Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis
Open accessAbstract
Trimethylamine (TMA) N-oxide (TMAO), a gut-microbiota-dependent metabolite, both enhances atherosclerosis in animal models and is associated with cardiovascular risks in clinical studies. Here, we investigate the impact of targeted inhibition of the first step in TMAO generation, commensal microbial TMA production, on diet-induced atherosclerosis. A structural analog of choline, 3,3-dimethyl-1-butanol (DMB), is shown to non-lethally inhibit TMA formation from cultured microbes, to inhibit distinct microbial TMA lyases, and to both inhibit TMA production from physiologic polymicrobial cultures (e.g., intestinal contents, human feces) and reduce TMAO levels in mice fed a high-choline or L-carnitine diet. DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in apolipoprotein e(-/-) mice without alterations in circulating cholesterol levels. The present studies suggest that targeting gut microbial production of TMA specifically and non-lethal microbial inhibitors in general may serve as a potential therapeutic approach for the treatment of cardiometabolic diseases.
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- Findingown data
DMB reduces choline-diet-enhanced atherosclerotic lesion development in Apoe−/− mice.
“and atherosclerotic lesion development in apolipoprotein e−/− mice”
Quote in the paperSubstantial claim - Findingown data
CutC/D from different microbial species differ in sensitivity to DMB inhibition.
“the sensitivity of CutC/D from different microbial species to DMB inhibition varied”
Quote in the paperNot a substantial claim - Findingown data
DMB inhibits conversion of d9-choline and d9-GPC to d9-TMA by recombinant cutC/D.
“DMB inhibited conversion of both d9-choline and [d9-N,N,N-trimethyl]glycerophosphocholine (d9-GPC) substrates into d9-TMA”
Quote in the paperSubstantial claim - Findingown data
The monitored microbial TMA lyase activity required both CutC and CutD.
“microbial TMA lyase enzyme activity monitored with this system required the presence of both CutC and CutD”
Quote in the paperSubstantial claim - Findingown data
DMB lowers TMAO levels in mice given a high-choline or high-carnitine diet.
“reduce TMAO levels in mice fed a high choline or carnitine diet”
Quote in the paperSubstantial claim
- Findingown data
P-choline increases cutC/D choline TMA lyase activity.
“the phosphonium analogue of choline (P-choline) showed a unique effect by augmenting cutC/D choline TMA lyase activity”
Quote in the paperNot a substantial claim - Findingown data
The expressed cutC/D complex from P. mirabilis acts as a microbial choline TMA lyase source.
“we subsequently cloned and expressed the cutC/D genes from P. mirabilis and confirmed that the expressed cutC/D gene complex serves as a microbial choline TMA lyase enzyme source”
Quote in the paperSubstantial claim - Findingown data
DMB does not change circulating cholesterol levels in Apoe−/− mice.
“without alterations in circulating cholesterol levels”
Quote in the paperSubstantial claim - Findingown data
DMB inhibits several distinct microbial TMA lyases.
“to inhibit distinct microbial TMA lyases”
Quote in the paperSubstantial claim - Findingown data
DMB inhibits TMA production in physiological polymicrobial cultures such as intestinal contents and human feces.
“to both inhibit TMA production from physiologic polymicrobial cultures (eg intestinal contents, human feces)”
Quote in the paperSubstantial claim - Findingown data
DMB inhibits choline TMA lyase activity in E. coli transformed with P. mirabilis cutC/D.
“DMB inhibited choline TMA lyase activity of E. coli transformed with cutC/D from P. mirabilis”
Quote in the paperSubstantial claim - Findingown data
DMB non-lethally suppresses TMA formation by cultured microbes.
“is shown to non-lethally inhibit TMA formation from cultured microbes”
Quote in the paperSubstantial claim - Findingown data
DMB does not block choline uptake by live microbes.
“no effect of DMB on choline uptake by the live microbes”
Quote in the paperSubstantial claim - Findingown data
Choline and GPC are preferred over d9-PC and d9-carnitine for TMA production by P. mirabilis lysates.
“choline and GPC also serve as preferred substrates over [d9-N,N,N-trimethyl]phosphatidylcholine (d9-PC) and [d9-N,N,N-trimethyl]carnitine (d9-carnitine) for TMA production from P. mirabilis lysates”
Quote in the paperNot a substantial claim - Findingown data
DMB reduces choline-diet-enhanced macrophage foam cell formation in Apoe−/− mice.
“DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation”
Quote in the paperSubstantial claim - Findingown data
DMB dose-dependently inhibits TMA production from choline or GPC by purified CutC and CutD.
“addition of DMB to anaerobic reaction mixtures containing both purified polypeptides showed dose-dependent inhibition in TMA production from either choline or GPC substrates”
Quote in the paperSubstantial claim - Findingown data
DMB inhibits TMA formation from each tested substrate in mouse cecal contents.
“addition of DMB inhibited TMA formation from each substrate”
Quote in the paperSubstantial claim- Rests on an assumption: Mouse cecal contents and human feces are physiological polymicrobial sources that represent gut microbial TMA lyase activity.
- Findingown data
DMB inhibited choline diet-dependent development of aortic root atherosclerotic plaque.
“inhibited choline diet-dependent accumulation of both macrophage cholesteryl ester accumulation (foam cell formation) and aortic root atherosclerotic plaque development.”
Quote in the paperSubstantial claim - Findingown data
In all mouse groups within each sex, the proportions of several taxa were associated to some degree with aortic root lesion area and with plasma TMA and TMAO levels.
“Further examination revealed the proportions of several taxa within all groups of mice within each gender were associated with aortic root lesion area and plasma TMA and TMAO levels to some extent (Tables S3 and S4).”
