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Cited by 475Gut microbiota and healthNutritional Studies and DietPolyamine Metabolism and Applications

Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease

Open access
Zeisel, Steven H., Warrier, Manya·2017·Annual Review of Nutrition
DOI 10.1146/annurev-nutr-071816-064732
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Abstract

Trimethylamine N-oxide (TMAO) is a biologically active molecule and is a putative promoter of chronic diseases including atherosclerosis in humans. Host intestinal bacteria produce its precursor trimethylamine (TMA) from carnitine, choline, or choline-containing compounds. Most of the TMA produced is passively absorbed into portal circulation, and hepatic flavin-dependent monooxygenases (FMOs) efficiently oxidize TMA to TMAO. Both observational and experimental studies suggest a strong positive correlation between increased plasma TMAO concentrations and adverse cardiovascular events, such as myocardial infarction, stroke, and death. However, a clear mechanistic link between TMAO and such diseases is not yet validated. Therefore, it is debated whether increased TMAO concentrations are the cause or result of these diseases. Here, we have tried to review the current understanding of the properties and physiological functions of TMAO, its dietary sources, and its effects on human metabolism. Studies that describe the potential role of TMAO in the etiology of cardiovascular and other diseases are also discussed.

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Crossref · 10.1146/annurev-nutr-071816-064732

Cites

133 of 133 references verified0 citation errors · 0 not checkable

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Claims the paper makes

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  • Premisenone given

    Observational and experimental studies indicate a strong positive relationship between higher plasma TMAO and adverse cardiovascular events such as myocardial infarction, stroke, and death.

    “Both observational and experimental studies suggest a strong positive correlation between increased plasma TMAO concentrations and adverse cardiovascular events, such as myocardial infarction, stroke, and death.”
    Quote in the paperSubstantial claim
  • Premisenone given

    Intestinal bacteria in the host make TMA from carnitine, choline, or choline-containing compounds.

    “Host intestinal bacteria produce its precursor trimethylamine (TMA) from carnitine, choline, or choline-containing compounds.”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    A clear mechanistic link between TMAO and diseases such as atherosclerosis has not yet been validated.

    “However, a clear mechanistic link between TMAO and such diseases is not yet validated.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Men with greater Firmicutes-to-Bacteroidetes enrichment produced more TMA after a challenge meal.

    “A recent study in men observed that people with higher Firmicutes to Bacteroidetes enrichment generated more TMA after a challenge meal (28).”
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  • Premisecitation

    Gut microbiota are necessary for dietary choline, choline-containing compounds, betaine, and L-carnitine to be converted to TMA.

    “We know that gut microbiota are required for these nutrients to be converted to TMA because gnotobiotic mice do not produce such TMA (1,96), and antibiotic treatment of standard mice decreases TMA formation (1).”
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  • Classified as probably not a substantial claim. 31

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    Premisenone given

    Most TMA is absorbed passively into the portal circulation and is efficiently oxidized to TMAO by hepatic FMOs.

    “Most of the TMA produced is passively absorbed into portal circulation, and hepatic flavindependent monooxygenases (FMOs) efficiently oxidize TMA to TMAO.”
    Quote in the paperSubstantial claim

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    Interpretationcitation

    TMAO is biologically active and has been proposed as a contributor to chronic human diseases such as atherosclerosis.

    “Trimethylamine N-oxide (TMAO) is a biologically active molecule and is a putative promoter of chronic diseases including atherosclerosis in humans.”
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    Premisecitation

    Some healthy women have modest trimethylaminuria at the onset of and during menstruation that then disappears.

    “In some normal healthy women, modest trimethylaminuria occurs just at the onset of and during menstruation and then disappears (82).”
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    • cites [82] Mitchell SC, 2001, Drug Metab. Dispos.

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    Premisecitation

    After 300 g/day of cooked brussels sprouts for three weeks, people had significant increases in urinary TMA/TMAO ratio, suggesting reduced TMA N oxidation.

    “After 300 g/day of cooked brussels sprouts for three weeks, people eating brussels sprouts showed significant increases in their urinary TMA/TMAO ratio, suggesting a decrease in TMA N oxidation (24).”
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    • cites [24] source

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    Premisecitation

    TMA can be used for methanogenesis in the gastrointestinal tract, and this pathway is active in human intestine bacteria including Methanomassiliicoccus, Methanomethylophilus, Methanobrevibacter smithii, and Methanosphaera stadtmanae.

