Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk
Open accessAbstract
Normal platelet function is critical to blood hemostasis and maintenance of a closed circulatory system. Heightened platelet reactivity, however, is associated with cardiometabolic diseases and enhanced potential for thrombotic events. We now show gut microbes, through generation of trimethylamine N-oxide (TMAO), directly contribute to platelet hyperreactivity and enhanced thrombosis potential. Plasma TMAO levels in subjects (n > 4,000) independently predicted incident (3 years) thrombosis (heart attack, stroke) risk. Direct exposure of platelets to TMAO enhanced sub-maximal stimulus-dependent platelet activation from multiple agonists through augmented Ca(2+) release from intracellular stores. Animal model studies employing dietary choline or TMAO, germ-free mice, and microbial transplantation collectively confirm a role for gut microbiota and TMAO in modulating platelet hyperresponsiveness and thrombosis potential and identify microbial taxa associated with plasma TMAO and thrombosis potential. Collectively, the present results reveal a previously unrecognized mechanistic link between specific dietary nutrients, gut microbes, platelet function, and thrombosis risk.
AI snapshot
Written from the paper’s full text.
TL;DR
The paper links gut microbial production of trimethylamine N-oxide (TMAO) to increased platelet reactivity and thrombotic risk. Across human cohort data and mouse, germ-free, and microbiota-transplantation experiments, TMAO is shown to enhance agonist-stimulated platelet activation and shorten thrombosis times.
Key findings
- In a cohort of more than 4,000 subjects, plasma TMAO independently predicted incident myocardial infarction or stroke over 3 years; the highest versus lowest TMAO quartile had an adjusted 1.64-fold risk increase (p<0.001), with TMAO values ranging from 0.06 to 312 µM.
- TMAO directly increased human platelet responsiveness to ADP, thrombin, and collagen; it enhanced adhesion of whole-blood platelets to collagen under shear in 11 subjects (p<0.0001) and augmented submaximal agonist-triggered intracellular calcium release and IP3 signaling without affecting resting calcium.
- In mice, raising plasma TMAO acutely increased FeCl3-induced carotid thrombosis, with TMAO-injected animals showing 93.0±12.5 µM versus 7.2±0.5 µM in controls (p<0.001) and shorter occlusion times.
- Dietary choline or TMAO supplementation increased plasma TMAO and prothrombotic phenotypes; the choline effect was suppressed by antibiotics and absent in germ-free mice unless TMAO was provided directly. Cecal transplantation transmitted differences in TMAO levels, platelet aggregation, and thrombosis potential, with plasma TMAO and occlusion time negatively correlated across groups (R=−0.62, p<0.001).
Methods
- Human analyses used the Genebank cohort (n=4007) with adjudicated 3-year follow-up for MI, stroke, death, or revascularization; platelet studies used blood from healthy volunteers prescreened for low fasting TMAO, with aggregometry, microfluidic collagen adhesion, calcium imaging, and IP3 measurement.
- Mouse studies used chemically defined chow, choline-supplemented, or TMAO-supplemented diets, with or without oral broad-spectrum antibiotics; thrombosis was assessed by FeCl3 or Rose Bengal carotid injury, and TMAO was measured by stable isotope dilution LC/MS/MS.
- Germ-free C57BL/6J mice, conventionalization, and cecal microbial transplantation from high-TMAO C57BL/6J versus low-TMAO NZW/LacJ donors were used; cecal microbiota were profiled by 16S rRNA sequencing and shotgun metagenomics.
Limitations
- The paper states that the platelet “chemical sensor” for TMAO remains unknown, that no eukaryotic TMAO receptor has been reported, and that whether TMAO acts through a dedicated receptor or as an allosteric modulator of existing signaling is unresolved.
- The paper notes that TMAO can enter cells but its intracellular site of action in platelets is unknown.
- Evident from the text: the human evidence is an observational cohort association rather than a randomized intervention, and much of the causal evidence comes from animal and ex vivo models; microbial taxa associations are correlational, and in vitro TMA-producing species did not consistently match in vivo abundance patterns.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 36 cited sources checked · 0 supported · 0 flagged
- Findingown data
In washed human platelets, 100 μM TMAO increased aggregation triggered by varying thrombin doses.
“similar results were observed using washed human platelets briefly incubated in the presence vs. absence of TMAO (100 µM) and varying doses of thrombin instead of ADP as agonist (Figure 1B, right).”
Quote in the paperSubstantial claim - Findingown data
When platelet-rich plasma from healthy donors with low TMAO was exposed to 100 μM TMAO, the ADP aggregation dose-response curve shifted leftward (p<0.0001).
“overall, a leftward shift (p<0.0001) in the dose-response curve in the presence of high TMAO levels was observed (Figure 1B, left).”
Quote in the paperSubstantial claim - Findingown data
In mice, intraperitoneal TMAO injection raised plasma TMAO about tenfold to roughly 93 μM, compared with about 7 μM in saline controls, at the time of carotid injury (p<0.001, n≥5 per group).
“At the time of the carotid artery injury (2h following TMAO i.p. injection), a >10-fold increase in plasma TMAO was observed that is well within the (patho)physiological range observed in humans (Figure 1E; 93.0±12.5 µM vs. 7.2±0.5 µM TMAO in TMAO vs. vehicle, respectively; p<0.001; n≥5 per group).”
Quote in the paperSubstantial claim - Findingown data
TMAO increased adhesion of platelets from whole blood to collagen-coated surfaces under physiological shear (p<0.0001, n=11).
“TMAO significantly (p<0.0001) increased platelet adhesion within whole blood to immobilized collagen under physiological shear force.”
Quote in the paperSubstantial claim - Findingown data
TMAO preincubation did not change resting platelet intracellular calcium.
“Pre-incubation with TMAO showed no effect on resting platelet [Ca2+]i (Figure 2A).”
Quote in the paperSubstantial claim
- Findingown data
Differential microbial choline TMA lyase activity was successfully transplanted from donor mice to germ-free recipients, measured by conversion of d9-choline to d9-TMA in cecum.
“Successful transplantation of differential microbial choline TMA lyase enzyme activity in the donors (measured by conversion of d9-choline into d9-TMA in cecum) was observed in the recipients following transplantation (Figure 5B).”
Quote in the paperSubstantial claim - Findingown data
Clear differences in cecal microbial community structure were observed between the donor mice.
“Clear differences in community structure were visualized between cecal microbes recovered from the donors”
Quote in the paperNot a substantial claim - Findingown data
When extracellular free calcium was removed with EGTA, TMAO still produced an initial several-fold enhancement of the thrombin-evoked intracellular calcium rise.
“As seen in Figure 2C (left), under these conditions, platelet activation in the presence of TMAO resulted in an initial several-fold enhancement in rise of [Ca2+]i, indicating an intracellular source of Ca2+ is sufficient for TMAO induced augmentation in stimulus dependent rise in [Ca2+]i.”
Quote in the paperSubstantial claim - Findingown data
TMAO did not significantly change the rate of calcium entry from the extracellular pool.
“Subsequent addition of excess Ca2+ to the external media reveals sustained increase in [Ca2+]i, but no significant effect of TMAO on Ca2+ entry rate from the extracellular pool (Figure 2C and 2D).”
Quote in the paperSubstantial claim - Findingown data
Of ten taxa characteristic of C57BL/6J donors, the proportions of seven in recipient cecal microbes either trended or were significantly positively associated with TMAO and negatively associated with time to cessation of flow.
“of the ten taxa identified as characteristic for C57BL/6J donors (Figure 6B, taxa depicted in red), examination of these in recipient cecal microbes revealed that the proportions of seven taxa either trended or were significantly positively associated with TMAO and negatively with time to cessation of flow”
Quote in the paperSubstantial claim - Findingown data
Across all mouse groups, plasma TMAO was negatively correlated with time to blood flow cessation after carotid injury (R=-0.62, p<0.001).
“Examination of the relationship between plasma TMAO levels and a quantitative measure of thrombosis potential (time to cessation of blood flow using the carotid artery injury model) across all groups of mice studied revealed a significant negative correlation (R=−0.62; p<0.001; Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
Recipients of C57BL/6J cecal microbes on a choline-supplemented diet had significantly shortened time to blood flow cessation in an in vivo thrombosis assay.
“recipients of the C57BL/6J cecal microbes maintained on the choline supplemented diet also showed significant shortening of time to blood flow cessation during in vivo thrombosis assay”
Quote in the paperSubstantial claim - Findingown data
In mixing experiments, the hyperresponsive platelet aggregation phenotype tracked with platelet-poor plasma from choline-fed mice, not with the source of washed platelets.
“As shown in Figure 3F, enhanced platelet aggregation responses in add-back/mixing studies revealed that the hyperresponsive phenotype followed the choline diet derived platelet-poor plasma. In contrast, the source of the washed platelets (chow vs. choline diet fed animals) failed to impact overall extent of platelet aggregation monitored.”
Quote in the paperSubstantial claim - Findingown data
TMAO augmented IP3 signaling in platelets stimulated submaximally with thrombin or ADP.
“Finally, TMAO was seen to augment inositol-1,4,5-trisphosphate (IP3) signaling pathways in platelets with either submaximal thrombin (Figure 2E) or ADP (Figure 2F) as agonists by quantifying inositol phosphate levels.”
Quote in the paperSubstantial claim - Findingown data
In mice, TMAO injection shortened the time to carotid artery occlusion after FeCl3 injury compared with saline (p<0.001).
“Further, the occlusion time, monitored by direct visualization of when platelets cease to pass downstream of the growing thrombus, is significantly (p<0.001) shorter in TMAO injected mice (Figure 1F).”
Quote in the paperSubstantial claim - Findingown data
Genus Prevotella and order YS2 from the Cyanobacteria phylum were C57BL/6J donor characteristic taxa that in recipients were positively associated with TMAO and negatively associated with time to occlusive clot formation after FDR adjustment.
“Genus Prevotella and order YS2 from the Cyanobacteria phylum are examples of C57BL/6J donor characteristic taxa identified by the LEfSe analyses that in recipients were positively associated (after FDR adjustment) with TMAO and negatively with time to occlusive clot formation”
Quote in the paperNot a substantial claim - Findingown data
In mice, diets supplemented with choline or TMAO shortened in vivo thrombosis time after FeCl3 carotid injury, indicating a more prothrombotic state.
