|
 
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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 6
| Issue : 1 | Page : 3-9 |
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Relationship between red meat metabolite trimethylamine N-oxide and cardiovascular disease
Angatu Yousuf1, David G McVey1, Shu Ye2
1 Department of Cardiovascular Sciences, University of Leicester, Leicester, England, United Kingdom
2 Department of Cardiovascular Sciences, University of Leicester, Leicester, England, United Kingdom; Cardiovascular Genetics Group, Shantou University Medical College, Shantou, China
| Date of Submission | 26-Feb-2021 |
| Date of Acceptance | 28-Apr-2021 |
| Date of Web Publication | 10-Jan-2022 |
Correspondence Address:
Prof. Shu Ye
Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Groby Road, Leicester LE3 9QP
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/hm.hm_8_21
Many cardiovascular diseases (CVD) are caused by the interplay of lifestyle and genetic factors. Studies have suggested an association between red meat consumption and increased CVD risk. There is evidence indicating that trimethylamine N-oxide (TMAO), a metabolite of red meat and other animal-derived foodstuffs, promotes CVD. Here, we undertake an overview of some of the reported investigations of the relationship between TMAO and CVD and briefly discuss possible underlying mechanisms.
Keywords: Cardiovascular disease, flavin monooxygenase-3, inflammation, lipid metabolism, trimethylamine N-oxide
How to cite this article:
Yousuf A, McVey DG, Ye S. Relationship between red meat metabolite trimethylamine N-oxide and cardiovascular disease. Heart Mind 2022;6:3-9 |
| Introduction | |  |
Lifestyle factors such as an unhealthy diet, smoking, and a lack of exercise play an important role in the development of cardiovascular diseases (CVDs), such as coronary artery disease (CAD). Recent studies have suggested that trimethylamine N-oxide (TMAO), a metabolite of red meat, promotes CVD. In this review, we undertake an overview of some of the reported investigations into the relationship between TMAO and CVD and briefly discuss possible underlying mechanisms.
| Trimethylamine N-oxide Production | | |
Phospholipid phosphatidylcholine (PC), choline, betaine, and L-carnitine are metabolized by gut microbes to produce trimethylamine, which is then absorbed into the hepatic portal circulation and converted to TMAO by flavin-containing monooxygenases, mainly flavin monooxygenase-3 (FMO3).[1],[2] PC, choline, and L-carnitine are found abundantly in animal-derived foods, including red meat, poultry, eggs, fish, and dairy products. Betaine is a direct oxidation product of choline. Choline is essential for many biological processes in humans, including phospholipid membrane formation, the synthesis of the neurotransmitter acetylcholine, lipid metabolism, and alongside betaine, as a donor of methyl groups in one-carbon methyl donor metabolic pathways.[3],[4] Choline is synthesized endogenously, but dietary supplementation is required as insufficient choline can lead to the development of fatty liver disease, skeletal muscle damage, and neurological disorders.[5],[6],[7],[8]
| Association Between Trimethylamine N-oxide and Cardiovascular Diseases | | |
In a landmark study, Wang et al. identified three metabolites of the dietary PC, namely choline, betaine, and TMAO, which predicted risk for CVD in a large cohort of stable patients undergoing elective cardiac evaluation, who then experienced myocardial infarction, stroke, or death within 3 years. Increased fasting plasma levels of TMAO, choline, and betaine were dose-dependently associated with the presence of CVD phenotypes in these patients.[1] Subsequently, several patient cohort studies followed, showing a similar relationship between TMAO levels and CVD markers [Figure 1].{Figure 1}
Using murine atherosclerosis models, the Wang et al. study characterized a link between dietary lipid intake, intestinal microflora, and atherosclerosis, via the gut microbiota-dependent pathway of TMAO generation.[1] The gut microbiota was shown to be mandatory for TMAO formation–suppression of the gut flora of mice with broad-spectrum antibiotics followed by feeding with deuterium-labeled PC prevented the detection of deuterated TMAO by mass spectrometry, while untreated mice showed a deuterated TMAO signal following mass spectrometry analysis.[1] Further, atherosclerosis-prone C57BL/6J apolipoprotein E-deficient mice fed a diet of choline- or TMAO-supplemented chow showed an increase in total aortic root atherosclerotic plaque area, compared to normal diet-fed mice. Analysis of plasma levels of choline, TMAO, and other known atherogenic markers in each of the dietary arms showed nominal changes in choline, cholesterol, triglycerides, lipoproteins, and glucose levels, but significant increases of TMAO in mice receiving either choline or TMAO supplementation, suggesting that TMAO is the microbiota-dependent metabolite promoting atherosclerosis.[1]