    “TMA can be used for methanogenesis in the gastrointestinal tract; in human intestine, this pathway is active in bacteria belonging to the genera Methanomassiliicoccus and Methanomethylophilus (18,21,38) as well as in Methanobrevibacter smithii and Methanosphaera stadtmanae (41).”
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    Premisereasoning

    Human FMO3 mutations that cause TMA excretion in sweat and breath manifest as fish-odor syndrome, or trimethylaminuria.

    “Thus, mutations in FMO3 in humans that result in excretion of TMA in sweat and breath present as fish-odor syndrome (trimethylaminuria).”
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    Premisecitation

    A genomewide association study found no significant host genetic influences on circulating TMAO and proposed that diet and gut microbes may be the main determinants of circulating TMAO.

    “Although FMO3 and FMO1 genes are important in the formation of TMAO, a genomewide association study failed to find any significant host genetic influences on circulating TMAO concentrations and proposed that dietary factors and gut microbes may be the major determinants of circulating TMAO concentrations (49).”
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    Premisecitation

    In patients with renal dysfunction, circulating TMAO rises as kidney function falls, and abnormally high TMAO resolves after kidney transplantation.

    “The circulating TMAO concentrations of patients with renal dysfunction increased as kidney function decreased, and abnormally high TMAO concentrations resolved after kidney transplantation (106)”
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    Premisecitation

    FMO3 expression in liver changes across development: mRNA and protein appear in 30% of first-trimester fetal livers, are absent in second and third trimesters, reappear by 21 postnatal days, and rise to 8% of adult levels at about 9 months, 20% by 11 years, and adult levels only after 18 years.

    “Both mRNA and protein were found in 30% of fetal livers in the first trimester of pregnancy but not in the second and third trimesters; however, they could be detected again by 21 postnatal days.Expression of FMO3 then gradually increased to 8% of adult levels at about age nine months, 20% by 11 years, and did not reach adult levels until after 18 years (64, 133).”
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    Interpretationcitation

    Some microbial metabolism that produces TMA remains undiscovered.

    “The elucidation of microbial TMA-generating pathways is ongoing, and it is likely that part of TMAproducing microbial metabolism remains undiscovered (41).”
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    • cites [41] source

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    Premisecitation

    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).”
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    Premisenone given

    Most trimethylaminuria cases follow autosomal recessive inheritance.

    “most cases of trimethylaminuria are inherited in an autosomal recessive pattern.”
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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Whether higher TMAO concentrations cause or result from these diseases is debated.

    “Therefore, it is debated whether increased TMAO concentrations are the cause or result of these diseases.”
    Quote in the paperSubstantial claim

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    Premisecitation

    FMO3 also accepts pharmaceutical substrates including cimetidine, chlorpromazine, ketoconazole, morphine, propranolol, ranitidine, sulindac, tamoxifen, and tyramine.

    “In addition to TMA, other substrates for FMO3 include the pharmaceutical drugs cimetidine, chlorpromazine, ketoconazole, morphine, propranolol, ranitidine, sulindac, tamoxifen and tyramine (71).”
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    • cites [71] Mackay RJ, 2011, Clin. Biochem. Rev.

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    Premisecitation

    Orthologs and homologs of CntA/CntB and YeaW/YeaX occur in diverse gut microbiota, including Gammaproteobacteria, Betaproteobacteria, Firmicutes, and Actinobacteria, and appear absent in Bacteroidetes.

    “Orthologs and homologs of the CntA/CntB and YeaW/YeaX gene pairs are found in a variety of gut microbiota: Gammaproteobacteria (Klebsiella pneumoniae, E. coli, Citrobacter, Providencia, and Shigella), Betaproteobacteria (Achromobacter), Firmicutes (Sporosarcina), and Actinobacteria; they appear to be absent in Bacteroidetes (41).”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Carriers of an FMO3 mutation may have mild trimethylaminuria symptoms or temporary fish-like body odor episodes.

    “Carriers of an FMO3 mutation may have mild symptoms of trimethylaminuria or experience temporary episodes of fish-like body odor (71).”
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    • cites [71] Mackay RJ, 2011, Clin. Biochem. Rev.

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    Premisecitation

    Small amounts of FMO1 mRNA are present in the adult small intestine.

    “Small amounts of FMO1 mRNA are also found in the adult small intestine (71).”
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    • cites [71] Mackay RJ, 2011, Clin. Biochem. Rev.

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  • May combine two claims.

    Premisenone given

    TMAO is a small molecule of 75.1 Da and is readily filtered by the kidneys.

    “TMAO is a small molecule (75.1 Da) and is readily filtered by the kidneys.”
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    Premisecitation

    Testosterone suppresses FMO3 expression and estrogen induces it.