Quote in the paperNot a substantial claim - Findingown data
DMB inhibits choline TMA lyase activity when both YeaW and YeaX are present.
“DMB inhibits choline TMA lyase enzyme activity in the presence of both YeaW and YeaX”
Quote in the paperSubstantial claim - Findingown data
DMB inhibited choline diet-dependent accumulation of macrophage cholesteryl esters (foam cell formation).
“inhibited choline diet-dependent accumulation of both macrophage cholesteryl ester accumulation (foam cell formation) and aortic root atherosclerotic plaque development.”
Quote in the paperSubstantial claim - Findingown data
The proportion of Clostridiales, the most abundant bacterial order in the cecum, was positively correlated with plasma TMA levels (r=0.35, p=0.03).
“It is also interesting to note that the proportion of the taxa Clostridiales, the most abundant bacterial order observed in cecum, was positively correlated to plasma TMA levels (r=0.35, p=0.03)”
Quote in the paperNot a substantial claim - Findingown data
Purified YeaW/X cleaves d9-carnitine, d9-γ-butyrobetaine, and d9-crotonobetaine to produce d9-TMA.
“Purified YeaW/X showed enzymatic cleavage of d9-carnitine, [d9-N,N,N-trimethyl]γ–butyrobetaine (d9-γ–butyrobetaine) and [d9-N,N,N-trimethyl]crotonobetaine (d9-crotonobetaine), producing d9-TMA”
Quote in the paperSubstantial claim - Findingown data
In male mice, the proportion of Clostridiaceae was strongly positively correlated with plasma TMA and TMAO levels and with atherosclerotic lesion area.
“For example, among male mice, proportions of the taxa Clostridiaceae were highly positively correlated with plasma TMA and TMAO levels, as well as atherosclerotic lesion area (Table S3).”
Quote in the paperNot a substantial claim - Findingown data
DMB significantly reduces the diet-enhanced macrophage foam cell formation (p<0.05).
“yet addition of DMB to the drinking water significantly reduced the observed diet enhanced macrophage foam cell formation (p<0.05 for comparison of choline vs. choline + DMB; Figures 4A and 4B)”
Quote in the paperSubstantial claim - Findingown data
CntA/B shows no TMA production from choline, PC, or GPC.
“examination of the substrate preference of CntA/B revealed no evidence of TMA production in the presence of alternative potential precursor substrates such as choline, PC or GPC”
Quote in the paperNot a substantial claim - Findingown data
All tested TMA-containing nutrients are substrates for TMA production by mouse cecal contents.
“All TMA containing nutrients examined served as substrates for TMA production by the polymicrobial enzyme source”
Quote in the paperSubstantial claim- Rests on an assumption: Mouse cecal contents and human feces are physiological polymicrobial sources that represent gut microbial TMA lyase activity.
- Findingown data
Chronic oral DMB treatment shows no evidence of liver or kidney tissue choline elevation in mice.
“No evidence of tissue choline elevation was noted in either liver or kidney following chronic oral DMB treatment in mice”
Quote in the paperSubstantial claim - Findingown data
DMB does not inhibit CntA/B-catalyzed cleavage of d9-carnitine.
“DMB showed no inhibitory effect on CntA/B catalyzed cleavage of d9-carnitine”
Quote in the paperSubstantial claim - Findingown data
DMB significantly inhibits choline-diet-dependent aortic root lesion development in male (p=0.006) and female (p=0.02) Apoe−/− mice.
“Remarkably, addition of DMB significantly inhibited the choline diet-dependent enhancement in aortic root lesion development in both males (p=0.006, Figure 4D) and females (p=0.02, Figure S4A).”
Quote in the paperSubstantial claim - Findingown data
DMB-treated Apoe−/− mice show a modest but significant increase in total hepatic FMO enzyme activity (p<0.0001).
“mice exposed to DMB showed not a reduction, but instead, a modest but statistically significant increase in total FMO hepatic enzyme activity (p<0.0001, Figure S4B).”
Quote in the paperNot a substantial claim - Findingown data
DMB is not detected in plasma or urine of mice chronically given DMB in drinking water.
“Despite extensive efforts we were unable to detect DMB in the plasma or urine of mice chronically exposed to DMB in the drinking water.”
Quote in the paperSubstantial claim - Findingown data
In male mice on a choline-supplemented diet, DMB exposure produced a strong tendency (p=0.06) toward a lower cecal proportion of Clostridiaceae.
“exposure to DMB promoted a strong tendency (p=0.06) to decrease the proportion of this taxon in mice fed a choline-supplemented diet (Figure 5B).”
Quote in the paperNot a substantial claim - Findingown data
Male mice given a choline-supplemented diet had a significant increase in the cecal proportion of Clostridiaceae.
“Further, male mice placed on a choline-supplemented diet showed significant increase in the cecal proportion of this taxon”
Quote in the paperSubstantial claim - Findingown data
Female mice given a choline-supplemented diet had a significant increase in the proportion of Clostridiales.
“Further, female mice placed on a choline-supplemented diet showed a significant increase in the proportions of this taxon”
Quote in the paperNot a substantial claim - Findingown data
DMB, a choline structural analogue, was used as a preliminary tool compound that inhibited microbe-dependent TMA and host TMAO formation from several distinct TMA-containing nutrients in vitro and in vivo.
“DMB, a structural analogue of choline, served as a preliminary tool compound to inhibit microbe-dependent TMA and host TMAO formation from multiple distinct TMA containing nutrients in vitro and in vivo.”