The Wang et al. study was one of the first studies to implicate TMAO in the development of CVD. Further, their work in mouse models demonstrated that the gut microbiota is a fundamental source of TMAO. Several subsequent studies have replicated and expanded upon this finding using both mouse models and human subjects, including studies by Senthong et al. and Randrianarisoa et al., which identified associations between TMAO and plaque burden in CAD patients and carotid intima–media thickness in prediabetes patients, respectively.[9],[10] Further, Koeth et al. identified an association between dietary intake of L-carnitine, the gut microbiota, and atherosclerosis.[2] Atherosclerosis-prone C57BL/6J apolipoprotein E-deficient mice were fed L-carnitine-supplemented chow following antibiotic-mediated suppression of the gut microbiota, resulting in inhibition of aortic root plaque formation. Mice fed the same diet without antibiotic treatment showed twice the amount of aortic root plaque development compared to normal chow-fed mice, indicating that a microbiota-derived L-carnitine metabolite, such as TMAO, is responsible for L-carnitine-induced atherosclerosis. Koeth et al. then utilized antibiotic suppression of the gut microbiota in human subjects and fed them deuterium-labeled L-carnitine and steak (a source of unlabeled, native L-carnitine). Both sources of L-carnitine resulted in elevated TMAO levels in untreated subjects, but this was significantly reduced in antibiotic-treated subjects. This work complements the Wang et al. study and reiterates the importance of the gut microbiota in atherosclerosis, and provides evidence that L-carnitine, in addition to PC and choline, promotes atherosclerosis via gut microbiota-derived TMAO.
In agreement with the aforementioned studies, Tang et al. also found an association between elevated TMAO levels and higher risk of adverse cardiovascular events in patients undergoing elective coronary angiography.[11] Tang et al. also examined the effect of antibiotic suppression of the human gut microbiota and found that antibiotic treatment significantly reduced postprandial levels of labeled and native TMAO following a meal containing deuterium-labeled PC and unlabeled PC. A subsequent study by Tang et al. examined plasma TMAO, choline, and betaine levels in chronic systolic heart failure patients and revealed that higher levels of these metabolites correlated with increased concentrations of the heart failure biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP).[12] Further, plasma TMAO was able to independently predict the risk of 5-year incident clinical events, with the highest risk observed for patients with both elevated TMAO and NT-proBNP. The work by Tang et al. replicated the association between TMAO and CVD in human patients as seen by Wang et al., demonstrated that the human gut microbiota is a source of PC-derived TMAO, and also implicated TMAO and other metabolites in heart failure, thereby expanding our understanding of the sources and clinical outcomes associated with TMAO.
TMAO has also been implicated in stroke risk. Nie et al. reported an association between serum TMAO and first stroke event in hypertensive patients without any other significant CVD. Compared to patients with a serum TMAO concentration in the lowest tertile (<1.79 μM), patients in a higher tertile (≥1.79 μM) were at increased risk of first stroke, implicating TMAO in elevated stroke risk in hypertensive patients.[13]
In separate cohorts of 140 and 220 chronic kidney disease (CKD) patients, Stubbs et al. examined the cross-sectional relationship of TMAO with kidney function and the longitudinal relationship of TMAO with coronary atherosclerosis burden and mortality, respectively.[14] In the first cohort, elevated serum TMAO concentrations showed a strong inverse association with estimated glomerular filtration rate and correlated with advancing CKD stage; the median serum TMAO concentration in dialysis-dependent, end-stage renal disease patients was approximately thirtyfold higher than in controls. However, this was reversed following renal transplantation in six patients, who showed a >6-fold reduction in median TMAO concentration after transplantation. In the second cohort, coronary angiography and long-term mortality follow-up showed that individuals in the highest serum TMAO concentration tertile carried a greater coronary atherosclerotic burden and a 16.5% lower 4-year survival rate than those in the lowest tertile. TMAO was independently associated with 4-year mortality, predicting a 19% increase in mortality for every 10 μM increment in serum concentration.[14] This study has demonstrated an association between TMAO and CVD in CKD patients, a frequent outcome of CKD. This suggests that interventions that reduce TMAO levels in CKD patients may reduce the elevated risk of adverse cardiovascular events. This study has also revealed a potential role of the kidney in TMAO metabolism, as CKD patients showed markedly reduced TMAO levels following kidney transplantation. It should, however, be considered that the reduction in TMAO may be due to alterations in diet and/or effects on the gut microbiota in response to the transplantation and subsequent pharmaceutical treatments. Despite this, further research exploring the interplay between the kidney, TMAO, and CVD in CKD patients is warranted.
