Trimethylamine-N-Oxide, a Metabolite Associated with Atherosclerosis, Exhibits Complex Genetic and Dietary Regulation
Open accessAbstract
Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis.
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Gut bacteria transform the choline part of dietary phosphatidylcholine into trimethylamine, which is then oxidized to TMAO by hepatic flavin-containing monooxygenases.
“Intestinal microbiota convert the choline moiety of dietary phosphatidylcholine into trimethylamine, which is subsequently converted into TMAO by hepatic flavin-containing monooxygenases (Fig. 3).20–23”
From Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk (2013) · cites this paper as [23]
The Introduction describes gut flora converting dietary choline to trimethylamine (TMA), and the Results show that FMO1 and FMO3 oxidize TMA to TMAO; another Results passage locates FMO3 expression and TMA-oxidizing activity in the liver. The paper does not specifically state that the choline comes from dietary phosphatidylcholine, so that part of the claim is not supported by our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredGut bacteria transform the choline part of dietary phosphatidylcholine into trimethylamine, which is then oxidized to TMAO by hepatic flavin-containing monooxygenases.
“Intestinal microbiota convert the choline moiety of dietary phosphatidylcholine into trimethylamine, which is subsequently converted into TMAO by hepatic flavin-containing monooxygenases (Fig. 3).20–23”
From Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk (2013) · cites this paper as [20]
The Introduction says gut flora convert dietary choline to trimethylamine, and the Results report that FMO1 and FMO3 oxidize trimethylamine to TMAO; the dietary-regulation Results also describe hepatic FMO3 activity. Our copy does not establish the more specific claim that the choline came from dietary phosphatidylcholine. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTMAO is derived primarily from dietary choline and carnitine through gut microbiota metabolism to TMA, which is absorbed and oxidized in the liver primarily by FMO3 to TMAO.
“TMAO is derived primarily from dietary choline and carnitine through the action of gut microbiota, which metabolize these constituents to trimethylamine (TMA).1, 11, 12 TMA is absorbed in turn and travels via the portal circulation to the liver, where it is oxidized by flavin‐containing monoxygenases, primarily FMO3, to TMAO.1, 11, 12”
From Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB (2016) · cites this paper as [12]
Hepatic FMO enzyme activity did not differ significantly between donor strains or among recipient groups after cecal microbial transplantation.
“In contrast, examination of hepatic FMO enzyme activity, which is responsible for converting TMA into TMAO (Wang et al., 2011; Bennett et al., 2013), revealed no significant differences between both donor mouse strains, and among the various recipient groups post cecal microbial transplantation (Figure S6, panel B).”
From Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk (2016) · cites this paper as Bennett et al., 2013
Host hepatic FMO3 is the main enzyme producing TMAO.
“host hepatic FMO3, the primary FMO responsible for TMAO production”
From Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis (2015) · cites this paper as Bennett et al., 2013
FMO3 regulates host lipid and sterol metabolism and atherosclerosis development.
“important regulators in host lipid and sterol metabolism, as well as atherosclerosis development”
From Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis (2015) · cites this paper as Bennett et al., 2013
Multiple lines of evidence show that the meta-organismal pathway producing TMAO is mechanistically linked to susceptibility to atherosclerosis.
“Multiple lines of evidence show the meta-organismal pathway involved in TMAO production is mechanistically linked to atherosclerosis susceptibility (Bennett et al., 2013; Gregory et al., 2015; Koeth et al., 2013; Wang et al., 2011).”
From Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis (2015) · cites this paper as Bennett et al., 2013
TMAO levels explain a significant portion of atherosclerosis aortic root development across multiple inbred mouse strains, and TMAO levels are influenced by hepatic Fmo3, which is regulated in part by FXR.
“Further investigations revealed that TMAO levels help to explain a significant portion of atherosclerosis aortic root development across multiple different inbred strains of mice, and that TMAO levels are influenced by hepatic Fmo3, which is under complex control, including regulation by the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor (54).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [54]
Increasing FMO3 in mice raised plasma TMAO, while reducing FMO3 lowered TMAO.
“Further, FMO3 overexpression in mice significantly increased plasma TMAO levels, while silencing FMO3 decreased TMAO levels (54).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [54]
TMA is converted to TMAO by an oxidation step carried out by host flavin-containing monooxygenases.
“The conversion from TMA to TMAO requires an oxidation step that is mediated by host enzyme machinery in the form of FMOs (54,(78)(79)(80)(81).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [54]
In humans and mice, hepatic FMO3 expression is lower in males than females and can be induced by dietary bile acids through an FXR-dependent pathway.
“In both humans and mice, hepatic FMO3 expression was observed to be reduced in males compared with females (25,54) and could be induced by dietary bile acids through a mechanism that involves FXR (54).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [54]
FMO1, FMO2, and FMO3 can each produce TMAO, but FMO3 has at least tenfold higher specific activity than the others.
“FMO1, FMO2, and FMO3 were all capable of forming TMAO, though the specific activity of FMO3 was at least 10-fold higher than that the other FMOs (54).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [54]
Studies across many inbred mouse strains linked strain and sex differences to hepatic FMO3 expression or activity, TMAO levels, and atherosclerosis.