“Consistently, in vivo thrombosis potential, as monitored by time to blood flow cessation in the carotid artery following FeCl3 injury, was shortened (indicating a more prothrombotic phenotype) in mice with heightened TMAO levels (choline or TMAO supplemented diet groups) (Figure 3D).”
Quote in the paperSubstantial claim - Findingown data
In germ-free mice, dietary TMAO significantly shortened the time to blood flow cessation.
“Moreover, provision of dietary TMAO within the germ-free mice (bypassing the need for gut microbes to elevate TMAO) resulted in significant shortening in the time to cessation of blood flow (Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
TMAO increased the rise in platelet intracellular calcium evoked by submaximal thrombin in a dose-dependent way.
“However, exposure to physiological levels of TMAO enhanced submaximal thrombin-evoked augmentation of platelet [Ca2+]i in a dose-dependent manner (Figure 2A and 2B).”
Quote in the paperSubstantial claim - Findingown data
Chronic supplemental dietary choline caused a significant shift in the overall cecal microbial community.
“Distinct (nonoverlapping) clusters were observed (Figure 4C, p<0.001 for Student’s t test with 1,000 Monte Carlo simulations) suggesting chronic exposure to supplemental dietary choline induced a significant rearrangement in the overall cecal microbial composition.”
Quote in the paperSubstantial claim - Findingown data
TMAO also increased the rise in platelet intracellular calcium triggered by submaximal ADP (1 μM).
“In parallel studies TMAO similarly increased submaximal ADP (1 µM) - triggered rise in platelet [Ca2+]i (Figure S2, panel A and B).”
Quote in the paperSubstantial claim - Findingown data
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).”
Quote in the paperSubstantial claim0 of 2 sources checked - Findingown data
Germ-free mice that received cecal contents from C57BL/6J donors had about twice the plasma TMAO level of mice that received cecal contents from NZW/LacJ donors when the recipients were on comparable diets.
“germ-free recipients following microbial transplantation with C57BL/6J cecal contents showed a significant ~ 2-fold increase in plasma TMAO levels compared to recipients on the comparable diets receiving microbial transplantation with NZW/LacJ cecal contents”
Quote in the paperSubstantial claim - Findingown data
Of fourteen taxa characteristic of NZW/LacJ donors, the proportions of eight in recipient cecal microbes either trended or were significantly negatively associated with TMAO and positively associated with time to cessation of flow.
“of the fourteen taxa identified as being characteristic of the NZW/LacJ donors in LEfSe analyses (Figure 6B, taxa depicted in blue), when examined in recipient cecal microbes, the proportions of eight taxa either trended or were significantly negatively associated with TMAO levels and positively associated with time to cessation of flow”
Quote in the paperSubstantial claim - Findingown data
TMAO supplementation increased ex vivo platelet aggregation responses to submaximal ADP, collagen, and arachidonic acid.
“Notably, TMAO supplementation similarly enhanced ex vivo platelet aggregometry responses to submaximal levels of each of the agonists examined (Figure 3C).”
Quote in the paperSubstantial claim - Findingown data
Oral antibiotics inhibited the effect of dietary choline on in vivo thrombosis.
“Importantly, the effect of dietary choline on in vivo thrombosis was inhibited by concurrent oral ABS administration, which suppresses the gut microbiota and TMAO levels (Figure 3D; TMAO levels in Figure 3B).”
Quote in the paperSubstantial claim - Findingown data
Mice given choline- or TMAO-supplemented diets for six weeks showed greater ex vivo ADP-induced platelet aggregation.
“In parallel, ex vivo platelet aggregation induced by ADP stimulation was significantly increased in these groups (Figure 3B).”
Quote in the paperSubstantial claim - Findingown data
TMAO's effect on platelet function is dose-dependent across the physiological range of TMAO concentrations observed in humans and animal models.
“the effect of TMAO on platelet function was also dose-dependent across the physiological range of TMAO concentrations observed in both humans and in animal models.”
Quote in the paperSubstantial claim - Findingown data
TMAO enhances IP3 generation in platelets.
“In addition, studies examining the effect of TMAO on IP3 generation in platelets, a second messenger signaling molecule produced by various phospholipase C isoforms that triggers intracellular Ca2+ release leading to platelet activation, similarly showed TMAO-dependent enhancement.”
Quote in the paperSubstantial claim - Interpretationown data
At physiological concentrations, TMAO directly increases human platelet responsiveness to several different agonists, including ADP, thrombin, and collagen.
“Cumulatively, the above data demonstrate that physiological levels of TMAO directly enhance platelet responsiveness to multiple distinct agonists (ADP, thrombin and collagen).”
Quote in the paperSubstantial claim - Premisecitation
Isotope tracer studies before and after oral antibiotics affirmed that gut microbes are obligatory for TMAO generation in humans.
“Moreover, an obligatory role for gut microbes in TMAO generation in humans was affirmed by two distinct studies involving ingestion of either isotope labeled phosphatidylcholine or isotope labeled carnitine as tracer before versus following exposure to an oral cocktail of poorly absorbed antibiotics to suppress intestinal microbes (Tang et al., 2013; Koeth et al., 2013).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
TMAO promotes platelet hyperresponsiveness by increasing stimulus-dependent release of calcium from intracellular stores.
“TMAO promotes platelet hyperresponsiveness by enhancing stimulus-dependent release of Ca2+ from intracellular Ca2+ stores”
Quote in the paperSubstantial claim - Interpretationown data
Intracellular calcium stores are sufficient to support TMAO's augmentation of stimulus-dependent platelet calcium rise.
“As seen in Figure 2C (left), under these conditions, platelet activation in the presence of TMAO resulted in an initial several-fold enhancement in rise of [Ca2+]i, indicating an intracellular source of Ca2+ is sufficient for TMAO induced augmentation in stimulus dependent rise in [Ca2+]i.”
Quote in the paperSubstantial claim - Interpretationown data
Gut microbes modulate thrombosis potential in vivo.
“The present studies reveal the interesting finding that gut microbes modulate thrombosis potential in vivo.”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse FeCl3 carotid artery injury model and platelet aggregometry measurements are valid proxies for human thrombosis and platelet function.
- Premisecitation
Multiple clinical studies have found associations between plasma TMAO and coronary atherosclerotic plaque burden and cardiovascular disease risk.
“Finally, an association between plasma TMAO levels and both the extent of coronary atherosclerotic plaque burden and CVD risks has been observed in multiple distinct clinical studies (Wang et al., 2011; Tang et al., 2013; Tang et al., 2014; Lever et al., 2014; Tang et al., 2015).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning
The influence of gut microbes on thrombosis risk via TMAO production requires a dietary input capable of producing TMA, such as choline or phosphatidylcholine.
“The influence of gut microbes on thrombosis risk via TMAO production requires the presence of an appropriate dietary input capable of producing TMA (e.g. foods rich in choline or phosphatidylcholine), the precursor for TMAO generation.”
Quote in the paperSubstantial claim - Interpretationown data
Gut microbes are required for the choline diet-dependent increase in thrombosis.
“Gut microbes play an obligatory role in choline diet dependent enhancement in thrombosis”
Quote in the paperSubstantial claim - Interpretationown data
Gut microbes, through TMAO generation, can directly modulate platelet hyperresponsiveness and clot formation rate in vivo.
“The present studies expand upon these findings, and show that gut microbes, via generation of TMAO, can directly modulate platelet hyperresponsiveness and clot formation rate in vivo.”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse FeCl3 carotid artery injury model and platelet aggregometry measurements are valid proxies for human thrombosis and platelet function.
- Premisecitation
Gut microbes take part in a metaorganismal pathway that contributes to atherosclerosis.
“recent studies reveal participation of gut microbes in a metaorganismal pathway that contributes to the development of atherosclerosis (Wang et al., 2011; Koeth et al., 2013; Tang et al., 2013; Gregory et al., 2015).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Gut microbes are obligatory for choline diet-enhanced thrombosis, as confirmed in germ-free mice and in conventional mice with versus without oral poorly absorbed broad-spectrum antibiotics.
“an obligatory role of gut microbes in choline dietenhanced thrombosis was confirmed both in studies using germ-free mice and in conventional mouse studies in the presence versus absence of oral poorly absorbed broad spectrum antibiotics.”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse FeCl3 carotid artery injury model and platelet aggregometry measurements are valid proxies for human thrombosis and platelet function.
- Interpretationown data
The in vivo microbial community context is more relevant to global TMA/TMAO production than the in vitro TMA-producing ability of a single species.
“These results underscore the complex community dynamic operating in vivo is more relevant to global TMA/TMAO production, as opposed to the in vitro ability of an individual microbial species to produce TMA from choline.”
Quote in the paperSubstantial claim - Premisecitation
Greater platelet reactivity is associated with larger end-organ injury and worse prognosis.
“enhanced platelet reactivity is associated with both the extent of end organ injury and adverse prognosis (Frossard et al., 2004; Tantry et al., 2013).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Circulating TMAO levels are associated with cardiovascular disease risks in multiple distinct clinical studies and cohorts.
“circulating levels of TMAO have been shown in multiple distinct clinical studies and cohorts to be associated with CVD risks”
Quote in the paperNot a substantial claim0 of 3 sources checked - Study design and conductown data
Platelet counts and other metabolic parameters did not differ in a way that explained the observed in vivo thrombosis effects.
“We also examined the impact of each dietary intervention on platelet counts, along with other metabolic parameters (Table S1), and saw no differences to account for the observed effects on in vivo thrombosis potential.”
Quote in the paperSubstantial claim - Premisecitation
Mechanistic work linking the TMAO production pathway to cardiovascular risk has focused on TMAO and FMO3 in atherosclerotic plaque development, sterol and glucose metabolism, and macrophage phenotype.
“Insights into the mechanisms through which the meta-organismal pathway responsible for TMAO production are associated with enhanced CVD risks have thus far focused on the involvement of TMAO and FMO3 in atherosclerotic plaque development, altered sterol and glucose metabolism, and changes in macrophage phenotype (Wang et al., 2011 ; Koeth et al., 2013; Miao et al., 2015 ; Shih et al., 2015; War”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
A diet rich in choline alters microbial composition and function.