    “Testosterone suppresses and estrogen induces FMO3 expression.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    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).”
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    Premisecitation

    After radiolabeled TMA or TMAO is given to people, 94.5% of the dose label is excreted in urine within 24 h, 4% in feces, and less than 1% in breath.

    “After administration of radiolabeled TMA or TMAO to people, 94.5% of the dose label was excreted in the urine within 24 h; only 4% of the dose was excreted in the feces and <1% in the breath (2).”
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    Premisenone given

    In the chicken nephron, TMAO is passively excreted in proximal tubules via a probenecid-sensitive luminal transporter, while TMA N-oxidation uses a quinidine-sensitive basal transporter.

    “It is passively excreted in the proximal tubules of the chicken nephron via a probenecid-sensitive transporter at the luminal side, whereas N-oxidation of TMA occurs via a quinidine-sensitive transporter at the basal side.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    TMAO may worsen several chronic diseases, including atherosclerosis, diabetes, and chronic kidney disease.

    “it may exacerbate several chronic diseases including atherosclerosis, diabetes, and chronic kidney diseases (20).”
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    Premisecitation

    In Britain, the estimated incidence of carrier status for trimethylaminuria is 1%.

    “In Britain, it is estimated that the incidence of carrier status for trimethylaminuria is 1% (82)”
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    • cites [82] Mitchell SC, 2001, Drug Metab. Dispos.

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    More than 300 variants or single-nucleotide polymorphisms have been reported in FMO3.

    “More than 300 variants or single-nucleotide polymorphisms have been reported in FMO3.”
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    Premisecitation

    FMO1 mRNA and protein are expressed in human liver in the first trimester, decline in the second and third trimesters, and disappear by about the third postnatal day in liver and kidney.

    “FMO1 mRNA and protein are expressed in the human liver during the first trimester, declining gradually in the second and third trimesters, and disappearing completely by about the third postnatal day in the liver and kidney (71).”
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    • cites [71] Mackay RJ, 2011, Clin. Biochem. Rev.

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    Premisecitation

    Colonizing gnotobiotic mice with choline-converting bacteria raises cecal TMA production and lowers serum choline.

    “Colonization of gnotobiotic mice with choline-converting bacteria not only increases cecal TMA production but also lowers serum choline concentration (96).”
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    Premisecitation

    The adequate choline intake is 550 mg/day for men and 425 mg/day for women, adjusted upward in pregnancy and lactation; the upper limit ranges from 1,000 mg/day in children to 3,500 mg/day in adults.

    “The adequate intake is 550 mg/day for men and 425 mg/day for women, with upward adjustment in pregnant and lactating women; the upper intake limit ranges from 1,000 mg/day in children to 3,500 mg/day in adults (56).”
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    • cites [56] Inst. Med., Natl. Acad., 1998

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    Premisecitation

    Choline occurs in foods as free choline and choline esters, and these forms are absorbed differently in the intestine.

    “Choline is present as free choline and choline esters (such as PtdCho) in foods (130), and these forms of choline are absorbed differently in the intestines.”
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    • cites [130] source

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    Premisecitation

    In a small study of healthy Bavarian subjects, fish, meat, or egg intake was not associated with plasma TMAO, but dairy intake was positively associated with plasma TMAO.

    “In a small study in healthy Bavarian subjects, dietary intake of fish, meat, or eggs was not associated with plasma TMAO concentrations, but dairy intake was positively associated with plasma TMAO concentrations (94).”
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    Premisecitation

    100 g of spinach contains 577 mg betaine, 100 g of cod or beef contains 7 mg betaine, and 100 g of eggs contains less than 1 mg betaine.

    “For example, 100 g of spinach contains 577 mg betaine, 100 g of cod or beef contain 7 mg betaine, and 100 g of eggs contain <1 mg betaine.”
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    In 1998, the US Institute of Medicine set adequate intake and tolerable upper intake values for choline based on limited human studies.

    “In 1998, the US Institute of Medicine (Food and Nutrition Board) established adequate intake and tolerable upper intake limit values for choline, based on limited human studies (56).”
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    Premisecitation

    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).”
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    The foods richest in betaine are plant foods, especially spinach, beets, and grains grown in high-osmotic environments.

    “The foods that contain the most betaine are of plant origin, especially spinach, beets and grains grown in high osmotic environments (129, 130).”
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    Premisecitation

    L-carnitine bioavailability is higher in vegetarians than in carnivores, so less carnitine reaches lower-intestine bacteria in vegetarians.

    “The bioavailability of L-carnitine in vegetarians (who are adapted to low-carnitine diets) was higher than in carnivores (42); therefore, less carnitine reaches the bacteria of the lower intestine in vegetarians.”
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    Premisecitation

    100 g of cod contains 89 mg total choline, 100 g of beef contains 73 mg, and 100 g of eggs contains 266 mg total choline.

