Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk

In the citing paper

“Numerous recent case–control and longitudinal studies have shown a striking association between trimethylamine N‐oxide (TMAO) levels and cardiovascular disease risks in a variety of cohorts.1, 2, 3, 4, 5, 6, 7, 8, 9, 10”

In the citing paper

“Plasma TMAO levels in subjects (N>4000) independently predicted incident (3 yr) thrombosis (heart attack, stroke) risk.”

In the citing paper

“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).”

In the citing paper

“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).”

In the citing paper

“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).”

In the citing paper

“circulating levels of TMAO have been shown in multiple distinct clinical studies and cohorts to be associated with CVD risks”

In the citing paper

“Animal model and human clinical studies demonstrate an obligatory role for gut microbiota in TMAO formation from TMA-containing nutrients including choline and phosphatidylcholine9, 10, L-carnitine8, and more recently, γ-butyrobetaine15, and to a lesser degree, the choline oxidation metabolite betaine11.”

In the citing paper

“In one large study of subjects with predominantly preserved renal function, we reported the prognostic value of TMAO for predicting three year risk for major adverse cardiovascular events (MACE = myocardial infarction, stroke or death) remained significant following adjustments for renal function 9.”

In the citing paper

“Specifically, gut microbiota-mediated metabolism of phosphatidylcholine, choline or L-carnitine each have been shown to ultimately produced trimethylamine-N-oxide (TMAO), and in multiple clinical studies, TMAO levels have been shown to be associated with cardiovascular risks8–10, 13.”

In the citing paper

“in multiple clinical studies, TMAO levels have been shown to be associated with cardiovascular risks8–10, 13.”

In the citing paper

“We have also established the obligatory role of intestinal microbiota in the production of TMAO from dietary choline and other TMA nutrients in humans, 16,17 and the association between elevated fasting levels of TMAO and higher incident risks of long-term MACEs.17”

In the citing paper

“Moreover, elevated levels of TMAO have been shown to predict increased prevalent cardiovascular disease (CVD) risk, and increased incident risk of major adverse cardiovascular events (MACE ¼ myocardial infarction, stroke, and death) in large-scale human clinical studies.14,16,17”

In the citing paper

“Interestingly, the administration of antibiotics in humans in our prior studies had limited effects on circulating choline and betaine levels, despite abolition of TMAO levels, upon ingestion of stable-isotope-labelled d9-PC.17”

In the citing paper

“Choline, betaine, and TMAO are all metabolites formed following ingestion of dietary PC. 14,17”

In the citing paper

“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”

In the citing paper

“both enhances atherosclerosis in animal models”

In the citing paper

“Our group has recently described a mechanistic link between intestinal microbe-dependent generation of trimethylamine-N-oxide (TMAO) and increased risk for future cardiovascular events (death, myocardial infarction, and stroke) by a pathway involving dietary nutrients such as phosphatidylcholine, choline, and carnitine (10,11).”

In the citing paper

“While TMAO has been shown to possess pro-atherogenic properties (10,11,17)”

In the citing paper

“The formation of TMA, which is subsequently metabolized to TMAO, depends on the presence of an intact gut microbiota [6]”

In the citing paper

“In multiple human studies, elevated TMAO has been independently associated with prevalent CVD and incident risks for MI, stroke, death, and revascularization.”

In the citing paper

“Specifically, patients in the upper quartile for TMAO levels (compared with the lowest quartile) had a significant, 2.5-fold increased risk of experiencing a major adverse cardiac event (MI, stroke, or death), independent of traditional cardiovascular risk factors, renal function, and medication use, as well as overall poorer event-free survival (37).”

In the citing paper

“a metabolite shown to be both mechanistically linked to atherosclerosis and whose levels are strongly linked to cardiovascular disease (CVD) risks.”

In the citing paper

“In an alternative subsequent expansion study of over 4,000 subjects undergoing elective coronary angiography, elevated TMAO levels predicted major adverse cardiac events such as death, myocardial infarction (MI), and stroke over a 3-year period.”

In the citing paper

“An obligatory role for gut microbiota in both TMA and TMAO formation from ingested PC was confirmed in animal model studies, which included germ-free mice (25), as well as human clinical investigations involving ingestion of egg yolk, isotope-labeled PC, and a cocktail of oral antibiotics (37).”

In the citing paper

“These observations highlight the obligatory role of intestinal microbiota in the generation of TMAO from multiple dietary nutrients, and TMAO as the proatherogenic species likely promoting the striking associations noted between plasma levels and both prevalent and incident CVD risks.”