“a diet rich in choline alters microbial composition and function.”
Quote in the paperSubstantial claim - Interpretationreasoning
The site of TMAO action in platelets is at a molecular level at or proximal to the IP3 generation step.
“These observations collectively suggest the site of TMAO action in platelets is at a molecular level at or proximal to this step.”
Quote in the paperSubstantial claim - Premisecitation
A Western diet enriched in TMAO precursors such as choline, phosphatidylcholine, and carnitine is associated with increased risk of myocardial infarction, stroke, and death.
“numerous large scale epidemiological studies have noted a relationship between a Western diet, which is enriched in known nutrient TMAO precursors (e.g. choline, phosphatidylcholine and carnitine), and enhanced risk for myocardial infarction, stroke and death”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationown data
Gut microbes, via TMAO generation, participate in modulating platelet function and generating a prothrombotic phenotype in vivo.
“the present work reveals the clinically relevant discovery that gut microbes, via generation of TMAO, participate in modulating platelet function and generation of a prothrombotic phenotype in vivo.”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse FeCl3 carotid artery injury model and platelet aggregometry measurements are valid proxies for human thrombosis and platelet function.
- Interpretationown data
Choline diet-enhanced platelet responsiveness and in vivo thrombosis potential are transmissible traits via cecal microbial transplantation.
“Cecal microbial transplantation studies confirm that both choline diet-enhanced platelet responsiveness and in vivo thrombosis potential are transmissible traits.”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse FeCl3 carotid artery injury model and platelet aggregometry measurements are valid proxies for human thrombosis and platelet function.
- May combine two claims. 30
- The quote only partly states this claim. 2
- Classified as probably not a substantial claim. 13
May combine two claims.
FindingcitationIn a cohort of 4007 stable patients evaluated electively for cardiac disease, higher plasma TMAO concentrations were linked to greater 3-year incidence of myocardial infarction or stroke, and this link remained after adjustment for cardiovascular history, standard risk factors, kidney function, and medications; the adjusted risk for the top versus bottom quartile was 1.64-fold (p<0.001).
“Plasma TMAO levels in subjects (N>4000) independently predicted incident (3 yr) thrombosis (heart attack, stroke) risk.”
- Also stated in: § Plasma TMAO levels predict incident thrombotic event risk (myocardial infarction and stroke) · plain
“Importantly, the association between TMAO and incident thrombosis risk was observed even following adjustments for CVD history, traditional CVD risk factors, renal function and medication use (4th quartile level versus 1st quartile, adjusted 1.64-fold risk, p<0.001; Figure 1A).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tang et al., 2013 source
Not checked in the free run.
- Also stated in: § Plasma TMAO levels predict incident thrombotic event risk (myocardial infarction and stroke) · plain
May combine two claims.
Findingown dataIn all mouse groups, nine cecal taxa had proportions associated with plasma TMAO, and fifteen had proportions associated with in vivo thrombosis time (FDR-adjusted p≤0.1).
“In further analyses of the detected cecal genera within all groups of mice, 9 taxa were identified whose proportions were significantly associated with plasma TMAO levels (FDR adjusted p≤0.1), and 15 taxa were identified whose proportions were significantly associated with in vivo thrombosis potential (i.e. occlusion time; FDR adjusted p≤0.1) (Table S2 and Figure S4, panel A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn germ-free mice, dietary choline did not produce TMA/TMAO or a prothrombotic phenotype.
“In contrast, within the germ-free mice, supplementation with choline no longer produced TMA (and hence TMAO) or the prothrombotic phenotype.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn mice supplemented with TMAO, oral antibiotics did not significantly alter plasma TMAO or platelet aggregation.
“Importantly, provision of ABS to the TMAO supplemented group did not have a significant effect on either plasma TMAO levels, or platelet aggregation (Figure 3B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA choline-supplemented diet caused a significant prothrombotic phenotype in C57BL/6J mice (p=0.0002 vs chow), while NZW/LacJ mice showed only a trend toward shorter occlusion time (p=0.07).
“Interestingly, whereas a choline supplemented diet fed to C57BL/6J mice provoked a significant prothrombotic phenotype (p=0.0002 relative to chow), the NZW/LacJ mice on the choline supplemented (versus chow) diet exhibited only a trend (p=0.07) toward reduced carotid artery occlusion time following FeCl3-induced injury (Figure S6, panel A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA brief 10-minute exposure to TMAO enhanced agonist-triggered intracellular calcium rise and platelet aggregation.
“The stimulatory effect of TMAO on platelet responsiveness to agonist was observed to occur rapidly, since only brief exposure (10 min) to TMAO significantly enhanced stimulus triggered rise in [Ca2+]i (data not shown) and platelet aggregation (Figure S2, panel C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe proportion of Lachnospiraceae in recipient cecal microbes was significantly associated with TMAO (p<0.0001) and with occlusion time (p=0.01).
“Lachnospiraceae with TMAO, p<0.0001, and with occlusion time, p=0.01”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataEight taxa were associated with both plasma TMAO and occlusion time; taxa linked to higher TMAO were linked to shorter occlusion time, and taxa linked to lower TMAO were linked to longer occlusion time.
“The proportions of 8 taxa were significantly associated with both plasma TMAO levels and occlusion time, and in every case, microbial taxa positively associated with higher plasma TMAO levels were associated with shorter time to blood flow cessation (more prothrombotic), whereas taxa significantly associated with reduced TMAO levels were associated with longer time to blood flow cessation (Table S”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRecipients of C57BL/6J cecal contents on a choline-supplemented diet had an approximately tenfold rise in plasma TMAO and increased platelet responsiveness to submaximal ADP compared with chow-fed controls.
“recipient mice following microbial transplantation with C57BL/6J cecal contents on the choline supplemented diet showed ~10-fold increase in plasma TMAO level and accompanying enhanced platelet responsiveness to submaximal ADP dose during platelet aggregometry studies compared with chow-fed controls”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe proportion of Allobaculum in recipient cecal microbes was significantly associated with plasma TMAO levels (p<0.0001) and with occlusion time (p=0.01).
“Allobaculum with TMAO, p<0.0001, and with occlusion time, p=0.01”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAllobaculum abundance was positively associated with TMAO and with shorter carotid occlusion time.
“For example, the proportion of Allobaculum, a high choline diet characteristic taxa, was significantly positively associated with TMAO levels and shortened internal carotid artery occlusion times (Figure 4E, left; Figure S4).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataGenus Peptococcaceae was characteristic of NZW/LacJ donors and in recipients was significantly negatively associated with TMAO and positively associated with in vivo time to occlusive clot formation.
“The genus Peptococcaceae is an example of a taxa identified as being characteristic of the NZW/LacJ donors and which was observed to be both significantly negatively associated with TMAO levels and positively associated with in vivo time to occlusive clot formation within recipients”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe proportion of Candidatus Arthromitus in recipient cecal microbes was significantly associated with TMAO (p<0.0001) and with occlusion time (p=0.007).
“Candidatus Arthromitus with TMAO, p<0.0001, and with occlusion time, p=0.007”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataRecipients of NZW/LacJ cecal microbes on a choline-supplemented diet had a blunted rise in TMAO relative to C57BL/6J recipients and a correspondingly smaller effect of the choline diet on platelet responsiveness and in vivo thrombosis potential.
“a blunted (relative to C57BL/6J) rise in TMAO in the recipients receiving NZW/LacJ cecal microbes and placed on choline supplemented diet was observed, with a correspondingly reduced effect of choline diet on both platelet responsiveness and in vivo thrombosis potential”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA high-choline diet shifted the microbial community composition within each recipient group, but the differences between and similarities with the respective donors remained visible.
“exposure to the high choline diet induced a shift in community composition within each recipient group, but the differences between (and similarities with their respective donor) the microbial community compositions in the respective recipients remained visible”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataMice given choline- or TMAO-supplemented diets for six weeks had higher plasma TMAO levels.
“Examination of plasma TMAO revealed elevated levels in mice provided dietary supplementation with either choline or TMAO.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter transplantation, recipients of C57BL/6J cecal microbes had cecal microbial composition similar to C57BL/6J donors, and recipients of NZW/LacJ cecal microbes had composition similar to NZW/LacJ donors.
“recipients of C57BL/6J cecal microbes showed cecal microbial composition similar to the C57BL/6J donors, and recipients of NZW/LacJ cecal microbes show cecal microbial composition similar to the NZW/LacJ donors”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataShotgun metagenomic sequencing of cecal microbiota from mice on three diets detected more than 6000 species and strains.
“Over 6000 species and strains were detected altogether.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn a Rose Bengal photochemical injury model, one week of dietary TMAO or choline raised plasma TMAO and significantly shortened occlusion time.
“Notably, dietary TMAO or choline supplementation each markedly increased plasma TMAO levels, and were accompanied by significant shortening of occlusion time (Figure 3E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOral broad-spectrum, poorly absorbed antibiotics reduced plasma TMAO and suppressed the increase in platelet aggregation caused by dietary choline.
“Moreover, the enhancing effect of dietary choline on platelet aggregation was suppressed in mice receiving oral ABS, which markedly reduces plasma TMAO levels (Figure 3A and 3B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLEfSe identified eight cecal taxa characteristic of choline versus chow diet; choline increased three genera and decreased five.
“In total, 8 taxa were identified through LEfSe analyses as being characteristic of choline vs. chow diet (Figure 4D), where choline diet significantly increased proportions of 3 genera (Figure S3, panels A, B and C) and decreased 5 genera (Figure S3, panels D, E, F,G and H).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataIsotope-labeled TMAO can enter cells.
“Studies with isotope labeled TMAO reveal it can enter cells (data not shown)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataTMAO's effect on platelet reactivity and in vivo thrombosis is rapid and reversible.
“the effect of TMAO on platelet reactivity and in vivo thrombosis was observed to be both rapid and reversible.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataCholine supplementation increases total cecal microbial choline TMA lyase activity, with parallel increases in plasma TMAO and in the proportions of specific taxa associated with TMAO.