“Recent studies among multiple different inbred strains of mice in a “mouse diversity panel” linked variations in strain and sex to hepatic expression/activity of FMO3, TMAO levels, and atherosclerosis (54).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [54]
Microbe-derived TMA travels quickly through the portal circulation to the liver, where hepatic FMOs efficiently oxidize it to TMAO.
“Gut microbe-produced TMA reaches the liver rapidly via the portal circulation, where a cluster of hepatic FMO enzymes efficiently oxidizes TMA into TMAO (54,82).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [54]
Phosphatidylcholine and TMAO are both mechanistically linked to atherosclerosis development.
“phosphatidylcholine, the major dietary source of choline, and the gut microbe-dependent metabolite, trimethylamine N -oxide (TMAO), 4 are both mechanistically linked to atherosclerosis development (5, 6, 8)”
From Transmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation (2015) · cites this paper as [8]
Elevated TMAO has been observed in patients with cardiovascular disease and atherosclerosis, highlighting a potential downside to increased protein intake.
“Elevated TMAO has been observed in patients with cardiovascular disease and atherosclerosis, highlighting a potential downside to increased protein intake.[15-17,22, 37]”
From The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level (2018) · cites this paper as [37]
TMAO is mainly derived from choline, which is metabolized to TMA by microbiota and then to TMAO by hepatic flavin monooxygenase 3.
“TMAO is a small organic compound, mainly derived from choline (found in foods such as red meat, fish, poultry, and eggs), which is metabolized to produce trimethylamine (TMA) by microbiota1, 4 and then to TMAO by the hepatic enzyme, flavin monooxygenase 3.1, 5”
FMO3 has tenfold higher specific activity in liver than FMO1.
“FMO3 has tenfold higher specific activity in the liver than does FMO1 (13).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [13]
Most TMA is absorbed into the hepatic portal circulation by passive diffusion across enterocyte membranes and is efficiently converted to TMAO by hepatic FMO1 and FMO3.
“Most TMA is absorbed into the hepatic portal circulation by passive diffusion across the enterocyte membranes and then is efficiently converted to TMAO by hepatic FMO1 and FMO3 (13); about 95% of TMA is oxidized as it is subsequently excreted in urine in a 3:95 TMA:TMAO ratio (132).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [13]
Cholic acid induces FMO3 through the bile acid-activated nuclear receptor FXR.
“The bile salt, cholic acid, induces FMO3 via the bile acid-activated nuclear receptor FXR (13).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [13]
FMO3 activity is 100 times higher in female than male mice, while human sex-related differences are more modest.
“Thus, FMO3 activity is 100 times higher in female than in male mice; more modest gender-related differences are observed in humans (13).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [13]
TMA is formed in male ejaculate and vaginal secretions, TMA formation may be regulated by sex hormones, and cycle-dependent TMA variations occur in women.
“TMA is formed in male ejaculate and vaginal secretions, and as noted in Section 2.2, TMA formation may be regulated by sex hormones (13), and cycle-dependent variations in TMA occur in women (82).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [13]
TMAO preserves the folded state of proteins and counteracts denaturants such as pH, urea, and high pressure.
“It retains the folded state of proteins and counteracts the effect of denaturants, such as pH, urea, and high pressure (6,13,29).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [13]
TMAO is generated by gut microbial conversion of dietary nutrients such as phosphatidylcholine, choline, and carnitine into TMA, followed by host liver oxidation to TMAO by FMOs.
“TMAO is generated via a meta-organismal pathway that begins with gut microbial conversion of dietary nutrients (e.g. phosphatidylcholine, choline, and carnitine) into trimethylamine (TMA), followed by host liver oxidation to TMAO by flavin monooxygenases (FMOs)29,30.”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [30]
FXR is a target of SIRT1 in metabolic regulation.
“It has been demonstrated that the gene encoding FMO3 is a direct FXR target gene, and FXR has been found to be a target of sirtuin 1 (SIRT1) in metabolic regulation (23, 34, 35).”
The gene encoding FMO3 is a direct FXR target gene.
“It has been demonstrated that the gene encoding FMO3 is a direct FXR target gene, and FXR has been found to be a target of sirtuin 1 (SIRT1) in metabolic regulation (23, 34, 35).”
Dietary choline is metabolized by intestinal microbiota to TMA, which is further metabolized by FMO enzymes, in particular FMO3, to produce TMAO in the liver.
“Dietary choline is metabolized by the intestinal microbiota to TMA, which is further metabolized by FMO enzymes, in particular, FMO3, to produce TMAO in the liver (23).”
The decreased serum TMAO levels in mice colonized with the "core plus all" community are plausibly caused by increased microbial degradation of cholic acid, which would result in lower fmo3 expression.
“Thus, it is plausible that the decreased levels of TMAO detected in sera of mice colonized with the “core plus all” community (Fig. 1C and Fig. 3A) are caused by increased microbial degradation of cholic acid, which would result in lower levels of fmo3 expression (27).”