Quote in the paperSubstantial claim - Findingown data
A chronic choline-supplemented diet significantly increases atherosclerotic plaque area about 2-fold in Apoe−/− mice (p=0.003 males; p=0.03 females) without atherogenic plasma lipid changes.
“Briefly, aortic root lesion plaque quantification revealed that mice on a chronic, choline-supplemented diet, as expected, showed significant enhancement in atherosclerotic plaque area (approximately 2-fold increase; p=0.003 males, Figures 4C and 4D; p=0.03 females, Figure S4A) despite no atherogenic changes in plasma lipids”
Quote in the paperSubstantial claim - Findingown data
DMB is rapidly metabolized by liver alcohol dehydrogenase at a rate similar to ethanol.
“DMB was found to be rapidly metabolized by liver alcohol dehydrogenase at a rate comparable to the substrate ethanol”
Quote in the paperNot a substantial claim - Findingown data
DMB substantially inhibits the choline-diet-induced rise in plasma TMAO.
“addition of DMB again substantially inhibited the choline diet-induced increase in plasma TMAO concentrations”
Quote in the paperSubstantial claim - Findingcitation
A choline-enriched diet increases endogenous macrophage foam cell generation about 2-fold in Apoe−/− mice (p=0.02).
“As was previously observed (Wang et al., 2011), a choline-enriched diet promoted marked increase in endogenous macrophage foam cell generation (approximately 2-fold on choline-supplemented diet; p=0.02)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wang et al., 2011 source
Not checked in the free run.
- Findingown data
The CutC/D complex does not efficiently use d9-carnitine or d9-PC as substrates.
“the CutC/D microbial TMA lyase complex does not effectively use either d9-carnitine or d9-PC as substrates”
Quote in the paperSubstantial claim - Findingown data
A choline-supplemented diet markedly raises plasma TMAO in Apoe−/− mice (11.8-fold, p<0.001).
“while TMAO was markedly elevated in the mice on the choline-supplemented diet (11.8-fold, p<0.001)”
Quote in the paperSubstantial claim - Findingown data
DMB exposure caused a significant decrease in the proportion of Clostridiales in female mice.
“exposure to DMB induced a significant decrease in the proportions of this taxon (Figure 5D; Table S4).”
Quote in the paperNot a substantial claim - Findingown data
DMB exposure most significantly reduces TMA and TMAO levels in all examined tissues and fluids, especially with choline diet supplementation.
“Notably, as expected with provision of an inhibitor of microbial TMA production, the most significant effects detected with DMB exposure were reductions in TMA and TMAO levels in all tissues and fluids examined (liver, kidney, plasma and urine), especially under conditions of choline diet supplementation”
Quote in the paperSubstantial claim - Findingown data
DMB inhibits TMA formation from choline and GPC in P. mirabilis lysates.
“in both instances, addition of DMB inhibited TMA formation”
Quote in the paperSubstantial claim - Premisecitation
Anaerobic choline degradation is thought to be the main intestinal source of TMA.
“Anaerobic choline degradation is believed to serve as the major source of TMA formation within the intestines”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
FMO3 regulates host lipid and sterol metabolism and atherosclerosis development.
“important regulators in host lipid and sterol metabolism, as well as atherosclerosis development”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
TMAO promotes atherosclerosis in animal models.
“both enhances atherosclerosis in animal models”
- Also stated in: § INTRODUCTION · plain
“a metabolite that accelerates atherosclerosis in animal models”
Quote in the paperSubstantial claim0 of 3 sources checked - Also stated in: § INTRODUCTION · plain
- Premisecitation
People with genetic FMO3 defects develop Fish Odor Syndrome from TMA accumulation and its odor.
“humans with genetic defects in FMO3 suffer from Fish Odor Syndrome due to the accumulation of TMA and its noxious odor”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cashman et al., 2003 source
Not checked in the free run.
- Premisecitation
Microbial choline TMA lyase is a glycyl radical enzyme complex of CutC and CutD encoded by adjacent genes.
“identification of a microbial choline TMA lyase was reported as a unique glycyl radical employing enzyme complex comprised of a catalytic polypeptide, CutC, and an associated activating protein, CutD, encoded by adjacent genes within a gene cluster”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Craciun and Balskus, 2012 source
Not checked in the free run.
- Premisecitation
Host hepatic FMO3 is the main enzyme producing TMAO.
“host hepatic FMO3, the primary FMO responsible for TMAO production”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Gut microbial TMA production may be a therapeutic target for cardiometabolic diseases.
“The present studies suggest gut microbial production of TMA specifically, and non-lethal microbial inhibitors in general, may serve as a potential therapeutic approach for the treatment of cardiometabolic diseases.”
Quote in the paperSubstantial claim- Rests on an assumption: Non-lethal targeting of the gut microbial TMA production pathway had not previously been explored as a way to lower TMAO and inhibit atherosclerosis.
- Rests on an assumption: Mouse-model results on diet-induced atherosclerosis and TMAO reduction can indicate a therapeutic approach for human cardiometabolic disease.
- Premisecitation
Choline, phosphatidylcholine, and carnitine are dietary precursors for TMAO production in mice and humans.
“choline, phosphatidylcholine and carnitine, trimethylamine (TMA)-containing nutrients abundant in foods like meat, egg yolk and high fat dairy products, serve as dietary precursors for trimethylamine N-oxide (TMAO) generation in mice and humans”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
FMO3 inhibition causes side effects including hepatic inflammation.
“FMO3 inhibition is also accompanied by several untoward side effects, including hepatic inflammation”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
TMAO is associated with cardiovascular risk in clinical studies.
