) Germany n = 25:276 Female: 16% Age: 68 ± 9.2 y BMI: 26.4 ± 3.1 Healthy subjects Randomized, single-blind, non-placebo-controlled, parallel study B vitamins (0.5 mg folic acid + 50 mg B-6 + 0.5 mg B-12) + cholecalciferol (1200 IU OD) + calcium carbonate (800 mg OD) Compared with cholecalciferol (1200 IU OD) + calcium carbonate (800 mg OD) 12 mo Plasma I: 4.2 (5.2) C: 4.3 (2.3) ↓** Uncontrolled
Borges et al. (42) Brazil n = 11:106 Female: 72% Age = 54.0 ± 22 y BMI: 24.6 ± 7 Subjects with CKD on HD Randomized, double-blind, parallel study Strain-specific probiotic formulation, 3 capsules (9 × 1013 CFU/d) Compared with placebo 3 mo Plasma I: 6.2 (2.6–14.9) C: 7.5 (3.1–17.7) NC* Uncontrolled
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1

n = 6. AXOS, arabinoxylan oligosaccharide; bid, twice daily; C, control; CKD, chronic kidney disease; HD, hemodialysis; HFD, high-fat diet; I, intervention; IU, international unit; LcS, Lactobacillus casei Shirota; NC, no change; NR, not reported; OD, once daily; TMAO, trimethylamine N-oxide.

2

Values are means ± SDs unless otherwise indicated.

3

Baseline TMAO concentration in micromolar (μM) = μmol/L unless otherwise indicated.

4

Outcome denotes effect of intervention on TMAO levels (increase or decrease).

5

Dietary intake of trimethylamine dietary precursors including seafood, fish, choline, l-carnitine, and betaine.

6

n = intervention: control groups.

7

“Controlled” indicates dietary intake of TMAO precursors was controlled; “uncontrolled” indicates dietary intake of TMAO precursors was not controlled.

8

Median (interquartile range).

*

P > 0.05.

**

P < 0.05.

***

P < 0.001.

Pharmacological agents

A total of 7 interventional studies involving 5 different pharmacological agents met the inclusion criteria (3, 31–35, 39). Pharmacological agents included metformin (n = 3), meldonium (n = 1), broad-spectrum antibiotic (n = 1), fenofibrate (n = 1), and aspirin (n = 1). Studies included n = 185 participants, both males and females, healthy (n = 3), with DM (n = 3), and unspecified (n= 1), and with a mean age of 50 ± 10 y. A summary of study characteristics is shown in Table 3. Study design included 1 open-label nonrandomized metabolomic study; 1 prospective nonrandomized clinical trial; 3 open-label, nonrandomized, non-placebo-controlled studies; 1 nonrandomized, non-placebo-controlled, crossover study; and 1 randomized, placebo-controlled, double-blind, crossover study. Study duration ranged from 3 wk to 12 mo. Concentrations of TMAO were quantified at baseline in serum (n = 3), plasma (n = 3), and urine (n = 1). Dietary status among the study participants was not controlled in 4 studies; however, 3 studies specified the type and the amount of food consumed during the intervention.

TABLE 3.

Characteristics and outcomes from studies that reported the effect of pharmacological agents on TMAO concentrations1

Reference and country Participant characteristics Study design Intervention compared with control Duration and follow-up Baseline TMAO concentration (μM)2 Outcome3 Dietary intake4
Huo et al. (34) China n = 15:205 Female: 53% Age: 57.2 ± 10.76 y BMI: 28.8 ± 2.39 Subjects with DM Open-label, nonrandomized metabonomic study Metformin Compared with no treatment 3 mo Serum NR ↑** Uncontrolled7
Cadeddu et al. (31) Italy n = 20 Female: 45% Age: 47 ± 13 y BMI: 30.8 ± 5.2 Subjects with DM Open-label, nonrandomized, non-placebo-controlled study Metformin (850 mg bid) 3 mo Serum NR ↑** Uncontrolled
Dambrova et al. (32) Latvia n = 8 Female: 50% Healthy subjects Open-label, nonrandomized interventional study Meldonium (500 mg bid) + TMA-rich diet (seafood) 3 wk Plasma 4.9 ± 1.3 ↓** Controlled
Tang et al. (3) United States n = 40 Healthy subjects Prospective, nonrandomized clinical trial Metronidazole (500 mg bid) plus ciprofloxacin (500 mg OD) + phosphatidylcholine diet 4 wk Plasma 4.2 ± 2.0 ↓↓*** Controlled
Lever et al. (35) United Kingdom n = 26 Female: 42% Age: 50 ± 15 y Healthy subjects Open-label, nonrandomized, non-placebo-controlled interventional study Fenofibrate tablet (145 mg OD) 6 wk Urine8 38.9 (21.4–49.0) NC* Uncontrolled
Velebova et al. (39) Prague, Czech Republic n = 40 Subjects with DM Randomized, placebo-controlled, double-blind, crossover study Metformin (2 g OD) Compared with placebo (not specified) 6 mo Serum 1.03 ± 1.29 NC* Uncontrolled
Hazen (33) United States n = 7: 95 Nonrandomized, non-placebo-controlled, crossover study Aspirin (81 mg OD) + choline diet Compared with choline diet only 12 mo Plasma I: 2.6 ± 0.3 C: 2.8 ± 0.4 ↓↓*** Controlled
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1