FMO3 expression is induced by bile acids via a mechanism involving the farnesoid X receptor (FXR).
“Expression of the main FMO enzyme involved in TMAO production from TMA, FMO3, is induced by bile acids via a mechanism that involves the farnesoid X receptor (FXR) (27).”
Previous studies in conventionally raised mice demonstrated that FMO3 is expressed at higher levels in females than in males.
“consistent with previous studies in conventionally raised mice which demonstrated that FMO3 is expressed at higher levels in females than in males (8, 27).”
Cholic acid stimulates FMO3 expression.
“Specifically, cholic acid stimulates FMO3 expression (27).”
Flavin monooxygenase 3 is downregulated by testosterone.
“is downregulated by testosterone (Bennett et al., 2013)”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Bennett et al., 2013
Trimethylamine produced by gut microbes is transported to the liver via the portal vein and readily metabolized by host hepatic flavin monooxygenases, mainly FMO3, into trimethylamine N-oxide.
“The TMA produced is then transported to liver via the portal vein and readily metabolized by host hepatic flavin monooxygenases (FMOs) (mainly FMO376) into TMAO9.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [76]
Human liver samples from female subjects show higher FMO1/3 expression and increased capacity for TMAO generation than those from males.
“Studies by Bennett et al. found that human liver samples from female subjects showed higher FMO1/3 expression, and therefore an increased capacity for TMAO generation, than those from males.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [76]
In gonadectomized male mice, testosterone reduces hepatic FMO3 expression; in ovariectomized female mice, estrogen increases hepatic FMO3 expression.
“Likewise, gonadectomized male mice treated with testosterone show reduced hepatic FMO3 expression, while ovariectomized female mice treated with estrogen exhibit increases in hepatic FMO3 expression76.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [76]
Rodents show significant sexual dimorphism in FMO3 expression and TMAO levels, with females showing higher levels and greater atherosclerosis capacity.
“Rodents show a significant sexual dimorphism with respect to FMO3 expression, and TMAO levels, with females showing higher levels (and greater atherosclerosis capacity9, 76).”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [76]
Trimethylamine N-oxide (TMAO) is a pro-atherogenic and pro-thrombotic metabolite produced from gut microbiota metabolism of dietary trimethylamine (TMA)-containing nutrients such as choline or carnitine.
“Systemic levels of trimethylamine N-oxide (TMAO), a pro-atherogenic and pro-thrombotic metabolite produced from gut microbiota metabolism of dietary trimethylamine (TMA)-containing nutrients such as choline or carnitine, predict incident cardiovascular event risks in stable primary and secondary prevention subjects.”
In people with adequate renal function, the rise in TMAO after high fish intake is transient.
“However, it is also clear that in people with adequate renal function, this rise in TMAO is transient.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [165]
High dietary fish intakes, especially of deep sea and cold water varieties more likely to contain TMAO, are associated with increases in urinary TMAO excretion.
“Nonetheless, high dietary fish intakes, especially of deep sea (and cold water) varieties of fish, which are more likely to contain TMAO, is associated with increases in urinary TMAO excretion165.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [165]
TMAO is rapidly cleared from the body after ingestion.
“Subsequent studies showed that TMAO is rapidly cleared from the body after ingestion157,165,191.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [165]
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- Authors
- Bennett, B. J., Vallim, T. Q. D. A., Wang, Z., Shih, D. M., Meng, Y., Gregory, J., Allayee, H., Lee, R., Graham, M., Crooke, R., Edwards, P. A., Hazen, S. L., & Lusis, A. J.
- Affiliations
- University of California, Los Angeles (US)
- Cleveland Clinic (US)
- University of Southern California (US)
- Corresponding author
- Bennett, Brian J.
- Lusis, Aldons J.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 17
- Issue
- 1
- Pages
- 49-60
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3771112
- OpenAlex
- W2046971089
- Cited by
- 1,070
- References
- 35
- Citations by year
- 2026: 75 · 2025: 88 · 2024: 88 · 2023: 95 · 2022: 116 · 2021: 102 · 2020: 107 · 2019: 90 · 2018: 81 · 2017: 50 · 2016: 67 · 2015: 59 · 2014: 32 · 2013: 19
- FWCI
- 64.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Cleveland Clinic
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL3 0568, HL28481, R01HL094322, P01HL030568, R00HL102223, K99HL102223, HL113452, P20HL113452, HL94322, K99/R00 HL102223, R01HL103866, HL103866, P01HL028481)
- National Institute of General Medical Sciences (T32GM088088)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Keywords
- trimethylamine N-oxide, atherosclerosis, flavin monooxygenase 3, gut microbiota, choline metabolism, bile acids, farnesoid X receptor, androgen regulation, sex differences, genetic variation, dietary regulation
- MeSH terms
- Receptor, Farnesoid X-Activated, Androgens, Animals, Base Sequence, Bile Acids and Salts, Choline, Diet, Female, Humans, Male, Methylamines, Oxygenases, Sex Factors, Down-Regulation, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Polymorphism, Single Nucleotide, Gene Silencing, Atherosclerosis, Mice, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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