“is associated with cardiovascular risks in clinical studies”
- Also stated in: § INTRODUCTION · plain
“Blood TMAO levels are associated with risks for both prevalent atherosclerotic heart disease and incident major adverse cardiac events in multiple independent cohorts”
Quote in the paperSubstantial claim0 of 3 sources checked - Also stated in: § INTRODUCTION · plain
- Interpretationown data
Non-lethal microbial inhibitors may be a therapeutic approach for cardiometabolic diseases.
“The present studies suggest gut microbial production of TMA specifically, and non-lethal microbial inhibitors in general, may serve as a potential therapeutic approach for the treatment of cardiometabolic diseases.”
Quote in the paperSubstantial claim- Rests on an assumption: Non-lethal targeting of the gut microbial TMA production pathway had not previously been explored as a way to lower TMAO and inhibit atherosclerosis.
- Rests on an assumption: Mouse-model results on diet-induced atherosclerosis and TMAO reduction can indicate a therapeutic approach for human cardiometabolic disease.
- Interpretationreasoning
The fact that DMB changed microbial composition suggests that some selective pressure occurs with exposure to the agent.
“the fact that there is any change in microbial composition induced by DMB suggests some degree of selective pressure is occurring with exposure to the agent”
Quote in the paperNot a substantial claim - Interpretationreasoning
The present studies suggest that selective, non-lethal microbial enzyme inhibitors targeting causative pathways, once identified, may be an effective and complementary strategy to current approaches for preventing and treating cardiometabolic diseases.
“The present studies suggest development of selective, non-lethal microbial enzyme inhibitors that target causative pathways, once they are revealed, may serve as an effective and complementary strategy to current approaches for the prevention and treatment of cardiometabolic diseases.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The recognition that gut microbes participate in cardiovascular and metabolic disease pathogenesis suggests that drugs aimed at the microbiome could be a therapeutic approach for cardiometabolic diseases.
“The recognition of gut microbes as participants in cardiovascular and metabolic disease pathogenesis suggests pharmacological interventions aimed at “drugging the microbiome” may potentially serve as a therapeutic approach for the treatment of cardiometabolic diseases.”
Quote in the paperSubstantial claim - Premisecitation
Because specific microbial enzyme activities or metabolites mechanistically linked to disease phenotypes were not known, therapeutic approaches other than dietary restriction have focused on changing gut microbial community composition using probiotics or prebiotics.
“Toward this end, in the absence of knowledge of specific microbial enzyme activities or their metabolites mechanistically linked to disease phenotypes, therapeutic approaches, aside from dietary restrictions, have thus far instead focused on altering gut microbial community composition through use of either defined microbial compositions (probiotics) or non-microbial substances that may secondari”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Petschow et al., 2013 source
Not checked in the free run.
- Premisecitation
Multiple lines of evidence show that the meta-organismal pathway producing TMAO is mechanistically linked to susceptibility to atherosclerosis.
“Multiple lines of evidence show the meta-organismal pathway involved in TMAO production is mechanistically linked to atherosclerosis susceptibility (Bennett et al., 2013; Gregory et al., 2015; Koeth et al., 2013; Wang et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
The present studies provide proof of concept that inhibiting microbial TMA production through microbial TMA lyase inhibition may be a potential therapeutic approach for preventing or treating atherosclerosis.
“The present studies provide proof of concept for the idea that inhibiting microbial TMA production, through microbial TMA lyase inhibition, may serve as a potential therapeutic approach for the prevention or treatment of atherosclerosis (Figure 6).”
Quote in the paperSubstantial claim - Interpretationown data
DMB has broad inhibitory activity across multiple microbial TMA lyase activities.
“suggesting broad inhibitory activity across multiple microbial TMA lyase enzyme activities”
Quote in the paperSubstantial claim- Rests on an assumption: Mouse cecal contents and human feces are physiological polymicrobial sources that represent gut microbial TMA lyase activity.
- Premisecitation
A causal role for gut microbes in disease is supported in part by fulfillment of one of Koch's postulates: transfer of a disease-related phenotype by transplanting gut microbes into a new host.
“A causal role for the involvement of gut microbes is in part based on the fulfillment of one of Koch’s postulates - namely, the transmission of a disease related phenotype with transplantation of gut microbial organisms to a new host (Cho and Blaser, 2012; Cox et al., 2014; Dumas et al., 2006; Gregory et al., 2015; Koch, 1880; Sandhu and Chase, 1986).”
Quote in the paperNot a substantial claim0 of 3 sources checked
- May combine two claims. 27
- Classified as probably not a substantial claim. 8
May combine two claims.
Findingown dataDMB occurs in some alcoholic beverages and oils, with highest observed levels of 25 mM.
“DMB was detected in some balsamic vinegars, red wines, and in some cold-pressed extra virgin olive oils and grape seed oils; highest levels observed of 25mM”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataDMB and TMSi-ETOH inhibit recombinant cutC/D choline TMA lyase with IC50 around 10 μM.
“showed roughly comparable cutC/D choline TMA lyase inhibitory activity with an IC50 in the ~10 μM range in the recombinant cutC/D system”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCutC is required for choline cleavage to TMA and for DMB inhibition in E. coli carrying cutC/D from P. mirabilis or D. alaskensis.
“An obligatory role of CutC in the enzymatic cleavage of choline to produce TMA (and DMB inhibition) in E. coli transformed with the cutC/D gene complex from either P. mirabilis or D. alaskensis was supported in both cases by control studies”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDMB blocks TMA production by live microbes and slows intact P. mirabilis conversion of d9-choline to d9-TMA.
