The Gut Microbial-Derived Metabolite Trimethylamine N-Oxide and Atrial Fibrillation: Relationships, Mechanisms, and Therapeutic Strategies

Figures & data

Figure 1 The metabolic pathway of TMAO and its adverse effects on the body. Created by ScienceSlides Software and Microsoft Office PowerPoint Software. High-cholinergic foods are metabolized by intestinal microbes to form TMA, most of which enter the portal system through the blood circulation and are transferred into TMAO by the FMOs in the liver. Elevated TMAO has adverse impacts on various diseases.

Abbreviations: TMA, trimethylamine; FMOs, flavin-containing monooxygenases; TMAO+, elevated TMAO.

Table 1 Clinical Investigations into TMAO and AF

Authors (Year)	Sample Groups	Summary of the Results	References
Svingen et al (2018)	Explored in 3797 patients with suspected stable angina in the Western Norway Coronary Angiography Cohort (WECAC), followed up for 7.3 years Verified in 3143 elderly participants in the community-based Hordaland Health Study (HUSK), followed up for 10.8 years	Plasma TMAO was associated with an improved reclassification of incident AF in two independent Norwegian cohorts with long-term follow-up.	[^Citation15]
Nguyen et al (2021)	78 patients from the AF-RISK study.	Higher levels of TMAO are associated with more progressed forms of AF.	[^Citation29]
Rexidamu et al (2019)	255 consecutive patients with first-ever acute ischemic stroke and 255 age and gender-matched controls	Higher TMAO levels were associated with increased risk of first ischemic stroke and worse neurological deficit in Chinese patients.	[^Citation50]
Gong et al (2019)	117 consecutive AF patients	Elevated serum TMAO levels were predictive of thrombus formation in AF patients.	[^Citation51]
Liang et al (2019)	68 patients with AF with ischemic stroke and 111 ones without ischemic stroke	The level of TMAO was correlated with the CHA2DS2-VASc score. TMAO was a risk factor for ischemic stroke. TMAO may guide antithrombotic therapy for patients with low and intermediate risk of embolism.	[^Citation52]

Table 2 Main Pathophysiological Mechanisms of TMAO in AF: Directly and Indirectly

Authors (Year)	Experimental Conditions	Major Findings	References
Yu et al (2018)	Canines	TMAO increased neural activity and the susceptibility of atrial to AF through the p65 NF-κB signaling pathway resulting in the expression of inflammatory cytokines	[^Citation35]
Li et al (2019)	Mice	TMAO induces cardiac hypertrophy and fibrosis via the Smad3 signaling pathway	[^Citation57]
Wang et al (2020)	Mice	DMB attenuated cardiac structural and electrical remodeling by reducing plasma TMAO concentrations, which negatively regulated the TGF-b1/Smad3 and p65 NF-kB signaling pathways.	[^Citation56]
Organ et al (2016)	Mice	Supplementing choline or TMAO significantly increased the severity of heart failure in mice.	[^Citation64]
Li et al (2019)	Mice	TMAO aggravated DOX-induced mouse cardiac fibrosis via activation of the NLRP3 inflammasome	[^Citation38]
Ke et al (2018)	Human	Elevated circulating TMAO during the aging process may deteriorate endothelial cell senescence and vascular aging through the repression of SIRT1 expression and increased oxidative stress, and the activation of the p53/p21/Rb pathway.	[^Citation39]

Table 3 Knowledge Gaps and Studies Needed to Be Performed

Knowledge Gaps	Studies Needed to Be Performed
Direct evidence of AF caused by TMAO	● A well-designed prospective cohort study without AF through targeted regulation of TMAO ● Create an animal model with high TMAO serum levels by supplementing choline, TMAO, or fecal transplantation to verify whether TMAO affects the AF matrix in a rapid atrial pacing AF model
Study on the intervention of diet/drugs on TMAO	● Validate in well-designed multi-center randomized controlled trials including subjects around the world
TMAO and Thrombosis Risk	● Validate and explore mechanisms in animal models ● Through targeted regulation of TMAO, validate in multi-center clinical randomized controlled trials
The influence and interaction of TMAO or/and other intestinal flora metabolites on AF	● Research on specific bacteria or flora in sterile animal models
TMAO and the recurrence of AF after ablation	● In the multi-center AF ablation cohort, targeting the metabolic pathway of TMAO and investigate the outcomes after AF catheter ablation, and finally, verifying it in an animal model

Figure 2 The underlying mechanism of AF caused by TMAO. Created by ScienceSlides Software and Microsoft Office PowerPoint Software. Elevated plasma TMAO levels can promote AF in different ways. Firstly, activating NLRP3 inflammatory bodies and the NF-κ B pathway leads to the release of inflammatory factors and further promotes NGF expression. Both inflammatory factors and NGF can stimulate atrial plexus and induce AF. On the other hand, TMAO can activate the TGF-β1/Smad3 signaling pathway, and the activated inflammatory factors further promote myocardial fibrosis and induce arrhythmia.

Abbreviations: TMA, trimethylamine; FMOs, flavin-containing monooxygenases; NGF, nerve growth factor; +, elevated.

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