“with choline supplementation, total cecal microbial choline TMA lyase activity was shown to increase, with parallel increases in both plasma TMAO levels and proportions of specific taxa associated with TMAO.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
FindingcitationElevated TMAO levels are independently associated with incident risk for thrombotic events (myocardial infarction or stroke) in over 4000 subjects, even after adjustment for multiple risk factors, medication use, and CVD status.
“elevated TMAO levels are independently associated with incident risk for thrombotic events (myocardial infarction or stroke) in subjects, even following adjustments for multiple risk factors, medication use and CVD status.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTMAO enhances platelet Ca2+ release and activation in response to multiple agonists (ADP, thrombin, collagen, and arachidonic acid) under submaximal stimulation; the effect is not stimulus specific.
“the effect of TMAO on platelet hyperresponsiveness is not stimulus specific; rather, multiple distinct agonists including ADP, thrombin, collagen and arachidonic acid all showed TMAO-dependent enhancement in Ca2+ release from platelet intracellular stores and activation in the setting of submaximal agonist stimulation”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationPlatelet activation, aggregation, and formation of an occlusive intra-arterial thrombus are essential steps in atherothrombotic disease.
“Platelet activation, aggregation and the subsequent generation of an occlusive intra-arterial thrombus are essential steps in atherothrombotic disease”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe TMAO meta-organismal pathway has clinical and mechanistic links with atherosclerotic plaque development and whole-body cholesterol and sterol metabolism.
“The TMAO meta-organismal pathway has been shown to possess numerous clinical and mechanistic links (Figure 7A) with both atherosclerotic plaque development and whole body cholesterol and sterol metabolism”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPlatelet hyperreactivity and thrombosis risk are increased in conditions linked to atherosclerotic heart disease, including hyperlipidemia, oxidative stress, and hyperglycemia.
“Platelet hyperreactivity and thrombosis risk are enhanced in the setting of numerous conditions associated with atherosclerotic heart disease, such as hyperlipidemia, oxidant stress, and hyperglycemia (Podrez et al., 2007; Chen et al., 2008; Zhu et al., 2012a).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationDietary nutrients containing TMA, such as phosphatidylcholine, choline, and carnitine, can be used by gut microbes as a carbon source; the TMA produced travels to the liver and is converted by host hepatic FMOs to TMAO.
“Briefly, specific trimethylamine (TMA) containing dietary nutrients, such as phosphatidylcholine, choline, and carnitine, can be used by gut microbes as a carbon fuel source. A waste product produced is TMA, which is carried via the portal circulation to the liver where it is rapidly converted by a family of enzymes, host hepatic flavin monooxygenases (FMOs), into TMA N-oxide (TMAO) (Wang et al.,”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wang et al., 2011 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Interpretationnone givenAdditional microbial TMA lyases beyond those already reported exist and can contribute to TMA/TMAO production.
“Moreover, additional microbial TMA lyases no doubt exist that can contribute to TMA/TMAO production besides those already reported.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationAnimal studies show that dietary TMAO is pro-atherogenic, and dietary precursors such as choline, carnitine, and gamma butyrobetaine accelerate atherosclerosis only when gut microbiota and TMA/TMAO generation are intact.
“Animal model studies show direct provision of TMAO within the diet is pro-atherogenic, and similarly, provision of its dietary precursors (e.g. choline, carnitine, gamma butyrobetaine) also accelerates atherosclerosis development, but only in the setting of intact gut microbiota and TMA/TMAO generation (Wang et al., 2011; Koeth et al., 2013; Koeth et al, 2014).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTargeted suppression of microbial TMA/TMAO production inhibits diet-induced atherosclerosis.
“targetted suppression of microbial TMA/TMAO production has recently been shown to inhibit diet induced atherosclerosis”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al, 2015 source
Not checked in the free run.
May combine two claims.
Interpretationown dataTMAO itself, not TMA, mediates the observed platelet hyperresponsiveness ex vivo and the pro-thrombotic phenotype in vivo.
“results of platelet aggregometry studies with direct addition of chemically pure TMAO, as well as studies employing germ-free mice and dietary TMAO supplementation, both strongly indicate that it is TMAO itself, and not TMA, that mediates the observed platelet hyperresponsiveness ex vivo, and the pro-thrombotic phenotype in vivo.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTMA is a well-known ligand for the olfactory G-protein coupled receptor TAAR5, which is specific for TMA and dimethylamine but reportedly does not recognize TMAO or numerous alternative methylamines.
“TMA is a well-known ligand for an olfactory G-protein coupled receptor, trace amine-associated receptor 5 (TAAR5), which is specific for TMA and dimethylamine, but reportedly does not recognize either TMAO or numerous alternative methylamines”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wallrabenstein et al., 2013 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTMAO has both hydrophobic and hydrophilic properties and can alter protein conformation and stability.
“TMAO is rather unique and possesses both hydrophobic and hydrophilic properties and the known ability to alter protein confirmation and stability”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll studies were repeated at least three independent times, with biological replicate numbers shown for each experiment.
“All studies were repeated at least 3 independent times with the number of biological replicates (animal numbers) for a given experiment shown.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenAdjustments were made for individual traditional risk factors including age, sex, SBP, LDL, HDL, triglycerides, smoking, diabetes, estimated creatinine clearance, medications, and CVD status.
“Adjustments were made for individual traditional risk factors including age, sex, SBP, LDL, HDL, triglycerides, smoking, diabetes, estimated creatinine clearance, medications, and CVD status.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAnti-platelet agents are a cornerstone of current pharmacological treatment and prevention of acute CVD complications, but their use is limited by bleeding risk.
“anti-platelet agents are a cornerstone of current pharmacological interventions for the treatment and prevention of acute complications of CVD. These interventions are, however, hampered by their potential for bleeding as a complication”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Jennings, 2009 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenHuman platelet donors were prescreened and confirmed to have fasting TMAO below 2.5 μM on the day of blood draw.
“Donors were prescreened and confirmed to have fasting TMAO <2.5 µM the day of blood draw.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Before this study, the involvement of gut microbes and TMAO in platelet function and thrombosis risk in vivo had not been reported.
“The involvement of gut microbes and TMAO in modulation of platelet function and thrombosis risks in vivo has not yet been reported.”
The paper relies on this without support.
The mouse FeCl3 carotid artery injury model and platelet aggregometry measurements are valid proxies for human thrombosis and platelet function.
“thrombosis potential (FeCl3 carotid artery injury model) in each group of mice are shown in Figure 5C and D.”
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?
The TMAO pathway promotes the development of atherosclerosis and thrombosis.
“The mechanism by which TMAO induces stroke is not well understood; however, it is widely established that the TMAO pathway promotes the development of atherosclerosis and thrombosis.11,26,27”
From Association of L-α Glycerylphosphorylcholine With Subsequent Stroke Risk After 10 Years (2021) · cites this paper as [27]
TMAO has been implicated in metabolic, cardiovascular, and cerebrovascular disease.
“The microbial-derived metabolite trimethylamine N-oxide (TMAO) has been implicated in metabolic [5], cardiovascular [6, 7], and cerebrovascular [8] disease.”
From The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease (2018) · cites this paper as [8]
TMAO has been implicated in cardiovascular diseases, contributing to platelet hyperreactivity, increased thrombosis risk, and endothelial dysfunction.
“TMAO has been implicated in cardiovascular diseases, contributing to platelet hyperreactivity, increased thrombosis risk, and endothelial dysfunction [63,64,65].”
From The Gut–Brain–Microbiota Connection and Its Role in Autism Spectrum Disorders (2025) · cites this paper as [63]
TMAO is primarily produced by the small intestinal microbiota from dietary precursors including choline, betaine, carnitine, and deoxycarnitine.
“Another gut-derived metabolite, Trimethylamine N-oxide (TMAO), is primarily produced by the small intestinal microbiota from dietary precursors, including choline, betaine, carnitine, and deoxycarnitine, which are abundant in meat, eggs, and dairy products.”
From The Gut–Brain–Microbiota Connection and Its Role in Autism Spectrum Disorders (2025) · cites this paper as [63]
Recent human observational and interventional studies show that TMAO levels can rise substantially (more than 10 micromol/L) with chronic supplementation.
“recent human observational and interventional studies show that TMAO levels can increase substantially (>10 lM) with chronic supplementation.4,5”
From Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women (2019) · cites this paper as [4]
TMAO directly interacts with human and murine platelets, increasing their responsiveness and promoting a prothrombotic phenotype.
“TMAO has been shown to directly interact with platelets (human and murine), increasing their responsiveness, and promoting a prothrombotic phenotype.4,5”
From Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women (2019) · cites this paper as [4]
Elevated levels of TMAO induce vascular inflammation and a direct prothrombotic effect by increasing platelet hyper-responsiveness to multiple agonists in both rodents and humans.
“Elevated level of TMAO induces vascular inflammation and a direct prothrombotic effect by increasing platelet hyper-responsiveness to multiple agonists in both rodents and humans, and might be involved in the pathogenesis of obesity and type 2 diabetes (90,91).”
From Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms (2018) · cites this paper as [90]
Using data from the other study instead of the first publication from the same cohort gave fundamentally similar results.
“We observed fundamentally similar results when we used data from the other study.15”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [15]
TMAO may signal through activation of mitogen-activated protein kinase and nuclear factor-κB pathways.
“TMAO also may signal via activation of mitogen-activated protein kinase and nuclear factor-κB (NF-κB) pathways (99, 136).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [136]
When mice were fed a chemically defined diet with 0.12% TMAO or 1% choline, ADP-induced platelet aggregation was significantly increased.
“In addition, when mice were fed a chemically defined diet supplemented with either 0.12% TMAO or 1% choline, platelet aggregation induced by adenosine diphosphate stimulation was significantly increased (136).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [136]
Multiple human and animal studies support mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks.
“multiple human and animal studies supporting both mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks have been reported8–16.”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [15]
TMAO levels are associated with thrombotic event risks such as heart attack and stroke.