“DMB was shown to block TMA production from live microbes, inhibiting the rate of intact P. mirabilis conversion of d9-choline into d9-TMA”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataChronic 16-week DMB exposure shows no toxicity evidence: no significant increases in circulating lipids, plasma choline, glucose, or insulin, and normal renal and liver function indices.
“Moreover, mice showed no evidence of toxicity to the chronic (16 week) DMB exposure, with no significant increases in circulating lipid levels, plasma choline, glucose or insulin levels, and normal indices of both renal (creatinine) and liver function (transaminase activities, bilirubin) (Table S1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBesides lowering plasma TMAO, DMB reduced the proportions of some microbial taxa associated with plasma TMA and TMAO levels and with aortic plaque extent.
“In addition to attenuating plasma levels of TMAO, DMB promoted reduction in proportions of some microbial taxa that are associated with plasma TMA and TMAO levels, and aortic plaque extent.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataChronic DMB exposure does not adversely affect liver lipid levels and histology shows no steatohepatitis.
“Further tissue biochemical studies confirmed chronic exposure to DMB did not adversely impact liver lipid (cholesterol, cholesteryl ester and triglyceride) levels, and histology (including Oil-Red-O and H&E) staining showed no signs of steatohepatitis”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataProteus penneri and Escherichia fergusonii have choline TMA lyase activity, consuming choline and producing TMA.
“Both Proteus penneri and Escherichia fergusonii were confirmed to possess choline TMA lyase activity, readily consuming choline and producing TMA”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDMB is a non-lethal inhibitor in P. mirabilis cultures in rich broth, with no adverse growth effect despite marked TMA lyase inhibition.
“DMB was shown to serve as a non-lethal inhibitor (i.e., not an antibiotic) in cultures of P. mirabilis grown in a rich nutrient broth under conditions that showed no adverse impact on cell growth despite marked inhibition in microbial TMA lyase activity”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDMB inhibits YeaW/X conversion of carnitine and crotonobetaine to TMA but not γ-butyrobetaine.
“DMB inhibited carnitine and crotonobetaine, but not γ–butyrobetaine, conversion into TMA”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDMB treatment had no significant effects on circulating cholesterol, choline, or other pro-atherogenic risk factors.
“DMB provision, despite no significant effects on circulating cholesterol, choline and other pro-atherogenic risk factors”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe proportions of S24-7 showed significant inverse associations with atherosclerotic plaque area and TMA levels, and a trend toward lower plasma TMAO.
“In contrast, proportions of S24-7, an abundant family from Bacterioidetes, showed significant inverse associations with both atherosclerotic plaque area and TMA levels and a trend toward reduced plasma TMAO (Figure 5E; Table S4).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataDMB significantly inhibits TMA production from each substrate in human feces except betaine and GPC, which show non-significant trends.
“DMB significantly inhibited TMA production from each substrate except for betaine and GPC, both of which showed a trend toward inhibition that was not statistically significant”
Quote in the paperSubstantial claim- Rests on an assumption: Mouse cecal contents and human feces are physiological polymicrobial sources that represent gut microbial TMA lyase activity.
May combine two claims.
Findingown dataThe predicted aldehyde metabolite is not detected in plasma or urine; further rapid metabolism to a carboxylic acid occurs, with 3,3-dimethylbutyrylcarnitine detected in urine.
“We could not detect the initial predicted metabolite, 3,3-dimethylbutyric aldehyde, in plasma or urine, but instead found evidence of further rapid metabolism to the carboxylic acid, with detection of the metabolite, 3,3-dimethylbutyrylcarnitine, in urine”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataDMB significantly lowers plasma TMAO in choline- and carnitine-supplemented C57BL/6J mice, similarly in males and females.
“Provision of DMB resulted in significant reduction in plasma TMAO levels in both the choline-supplemented and the carnitine-supplemented groups, with similar results observed for both male and female mice (Figures 3D and 3E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCecal community structure differed between mice fed standard chow with 0.07% choline and those fed a 1.0% choline diet, and these differences were larger when DMB was present.
“Global analyses of community structure showed differences between the chow (0.07% choline) versus high choline (1.0%) diet fed groups, which became more pronounced in the presence of DMB (Figures 5A and 5C).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataDMB markedly inhibits choline utilization for TMA production in P. penneri and E. fergusonii cultures without inhibiting bacterial growth.
“Similar to results observed with P. mirabilis, addition of DMB to a rich nutrient broth in cultures (as exists in the gut lumen) of either Proteus penneri or Escherichia fergusonii markedly inhibited choline utilization to produce TMA but showed no inhibitory effect on bacterial growth”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAll tested nutrient precursors produce TMA in human feces, with more production from choline-related nutrients than carnitine.
“all nutrient precursors examined produced TMA, with greater extent of production from nutrients structurally related to choline (Figure 2D) compared to carnitine”
Quote in the paperNot a substantial claim- Rests on an assumption: Mouse cecal contents and human feces are physiological polymicrobial sources that represent gut microbial TMA lyase activity.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataMice on choline diet with DMB show modest elevations in plasma and kidney betaine compared with choline diet without DMB.
“modest elevations in plasma and kidney betaine levels were observed in mice on choline diet with DMB (vs. choline diet without DMB)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOral DMB significantly lowers plasma TMAO, while comparable subcutaneous DMB does not.
“while orally administered DMB resulted in significant reduction in plasma TMAO levels, a comparable amount of DMB administered subcutaneously failed to reduce plasma TMAO levels”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe prevalence of Lachnospiraceae was strongly associated with TMA and TMAO levels and showed a trend toward greater aortic root plaque area.