    “For example, 100 g of cod contains 89 mg total choline (choline + PtdCho + phosphocholine + sphingomyelin + glycerophosphocholine) compared to 100 g of beef, which contains 73 mg total choline, or 100 g of eggs, which contain 266 mg total choline (28).”
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    Premisecitation

    100 g of cod contains 300 mg TMAO, whereas 100 g of beef or egg contains less than 1 mg TMAO.

    “For example, 100 g of cod contains 300 mg TMAO compared to 100 g of beef or of egg, which contain <1 mg TMAO (28).”
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    Premisecitation

    TAAR5 is the most highly expressed TAAR gene in humans and may act as an olfactory detector of TMA that elicits innate behaviors.

    “TAAR5 is the most highly expressed TAAR gene in humans and may constitute an olfactory detector of TMA that elicits innate behaviors (117).”
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    Premisecitation

    TMAO production after an L-carnitine challenge was significantly greater in omnivores than vegans, and specific bacterial taxa were associated with dietary status and plasma TMAO.

    “TMAO production, following a challenge with L-carnitine, was significantly greater in omnivores versus vegans, and there were specific bacterial taxa associated with both dietary status and plasma TMAO concentration (63).”
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    Premisecitation

    Plants use betaine in their roots as an osmolyte to help retain intracellular water.

    “Plants use betaine in their roots as an osmolyte to help them retain intracellular water (33).”
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    Premisecitation

    TMAO and TMA are present at high concentrations in fish and other seafood, with marine fish having higher concentrations than freshwater fish.

    “TMAO and TMA are present in high concentrations in fish and other seafood.Marine fish (e.g., cod, haddock, halibut, herring, skate) have higher concentrations than do freshwater fish (e.g., trout) (9).”
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    Premisecitation

    Animal products such as meat, fish, poultry, and milk are highest in carnitine, while plants contain little carnitine.

    “Animal products like meat, fish, poultry, and milk (whey fraction) are highest in carnitine, whereas plants contain little carnitine (42).”
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    Premisecitation

    About 15% of egg PtdCho was converted to TMA, and peak plasma TMA occurred 6 to 8 h after egg ingestion.

    “About 15% of the PtdCho in eggs was converted to TMA, and peak plasma TMA concentrations were achieved between 6 and 8 h after ingestion of the eggs (79).”
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    Premisecitation

    The foods richest in choline are animal foods, especially eggs and liver, but most foods eaten contain some choline or choline compounds.

    “The foods that contain the most choline are of animal origin, especially eggs and liver; however, most of the foods we eat contain some amounts of choline or choline compounds (129, 130).”
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    Premisecitation

    100 g of asparagus contains 0.2 mg carnitine, 100 g of egg contains less than 1 mg, 100 g of cod contains 4 mg, and 100 g of beef contains 39 mg carnitine.

    “For example, 100 g of asparagus contains 0.2 mg carnitine, 100 g of egg contains <1 mg carnitine, 100 g of cod contains 4 mg carnitine while 100 g of beef contains 39 mg carnitine, (28).”
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    • cites [28] source

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    Premisecitation

    TMAO is a tissue osmolyte and a molecular chaperone that stabilizes proteins.

    “TMAO is an osmolyte in tissues and acts as a molecular chaperone that stabilizes proteins.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Choline is absorbed in the small intestine by mediated transport, whereas PtdCho is absorbed intact through lymph or hydrolyzed by pancreatic lipases and absorbed as glycerophosphocholine.

    “Choline is absorbed in the small intestine via mediated transport, whereas PtdCho is absorbed intact via the lymphatic system or is hydrolyzed by pancreatic lipases and absorbed as glycerophosphocholine (125).”
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    Premisecitation

    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).”
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    • cites [29] source

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    Premisecitation

    Human TAAR5 is selectively activated by TMA in a concentration-dependent manner but not by TMAO.

    “Human TAAR5 can be selectively activated in a concentrationdependent manner by TMA but not by TMAO (117).”
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    • cites [117] source

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    Premisecitation

    High circulating TMAO increases cholesterol influx into peritoneal macrophages, while cholesterol efflux or biosynthesis appears unchanged.

    “Even though high concentrations of circulating plasma TMAO increase cholesterol influx to peritoneal macrophages (118), cholesterol efflux or cholesterol biosynthesis appears to be unchanged.”
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    Premisecitation

    Trace amine-associated receptors are G protein-coupled receptors and olfactory receptors.