In the citing paper

“More recent studies examining ingestion of either hard-boiled egg or egg yolk (37,38,62) or ingestion of trimethyl-d9-PC (37) have confirmed direct generation of TMAO from PC ingestion in humans.”

In the citing paper

“In vivo studies in which trimethyl-d9-labeled betaine or PC were ingested showed a direct generation of d9-TMA and d9-TMAO within plasma and urine (37,39,55).”

In the citing paper

“Choline (free and esterified forms) and L-carnitine are the most common dietary nutrients ingested that produce TMA and TMAO (30,(37)(38)(39)55).”

In the citing paper

“Our laboratory has elucidated a link between intestinal microbiota, dietary trimethylamine-containing nutrients ( e.g. choline, phosphatidylcholine, and carnitine), andcardiovasculardisease(5-7).”

In the citing paper

“plasma levels in subjects are associated with prevalent and incident cardiovascular disease risks (5, 7, 9, 10).”

In the citing paper

“An obligatory role for gut microbes in TMAO formation in both mice (5, 6) and humans (7) was shown”

In the citing paper

“Elevated plasma TMAO levels are observed in subjects at risk for incident cardiovascular disease (CVD) development and adverse CVD events including heart attack, stroke, and death.[1][2][3][4]”

In the citing paper

“Trimethylamine N-oxide (TMAO) is a gut microbiota-generated metabolite with mechanistic links to the pathogenesis of atherosclerotic heart disease.[1][2][3][4][5]”

In the citing paper

“Studies have also shown dose-dependent TMA/TMAO formation with egg ingestion.2,18”

In the citing paper

“Trimethylamine N-oxide is generated via a metaorganismal pathway that begins with gut microbiota-dependent formation of trimethylamine (TMA) from TMA containing nutrient precursors (Figure 1A).[1][2][3]16”

In the citing paper

“In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events.”

In the citing paper

“some studies performed with antibiotics in rats and humans reveal that the production of TMA and TMAO is almost totally suppressed with the use of broad-spectrum antibiotics, such as Ciprofloxacin, Vancomycin or Metronidazole. However, the levels of TMAO return to normal after one month of the withdrawal of the antibiotics [7,52].”

In the citing paper

“Indeed, elevated plasma TMAO levels have been found in people at risk of CVD. These patients usually show greater concentrations of the TMAO precursors too.”

In the citing paper

“In this context, it is thought that TMAO could serve as a biomarker in humans to predict prevalence of CVD and increased incidence of major adverse cardiovascular events (MACE), such as myocardial infarction, stroke and even death [7,14,52,53,54,55].”

In the citing paper

“However, one month after the withdrawal of antibiotics, TMAO levels are detectable again [52].”

In the citing paper

“Moreover, antibiotics do not only kill harmful bacteria, but could affect the beneficial too [52].”

In the citing paper

“Albeit the use of antibiotics is effective in the suppression of microbiota that produces TMA, the chronic use of antibiotics is not viable since it can lead to resistant bacterial strains and repopulation.”

In the citing paper

“The use of broad spectrum antibiotics such us ciprofloxacin and metronidazole leads to near almost complete suppression of TMAO levels.”

In the citing paper

“Elevated TMAO has been observed in patients with cardiovascular disease and atherosclerosis, highlighting a potential downside to increased protein intake.[15-17,22, 37]”

In the citing paper

“Recently, it has been shown that gut microbial production of trimethylamine N-oxide (TMAO) from dietary choline and l-carnitine increases the risk of developing cardiovascular disease in both mice and humans, independently of traditional cardiometabolic risk factors (89).”

In the citing paper

“Recent studies by Wang and Tang et al reported that circulating concentrations of trimethylamine N‐oxide (TMAO), a metabolite derived from the gut microbiota, were predictive of prevalent cardiovascular diseases (CVDs)1 and future cardiovascular events3 in clinical cohorts.”

In the citing paper

“All of the studies included clinical cohorts, including patients at higher cardiovascular risk, that is, enriched for baseline heart disease,3, 8, 12, 13, 14, 15, 16, 17, 21 kidney disease,10, 11, 18, 19, 20, 22, 23 peripheral artery disease,25 or diabetes mellitus.7, 26”

In the citing paper

“Of the 19 publications, a total of 16 publications, including 19 data points, were eligible for our main analysis to calculate a pooled RR of elevated TMAO levels as compared with low levels3, 7, 8, 10, 11, 13, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26 (Table 1 and Figure 1).”