“Similarly, prevalence of the taxon Lachnospiraceae was highly associated with TMA and TMAO levels and showed a trend toward increased aortic root plaque area.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn female mice, the order Clostridiales and the genus Ruminococcus were each strongly positively correlated with plasma TMA and TMAO levels and with atherosclerotic lesion area.
“For female mice, the order Clostridiales and the genus Ruminococcus were each highly positively correlated with both plasma TMA and TMAO levels, as well as atherosclerotic lesion area (Table S4).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDMB appears in plasma and urine 30 minutes after intraperitoneal administration but not after oral gavage.
“DMB was detected in both plasma and urine 30 minutes following intraperitoneal route, but not following bolus administration by gastric gavage”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCholine C-N bond cleavage to TMA and acetaldehyde was reported in Proteus mirabilis extracts.
“The cleavage of the C-N bond of choline to form TMA and acetaldehyde was reported with extracts of Proteus mirabilis”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sandhu and Chase, 1986
Not checked in the free run.
May combine two claims.
PremisecitationCholine-diet-enhanced atherosclerosis susceptibility and TMA/TMAO formation are transmissible traits.
“both choline-diet enhanced atherosclerosis susceptibility and TMA/TMAO formation are transmissible traits”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gregory et al., 2015 source
Not checked in the free run.
May combine two claims.
PremisecitationMammalian TMAO formation proceeds in two metaorganismal steps: gut microbes make TMA, then host hepatic FMOs convert TMA to TMAO.
“TMAO formation in mammals occurs via a two-step metaorganismal pathway”
- Also stated in: § INTRODUCTION · plain
“gut microbes form TMA, and then host hepatic flavin monooxygenases (FMOs) catalyze the conversion of TMA into TMAO”
Quote in the paperSubstantial claim0 of 2 sources checked- Also stated in: § INTRODUCTION · plain
May combine two claims.
PremisecitationAntisense suppression of host FMO3 lowers circulating TMAO and diet-enhanced atherosclerosis in animal models.
“suppression of the host enzyme, FMO3, through antisense oligonucleotide-based approach, results in reduction of both circulating TMAO levels and diet-enhanced atherosclerosis in animal models”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCholine dehydrogenase is expressed mainly in liver and kidney and converts choline to betaine aldehyde, an intermediate in betaine generation.
“Choline dehydrogenase is expressed mainly in the liver and kidney and catalyzes conversion of choline into betaine aldehyde, an intermediate in the generation of betaine”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Cafiero, 1951
Not checked in the free run.
- cites Tan et al., 1981 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGut microbes act as a filter for the largest environmental exposure, what we eat.
“Gut microbes serve as a filter for our largest environmental exposure–what we eat.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Brown and Hazen, 2015
Not checked in the free run.
May combine two claims.
PremisecitationGut microbes also act as a dynamic endocrine organ, producing biologically active metabolites in response to specific nutrient inputs; these metabolites can enter the circulation and affect distant host sites.
“They also function, fundamentally, as a dynamic endocrine organ, generating biologically active metabolites in response to specific nutrient inputs that can enter the circulation and elicit biological effects at distant sites within the host (Brown and Hazen, 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Brown and Hazen, 2015
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMany species within Clostridiales have been reported to break down choline.
“many Clostridiales species have been reported to cleave choline (Moller et al., 1986).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Moller et al., 1986 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIntraperitoneal DMB increases liver choline content 30 minutes later through competitive inhibition of choline dehydrogenase.
“It has previously been reported that 30 minutes after intraperitoneal administration of DMB, through competitive inhibition of choline dehydrogenase, the choline content of liver tissues increases”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Barlow and Marchbanks, 1985
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe gut microbiome is highly dynamic and adaptable, changing with dietary inputs and with the presence or absence of different diseases.
“Nonetheless, the gut microbiome is known to be remarkably dynamic and adaptive, including changes in response to different dietary inputs, as well as the presence versus absence of distinct diseases (Cox et al., 2014; Koren et al., 2011; Wu et al., 2011).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe DMB-induced change in microbial composition raises the possibility that resistance could develop.
“and thus raises the possibility of development of resistance.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Non-lethal targeting of the gut microbial TMA production pathway had not previously been explored as a way to lower TMAO and inhibit atherosclerosis.
“Reduction in TMAO levels by non-lethally targeting the gut microbial pathway(s) involved in TMA production has not yet been explored as a potential therapeutic approach to inhibit atherosclerosis.”
The paper relies on this without support.
Mouse-model results on diet-induced atherosclerosis and TMAO reduction can indicate a therapeutic approach for human cardiometabolic disease.
“The present studies suggest gut microbial production of TMA specifically, and non-lethal microbial inhibitors in general, may serve as a potential therapeutic approach for the treatment of cardiometabolic diseases.”
The paper relies on this without support.
Mouse cecal contents and human feces are physiological polymicrobial sources that represent gut microbial TMA lyase activity.
“We next examined mouse cecal contents as a physiological polymicrobial source of TMA lyase activities”
“we used human feces from healthy donors as another physiological polymicrobial source of TMA lyase activity”
The paper relies on this without support.
The effect of small molecule antagonists for the critical initiating microbial TMA lyase step on atherosclerosis development has not yet been reported.
“However, the effect of small molecule antagonists for the critical initiating microbial TMA lyase step on atherosclerosis development has not yet been reported.”
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?
Targeted 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”
From Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk (2016) · cites this paper as Wang et al, 2015
Decreasing systemic TMAO levels is a rational potential therapeutic strategy for decreasing risks for development and progression of atherosclerotic heart disease.