“Parallel clinical studies reveal TMAO levels are associated with thrombotic event risks (heart attack and stroke)15”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [15]
TMAO alters calcium signaling in platelets, enhancing responsiveness and in vivo thrombosis potential in animal models.
“recent studies reveal TMAO alters calcium signaling in platelets, enhancing responsiveness and in vivo thrombosis potential in animal models15.”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [15]
Choline supplementation shortened carotid artery vessel occlusion time in the FeCl3 injury model.
“Choline supplementation resulted in marked TMAO elevation and shortening of vessel occlusion time (p<0.0001) as previously reported15”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [15]
Trimethylamine N-oxide has been shown to promote platelet reactivity and thrombosis potential, vascular inflammation and inflammasome activation, and heightened heart failure and chronic kidney disease related phenotypes in animal models.
“It has also been shown to promote platelet reactivity and thrombosis potential14, 83–85, vascular inflammation and inflammasome activation86–88, heightened heart failure89–91 and CKD92–95 related phenotypes in animal models (Figure 2).”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [83]
Multiple studies have confirmed through genetic gain and loss of function studies in mice that manipulation of trimethylamine and trimethylamine N-oxide levels in vivo alters platelet responsiveness, rate of clot generation, and thrombosis potential.
“Multiple studies have confirmed through both genetic gain (as global FMO3 transgene) and loss (via anti-sense oligonucleotide to FMO3, and via global FMO3 knock out) of function studies in mice that manipulation of TMA and TMAO levels in vivo alters platelet responsiveness, rate of clot generation, and thrombosis potential83, 84, 119.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [83]
Direct exposure of platelets to TMAO enhanced sub-maximal stimulus-dependent platelet activation from multiple agonists through augmented Ca2+ release from intracellular stores.
“Direct exposure of platelets to TMAO enhanced sub-maximal stimulus-dependent platelet activation from multiple agonists through augmented Ca2+ release from intracellular stores.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [40]
Gut microbe-derived TMAO enhances platelet responsiveness and thrombosis in vivo.
“Zhu and colleagues [40] showed that gut microbe-derived TMAO enhances platelet responsiveness and thrombosis in vivo.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [40]
In humans, plasma TMAO levels independently predicted incident thrombosis (heart attack, stroke) risk.
“In addition, studies in humans also showed that plasma TMAO levels independently predicted incident thrombosis (heart attack, stroke) risk [40].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [40]
Collectively, these findings provide evidence for a mechanistic link between gut microbes, platelet function, and thrombosis risk.
“Collectively, these findings provide evidence for a mechanistic link between gut microbes, platelet function, and thrombosis risk [40].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [40]
TMAO interacts with platelets, altering stimulus-dependent calcium signalling, fostering platelet hyperreactivity and enhanced thrombosis potential in vivo.
“This is particularly relevant given that recent human platelet and animal model studies reveal that TMAO interacts with platelets, altering stimulus-dependent calcium signalling, fostering platelet hyperreactivity and enhanced thrombosis potential in vivo.5”
Elevated systemic levels of TMAO among stable subjects (n = 4007) undergoing elective diagnostic cardiac evaluations predict incident thrombotic event risks.
“Finally, recent clinical studies have shown that elevated systemic levels of TMAO among stable subjects (n = 4007) undergoing elective diagnostic cardiac evaluations predict incident thrombotic event risks.5”
TMAO has a prothrombotic effect by altering platelet calcium signalling, rendering platelets more responsive to agonists, increasing the risk of in vivo thrombus formation.
“In addition, TMAO has a prothrombotic effect by altering platelet calcium signalling, rendering platelets more responsive to agonists, increasing the risk of in vivo thrombus formation.5”
In cardiovascular disease, atherosclerosis and increased platelet activation were shown to be transmittable with microbial transplantation and linked to elevated TMAO production.
“In the setting of cardiovascular disease, both atherosclerosis and increased platelet activation were shown to be transmittable with microbial transplantation and linked to elevated trimethylamine N-oxide (TMAO) production, a novel microbiota-obligate metabolite that we will review in detail in later sections81,82.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [82]
Kummen et al. observed multiple genus belonging to the Lachnospiraceae family to be decreased in HF, but this family has consistently demonstrated positive associations with plasma TMAO levels.
“Lastly, Kummen et al. observed multiple genus belonging to the Lachnospiraceae family to be decreased in HF93, but interestingly, this family has also consistently demonstrated positive associations with plasma TMAO levels82,96.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [82]
Dietary precursors yield TMA through microbial enzyme complexes, enter portal circulation, and are metabolized by liver FMO (primarily FMO3) to produce TMAO.
“These nutrients, found in high-fat foods, yield TMA through the action of multiple microbial enzyme complexes (described in a later section) and enters the portal circulation where further metabolism by host enzymes in the liver, called flavin-containing monooxygenases (FMO and primarily the FMO3 isoform), produce TMAO (FIG. 3).”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [82]
The TMA/TMAO pathway represents a novel union between diet, gut microbiota, and both atherosclerosis and thrombosis risks.
“Recent work from our group has demonstrated, for the first time, that the trimethylamine (TMA)/trimethylamine N-oxide (TMAO) pathway represents a novel union between diet, gut microbiota, and both atherosclerosis and thrombosis risks82,96,156–159.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [82]
TMAO is generated from dietary precursors that contain the TMA moiety, such as phosphatidylcholine, choline, and L-carnitine.
“TMAO is generated from dietary precursors that contain the TMA moiety such as phosphatidylcholine, choline, and L-carnitine.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [82]
TMAO acts to potentiate platelet reactivity through alterations in stimulus-dependent calcium signaling.
“Mechanistic studies show that TMAO acts to potentiate platelet reactivity through alterations in stimulus-dependent calcium signaling.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [82]
Fecal transplantation demonstrated that choline diet-mediated heightened thrombosis potential in vivo is a transmittable trait.
“Finally, fecal transplantation further demonstrated that choline diet-mediated heightened thrombosis potential in vivo is a transmittable trait82.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [82]
Microbial transplantation studies confirmed that heightened TMAO generation, platelet responsiveness, and thrombosis potential may be transmitted from donor to recipient.
“Similarly, microbial transplantation studies have confirmed that heightened TMAO generation, platelet responsiveness, and thrombosis potential may be transmitted from donor to recipient82.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [82]
Plasma TMAO levels are associated with incident thrombotic event risk.
“Extending the original findings of the relationship between TMAO and atherogenesis, we have also demonstrated that plasma TMAO levels are associated with incident thrombotic event risk82,172.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [82]
Increased calcium release from platelets and enhanced activation was observed following stimulation from sub-maximal levels of multiple agonists such as ADP, thrombin, and collagen.
“Increased calcium release from platelets and enhanced activation was observed following stimulation from sub-maximal levels of multiple different agonists such as ADP, thrombin, and collagen82.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [82]
TMAO potentiates alternative signal transduction processes such as intracellular calcium signaling and platelet reactivity, or sustained increases in blood pressure after angiotensin infusion.
“It is of interest that TMAO has been reported to potentiate alternative signal transduction processes such as intracellular calcium signaling and platelet reactivity, or sustained increases in blood pressure after angiotensin infusion82,178.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [82]
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.
Conflicting diet durations for germ-free mice
MinorThe results say all mice in the germ-free thrombosis study received their diets for six weeks, whereas the experimental procedures specify three weeks of sterile diets for germ-free mice.
“All mice were maintained on the indicated diets for 6 weeks, and plasma was recovered for TMAO analyses on the day of the in vivo thrombosis assay.”
“Germ-free C57BL/6J female mice bred and housed at the National Gnotobiotic Rodent Resource Center, University of North Carolina (UNC) were used in various studies. Mice were exposed to 3 weeks of the indicated chemically defined sterile diets as described in Supplemental Experimental Procedures.”
Cites
An obesity-associated gut microbiome with increased capacity for energy harvest
Turnbaugh, P. J., Ley, R. E., Mahowald, M. A., Magrini, V., Mardis, E. R., & Gordon, J. I. (2006) · Nature · doi:10.1038/nature05414 · Cited by 12,444 · see citing works
The gut microbiota as an environmental factor that regulates fat storage
Bäckhed, F., Ding, H., Wang, T., Hooper, L. V., Koh, G. Y., Nagy, A., Semenkovich, C. F., & Gordon, J. I. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407076101 · Cited by 6,245 · see citing works
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., DuGar, B., Feldstein, A. E., Britt, E. B., Fu, X., Chung, Y.-M., et al. (2011) · Nature · doi:10.1038/nature09922 · Cited by 5,597 · see citing works
Self-citationIntestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis
Koeth, R. A., Wang, Z., Levison, B. S., Buffa, J. A., Org, E., Sheehy, B. T., Britt, E. B., Fu, X., Wu, Y., Li, L., et al. (2013) · Nature Medicine · doi:10.1038/nm.3145 · Cited by 4,386 · see citing works
Self-citationIntestinal microbial metabolism of phosphatidylcholine and cardiovascular risk
Tang, W. H. W., Wang, Z., Levison, B. S., Koeth, R. A., Britt, E. B., Fu, X., Wu, Y., & Hazen, S. L. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1109400 · Cited by 3,402 · cited 8× · see citing works
“Human studies The association between TMAO levels and incident thrombotic event risk was examined in the Genebank Study (Tang et al., 2013).”