In the citing paper

“Wang et al. identified a novel pathway linking dietary lipid intake, the intestinal microbiota, and atherosclerosis (Figure 3)57, 58.”

In the citing paper

“Catabolism of choline by the intestinal microbiota results in the formation of the gas, trimethylamine (TMA), which is metabolized by the liver into trimethylamine oxide (TMAO)—a small molecule that is strongly associated with the increased risk for coronary vascular disease in humans.”

In the citing paper

“The intestinal microbiota may also contribute to development of atherosclerosis by producing metabolites of the dietary lipid phosphatidylcholine that are associated with the risk for coronary vascular disease.”

In the citing paper

“However, consumption of ≥2 eggs, which contain mostly PtdCho, results in increased formation of TMAO (79,110).”

In the citing paper

“During three years of follow-up in patients (n = 4,007) undergoing elective coronary angiography, increased plasma concentrations of TMAO were associated with increased risks of major adverse cardiovascular events (110).”

In the citing paper

“In individuals undergoing elective coronary angiography, plasma TMAO concentrations were correlated with increased serum glucose and the patient's diabetic state (110).”

In the citing paper

“multiple human and animal studies supporting both mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks have been reported8–16.”

In the citing paper

“A recent metabolomics approach identified that plasma trimethylamine-N-oxide (TMAO), a choline metabolite, is a novel and independent risk factor for promoting AS (2, 3).”

In the citing paper

“TMAO has been shown to induce AS by affecting cholesterol metabolism through inhibiting hepatic bile acid (BA) synthesis (2–4).”

In the citing paper

“Recently, plasma TMAO was identified as a metabolite strongly associated with AS (2–4).”

In the citing paper

“Previous studies suggest that TMAO partially contributes to the development of AS by regulating the major pathway of cholesterol metabolism and the bile acid synthetic pathway.4, 5, 6”

In the citing paper

“Trimethylamine‐N‐oxide (TMAO) has recently been identified as a novel and independent risk factor for promoting atherosclerosis through inducing vascular inflammation.”

In the citing paper

“In a large independent clinical cohort (n=4007), elevated TMAO levels were associated with significantly increased risk for major adverse cardiovascular events (2.54 for highest versus lowest TMAO quartile; P<0.001).5”

In the citing paper

“Within the cohort examined, the hazard ratio for TMAO was significantly higher than that for traditional risk factors such as LDL cholesterol.”

In the citing paper

“Furthermore, elevated TMAO levels retained a strong prognostic value for predicting the incidence of adverse cardiovascular events, even after adjustment for traditional risk factors and renal function.5”

In the citing paper

“Recently, plasma TMAO was identified as a novel and independent risk factor for promoting AS.”

In the citing paper

“Hazen and coworkers showed that consumption of foods rich in choline or carnitine, such as eggs, milk, liver, meat, or fish, produced high concentrations of TMAO in both humans and animals who possessed the requisite microbiota for metabolizing choline or carnitine to trimethylamine, the immediate precursor of TMAO (108, 171, 172).”

In the citing paper

“Subjects from a cohort of .2000patients with cardiovascular disease, who were in the highest quartile for plasma TMAO concentrations, had a .2-foldrisk of a heart attack or stroke compared with subjects from the lowest quartile (108, 172).”

In the citing paper

“The microbiota play an important role in choline diet–induced trimethylamine N-oxide production, which has been implicated in CVD.”

In the citing paper

“These observations are of interest because high TMAO levels linked to TMA oxidation by the human hepatic flavin monooxygenase FMO3 have been associated with cardiovascular diseases (CVDs) (Tang et al., 2013; Wang et al., 2011), while it is known that RYGB is associated with a lower CVD risk (Sjöström et al., 2012).”

In the citing paper

“Likewise, gut microbes can also convert otherwise beneficial dietary compounds, such as choline, into metabolites that are detrimental to human health (7–10).”

In the citing paper

“a metabolite linked to accumulation of cholesterol in macrophages and foam cell deposition127, and higher risk of a major adverse cardiac event128.”

In the citing paper

“Also in humans, PC or LC administration augmented TMA plasma levels, and increased the risk for cardiovascular disease; notably, antibiotic treatment dramatically reduced TMA levels in these subjects [68, 70].”

In the citing paper

“a series of recent studies [68-70] revealed a link between microbiota and atherogenesis.”

In the citing paper

“Food is a major factor that shapes the proportional representation of organisms present in the gut microbial community (microbiota), and its gene content (microbiome).”

In the citing paper

“The microbiota/microbiome in turn plays an important role in extracting and metabolizing dietary ingredients9-14.”