“Thus, decreasing systemic levels of TMAO has become a rational potential therapeutic strategy for decreasing risks for the development and progression of atherosclerotic heart disease.8,[13][14][15]”
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 [8]
High plasma TMAO levels are associated with risk for developing atherosclerosis.
“studies suggesting an association between high plasma TMAO levels and risk for developing atherosclerosis have increased markedly [7,13,14,15,16,17]”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [17]
TMAO increases expression in macrophages of scavenger receptors CD36 and SR-A1, which promote lipid accumulation and foam cell formation.
“Additionally, TMAO increases the expression in macrophages of scavenger receptors CD36 and SR-A1, which promote lipid accumulation and foam cell formation [7,17].”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [17]
DMB cannot avoid complete TMAO synthesis because it cannot inhibit the conversion of GBB to TMA.
“Although it inhibits the transformation of choline, carnitine and crotonobetaine into TMA in mice and rats, DMB is not able to avoid the complete TMAO synthesis as it cannot inhibit the conversion of GBB to TMA [8,17,32,38].”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [17]
DMB inhibits the transformation of choline, carnitine and crotonobetaine into TMA in mice and rats.
“Although it inhibits the transformation of choline, carnitine and crotonobetaine into TMA in mice and rats, DMB is not able to avoid the complete TMAO synthesis as it cannot inhibit the conversion of GBB to TMA [8,17,32,38].”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [17]
3,3-dimethyl-1-butanol, a nontoxic choline analog, inhibited conversion of choline, carnitine, and crotonobetaine, but not γ-butyrobetaine, to TMA.
“A nontoxic structural analog of choline, 3,3-dimethyl-1-butanol, inhibited the conversion of choline, carnitine, and crotonobetaine (but not γ-butyrobetaine) to TMA (119).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [119]
3,3-dimethyl-1-butanol significantly lowered plasma TMAO and mitigated choline-enhanced macrophage foam cell formation and atherosclerosis in Apoe-/- mice.
“It also significantly lowered plasma TMAO concentrations and mitigated choline-enhanced macrophage foam cell formation and atherosclerosis in Apo e -/-mice (119).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [119]
In atherosclerosis-prone ApoE−/− mice on a choline-supplemented diet, DMB lowered plasma TMAO and attenuated macrophage cholesterol accumulation, foam cell formation, and atherosclerotic lesion development.
“When given to atherosclerosis-prone ApoE−/− mice on a choline-supplemented diet, plasma TMAO levels were significantly lowered, and concurrently, macrophage cholesterol accumulation, foam cell formation and atherosclerotic lesion development were attenuated35.”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [35]
DMB inhibits microbial choline TMA lyase activity in vitro and in vivo.
“We recently reported the use of a natural product, 3,3-dimethyl-1-butanol (DMB), as a tool drug that inhibits microbial choline TMA lyase activity in vitro and in vivo35.”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [35]
3,3-Dimethyl-1-butanol can reduce TMAO levels by inhibiting the formation of TMA from microbes in mice, thereby attenuating choline diet-enhanced atherosclerosis.
“Meanwhile, a recent report showed that 3,3-dimethyl-1-butanol can reduce TMAO levels by inhibiting the formation of TMA from microbes in mice, thereby attenuating choline diet-enhanced AS (39).”
In mice, blocking the microbial enzyme TMA lyase lowers circulating TMAO and prevents atherosclerosis.
“An inhibitor of TMA lyase that stops the microbial synthesis of TMA and therefore reduces the levels of circulating TMAO prevents the development of atherosclerosis in mice121.”
From Diet–microbiota interactions as moderators of human metabolism (2016) · cites this paper as [121]
Feeding mice an analogue of choline that inhibits TMA production by blocking microbial TMA lyases prevents atherosclerosis in mice.
“feeding mice an analogue of choline, which inhibits TMA production by blocking microbial TMA lyases, could prevent atherosclerosis in mice [71].”
From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [71]
Trimethylamine N-oxide has been shown to enhance atherosclerosis in most, but not all, mechanistic and animal model studies.
“TMAO has been shown to enhance atherosclerosis in most, but not all, mechanistic and animal model studies7, 9, 78–82.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [78]
When fed to animals, DMB inhibits choline diet-dependent TMAO generation, reduces macrophage foam cell formation, and inhibits aortic atherosclerotic plaque development.
“When fed to animals, DMB inhibited choline diet-dependent TMAO generation, reduced macrophage foam cell formation, and inhibited aortic atherosclerotic plaque development78.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [78]
DMB serves as a non-lethal microbial enzyme inhibitor of choline→TMA transformation and reduces TMAO production in vivo without affecting microbial fitness.
“Through a series of studies, DMB was shown to serve as a non-lethal microbial enzyme inhibitor of choline→TMA transformation, and to reduce TMAO production in vivo without affecting microbial fitness78.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [78]
Diet containing choline, TMAO or betaine can enhance up-regulation of multiple macrophage scavenger receptors linked to atherosclerosis.
“Wang et al. showed that diet containing choline, TMAO or betaine could enhance up-regulation of multiple macrophage scavenger receptors that are linked to atherosclerosis [32,38].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [38]
DMB promoted reduction in microbial taxa associated with plasma TMA and TMAO levels and reduced the choline-diet-dependent enhancement in aortic root atherosclerotic lesion development.
“Furthermore, DMB promoted reduction in microbial taxa that are associated with plasma TMA and TMAO levels and also reduced the choline-diet-dependent enhancement in aortic root atherosclerotic lesion development [38].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [38]
DMB is a structural analog of choline and an inhibitor for TMA formation through inhibition of microbial TMA lyases.