The aforedescribed studies have progressively provided key evidence for the role of TMAO in multiple CVDs (including atherosclerosis and CAD, heart failure and stroke) and have demonstrated a fundamental role of the gut microbiota in the production of TMAO from dietary sources.
| Potential Mechanisms Through which Trimethylamine N-oxide Promotes Cardiovascular Disease | | |
Since several studies have alluded to the direct involvement of TMAO in processes that drive the development of atherosclerosis, the exact mechanisms by which TMAO contributes to atherosclerotic plaque formation are currently under investigation and are beginning to be elucidated. Findings thus far tend to fall into four main themes of pathogenesis-enzymatic activity, cholesterol metabolism, oxidative stress, and inflammation with interlinking modes of action [Figure 2].{Figure 2}
Flavin monooxygenase-3
With approximately 50% identical amino acid sequences, the FMOs are a family of five enzymes, FMO1-5.[15] FMOs catalyze the oxidation of nucleophilic heteroatom-containing substrates in the liver.[16] Of these five enzymes, FMO1, 2, and 3 have been shown to be able to metabolize TMA to TMAO. FMO2 activity was negligibly low, whereas FMO1 and FMO3 showed significant activity, with FMO3 exhibiting a tenfold higher activity than FMO1 and the most abundant isoform expressed in human liver.[15],[17] Examination of paired liver and plasma samples from subjects undergoing elective liver biopsy showed a positive association between plasma TMAO levels and hepatic FMO3 expression.[18] FMO3 is therefore the principle hepatic enzyme that oxidizes TMA to TMAO and prior evidence implicates FMO3 in atherosclerosis.[1],[18]
FMO3 knockdown has been shown to normalize plasma TMAO levels in chow-fed LIRKO mice and prevented atherogenesis in Paigen-fed LIRKO mice.[19] In Western diet-fed low-density lipoprotein receptor (LDLR)-knockout mice, FMO3 knockdown halved circulating TMAO levels and significantly attenuated atherosclerotic lesion area.[20] Warrier et al. also found that FMO3 knockdown in mouse promoted baseline and liver X-receptor-induced reverse cholesterol transport (RCT).[21] RCT is the efflux of cholesterol from macrophages to extracellular high-density lipoprotein-based acceptors that transport cholesterol to the liver for subsequent metabolism.[22] This mechanism may contribute to the atheroprotection engendered by FMO3 knockdown in the aforementioned studies.[18],[19]
In a study examining the role of TMAO and FMO3 on gallstones, FMO3 expression was upregulated in response to a choline-supplemented diet in mouse.[23] This suggests that TMAO, or its precursor metabolites, may upregulate FMO3, thereby potentially generating a positive feedback loop and upregulating TMAO production.