    “Trace amine-associated receptors (TAARs) belong to the family of G protein-coupled receptors and are olfactory receptors (117).”
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    Premisecitation

    Carnitine can be synthesized endogenously from lysine and methionine in kidney, liver, and brain.

    “Carnitine also can be synthesized endogenously from two essential amino acids, lysine and methionine (63).This occurs in kidney, liver, and brain (42).”
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    Interpretationreasoning

    These processes appear to be regulated by TMA or by other unidentified enzymatic substrates or products of FMO3.

    “Rather, these processes appear to be regulated by either TMA or other unidentified enzymatic substrates or products of FMO3.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Antibiotics eliminated the FMO3 substrate TMA and normalized intestinal cholesterol absorption and fecal neutral sterol loss in FMO3 antisense oligonucleotide-treated mice.

    “The administration of antibiotics eliminated the FMO3 substrate TMA and normalized intestinal cholesterol absorption and fecal neutral sterol loss seen in FMO3 antisense oligonucleotide-treated mice (121).”
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    Premiseown data

    In both clinical cohorts, kidney function was not normal; mean GFRs were 73 and 74 mL/min (range 60-87), compatible with some loss of kidney function.

    “In both the clinical cohorts, kidney function was not normal [normal glomerular filtration rate (GFR) is ∼100 mL/min]; the mean GFRs in both groups were 73 and 74 mL/min, respectively (range 60-87), values compatible with some loss of kidney function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Dietary TMAO supplementation decreased intestinal cholesterol absorption, consistent with reduced Niemann-Pick C1-like 1 expression.

    “Dietary supplementation of TMAO also decreased intestinal cholesterol absorption.The effect is consistent with reduced expression of the cholesterol transporter Niemann-Pick C1-like 1 but again does not explain reductions in RCT (118).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    People at risk for cardiovascular disease and stroke have high plasma TMAO and higher plasma concentrations of the TMAO precursors choline, betaine, and carnitine.

    “People at risk for CVD and stroke have high plasma TMAO concentrations; they also have higher concentrations of the TMAO precursors, i.e., choline, betaine, and carnitine in plasma.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    FMO3 knockdown in C57Bl/6 female mice greatly reduced hepatic FMO3 expression, increased plasma TMA, and reduced TMAO.

    “When C57Bl/6 female mice were fed either a low-or high-cholesterol diet, FMO3 knockdown greatly reduced hepatic FMO3 expression with corresponding increases in plasma TMA concentrations and reductions in TMAO concentrations (121).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FMO3 inhibition stimulated fecal neutral sterol loss and basal and liver X receptor-dependent macrophage reverse cholesterol transport.

    “FMO3 inhibition stimulated fecal neutral sterol loss and basal and liver X receptor-dependent macrophage RCT (121).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both studies conclude that FMO3 inhibition has positive effects on cholesterol and glucose homeostasis and that TMAO does not appear to be a critical player.

    “Thus, both studies conclude that FMO3 inhibition has definite positive effects on cholesterol and glucose homeostasis and that TMAO does not seem to be a critical player.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    That study concluded plasma TMAO was confounded by impaired kidney function because it increased with declining GFR.

    “The study concluded that plasma concentrations of TMAO were confounded by impaired kidney function because it was increased with declining GFR (85).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FMO3 knockdown altered intestinal cholesterol absorption, hepatic cholesterol ester storage, and macrophage reverse cholesterol transport in a dietary cholesterol-dependent manner.

    “FMO3 knockdown altered several steps of cholesterol balance, including intestinal cholesterol absorption, hepatic cholesterol ester storage, and macrophage RCT in a dietary cholesterol-dependent manner (121).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Mouse peritoneal macrophages incubated with TMA express scavenger receptors, accumulate cholesterol, and form foam cells.

    “Mouse peritoneal macrophages incubated with TMA express scavenger receptors, accumulate cholesterol, and form foam cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The choline doses used in that mouse heart failure study were twelve times higher than normal mouse diet choline and were not physiologic.

    “Interpretation of such results is difficult, as normal mouse diets contain 0.1% choline, and the authors treated mice with amounts of choline twelve times higher; these levels are not physiologic.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Normal mouse diets contain 0.1% choline.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    This cohort had a mean eGFR of 83 mL/min.

    “This cohort had a mean eGFR of 83 mL/min (63).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMAO feeding did not change hepatic cholesterol exporter expression, but it caused striking reductions in bile acid pool size and species and reduced expression of Cyp7a1 and Cyp27a1.

    “TMAO feeding did not change the expression of hepatic cholesterol exporters, but striking reductions in bile acid pool size and species, along with reduced expression of the cytochrome P450 family of enzymes, Cyp7a1 and Cyp27a1, were noted (118).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These results suggest that although chronic TMAO elevation can be harmful in mice, FMO3's ability to reorganize cholesterol balance is most likely not mediated through TMAO.