InfluentialSelf-citationMechanisms of Thrombus Formation
Furie, B., & Furie, B. C. (2008) · New England Journal of Medicine · doi:10.1056/nejmra0801082 · Cited by 1,926 · see citing works
Cox, L. M., Yamanishi, S., Sohn, J., Alekseyenko, A. V., Leung, J. M., Cho, I., Kim, S. G., Li, H., Gao, Z., Mahana, D., et al. (2014) · Cell · doi:10.1016/j.cell.2014.05.052 · Cited by 1,859 · see citing works
Wang, Z., Roberts, A. B., Buffa, J. A., Levison, B. S., Zhu, W., Org, E., Gu, X., Huang, Y., Zamanian-Daryoush, M., Culley, M. K., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.055 · Cited by 1,317 · see citing works
Self-citationTang, W. H. W., Wang, Z., Kennedy, D. J., Wu, Y., Buffa, J. A., Agatisa-Boyle, B., Li, X. S., Levison, B. S., & Hazen, S. L. (2015) · Circulation Research · doi:10.1161/circresaha.116.305360 · Cited by 1,223 · see citing works
Self-citationBennett, B. J., Vallim, T. Q. D. A., Wang, Z., Shih, D. M., Meng, Y., Gregory, J., Allayee, H., Lee, R., Graham, M., Crooke, R., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2012.12.011 · Cited by 1,070 · see citing works
Self-citationSeldin, M. M., Meng, Y., Qi, H., Zhu, W., Wang, Z., Hazen, S. L., Lusis, A. J., & Shih, D. M. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.115.002767 · Cited by 911 · see citing works
Self-citationTantry, U. S., Bonello, L., Aradi, D., Price, M. J., Jeong, Y.-H., Angiolillo, D. J., Stone, G. W., Curzen, N., Geisler, T., ten Berg, J., et al. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2013.07.101 · Cited by 910 · see citing works
Romano, K. A., Vivas, E. I., Amador-Noguez, D., & Rey, F. E. (2015) · mBio · doi:10.1128/mbio.02481-14 · Cited by 777 · see citing works
Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme
Craciun, S., & Balskus, E. P. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1215689109 · Cited by 701 · see citing works
Tang, W. H. W., Wang, Z., Fan, Y., Levison, B., Hazen, J. E., Donahue, L. M., Wu, Y., & Hazen, S. L. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2014.02.617 · Cited by 681 · see citing works
Self-citationWang, Z., Tang, W. H. W., Buffa, J. A., Fu, X., Britt, E. B., Koeth, R. A., Levison, B. S., Fan, Y., Wu, Y., & Hazen, S. L. (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu002 · Cited by 559 · see citing works
Self-citationγ-Butyrobetaine Is a Proatherogenic Intermediate in Gut Microbial Metabolism of L-Carnitine to TMAO
Koeth, R. A., Levison, B. S., Culley, M. K., Buffa, J. A., Wang, Z., Gregory, J. C., Org, E., Wu, Y., Li, L., Smith, J. D., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.006 · Cited by 546 · see citing works
Self-citationPlatelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype
Podrez, E. A., Byzova, T. V., Febbraio, M., Salomon, R. G., Ma, Y., Valiyaveettil, M., Poliakov, E., Sun, M., Finton, P. J., Curtis, B. R., et al. (2007) · Nature Medicine · doi:10.1038/nm1626 · Cited by 513 · cited 2× · see citing works
“Platelet hyperreactivity and thrombosis risk are enhanced in the setting of numerous conditions associated with atherosclerotic heart disease, such as hyperlipidemia, oxidant stress, and hyperglycemia (Podrez et al., 2007; Chen et al., 2008; Zhu et al., 2012).”
Self-citationTransmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation
Gregory, J. C., Buffa, J. A., Org, E., Wang, Z., Levison, B. S., Zhu, W., Wagner, M. A., Bennett, B. J., Li, L., DiDonato, J. A., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.618249 · Cited by 486 · see citing works
Self-citationTrøseid, M., Ueland, T., Hov, J. R., Svardal, A., Gregersen, I., Dahl, C. P., Aakhus, S., Gude, E., Bjørndal, B., Halvorsen, B., et al. (2015) · Journal of Internal Medicine · doi:10.1111/joim.12328 · Cited by 464 · see citing works
Rohrmann, S., Overvad, K., Bueno-de-Mesquita, H. B., Jakobsen, M. U., Egeberg, R., Tjønneland, A., Nailler, L., Boutron-Ruault, M.-C., Clavel-Chapelon, F., Krogh, V., et al. (2013) · BMC Medicine · doi:10.1186/1741-7015-11-63 · Cited by 454 · see citing works
Jennings, L. (2009) · Thrombosis and Haemostasis · doi:10.1160/th09-03-0192 · Cited by 436 · see citing works
The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance
Warrier, M., Shih, D. M., Burrows, A. C., Ferguson, D., Gromovsky, A. D., Brown, A. L., Marshall, S., McDaniel, A., Schugar, R. C., Wang, Z., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2014.12.036 · Cited by 414 · see citing works
Self-citationOrgan, C. L., Otsuka, H., Bhushan, S., Wang, Z., Bradley, J., Trivedi, R., Polhemus, D. J., Tang, W. H. W., Wu, Y., Hazen, S. L., et al. (2016) · Circulation: Heart Failure · doi:10.1161/circheartfailure.115.002314 · Cited by 382 · see citing works
Self-citationFlavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis
Miao, J., Ling, A. V., Manthena, P. V., Gearing, M. E., Graham, M. J., Crooke, R. M., Croce, K. J., Esquejo, R. M., Clish, C. B., Morbid Obesity Study Group, et al. (2015) · Nature Communications · doi:10.1038/ncomms7498 · Cited by 368 · see citing works
Calcium Signaling in Human Platelets
RINK, T. J., & Sage, S. O. (1990) · Annual Review of Physiology · doi:10.1146/annurev.ph.52.030190.002243 · Cited by 350 · see citing works
Shih, D. M., Wang, Z., Lee, R., Meng, Y., Che, N., Charugundla, S., Qi, H., Wu, J., Pan, C., Brown, J. M., et al. (2015) · Journal of Lipid Research · doi:10.1194/jlr.m051680 · Cited by 335 · see citing works
Self-citationWang, Z., Levison, B. S., Hazen, J. E., Donahue, L., Li, X.-M., & Hazen, S. L. (2014) · Analytical Biochemistry · doi:10.1016/j.ab.2014.03.016 · Cited by 320 · see citing works
Self-citationPlatelet function predicts myocardial damage in patients with acute myocardial infarction
Frossard, M., Fuchs, I., Leitner, J. M., Hsieh, K., Vlcek, M., Losert, H., Domanovits, H., Schreiber, W., Laggner, A. N., & Jilma, B. (2004) · Circulation · doi:10.1161/01.cir.0000141575.92958.9c · Cited by 254 · see citing works
Lever, M., George, P. M., Slow, S., Bellamy, D., Young, J. M., Ho, M., McEntyre, C. J., Elmslie, J. L., Atkinson, W., Molyneux, S. L., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0114969 · Cited by 223 · see citing works
Chen, K., Febbraio, M., Li, W., & Silverstein, R. L. (2008) · Circulation Research · doi:10.1161/circresaha.108.172064 · Cited by 202 · see citing works
Self-citationMicrobiology Meets Big Data: The Case of Gut Microbiota–Derived Trimethylamine
Falony, G., Vieira-Silva, S., & Raes, J. (2015) · Annual Review of Microbiology · doi:10.1146/annurev-micro-091014-104422 · Cited by 187 · see citing works
Correcting temperature-sensitive protein folding defects
Brown, C. R., Hong-Brown, L. Q., & Welch, W. J. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119302 · Cited by 176 · see citing works
Human Trace Amine-Associated Receptor TAAR5 Can Be Activated by Trimethylamine
Wallrabenstein, I., Kuklan, J., Weber, L., Zborala, S., Werner, M., Altmüller, J., Becker, C., Schmidt, A., Hatt, H., Hummel, T., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054950 · Cited by 122 · see citing works
Zhu, W., Li, W., & Silverstein, R. L. (2012) · Blood · doi:10.1182/blood-2011-10-387506 · Cited by 122 · see citing works
Self-citationChemical chaperone rescue of mutant human cystathionine β-synthase
Singh, L. R., Chen, X., Kožich, V., & Kruger, W. D. (2007) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2007.04.011 · Cited by 85 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Iqbal, 2008, Dietary patterns and the risk of acute myocardial infarction in 52 countries: results of the INTERHEART study, Circulation, 118, 1929, 10.1161/CIRCULATIONAHA.107.738716 · DOI · Paper page
Cited by
Sorted by citations
Gut microbiota in human metabolic health and disease
Fan, Y., & Pedersen, O. (2021) · Nature Reviews Microbiology · doi:10.1038/s41579-020-0433-9 · Cited by 4,724 · see citing works
You are what you eat: Diet, health and the gut microbiota
Zmora, N., Suez, J., & Elinav, E. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0061-2 · Cited by 1,792 · see citing works
Dysbiosis and the immune system
Levy, M., Kolodziejczyk, A. A., Thaiss, C. A., & Elinav, E. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2017.7 · Cited by 1,769 · see citing works
The gut microbiome in atherosclerotic cardiovascular disease
Jie, Z., Xia, H., Zhong, S.-L., Feng, Q., Li, S., Liang, S., Zhong, H., Liu, Z., Gao, Y., Zhao, H., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00900-1 · Cited by 1,638 · see citing works
Dietary lipids, gut microbiota and lipid metabolism
Schoeler, M., & Caesar, R. (2019) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-019-09512-0 · Cited by 1,163 · see citing works
The intestinal microbiota fuelling metabolic inflammation
Tilg, H., Zmora, N., Adolph, T. E., & Elinav, E. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-019-0198-4 · Cited by 1,089 · see citing works
Gut microbiota and cardiovascular disease.
Witkowski, M., Weeks, T. L., & Hazen, S. L. (2020) · Circulation Research · doi:10.1161/circresaha.120.316242 · Cited by 1,051 · see citing works
Self-citationNogal, A., Valdes, A. M., & Menni, C. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1897212 · Cited by 917 · see citing works
Postler, T. S., & Ghosh, S. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.05.008 · Cited by 876 · see citing works
“Beyond a direct effect on atherosclerosis, TMAO has also been reported to increase platelet responsiveness by enhancing intracellular Ca2+ release, thus increasing the likelihood of thrombotic events and thereby cardiovascular disease (Zhu et al., 2016).”
