Protective Effect and Mechanism of Short‐Chain Fatty Acids, the Metabolites of Gut Microbiota, on Atrial Fibrillation

ABSTRACT Atrial fibrillation (AF) is one of the most common arrhythmias with complex pathogenesis. Recent studies showed that gut microbiota and its metabolic products, especially short‐chain fatty acids (SCFAs), are closely linked to the onset and progression of AF. In this review, the alterations about SCFAs in AF patients were primarily summarized, and the potential mechanisms of SCFAs on the onset and progression of AF were further outlined. For the alterations, the contents of SCFAs in the circulatory system of AF patients were reduced, mainly ascribed to the dysregulation of SCFAs‐producing gut microbiota and/or the reduction of genetic expression involved in the synthesis of SCFAs in the gut microbiota. For the potential mechanisms, SCFAs alleviate AF by inhibiting inflammation, relieving endoplasmic reticulum (ER) stress, mitigating oxidative stress, and improving atrial remodeling. Specifically, (1) SCFAs suppress inflammatory responses in AF mainly via activating GPCR, inhibiting the NLRP3 inflammasome, inhibiting HDAC activity, regulating vascular endothelial function, and maintaining gut barrier integrity. (2) SCFAs relieve ER stress in AF by reducing the expression of ER stress markers pPERK and/or CHOP, and correct ion current and calcium homeostasis disorders caused by TMAO. (3) SCFAs mitigate oxidative stress in AF by reducing mitochondrial damage and regulating Nrf2 pathways. (4) SCFAs improve atrial remodeling in AF by alleviating atrial structural and electrical remodeling. This review explores the regulatory mechanisms of SCFAs in alleviating AF from the gut–heart axis perspective, providing novel insights into AF prevention and treatment strategies.