n = 7. bid, twice daily; C, control; DM, diabetes mellitus; HD, hemodialysis; I, intervention; NC, no change; NR, not reported; OD, once daily; tab, tablet; TMA, trimethylamine; TMAO, trimethylamine N-oxide.

2

Baseline TMAO concentration in micromolar (μM) = μmol/L unless otherwise indicated.

3

Outcome denotes effect of intervention on TMAO levels (increase or decrease).

4

Dietary intake of trimethylamine dietary precursors including seafood, fish, choline, l-carnitine, and betaine.

5

n = intervention: control groups.

6

Values are means ± SDs unless otherwise indicated.

7

“Controlled” indicates dietary intake of TMAO precursors was controlled; “uncontrolled” indicates dietary intake of TMAO precursors was not controlled.

8

Median (interquartile range) urine excretions (mmol/mol creatinine).

*

P > 0.05.

**

P < 0.05.

***

P < 0.001.

Metformin

Three studies assessed the effects of metformin on TMAO concentrations in patients with DM (31, 34, 39). TMAO serum concentrations were measured after 3 mo of metformin treatment in 3 studies; however, only 1 study reported baseline concentrations (39). Serum TMAO concentrations were markedly increased in the metabolomic study and the nonrandomized trial (31, 34), whereas the crossover trial did not provide any evidence of an effect of metformin on TMAO serum concentrations (39).

Meldonium

One human study assessed the impact of meldonium as a metabolic modulator on TMAO plasma concentrations in 8 healthy participants (32), with an equal number of males and females. Plasma TMAO concentrations were increased up to 16-fold following administration of a TMA-rich diet, which included approximately 150 g of fish and sea products such as salmon, cod, herring, or shrimps. After the addition of meldonium to the TMA-rich diet, TMAO plasma concentrations increased 9-fold, a significant reduction in TMAO plasma concentrations from that seen in participants on the TMA-rich diet alone.

Antibiotics/antimicrobials

One study assessed the impact of broad-spectrum antibiotics, including metronidazole and ciprofloxacin, on TMAO concentrations (3). Forty healthy participants were assigned to a phosphatidylcholine challenge for 4 wk. Dietary phosphatidylcholine challenge consisted of the ingestion of 2 hard-boiled eggs including yolk (∼250 mg of total choline in each) by study participant during their first visit. Participants were assigned to receive broad-spectrum antibiotics, including metronidazole and ciprofloxacin, for 1 wk, followed by a second phosphatidylcholine challenge during their second visit. After 1 mo of antibiotic discontinuation, study participants were again challenged during their third visit. Plasma TMAO concentrations were found to be high after egg ingestion; however, after treatment with antibiotics for 1 wk, TMAO concentrations were rendered undetectable. In addition, TMAO was detected in the intervention group 4 wk after ceasing the antibiotic intervention (3).

Fenofibrate

Fenofibrate is one of the pharmacological agents that have been investigated for their effect on TMAO renal excretion (35, 43). Urine TMAO samples were quantified following administration of fenofibrate for 6 wk. This study showed that urinary TMAO concentrations were not affected by fenofibrate treatment.

Aspirin

A crossover design study, with a washout period of 4 mo, was used to examine the effects of aspirin on plasma TMAO concentrations and platelet aggregation in volunteers on a diet rich in choline equivalent to the intake of 2 hard-boiled eggs on a daily basis (33). TMAO was measured at baseline, 1 mo, and 2 mo. Aspirin therapy significantly reduced TMAO concentrations as well as the prothrombotic effect associated with a high-choline diet.

