Targeting TMAO and its metabolic pathway for cardiovascular diseases treatment

Abstract

Given the prevalence of cardiovascular diseases (CVDs), as one of the most important non-communicable diseases (NCDs), the recognition of diagnostic biomarkers and potential treatment methods is very crucial. Today gut microbiota composition and its derived metabolites modification are known as one of the recent therapeutic strategies. Studies show that Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite that may be involved in the development of cardiovascular diseases, including ischemic disease and atherosclerosis, atrial fibrillation and arrhythmia, and heart failure. Due to existing some disagreements in this manner, future studies are needed to obtain a definitive sight of the association between this metabolite and CVDs. TMAO may be beneficial as a prognostic marker, which represents the degree of gut microbiota dysbiosis and subsequently CVD events and also different therapies methods based on TMAO and its metabolic pathways can be the target of clinical trial on cardiovascular disease and/or its prevention.

Gut microbe-derived metabolites such as trimethylamine-N-oxide (TMAO), L-carnitine, short-chain fatty acids (SCFAs), lipopolysaccharide (LPS) and secondary bile acids, have been shown to affect the progression of cardiovascular disease (CVD) [1, 2]. In particular, TMAO is a molecule produced from choline, betaine, and carnitine originated from dietary intake, in association with gut microbial metabolism. Several variables including diet, gut microbiota composition, drug administration and liver flavin monooxygenase function, specify the plasma level of TMAO. In the human intestine, the initiator compounds are converted into Trimethylamine (TMA) by various enzymes such as TMA lyase which converts choline (and its componds phosphatidylcholine, phosphocholine, sphingomyelin) to TMA, betaine reductase which reduces betaine to TMA and the other main enzyme carnitine oxidoreductase which converts L-carnitine to TMA. TMA is able to be absorbed from the intestine. This absorbed TMA is transmitted to the liver where it is transformed into TMAO by flavin-dependent monoxygenase (FMO) isoforms 1 and 3. Various dietary sources, such as mushrooms, some meat products (mostly liver and kidney) and beans are containing ergothioneine, a histidine-derived biogenic amine that can degrade by ergothionase enzyme to TMA. Also The TMAO in nature way can be found in seafoods like fish [3]. Although the major part of TMAOs are excreted by the renal system or will be reduced to TMA by the trimethylamine-N-oxide reductase enzyme in the intestine [4], the plasma level of TMAO and its association with non-communicable diseases is very controversial.

Numerous studies have been done on TMAO level contribution in ischemic disease and atherosclerosis, atrial fibrillation and arrhythmia and heart failure incidence that most of them present significant positive association of TMAO and cardiovascular events [5–7]. Evidences also demonstrate the involvement of TMAO in the etiology of other diseases, such as kidney failure, diabetes, and cancers [8]. Increase the risk of atherosclerosis in association with elevate TMAO level have been observed in human clinical studies. Atherosclerosis is a chronic inflammatory disease, and inducing of inflammatory factors during the course of the disease is predictable. High TMAO level increases the expression of pro-inflammatory genes including inflammatory cytokines, adhesion molecules and chemokines, throughout NF-kappa B (NF-κB) pathway activation. Oxidative stress and increase inflammatory cytokines such as IL-18 and IL-1β could also be caused by TMAO. Moreover TMAO level increasing can led to platelet hyperreactivity and thrombosis [9]. TMAO through affects myocardial hypertrophy and fibrosis, induces an inflammatory response and exacerbates mitochondrial dysfunction could be the heart failure inducement too [4]. The association between elevated TMAO levels and the risk of cardiovascular events, is practical also across different age, BMI, smoking, degree of kidney function and diabetes mellitus groups and whether the follow‐up duration, lipids, blood pressure, or C‐reactive protein (CRP) levels were controlled in trials [1].

It is to be noted that, not many of clinical studies couldn’t find an strong association between TMAO Level and CVDs [10, 11] and also some studies show that L-carnitine, one of the important initiator compounds of TMAO generation process, has a role in lipid and glucose metabolism which has a positive effect on heart condition [12, 13]. So there is a little doubt in this regard and to reach an accurate conclusion, future studies are needed to obtain a definitive sight of the association between this metabolite and CVDs.

Best of our knowledge, TMAO may be beneficial as a prognostic marker, which represents the degrees of gut microbiota dysbiosis and subsequently CVD events. Although more studies enrolling patients with different eating habits, lifestyles, races, age, sex and underlying diseases is necessary to approve whether TMAO can be widely used as a prognostic marker or not. Another question is whether TMAO and its metabolic pathways can be the target of clinical trial on cardiovascular disease and/or its prevention?

The theory of metaorganism deals with the interaction between the microbiota and the host in maintaining health or the occurrence of various diseases such as obesity, diabetes, liver steatosis, cancer, osteoporosis and particularly CVD, so metaorganism well explains the TMAO metabolic pathways and their association with CVD. In this matter, meta-organism presents different potential aspects for studies, including, the dietary compounds that can participate in microbial metabolic pathways, microbiota and its derived enzymes that produce TMA from dietary sources, host enzymes that transform TMA to TMAO, and molecular mechanisms by which TMAO affects cholesterol and sterol metabolisms that leads to CVD [14].

Some therapeutic methods such as dietary modifications (low fat and High Fiber Diet), gut microbiota regulating (consume of prebiotics or probiotics and fecal microbial transplantation) [15] and prescription of some other natural and chemical compounds that could step in TMAO metabolism, have been suggested so far [9, 16]; but it seems that medical/pharmaceutical biotechnology can offer new treatment strategies. These include the construction of monoclonal antibodies and engineered antibodies like single-chain variable fragment (scFv) that could intervene in TMA generation or conversion of TMA to TMAO throughout inhibition of the TMAO-producing enzymes function. Find the best way to express antibodies that inhibit the activity of hepatic FMO enzymes or bacterial TMA lyase and carnitine oxidoreductase with among different technologies (phage display, use of e. coli or yeasts expression systems and expression in mammalian cell lines) in the first phase, and testing the effectiveness of them in randomized controlled trials in the second phase, can make an excellent difference in prevention and clinical treatment of cardiovascular disease.

Authors’ contributions

ZHT drafted the manuscript. SHR designed the study and helped to draft the manuscript. Both authors read and approved the final manuscript.

Data availability

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Conflict of interests

The authors declare that they have no conflict interests.