BackgroundDietary metabolism, the gut microbiome, and heart failure
Tang, W. H. W., Li, D. Y., & Hazen, S. L. (2019) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0108-7 · Cited by 789 · see citing works
Self-citationA Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors
Nemet, I., Saha, P. P., Gupta, N., Zhu, W., Romano, K. A., Skye, S. M., Cajka, T., Mohan, M. L., Li, L., Wu, Y., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.016 · Cited by 784 · see citing works
Self-citationHealth Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms
Tosti, V., Bertozzi, B., & Fontana, L. (2018) · The Journals of Gerontology: Series A · doi:10.1093/gerona/glx227 · Cited by 762 · see citing works
The gut microbiome and liver cancer: mechanisms and clinical translation
Yu, L.-X., & Schwabe, R. F. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.72 · Cited by 634 · see citing works
Dynamic modulation of the gut microbiota and metabolome by bacteriophages in a mouse model
Hsu, B. B., Gibson, T. E., Yeliseyev, V., Liu, Q., Lyon, L., Bry, L., Silver, P. A., & Gerber, G. K. (2019) · Cell Host & Microbe · doi:10.1016/j.chom.2019.05.001 · Cited by 573 · see citing works
Schiattarella, G. G., Sannino, A., Toscano, E., Giugliano, G., Gargiulo, G., Franzone, A., Trimarco, B., Esposito, G., & Perrino, C. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx342 · Cited by 563 · see citing works
Microbial regulation of organismal energy homeostasis
Cani, P. D., Van Hul, M., Lefort, C., Depommier, C., Rastelli, M., & Everard, A. (2019) · Nature Metabolism · doi:10.1038/s42255-018-0017-4 · Cited by 569 · see citing works
Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential
Roberts, A. B., Gu, X., Buffa, J. A., Hurd, A. G., Wang, Z., Zhu, W., Gupta, N., Skye, S. M., Cody, D. B., Levison, B. S., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0128-1 · Cited by 552 · see citing works
Self-citationHeianza, Y., Ma, W., Manson, J. E., Rexrode, K. M., & Qi, L. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.116.004947 · Cited by 544 · see citing works
Gut microbiota and dysbiosis in Alzheimer's disease: Implications for pathogenesis and treatment
Liu, S., Gao, J., Zhu, M., Liu, K., & Zhang, H.-L. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02073-3 · Cited by 516 · see citing works
Wang, Z., Bergeron, N., Levison, B. S., Li, X. S., Chiu, S., Jia, X., Koeth, R. A., Li, L., Wu, Y., Tang, W. H. W., et al. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehy799 · Cited by 496 · see citing works
Self-citationTrimethylamine N-oxide: the good, the bad and the unknown.
Velasquez, M., Ramezani, A., Manal, A., & Raj, D. (2016) · Toxins · doi:10.3390/toxins8110326 · Cited by 504 · see citing works
Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease
Zeisel, S. H., & Warrier, M. (2017) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064732 · Cited by 475 · see citing works
The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease
Vogt, N. M., Romano, K. A., Darst, B. F., Engelman, C. D., Johnson, S. C., Carlsson, C. M., Asthana, S., Blennow, K., Zetterberg, H., Bendlin, B. B., et al. (2018) · Alzheimer's Research & Therapy · doi:10.1186/s13195-018-0451-2 · Cited by 471 · see citing works
Li, X. S., Obeid, S., Klingenberg, R., Gencer, B., Mach, F., Räber, L., Windecker, S., Rodondi, N., Nanchen, D., Muller, O., et al. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehw582 · Cited by 479 · see citing works
Self-citationInflammation and cardiovascular disease: From mechanisms to therapeutics
Alfaddagh, A., Martin, S. S., Leucker, T. M., Michos, E. D., Blaha, M. J., Lowenstein, C. J., Jones, S. R., & Toth, P. P. (2020) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2020.100130 · Cited by 473 · see citing works
Microbial modulation of cardiovascular disease
Brown, J. M., & Hazen, S. L. (2018) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2017.149 · Cited by 440 · see citing works
Self-citationTrimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction
Chen, S., Henderson, A., Petriello, M. C., Romano, K. A., Gearing, M., Miao, J., Schell, M., Sandoval-Espinola, W. J., Tao, J., Sha, B., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.08.021 · Cited by 427 · see citing works
Gut Microbiota: An Integral Moderator in Health and Disease
Feng, Q., Chen, W.-D., & Wang, Y.-D. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.00151 · Cited by 407 · see citing works
The progress of gut microbiome research related to brain disorders
Zhu, S., Jiang, Y., Xu, K., Cui, M., Ye, W., Zhao, G., Jin, L., & Chen, X. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-1705-z · Cited by 419 · see citing works
Role of the gut microbiota in type 2 diabetes and related diseases
Yang, G., Wei, J., Liu, P., Zhang, Q., Tian, Y., Hou, G., Meng, L., Xin, Y., & Jiang, X. (2021) · Metabolism · doi:10.1016/j.metabol.2021.154712 · Cited by 418 · see citing works
Fecal Microbiota Transplantation in Neurological Disorders
Vendrik, K. E. W., Ooijevaar, R. E., de Jong, P. R. C., Laman, J. D., van Oosten, B. W., van Hilten, J. J., Ducarmon, Q. R., Keller, J. J., Kuijper, E. J., & Contarino, M. F. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00098 · Cited by 413 · see citing works
Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus
Targher, G., Lonardo, A., & Byrne, C. D. (2018) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.173 · Cited by 397 · see citing works
Precup, G., & Vodnar, D.-C. (2019) · British Journal of Nutrition · doi:10.1017/s0007114519000680 · Cited by 378 · see citing works
Wu, K., Yuan, Y., Yu, H., Dai, X., Wang, S., Sun, Z., Wang, F., Fei, H., Lin, Q., Jiang, H., et al. (2020) · Blood · doi:10.1182/blood.2019003990 · Cited by 345 · see citing works
Chu, H., Duan, Y., Yang, L., & Schnabl, B. (2019) · Gut · doi:10.1136/gutjnl-2018-316307 · Cited by 354 · see citing works
Mirji, G., Worth, A., Bhat, S. A., El Sayed, M., Kannan, T., Goldman, A. R., Tang, H.-Y., Liu, Q., Auslander, N., Dang, C. V., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abn0704 · Cited by 327 · see citing works
l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans
Koeth, R. A., Lam-Galvez, B. R., Kirsop, J., Wang, Z., Levison, B. S., Gu, X., Copeland, M. F., Bartlett, D., Cody, D. B., Dai, H. J., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci94601 · Cited by 327 · see citing works
Self-citationWorthmann, A., John, C., Rühlemann, M. C., Baguhl, M., Heinsen, F.-A., Schaltenberg, N., Heine, M., Schlein, C., Evangelakos, I., Mineo, C., et al. (2017) · Nature Medicine · doi:10.1038/nm.4357 · Cited by 318 · see citing works
Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction
Boini, K. M., Hussain, T., Li, P.-L., & Koka, S. S. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000484623 · Cited by 302 · see citing works
Evenepoel, P., Poesen, R., & Meijers, B. (2017) · Pediatric Nephrology · doi:10.1007/s00467-016-3527-x · Cited by 305 · see citing works
Trimethylamine N-oxide promotes atherosclerosis via CD36-dependent MAPK/JNK pathway
Geng, J., Yang, C., Wang, B., Zhang, X., Hu, T., Gu, Y., & Li, J. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.11.016 · Cited by 297 · see citing works
Schugar, R. C., Shih, D. M., Warrier, M., Helsley, R. N., Burrows, A., Ferguson, D., Brown, A. L., Gromovsky, A. D., Heine, M., Chatterjee, A., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.05.077 · Cited by 291 · see citing works
Self-citationZhu, W., Wang, Z., Tang, W. H. W., & Hazen, S. L. (2017) · Circulation · doi:10.1161/circulationaha.116.025338 · Cited by 274 · see citing works
Self-citationMicrobial impact on cholesterol and bile acid metabolism: current status and future prospects
Kriaa, A., Bourgin, M., Potiron, A., Mkaouar, H., Jablaoui, A., Gérard, P., Maguin, E., & Rhimi, M. (2019) · Journal of Lipid Research · doi:10.1194/jlr.r088989 · Cited by 264 · see citing works
Rethinking healthy eating in light of the gut microbiome
Armet, A. M., Deehan, E. C., O’Sullivan, A. F., Mota, J. F., Field, C. J., Prado, C. M., Lucey, A. J., & Walter, J. (2022) · Cell Host & Microbe · doi:10.1016/j.chom.2022.04.016 · Cited by 252 · see citing works
Linking the Microbiota, Chronic Disease, and the Immune System
Hand, T. W., Vujkovic-Cvijin, I., Ridaura, V. K., & Belkaid, Y. (2016) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2016.08.003 · Cited by 247 · see citing works
Non-alcoholic fatty liver and the gut microbiota
Bashiardes, S., Shapiro, H., Rozin, S., Shibolet, O., & Elinav, E. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.06.003 · Cited by 241 · see citing works
Saji, N., Niida, S., Murotani, K., Hisada, T., Tsuduki, T., Sugimoto, T., Kimura, A., Toba, K., & Sakurai, T. (2019) · Scientific Reports · doi:10.1038/s41598-018-38218-7 · Cited by 224 · see citing works
Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia
Connell, E., Le Gall, G., Pontifex, M. G., Sami, S., Cryan, J. F., Clarke, G., Müller, M., & Vauzour, D. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00548-6 · Cited by 208 · see citing works
Deciphering the Chemical Lexicon of Host–Gut Microbiota Interactions
Nicolas, G. R., & Chang, P. V. (2019) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2019.04.006 · Cited by 195 · see citing works
