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

Abstract

Accumulating evidence has demonstrated that gut microbial-derived metabolite trimethylamine N-oxide (TMAO) plays a crucial role in the pathogenesis of many diseases and can be served as a prognostic biomarker for several cardiovascular disorders, including arrhythmia. Recently, some studies have documented that TMAO was associated with the occurrence, progression, recurrence, and embolism risk of atrial fibrillation (AF). The activation of related inflammatory signal pathways and the cardiac sympathetic nervous system (CSNS) caused by elevated TAMO may be the underlying mechanism. It is worth noting that intervention in the metabolic pathway of TMAO may be an underlying therapeutic target of AF. In addition, standardized and individualized treatment strategies in clinical practice may be of great significance for AF patients, particularly those with high serum TMAO concentrations. However, there are also contradictions in the current research on TMAO and AF. Moreover, notwithstanding the positive preclinical and clinical findings, data supporting a direct association between TMAO and AF is a paucity. Thus, conclusive evidence from preclinical studies and multi-center randomized controlled trials to reveal the essential relationship between TMAO and AF is needy. In this review, we have attempted to summarize recent studies on TMAO and AF, highlighted the potential therapeutic strategies for AF patients, followed by a discussion on directions for future research in this field.

Keywords: TMAO; atrial fibrillation; trimethylamine N-oxide.

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.

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.