“3,3-dimethyl-1-butanol (DMB) is a structural analog of choline and an inhibitor for TMA formation through inhibition of microbial TMA lyases.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [38]
DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in apoE−/− mice without alterations in circulating cholesterol levels.
“DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in apoE−/− mice without alterations in circulating cholesterol levels [38].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [38]
DMB, by inhibiting microbial choline and carnitine TMA lyase activities in vivo, appears to prevent foam cell formation and aortic atherosclerotic plaque formation while maintaining normal gut flora.
“Particularly promising is the effective experimental use of 3,3-dimethyl-1-butanol (DMB), which by inhibiting microbial choline and carnitine TMA lyase activities in vivo appears to prevent foam cell formation and aortic atherosclerotic plaque formation, while maintaining a normal gut flora.38”
A drug that selectively targets microbial TMA production and lowers plasma TMAO can inhibit diet-induced atherosclerosis in animal models.
“Furthermore, experimental evidence suggests that the use of a drug that selectively targets microbial TMA production and lowers plasma TMAO levels in the host can serve as a means of inhibiting diet-induced atherosclerosis in animal models.38”
TMAO is modifiable both with diet and with potential therapeutics under development.
“The importance of our findings is underlined by the modifiable nature of TMAO, both with diet, and with potential therapeutics under development, offering new prospects for treatment strategies at both levels of primary and secondary prevention.”
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 [96]
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 [96]
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 [96]
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 [96]
DMB was developed as a competitive inhibitor against CutC catalyzed choline TMA-lyase activity to reduce TMAO production.
“In a study by Wang et al., DMB was developed as a competitive inhibitor against CutC catalyzed choline TMA-lyase activity to reduce the production of TMAO96.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [96]
DMB exposure reduces atherosclerosis progression in the apolipoprotein E−/− mouse model without significant adverse toxicity.
“exposure to DMB was shown to also effectively reduce atherosclerosis progression in the apolipoprotein E−/− mouse model without significant adverse toxicity96.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [96]
DMB is non-lethal to human commensals possessing CutC and suppresses TMA production in cultured human commensals and lowers TMAO in mice on a choline supplemented diet.
“This inhibitor was found to be non-lethal to human commensals possessing CutC and fostered suppression of both TMA production in cultured human commensals and TMAO lowering in mice on a choline supplemented diet.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [96]
DMB is present in extra-virgin olive oil, a major component of the Mediterranean diet.
“DMB was also observed to be present in some cold-pressed extra-virgin olive oils96, a major component of the Mediterranean diet.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [96]
DMB inhibits TMAO production.
“which inhibits TMAO production”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [96]
Inhibition of gut microbiota-dependent TMAO production is a promising strategy for the treatment of atherosclerosis.
“Inhibition of gut microbiota-dependent TMAO production has been shown as a promising strategy for the treatment of atherosclerosis14.”
From The gut microbiome in atherosclerotic cardiovascular disease (2017) · cites this paper as [14]
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.
Reported TMAO fold increase does not match the group means
MajorThe reported mean TMAO concentration is 22.1 μM for the choline group and 1.02 μM for the chow group. That is a 21.7-fold increase, not 11.8-fold.
Reported 11.8 · recomputed 21.666667
“TMAO was markedly elevated in the mice on the choline-supplemented diet (11.8-fold, p<0.001), addition of DMB again substantially inhibited the choline diet-induced increase in plasma TMAO concentrations (mean ± SD, in μM, for the four groups: chow, choline, chow + DMB and choline + DMB, are 1.02 ± 0.09, 22.1 ± 2.1”
P-values for DMB's atherosclerosis effect differ within the same paragraph
MinorThe paragraph gives p=0.003 for males and p=0.01 for females when describing DMB-mediated attenuation, but later gives p=0.006 and p=0.02, respectively, for DMB's inhibition of the choline-diet effect.
“(DMB mediated attenuation of atherosclerosis) were observed in both male and female mice (p=0.003 and p=0.01, respectively)”
“addition of DMB significantly inhibited the choline diet-dependent enhancement in aortic root lesion development in both males (p=0.006, Figure 4D) and females (p=0.02, Figure S4A).”
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- Authors
- 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., DiDonato, A. J., Fu, X., Hazen, J. E., Krajcik, D., DiDonato, J. A., Lusis, A. J., & Hazen, S. L.
- Affiliations
- Cleveland Clinic (US)
- University of California, Los Angeles (US)
- Corresponding author
- Wang, Zeneng
- Hazen, Stanley L.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 163
- Issue
- 7
- Pages
- 1585-1595
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4871610
- OpenAlex
- W2207436601
- Cited by
- 1,317
- References
- 34
- Citations by year
- 2026: 97 · 2025: 125 · 2024: 105 · 2023: 139 · 2022: 168 · 2021: 158 · 2020: 157 · 2019: 97 · 2018: 100 · 2017: 92 · 2016: 73 · 2015: 3
- FWCI
- 38.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Public Health Service (R01106000, P01 H28481)
- National Heart, Lung, and Blood Institute (P20HL113452, R01HL103866, P01HL028481)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106000)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- trimethylamine N-oxide, gut microbiota, atherosclerosis, 3,3-dimethyl-1-butanol, choline, L-carnitine, foam cells, atherosclerotic plaque, ApoE-deficient mice, cardiometabolic disease, dietary choline
- MeSH terms
- Hexanols, Animals, Apolipoproteins E, Cholesterol, Choline, Diet, Feces, Foam Cells, Humans, Lyases, Methylamines, Mice, Inbred C57BL, Gastrointestinal Tract, Atherosclerosis, Mice, Microbiota
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