    “These results suggest that, although chronic elevation of TMAO can be detrimental in mice, the ability of FMO3 to reorganize cholesterol balance is most likely not mediated through TMAO.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Taken together, the results provide evidence that TMAO alters cholesterol elimination pathways and causes reductions in reverse cholesterol transport.

    “Taken together these results provide evidence that TMAO alters pathways for cholesterol elimination from the body and causes reductions in RCT.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Humans carry about 75% of plasma cholesterol in LDL particles, while mice carry most cholesterol in HDL particles.

    “Humans carry about 75% of their plasma cholesterol in low-density lipoprotein (LDL) particles, whereas mice carry most of their cholesterol in high-density lipoprotein (HDL) particles (57).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Jawien J, 2004, J. Physiol. Pharmacol.

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    There are strong data suggesting an association between TMAO and CVD risk, but equally strong inconsistencies.

    “Thus, there are strong data that suggest an association between TMAO and CVD risk, but there are equally strong inconsistencies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A meta-analysis of 11 studies and 13 cohorts (n=222,364) found fish consumption inversely associated with CVD and possibly reduced CVD mortality.

    “A meta-analysis of 11 eligible studies and 13 cohorts (n = 222,364) found that fish consumption was inversely associated with CVD and may even reduce mortality due to CVD (50,51).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] source

      Not checked in the free run.

    • cites [51] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Existing mouse data may support the hypothesis that TMAO causes atherosclerosis, but extrapolation from a particular mouse model to humans should be cautious.

    “Thus, the existing mouse data may support the hypothesis that TMAO causes atherosclerosis, but given the concerns discussed above, we should be cautious about extrapolating data from a particular mouse model to humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Chronic choline supplementation of LDLR-/- mice increased plasma TMAO and increased expression of inflammatory genes in vascular cells.

    “Chronic choline supplementation of atherosclerosis-prone low-density lipoprotein receptor (LDLR -/-) mice increased plasma TMAO concentrations and increased expression of inflammatory genes in vascular cells (52).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Herlaar E, 1999, Trends Mol. Med.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Uremia accelerates atherosclerosis and arterial calcification in patients with chronic renal failure.

    “Uremia accelerates atherosclerosis and arterial calcification in patients with chronic renal failure (22,74).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] source

      Not checked in the free run.

    • cites [74] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Apo E-knockout mice have a shift in plasma lipoproteins from HDL to cholesterol-enriched remnants of chylomicrons and VLDLs, and phenotypes similar to Apo E-deficient humans.

    “Apo E-knockout mice have a shift in plasma lipoproteins from HDL, the major lipoprotein in wild-type mice, to cholesterolenriched remnants of chylomicrons and VLDLs, and these mice have phenotypes similar to those of Apo E-deficient humans (57).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Jawien J, 2004, J. Physiol. Pharmacol.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Serum TMAO was inversely associated with eGFR and markedly higher in dialysis patients.

    “Serum concentration of TMAO was inversely associated with eGFR and was markedly higher in patients receiving dialysis (59,81); hemodialysis efficiently removed TMAO from blood (8).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [59] source

      Not checked in the free run.

    • cites [81] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    TMAO is cleared from plasma by the kidney.

    “TMAO is cleared from plasma by the kidney.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    If TMAO causes CVD, eating more fish should increase heart disease risk; it does not.

    “If TMAO causes CVD, then eating more fish should be associated with increased risk for heart disease; it is not.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Fish contain high concentrations of TMA, and gut bacteria convert this TMA to TMAO in people who eat fish.

  • May combine two claims.

    Premisereasoning

    TMAO is excreted by the kidneys and is elevated in patients with kidney disease.

    “As noted above in Section 2.3, TMAO is excreted by the kidneys, and this metabolite is elevated in patients with kidney disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Those macrophages had excess cholesterol accumulation and foam cell formation.

    “These macrophages had excess cholesterol accumulation and foam cell formation (118).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased TMAO was associated with systemic inflammatory markers and predicted reduced five-year survival.

    “Increased TMAO concentrations were associated with systemic inflammatory markers and predicted a reduced fiveyear survival (81).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Apo E knockout mice are considered one of the most relevant models for atherosclerosis because they are hypercholesterolemic and develop spontaneous arterial lesions.

    “Apo E knockout mice are considered to be one of the most relevant models for atherosclerosis because they are hypercholesterolemic and develop spontaneous arterial lesions (87).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMA can be used for methanogenesis in the gastrointestinal tract, and bacteria of the genera Methanomassiliicoccus and Methanomethylophilus have this pathway.