Discussion

The aim of this systematic review was to determine whether dietary supplements or pharmacological interventions can modulate TMAO concentrations. It is important to map the evidence regarding different therapeutic approaches that could potentially have an influence on TMAO production and excretion or a role in pathogenesis. Modulation of the gut microbiota, which can alter their TMA-producing capacity, is potentially a logical intervention strategy in the prevention or treatment of TMAO-induced metabolic diseases (1, 6, 8, 44). Rogers and Aronoff (45) found differences in the relative abundance of specific bacteria between individuals, depending on the number and type of medications used. In addition, FMO3 plays a major role in the regulation of TMAO circulating concentrations; however, targeting FMO3 to modulate TMAO concentrations remains unfavorable because of the accumulation of TMA, resulting in trimethylaminuria (19). Oral ingestion of prebiotics and probiotics can modulate the human gut microbiota composition by selectively stimulating the growth and/or activity of one or more bacteria in the colon (microbiota) or by suppressing the growth of harmful microorganisms. Pre- and probiotics are well known to improve host well-being and health by transforming the gut flora to its normal composition after it has been affected by dietary and environmental stresses (25, 27, 46, 47). Three different types of oral probiotics were studied in this review, exerting their effects through several unique mechanisms. First, LcS is a typical probiotic strain that has been reported in randomized controlled trials to significantly influence the gut microbiota composition by increasing the total bacterial count and maintaining the anaerobic environment in the large intestine (48). Second, VSL#3 has been reported to be a probiotic cocktail supplement of different strains of lactic acid–producing bacteria, including Streptococcus thermophiles, Lactobacillus acidophilus, Lactobacillus delbrueckii ssp. bulgaricus. Third, a strain-specific probiotic formulation (Renadyl) has been reported to improve CKD signs and symptoms by utilizing nitrogenous uremic toxins as nutrients to maintain the gut ecosystem and prevent their accumulation to high toxic levels (49). Although their efficacy in directly and indirectly modulating the gut microbiota in human hosts has long been established (30, 50), none of these probiotics altered TMAO concentrations.

Notably, none of the 3 probiotics studied was specifically focused on TMAO-producing bacteria or their contribution to TMA–TMAO production. Studies in humans and animals suggested that several families of bacteria are engaged in TMA–TMAO production, such as Deferribacteraceae, Enterobacteriaceae, Anaeroplasmataceae, and Prevotellaceae (4, 15, 51). An in vitro study identified 9 strains of bacteria capable of producing TMA from choline using isolates of bacteria in the human intestine. These encompassed the 2 major phyla (Bacteroidetes and Firmicutes) found in the human gut and included Anaerococcus hydrogenalis, Clostridium asparagiforme, Clostridium hathewayi, Clostridium sporogenes, Escherichia fergusonii, Proteus penneri, Providencia rettgeri, and Edwardsiella tarda (52, 53). Therefore, future studies involving manipulation of one or more of the TMA–TMAO-producing microorganisms are warranted. AXOS are prebiotic carbohydrates that result from the enzymatic hydrolysis of cereal arabinoxylans in the colon, and they act by promoting the activity of specific beneficial colonic bacteria, particularly Bifidobacteria (37, 54). AXOS showed a small but significant effect on serum TMAO concentrations in CKD patients. However, this finding cannot be generalized, taking into consideration the study participants’ health status, origin, and the study power. Activities of both probiotics and prebiotics may depend on the strain, dose, duration, and components used to exert their effects (25, 46). In addition, the studies involving probiotics supplementation for 4–12 wk found this period of time to be sufficient to alter the gut microbiota (30, 55). However, it is yet undetermined whether this duration was adequate to influence TMAO concentrations. In the AXOS study, participants with dietary changes were excluded because the diet has the potential to interfere with prebiotic effects. This was not the case with the LcS and Renadyl probiotics because the participants’ diet was not controlled, and this was considered to be a study limitation.

The only study on dietary supplements involving l-carnitine found a significant increase in plasma TMA and TMAO concentrations after its consumption in HD patients. l-Carnitine has been suggested for use in multiple diseases, including atherosclerosis and CKD, to protect against vascular injury; however, the benefit of carnitine supplementation remains questionable and has not been confirmed in clinics.

A study involving fat-soluble vitamins (vitamin D-3) and water-soluble vitamins (B vitamins) showed a significant effect on lowering plasma TMAO concentrations; however, the mechanism by which they exerted their beneficial effect was not suggested, and B vitamin status in the study participants at baseline was not taken into consideration (36). To date, studies suggest that only choline is involved in functions that overlap with those of folate and other B vitamins, and in the case of folate (B vitamin) deficiency in diet, the need for dietary choline arises because it is the primary methyl donor (56). Therefore, the status of B vitamins should be taken into consideration in all study participants because their concentrations might confound the results and mask the true association between choline and the observed outcome.