In the citing paper

“This is exemplified by trimethylamine (TMA), a microbial metabolite that is produced by various taxa of the gut microbiota from dietary quaternary amines, mainly choline and carnitine. TMA is absorbed via the intestinal epithelium and further oxidized to trimethylamine N-oxide (TMAO), which was associated with atherosclerosis and severe cardiovascular disease in several independent studies [1–4].”

In the citing paper

“The first studies revealing a potential causal link between the gut microbiome and CVD focused on trimethylamine N-oxide (TMAO), a metaorganismal metabolite formed following ingestion of dietary nutrients abundant in a Western diet (e.g. lecithin, choline, carnitine)7–9.”

In the citing paper

“Through these and other studies, generation of TMAO in humans and mice has been shown to occur via a multistep, metaorganismal pathway starting with the dietary precursors choline9, phosphatidylcholine8, 9, and carnitine7.”

In the citing paper

“Further evidence that the production of TMAO is dependent on metabolism by intestinal microbiota is provided by studies in healthy humans given phosphatidylcholine challenge, in which the plasma levels of TMAO were suppressed by oral administration of broad spectrum antibiotics [14].”

In the citing paper

“TMAO is then either transported to the tissues for accumulation as an osmolyte or, more commonly, cleared by the kidney [3,9,13,14].”

In the citing paper

“Indeed, in health participants, suppression of intestinal microbiota with oral broad spectrum antibiotic reduced plasma TMAO levels after a phosphatidylcholine challenge [14].”

In the citing paper

“TMAO levels increased one month after stopping antibiotics [14].”

In the citing paper

“The mechanisms through which hPDI could reduce CHD risk are likely shared with the mechanisms for type 2 diabetes risk reduction.(2, 24–32)”

In the citing paper

“all of which could aid in weight loss/maintenance, enhance glycemic control and insulin regulation, improve lipid profile, reduce blood pressure, improve vascular health, decrease inflammation, and foster more favorable diet- gut microbiome interactions (e.g. through lowered levels of trimethylamine N-oxide), thereby lowering CHD risk.”

In the citing paper

“Gut microbes transform phosphatidylcholine and l‐carnitine from ingested nutrients to trimethylamine, which is absorbed and further oxidized by hepatic flavin monooxygenase to trimethylamine‐N‐oxide (TMAO)”

In the citing paper

“a metabolite that could promote atherogenesis partly by promoting the formation of foam cells from macrophages.4, 5”

In the citing paper

“Although the TMAO level has been suggested to be involved in atherosclerosis,4, 5”

In the citing paper

“many cohort studies have suggested that an increased number of adverse outcomes are associated with high TMAO levels,4, 5, 6, 7”

In the citing paper

“However, recent data suggest that it may also play a role in the development and maintenance of CVD and metabolic disorders such as obesity, diabetes and metabolic syndrome11–14.”

In the citing paper

“Indeed, consumption of choline and L-carnitine rich diets offer the necessary precursors for the production of TMAO.2,3”

In the citing paper

“Several recent studies have identified trimethylamine N-oxide, a metabolite of the gut microbiota, as an independent risk factor for cardiovascular disease.17,18,34”

In the citing paper

“Trimethylamine (TMA) and TMA N-oxide, which are gut microbiota metabolites of dietary phosphatidylcholine, are known to be associated with cardiovascular disease and with the atherosclerosis process in particular.3,4”

In the citing paper

“its ability to reverse fibrosis in patients with nonalcoholic steatohepatitis (NASH) was demonstrated in a proof-of-concept study followed by a randomized control trial (RCT)150,151.”

In the citing paper

“Despite an explosion of associative studies involving the microbiome and vascular and cardiovascular diseases, few connections have been identified with mechanistic certainty[2,3].”

In the citing paper

“higher plasma levels of the vascular toxin trimethylamine-N-oxide (TMAO) conferred an increased risk of major cardiovascular events during a 3-year follow-up.157 They also demonstrated that plasma TMAO is the product of gut microbial metabolism of dietary choline to trimethylamine (TMA), followed by hepatic oxidation of TMA to TMAO.”

In the citing paper

“associations between gut ecology and cancer [16], cardiovascular disease [17], obesity [6], diabetes [18], and muscle wasting [19]”

In the citing paper

“Previous studies have shown that the gut microbiota metabolizes choline, phosphatidylcholine, and l-carnitine to produce trimethylamine (TMA), which is oxidized in the liver into the proatherogenic metabolite, trimethylamine-N-oxide (TMAO)11–13.”