    “TMA can be used for methanogenesis in the gastrointestinal tract, and bacteria belonging to the genera Methanomassiliicoccus and Methanomethylophilus have this pathway (18,21,38,41).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] source

      Not checked in the free run.

    • cites [21] source

      Not checked in the free run.

    • cites [38] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockdown of FMO3 in LIRKO mice suppressed FoxO1 expression and improved glucose tolerance by upregulating SREBP2.

    “Knockdown of FMO3 in LIRKO mice suppressed FoxO1 expression (and improved glucose tolerance) by upregulating sterol regulatory element binding protein 2 (SREBP2) (77).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TMAO was used as a urinary marker in a mouse model of gastric tumorigenesis.

    “TMAO was used also as a urinary marker in a mouse model of gastric tumorigenesis (60).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Oral charcoal adsorbent AST-120 has been clinically used to remove uremic toxins such as indoxyl sulfate in advanced renal failure.

    “To this end, oral charcoal adsorbent (AST-120) has been clinically used to remove uremic toxins, such as indoxyl sulfate, in patients with advanced renal failure (86).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In C57BL/6J mice fed high-choline or TMAO-supplemented diets for six weeks, plasma TMAO increased and was associated with increases in tubulointerstitial fibrosis, collagen deposition, and kidney injury marker-1.

    “When C57BL/6J mice were fed either a high-choline diet or a diet supplemented with TMAO for six weeks, plasma concentrations of TMAO increased and were associated with corresponding increases in tubulointerstitial fibrosis and collagen deposition, as well as increases in kidney injury marker-1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    That study concluded increased TMAO excretion could be due to tubulointerstitial distortions.

    “The study concluded that this increased excretion of TMAO could be due to tubulointerstitial distortions (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SREBP2 directly activates microRNA 182, which regulates FoxO1 expression.

    “SREBP2 directly activates microRNA 182, which in turn regulates FoxO1 expression (77).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LIRKO mice cannot respond to insulin in the liver and display features of diabetes such as hyperglycemia, hyperinsulinemia, and dyslipidemia.

    “Liver insulin receptor knockout (LIRKO) mice are unable to respond to insulin in the liver and display several features of diabetes, such as hyperglycemia, hyperinsulinemia, and dyslipidemia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Existing mouse data may support the hypothesis that TMAO causes renal disease, but extrapolation from a particular mouse model to humans should be cautious.

    “Thus, the existing mouse data may support the hypothesis that TMAO causes renal disease, but given the concerns discussed in Section 5.1.4,scientists and clinicians should be cautious about extrapolating data from a particular mouse model to humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Introducing Lactobacillus paracasei in mice expressing human baby flora decreased fecal choline and was associated with reduced TMA and dimethylamine in liver and plasma lipoproteins.

    “Even though it needs to be demonstrated in humans, introducing Lactobacillus paracasei in mice expressing human baby flora decreased fecal choline and was associated with reduced concentrations of TMA and dimethylamine in the liver and plasma lipoproteins (73).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    Accumulation of TMAO in ESRD patients on chronic hemodialysis is mainly due to a previously unrecognized limitation of chronic dialysis.

    “It was suggested that the accumulation of TMAO in end-stage renal disease patients who receive chronic hemodialysis is mainly due to the previously unrecognized limitation of chronic dialysis (45).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In high-fat-fed C57Bl/6 mice, TMAO feeding increased diet-induced glucose intolerance, as measured by higher fasting insulin and HOMA-IR, along with altered insulin signaling and increased inflammatory markers.

    “In high-fat-fed C57Bl/6 mice, TMAO feeding increases the glucose intolerance induced by the diet as measured by higher fasting insulin levels and the homeostasis model assessment (HOMA) for insulin resistance scores along with altered insulin signaling and increased inflammatory markers (44).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The investigators did not determine with antibiotics whether conversion of choline to TMAO was required for the choline effects.

    “And the investigators did not determine, using antibiotics, whether conversion of choline to TMAO was required for the choline effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Long-term antibiotic use can promote antibiotic-resistant bacterial strains and repopulation of microbes after withdrawal.

    “However, long-term usage of antibiotics can promote the emergence of antibiotic-resistant bacterial strains and repopulation of microbes after its withdrawal.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMAO is cleared more efficiently than urea by normal kidney function but not by dialysis.

    “TMAO is cleared more efficiently than urea by the normal kidney function but not by dialysis (45).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    3,3-dimethyl-1-butanol significantly lowered plasma TMAO and mitigated choline-enhanced macrophage foam cell formation and atherosclerosis in Apoe-/- mice.