The only study on broad-spectrum antibiotics, including metronidazole and ciprofloxacin, showed a remarkable suppression of TMAO concentrations when administered following a phosphatidylcholine diet. However, TMAO concentrations subsequently increased 1 mo after antibiotic cessation. It is not clear whether this finding is due to a phenomenon called “antibiotic-resistant intestinal microbiota” or whether it may be due to TMAO's ability to identify a different pathway within intestinal microbiota amenable to therapeutic modulation (3). This effect needs to be investigated further in randomized control trials to determine the long- and short-term impact of systemic and local antibiotics on TMAO concentrations.

The majority of the pharmacological agents studied involving metformin, meldonium, and fenofibrate did not suppress TMAO-producing bacteria or inhibit the TMA–lyase enzyme. Although there was no rationale for investigating its effects, meldonium showed a beneficial effect on TMAO concentrations through altering TMA–TMAO gut microbiota-dependent production (32). On the other hand, metformin was found to significantly increase TMAO concentrations in 2 nonrandomized, non-placebo-controlled studies (31, 34). However, no association was reported in the placebo-controlled, crossover studies. Therefore, carefully designed randomized controlled trials to identify the specific mechanism of these pharmacological agents in modulating TMAO concentrations are warranted. The nonsteroidal anti-inflammatory drug aspirin has been reported to suppress TMAO concentrations via inhibiting microbial TMA–lyase activity and reducing the proatherogenic effects associated with a high-choline diet (33). This finding highlights the need to initiate aspirin as a prophylaxis therapy to prevent platelet hyperactivity and clot formation risk or to treat other diseases associated with elevated TMAO concentrations.

The current review has several limitations. Although a comprehensive search strategy was used with no time restriction, only articles published in English were included. The significant heterogeneity within the studies included in this review may have arisen from the methodology used in the individual studies. The discrepancies found regarding study duration, drug dosing, and the small number of participants included in the studies make it challenging to generalize these findings to other populations. In addition, these studies were conducted on different populations with different dietary patterns; however, dietary status was not controlled among most of study subjects, which could potentially confound study outcomes. None of the pharmacological agents studied, except aspirin, were focusing on the two main proposed mechanisms for targeting TMAO concentrations. All but 5 studies were non-placebo-controlled studies; thus, their findings might be confounded by other factors. Finally, not all studies included in this review reported TMAO concentrations at baseline; therefore, the change from preintervention concentrations could not be described, and thus the effect of some pharmacological agents is difficult to interpret.

Conclusion

To date, studies involving dietary supplements and pharmacological agents have been opportunistic and are missing a sound rationale for intervention with the test products. In addition, a controlled dietary status among the study subjects should be taken into consideration when conducting future intervention trials to prevent any confounding on TMAO concentrations. Investigators should aim at either suppressing TMAO–gut microbiota-dependent production or blocking TMAO formation through TMA–lyase enzyme inhibition. Despite the clinical benefit of TMAO precursors such as choline and l-carnitine, their consumption was associated with an increased concentration of TMAO. Therefore, their use should be minimized, and either blocking their conversion to TMAO or suppressing their concentrations by pro- and/or prebiotics, antibiotics, or other pharmaceutical agents may be the way forward for future research.

ACKNOWLEDGEMENTS

We thank the University of Newcastle Medical Librarian, Ms. Debbie Booth, for her assistance with database searches. The authors’ responsibilities were as follows—NAK, KA Abbott, and MLG: designed the study; NAK and KA Abbott: conducted the research; NAK: prepared the manuscript with contributions from KA Abbott, KA Alburikan, HAA, ES, and MLG; and all authors: read and approved the final manuscript.

Notes

The authors reported no funding received for this study.

Author disclosures: NAK, KA Abbott, KA Alburikan, HAA, ES, and MLG, no conflicts of interest.

Supplemental Table 1 is available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at https://academic.oup.com/advances.

Abbreviations used: AXOS, arabinoxylan oligosaccharide; CKD, chronic kidney disease; CVD, cardiovascular disease; FMO3, flavin monooxygenase 3; HD, hemodialysis; LcS, Lactobacillus casei Shirota; TMA, trimethylamine; TMAO, trimethylamine N-oxide.

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