Qu, W., Yuan, X., Zhao, J., Zhang, Y., Hu, J., Wang, J., & Li, J. (2017) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700118 · Cited by 195 · see citing works
Skye, S. M., Zhu, W., Romano, K. A., Guo, C.-J., Wang, Z., Jia, X., Kirsop, J., Haag, B., Lang, J. M., DiDonato, J. A., et al. (2018) · Circulation Research · doi:10.1161/circresaha.118.313142 · Cited by 189 · see citing works
Self-citationPastori, D., Carnevale, R., Nocella, C., Novo, M., Santulli, M., Cammisotto, V., Menichelli, D., Pignatelli, P., & Violi, F. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.117.005784 · Cited by 182 · see citing works
Gut Microbiota and Ischemic Stroke: The Role of Trimethylamine N-Oxide
Nam, H. S. (2019) · Journal of Stroke · doi:10.5853/jos.2019.00472 · Cited by 176 · see citing works
Trimethylamine N‐oxide: breathe new life
Subramaniam, S., & Fletcher, C. (2018) · British Journal of Pharmacology · doi:10.1111/bph.13959 · Cited by 171 · see citing works
Griffin, N. W., Ahern, P. P., Cheng, J., Heath, A. C., Ilkayeva, O., Newgard, C. B., Fontana, L., & Gordon, J. I. (2017) · Cell Host & Microbe · doi:10.1016/j.chom.2016.12.006 · Cited by 164 · see citing works
Zhu, W., Buffa, J. A., Wang, Z., Warrier, M., Schugar, R., Shih, D. M., Gupta, N., Gregory, J. C., Org, E., Fu, X., et al. (2018) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.14234 · Cited by 161 · see citing works
Self-citationJäckel, S., Kiouptsi, K., Lillich, M., Hendrikx, T., Khandagale, A., Kollar, B., Hörmann, N., Reiss, C., Subramaniam, S., Wilms, E., et al. (2017) · Blood · doi:10.1182/blood-2016-11-754416 · Cited by 156 · see citing works
Alisson-Silva, F., Kawanishi, K., & Varki, A. (2016) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2016.07.002 · Cited by 156 · see citing works
TMAO is Associated with Mortality: Impact of Modestly Impaired Renal Function
Gruppen, E. G., Garcia, E., Connelly, M. A., Jeyarajah, E. J., Otvos, J. D., Bakker, S. J. L., & Dullaart, R. P. F. (2017) · Scientific Reports · doi:10.1038/s41598-017-13739-9 · Cited by 146 · see citing works
Röytiö, H., Mokkala, K., Vahlberg, T., & Laitinen, K. (2017) · British Journal Of Nutrition · doi:10.1017/s0007114517002100 · Cited by 128 · see citing works
The Gut Microbiome and Individual-Specific Responses to Diet
Leshem, A., Segal, E., & Elinav, E. (2020) · mSystems · doi:10.1128/msystems.00665-20 · Cited by 109 · see citing works
The Gut Microbiome as Therapeutic Target in Central Nervous System Diseases: Implications for Stroke
Winek, K., Dirnagl, U., & Meisel, A. (2016) · Neurotherapeutics · doi:10.1007/s13311-016-0475-x · Cited by 108 · see citing works
Sankowski, B., Księżarczyk, K., Raćkowska, E., Szlufik, S., Koziorowski, D., & Giebułtowicz, J. (2020) · Clinica Chimica Acta · doi:10.1016/j.cca.2019.10.038 · Cited by 105 · see citing works
Guertin, K. A., Li, X. S., Graubard, B. I., Albanes, D., Weinstein, S. J., Goedert, J. J., Wang, Z., Hazen, S. L., & Sinha, R. (2017) · Cancer Epidemiology, Biomarkers & Prevention · doi:10.1158/1055-9965.epi-16-0948 · Cited by 96 · see citing works
Self-citationAldana-Hernández, P., Leonard, K.-A., Zhao, Y.-Y., Curtis, J. M., Field, C. J., & Jacobs, R. L. (2020) · The Journal of Nutrition · doi:10.1093/jn/nxz214 · Cited by 91 · see citing works
Cheng, X., Qiu, X., Liu, Y., Yuan, C., & Yang, X. (2019) · Thrombosis Research · doi:10.1016/j.thromres.2019.02.028 · Cited by 90 · see citing works
Caracausi, M., Ghini, V., Locatelli, C., Mericio, M., Piovesan, A., Antonaros, F., Pelleri, M. C., Vitale, L., Vacca, R. A., Bedetti, F., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-20834-y · Cited by 84 · see citing works
Farhangi, M. A., Vajdi, M., & Asghari-Jafarabadi, M. (2020) · Nutrition Journal · doi:10.1186/s12937-020-00592-2 · Cited by 72 · see citing works
Lei, W., Cheng, Y., Liu, X., Gao, J., Zhu, Z., Ding, W., Xu, X., Li, Y., Ling, Z., Jiang, R., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1582119 · Cited by 68 · see citing works
Shih, D. M., Zhu, W., Schugar, R. C., Meng, Y., Jia, X., Miikeda, A., Wang, Z., Zieger, M., Lee, R., Graham, M., et al. (2019) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.119.312592 · Cited by 67 · see citing works
Self-citationPolsinelli, V. B., Sinha, A., & Shah, S. J. (2017) · Current Heart Failure Reports · doi:10.1007/s11897-017-0370-8 · Cited by 64 · see citing works
New technologies for developing phage-based tools to manipulate the human microbiome
Khan Mirzaei, M., & Deng, L. (2022) · Trends in Microbiology · doi:10.1016/j.tim.2021.04.007 · Cited by 53 · see citing works
Voigt, R. M., Wang, Z., Brown, J. M., Engen, P. A., Naqib, A., Goetz, C. G., Hall, D. A., Metman, L. V., Shaikh, M., Forsyth, C. B., et al. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105780 · Cited by 51 · see citing works
Self-citationThe Role of Microbiota in Cardiovascular Risk: Focus on Trimethylamine Oxide
Al-Rubaye, H., Perfetti, G., & Kaski, J.-C. (2019) · Current Problems in Cardiology · doi:10.1016/j.cpcardiol.2018.06.005 · Cited by 43 · see citing works
Quan, L., Yi, J., Zhao, Y., Zhang, F., Shi, X.-T., Feng, Z., & Miller, H. L. (2020) · NeuroToxicology · doi:10.1016/j.neuro.2019.10.012 · Cited by 44 · see citing works
The Gut–Brain–Microbiota Connection and Its Role in Autism Spectrum Disorders
Młynarska, E., Barszcz, E., Budny, E., Gajewska, A., Kopeć, K., Wasiak, J., Rysz, J., & Franczyk, B. (2025) · Nutrients · doi:10.3390/nu17071135 · Cited by 44 · see citing works
Gut microbiota dysbiosis associated with bile acid metabolism in neonatal cholestasis disease
Li, M., Liu, S., Wang, M., Hu, H., Yin, J., Liu, C., & Huang, Y. (2020) · Scientific Reports · doi:10.1038/s41598-020-64728-4 · Cited by 41 · see citing works
Association of L-α Glycerylphosphorylcholine With Subsequent Stroke Risk After 10 Years
Lee, G., Choi, S., Chang, J., Choi, D., Son, J. S., Kim, K., Kim, S. M., Jeong, S., & Park, S. M. (2021) · JAMA Network Open · doi:10.1001/jamanetworkopen.2021.36008 · Cited by 37 · see citing works
Plasma Trimethylamine N-Oxide (TMAO): Associations with Cognition, Neuroimaging, and Dementia
Yaqub, A., Vojinovic, D., Vernooij, M. W., Slagboom, P. E., Ghanbari, M., Beekman, M., van der Grond, J., Hankemeier, T., van Duijn, C. M., Ikram, M. A., et al. (2024) · Alzheimer's Research & Therapy · doi:10.1186/s13195-024-01480-1 · Cited by 37 · see citing works
Zhao, Y., Yang, N., Gao, J., Li, H., Cai, W., Zhang, X., Ma, Y., Niu, X., Yang, G., Zhou, X., et al. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700299 · Cited by 29 · see citing works
Buawangpong, N., Pinyopornpanish, K., Phrommintikul, A., Chindapan, N., Devahastin, S., Chattipakorn, N., & Chattipakorn, S. C. (2022) · Food & Function · doi:10.1039/d2fo02021a · Cited by 12 · see citing works
Dai, L., Schurgers, L., Shiels, P. G., & Stenvinkel, P. (2021) · Clinical Science · doi:10.1042/cs20201452 · Cited by 11 · see citing works
- Authors
- Zhu, W., Gregory, J. C., Org, E., Buffa, J. A., Gupta, N., Wang, Z., Li, L., Fu, X., Wu, Y., Mehrabian, M., Sartor, R. B., McIntyre, T. M., Silverstein, R. L., Tang, W. H. W., DiDonato, J. A., Brown, J. M., Lusis, A. J., & Hazen, S. L.
- Affiliations
- Cleveland Clinic (US)
- University of California, Los Angeles (US)
- Cleveland State University (US)
- University of North Carolina at Chapel Hill (US)
- Medical College of Wisconsin (US)
- Corresponding author
- Hazen, Stanley L.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 165
- Issue
- 1
- Pages
- 111-124
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4862743
- OpenAlex
- W2295882128
- Cited by
- 1,968
- References
- 36
- Citations by year
- 2026: 181 · 2025: 215 · 2024: 201 · 2023: 256 · 2022: 257 · 2021: 238 · 2020: 186 · 2019: 163 · 2018: 116 · 2017: 103 · 2016: 49
- FWCI
- 136.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- EngagedScholarship @ Cleveland State University (Cleveland State University) (submittedVersion)
- UNC Libraries
- Funders
- Office of Dietary Supplements (R01 HL103866, R01DK106000, P20 HL113452)
- American Heart Association
- Pfizer
- Cleveland Clinic
- Case Western Reserve University (UL1TR000439)
- Esperion Therapeutics
- National Institutes of Health (1s10od016346-01a1, UL1TR000439, DK034987, HL‐28481, HL122283, HL30568, P40OD010995)
- National Heart, Lung, and Blood Institute (HL3 0568, HL28481, P01HL030568, R01HL103931, R01HL111614, P20HL113452, P01HL076491, P01HL098055, R01HL103866, R01HL122283, P01HL028481)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106000, P30DK034987)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- trimethylamine N-oxide, gut microbiota, platelet hyperreactivity, thrombosis risk, platelet activation, calcium release from intracellular stores, dietary choline, germ-free mice, microbial transplantation, cardiovascular disease, stroke, myocardial infarction
- MeSH terms
- Gastrointestinal Microbiome, Animals, Blood Platelets, Calcium, Cecum, Chlorides, Choline, Diet, Female, Ferric Compounds, Germ-Free Life, Humans, Methylamines, Mice, Inbred C57BL, Thrombosis, Carotid Artery Injuries, Mice
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 2026-10-05.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.
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 ›
Are you an author, or do you see a problem with this page? Request a review