Biliary cholesterol metabolism
TMAO-induced disturbances in lipid homeostasis have been suggested as a potential contributor to atherogenesis.[2],[24] Lipid homeostasis is maintained through bile acids (BAs), which facilitate the absorption of fat-soluble vitamins, lipids, and cholesterol in the small intestine and mediate surplus cholesterol elimination by the liver.[25] Derived from cholesterol, BAs are synthesized by hepatocytes and secreted into the bile.[26] BA synthesis has been shown to be inhibited by TMAO via downregulation of the enzyme cholesterol 7α-hydroxylase (CYP7A1), which hydroxylates cholesterol to 7α-hydroxy-cholesterol and is the first and rate-limiting step in BA formation.[1],[2],[26],[27] TMAO-fed apolipoprotein E-deficient mice showed significantly reduced hepatic expression of Cyp7a1 and Cyp27a1, as well as the BA transporters Oatp1, Oatp4, Mrp2, and Ntcp.[2] This mechanism may account for the reduced BA pool of mice fed with TMAO-supplemented chow, compared to normal chow-fed controls, observed by Koeth et al.[2] Bile acids have been shown to reduce circulating triglycerides, suggesting that a TMAO-induced decrease in bile acids may elevate triglyceride levels and promote foam cell formation.[28]
Macrophage cholesterol metabolism
TMAO is also believed to affect macrophage cholesterol transport by increasing the expression of macrophage scavenger receptors (SR). SRs are cell membrane glycoprotein receptors that mediate the binding and uptake of circulating modified lipoproteins carrying triglycerides, cholesteryl esters, and free cholesterol, a process of cholesterol influx called forward cholesterol transport (FCT).[29],[30] In the Wang et al. study, two macrophage SRs, CD36 and SR-A1, which have been shown to be atherogenic, were found to be upregulated at both the mRNA and protein levels in choline-, betaine-, or TMAO-fed C57BL/6J apolipoprotein E-deficient mice.[1],[31],[32],[33] Similarly, TMAO treatment of J774A.1 macrophages (a tumoral murine macrophage cell line) resulted in upregulation of SR-A1 expression and protein levels.[34] This upregulation of SR expression leads to an increase in the level of FCT, thereby resulting in macrophages becoming lipid-laden foam cells, an early pathological hallmark of atherosclerosis.[1],[35] Furthermore in the Wang et al. study, the aforementioned hyperlipidemic mice were treated with broad-spectrum antibiotics to suppress the gut microbiota and fed either normal or choline-supplemented chow and compared to untreated mice fed the same diets.[1] The antibiotic-free group fed a normal diet showed modest foam cell development, while a high-choline diet in antibiotic-free mice showed amplified foam cell formation, with larger CD36 immunoreactive surface areas, a threefold increase in aortic root plaque lesion size, and elevated plasma TMAO levels. Conversely, antibiotic treatment inhibited choline-dependent foam cell formation and resulted in virtually undetectable plasma TMAO levels in both dietary arms. In addition, while dietary supplementation with choline or TMAO showed increased peritoneal macrophage cholesterol content and elevated plasma levels of TMAO, mice fed chow containing 3,3-dimethyl-1-butanol (DMB, a choline analog) showed no increase in plasma TMAO or macrophage cholesterol accumulation, implicating TMAO as the underlying factor.[1]
As well as FCT, RCT in macrophages may also be affected by TMAO. As previously described, RCT is the efflux of surplus intracellular cholesterol to extracellular lipoprotein acceptors, which in macrophages is mainly facilitated by the plasma membrane ATP cassette transporter type 1 (ABCA1).[36] In vitro mRNA expression of ABCA1 was shown to be significantly decreased in J774A.1 macrophages that were treated for 24 h with 150 μM and 300 μM of TMAO, while ABCA1 protein levels were significantly reduced by treatment with 75 μM and 150 μM TMAO.[34] The Koeth et al. study found that treatment of mouse peritoneal macrophages with 300 μM TMAO for 18 h resulted in a modest but significant decrease in ABCA1 expression.[2] The macrophage response to TMAO is therefore twofold, increasing lipid uptake while reducing cholesterol efflux. These effects in combination with dysregulated lipid metabolism via altered bile acid synthesis (discussed previously) are likely to promote foam cell formation.