    “It also significantly lowered plasma TMAO concentrations and mitigated choline-enhanced macrophage foam cell formation and atherosclerosis in Apo e -/-mice (119).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    FMOs are major xenobiotic metabolizing enzymes.

    “One should also consider the side effects associated with inhibiting FMOs as they are major xenobiotic metabolizing enzymes (23).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibiting FMO enzymes may not be ideal because it causes TMA accumulation, leading to fishy odor and inflammation as observed in antisense oligonucleotide-treated mice.

    “Inhibiting FMO enzymes, however, may not be ideal as it causes accumulation of TMA, leading to a fishy odor and inflammation as observed in antisense oligonucleotide-treated mice (102, 121).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [102] source

      Not checked in the free run.

    • cites [121] source

      Not checked in the free run.

100 of 100

  • The paper relies on this without support.

    Plasma TMAO concentration is a valid proxy for the biologically relevant TMAO exposure at target tissues.

    “Both observational and experimental studies suggest a strong positive correlation between increased plasma TMAO concentrations and adverse cardiovascular events, such as myocardial infarction, stroke, and death.”
    “TMAO-mediated atherosclerosis could potentially be a significant cause of heart and kidney disease, but the underlying mechanisms whereby TMAO is related to heart and kidney disease need to be fully elucidated and validated.”

  • The paper relies on this without support.

    Fish contain high concentrations of TMA, and gut bacteria convert this TMA to TMAO in people who eat fish.

    “Fish contain high concentrations of TMA, which are converted to TMAO by bacteria in the gut of people who eat fish.”

  • The paper relies on this without support.

    Renal clearance determines plasma TMAO concentrations.

    “Because renal clearance is a determinant of plasma TMAO concentrations, kidney function and TMAO must be correlated even if TMAO does not cause kidney damage.”

  • The paper relies on this without support.

    Normal mouse diets contain 0.1% choline.

    “Interpretation of such results is difficult, as normal mouse diets contain 0.1% choline, and the authors treated mice with amounts of choline twelve times higher; these levels are not physiologic.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The paper gives conflicting sites for conversion of TMA to TMAO

    Minor

    The fish discussion attributes conversion of TMA to TMAO to gut bacteria, whereas the paper's pathway description assigns that conversion to enzymes in the liver.

  • The macrophage evidence is described as a different experiment

    Minor

    The evidence summary says macrophages were incubated with TMA. The detailed account instead describes macrophages taken from mice fed TMAO, changing both the compound and how the cells were exposed.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 9

  1. Chebotareva NA, 2007, Biochemistry, 72, 1478
  2. Hand SC, 1986, Am. J. Physiol., 250, R505
  3. Herlaar E, 1999, Trends Mol. Med., 5, 439
  4. Jawien J, 2004, J. Physiol. Pharmacol., 55, 503
  5. Mackay RJ, 2011, Clin. Biochem. Rev., 32, 33
  6. Mitchell SC, 2001, Drug Metab. Dispos., 29, 517
  7. US Dep. Aric., 2008, USDA Database for the Choline Content of Common Foods, Release 2
  8. Zeisel SH, 1986, Cancer Res, 46, 6136
  9. 10.1093/jn/133.5.1302 · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Zeisel, S. H., & Warrier, M.
Affiliations
University of North Carolina System (US)
Corresponding author
Zeisel, Steven H.
ORCID
Zeisel, Steven H.
Venue
Annual Review of Nutrition
Publisher
Annual Reviews
Published
2017-08-21
Volume
37
Issue
1
Pages
157-181
ISSN
  • 0199-9885 (ISSN-L)
  • 1545-4312
DOI
10.1146/annurev-nutr-071816-064732
OpenAlex
W2566137938
Cited by
475
References
133
Citations by year
2026: 25 · 2025: 60 · 2024: 57 · 2023: 75 · 2022: 64 · 2021: 70 · 2020: 51 · 2019: 42 · 2018: 26 · 2017: 4
FWCI
3.18
Type
journal article
Language
en
Open access
Licence
www.annualreviews.org/licenses/tdm (tdm)
Locations
  • Annual Review of Nutrition (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
Keywords
trimethylamine N-oxide, trimethylamine, gut microbiota, cardiovascular disease, heart disease, kidney disease, atherosclerosis, flavin-dependent monooxygenase, L-carnitine, choline, food sources, myocardial infarction, stroke
MeSH terms
Animals, Bacteria, Diet, Female, Heart Diseases, Humans, Kidney Diseases, Liver, Male, Methylamines, Microbiota

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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