Journal of Diabetes & Metabolic Disorders (2021) 20:1095–1097

https://doi.org/10.1007/s40200-021-00819-x

COMMENTARY

Targeting TMAO and its metabolic pathway for cardiovascular diseases

treatment
Zahra Hoseini‑Tavassol1 · Shirin Hasani‑Ranjbar1

Received: 17 March 2021 / Accepted: 11 May 2021 / Published online: 17 May 2021
© Springer Nature Switzerland AG 2021

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 Trimethyl-
amine 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.

Keywords Cardiovascular disease · Gut Microbiota · Trimethylamine N-oxide (TMAO) · Biomarkers · Therapeutics

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 dis-
ease (CVD) [1, 2]. In particular, TMAO is a molecule pro-
duced from choline, betaine, and carnitine originated from
dietary intake, in association with gut microbial metabolism.
Several variables including diet, gut microbiota composi-
tion, drug administration and liver flavin monooxygenase
function, specify the plasma level of TMAO. In the human
intestine, the initiator compounds are converted into Tri-
methylamine (TMA) by various enzymes such as TMA lyase
which converts choline (and its componds phosphatidyl-
choline, 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
* Shirin Hasani‑Ranjbar
sh_hasani@tums.ac.ir; shirinhasanir@yahoo.com
1
Obesity and Eating Habits Research Center, Endocrinology
and Metabolism Clinical Sciences Institute, Tehran
University of Medical Sciences, Tehran, Iran
(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 sea-
foods 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 intes-
tine [4], the plasma level of TMAO and its association with
non-communicable diseases is very controversial.
Numerous studies have been done on TMAO level contri-
bution in ischemic disease and atherosclerosis, atrial fibril-
lation 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. Athero-
sclerosis 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

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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 con-
trolled 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 conclu-
sion, 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 eat-
ing 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 clini-
cal 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-organ-
ism presents different potential aspects for studies, includ-
ing, 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 metabo-
lism, have been suggested so far [9, 16]; but it seems that
medical/pharmaceutical biotechnology can offer new treat-
ment strategies. These include the construction of monoclo-
nal antibodies and engineered antibodies like single-chain
variable fragment (scFv) that could intervene in TMA
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Journal of Diabetes & Metabolic Disorders (2021) 20:1095–1097
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 car-
nitine 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 con-
trolled trials in the second phase, can make an excellent
difference in prevention and clinical treatment of cardio-
vascular 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 Not applicable.
Declarations
Consent for publication Not applicable.
Ethics approval and consent to participate Not applicable.
Conflict of interests The authors declare that they have no conflict in-
terests.
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