Inflammation and oxidative stress
Oxidative stress and inflammation are inextricably linked - either may instigate or exacerbate the other. Together, they play a critical role in atherogenesis, which has been shown to be influenced by TMAO through various pathways.[37],[38],[39],[40],[41]
The transcription factor nuclear factor kappa-light- chain-enhancer of activated B cells (NF-κB) plays a key role in inflammation through upregulation of pro-inflammatory genes. Multiple signaling pathways can lead to NF-κB activation, usually in response to pathogens or stress.[41] A study by Seldin et al. showed elevated phosphorylation of NF-κB and its upstream activators mitogen-activated protein kinase and extracellular signal-regulated kinase ½ (ERK1/2) in the aorta, 30 min after intraperitoneal injection of TMAO at a circulating concentration of 100 μM into atherosclerosis-prone, LDLR-deficient mice.[42] TMAO also increased the nuclear abundance of NF-κB and elevated the mRNA expression of interleukin-6 (IL-6), cyclooxygenase-2, E-selectin, and intercellular adhesion molecule 1.[42]
TMAO-induced oxidative stress has been shown to cause an inflammatory response in human umbilical vein endothelial cells via the thioredoxin-interacting protein 1, NLR family pyrin domain containing 3 (TXNIP-NLRP3) inflammasome, resulting in endothelial dysfunction.[43] Located within the tunica intima in direct contact with the blood, endothelial cells are likely exposed to circulating TMAO which may contribute to endothelial activation and dysfunction and the initiation of atherosclerosis.
Protein conformation and endoplasmic reticulum stress
The endoplasmic reticulum (ER) is responsible for directing correct protein folding, posttranslational modification, and trafficking. When the capacity of the ER to process proteins is exceeded, the accumulation of unfolded/misfolded proteins in the ER results in ER stress, initiating the unfolded protein response (UPR). The UPR triggers oxidative stress and inflammation and has been implicated in endothelial dysfunction.[44],[45] TMAO has been shown to act as both a protein denaturant and stabilizer and has been demonstrated to directly activate PKR-like ER kinase (PERK; EIF2AK3), a member of the UPR pathway, in mouse, resulting in upregulation of FoxO1, a transcription factor that has been shown to be involved in glucose production, macrophage polarization and inflammation, and vascular smooth muscle cell proliferation and migration.[34],[45],[46],[47],[48],[49],[50],[51]
Furthermore, TMAO has been found to induce mRNA and protein expression of glucose-regulated protein 78, the ER isoform of heat shock protein 70 (HSP70) that is a hallmark of ER stress and UPR activation.[34] Reactive oxygen species generated by ER stress activates the TXNIP-NLRP3 inflammasome, leading to increased IL-1β maturation and secretion.[52],[53] UPR also instigates pro-inflammatory NF-κB signaling.[44] Furthermore, ER stress may explain both the reduction of ABCA1 expression and increase of CD36 and SR-A1 expression that has been observed after TMAO stimulation in vivo and in vitro, as described above.[1] Inducers of ER stress and UPR have been shown to downregulate ABCA1 protein levels while upregulating CD36 and SR-A1 protein levels in macrophages, thereby impairing cholesterol efflux and inducing lipid accumulation, promoting foam cell formation.[34],[54],[55],[56],[57]
| Conclusion | | |
TMAO is a dietary metabolite extensively associated with CVDs, most notably CAD and atherosclerosis, but also heart failure and stroke. The gut microbiota is a fundamental source of TMAO via the metabolism of dietary choline, PC, and betaine to TMA, which is then converted to TMAO by hepatic FMO3, which has itself been shown to be upregulated by dietary choline.
The effects of TMAO on CVD are many and varied, with effects observed in both the liver and vascular wall, resulting in alterations in lipid metabolism and vascular cell behaviors that are associated with atherosclerosis initiation and progression. It is therefore important that further examination of the effects of TMAO on hepatic and vascular cells is performed to determine both the cell behavior changes induced by TMAO and the molecular mechanisms driving atherosclerosis initiation and progression, and whether TMAO also influences plaque stability and the late-stage outcomes of CAD. In addition, future studies should also investigate the role of TMAO in other CVDs, such as heart failure, to elucidate the mechanisms underlying TMAO's association with these diseases. It is envisaged that such studies may identify novel targets for pharmaceutical interventions that abrogate the effects of TMAO on CVD.
Another research area that is currently under-explored is the influence of genetic polymorphisms on the response to TMAO. Identification of such polymorphisms may help to identify hitherto undiscovered molecular pathways influenced by TMAO and also aid in personalized risk stratification.
In summary, TMAO has been associated with multiple CVDs. Although the underlying mechanisms are not understood fully, pathways involving cholesterol metabolism, oxidative stress, and inflammation have all been shown to be influenced by TMAO. Further examination of the role that TMAO plays in CVD may lead to interventions that reduce the impact of TMAO on CVD development and progression.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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