Fig. 2

Molecular pathways of gut microbiome and the metabolites involved in atrial fibrillation (AF) progression. The pathogenesis of AF is ordinarily based on the substrate, including re-entry-promoting structures, connexin (Cx), and electrical remodeling, as well as Ca²⁺-handling remodeling facilitated by triggered activity. The TLR4/MyD88/NF-κB pathway primes and triggers the atrial NACHT, LRR, and PYD domains-containing protein-3 (NLRP3) inflammasome in response to lipopolysaccharides (LPS) stimulation, resulting in elevated secretion of downstream cytokines such as IL-1. Intestinal flora shape trimethylamine oxide (TMAO) synthesis, facilitate M1 macrophage polarization and pyroptosis and accentuate atrial structural remodeling. TMAO decreases Cx40 expression and Cx43 phosphorylation, possibly as a result of its contribution to increased infiltration of inflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) in atrial tissue. Short-chain fatty acids (SCFAs) from intestinal symbionts attenuated NLRP3 signaling-mediated atrial fibrosis via GPR43 and downregulated the expression levels of phosphorylated calmodulin kinase II (CaMKII) and CaMKII-related ryanodine receptor 2 (RyR2) phosphorylation in the atria, thereby preventing Ca²⁺-handling disruption. Phenylacetylglutamine (PAGln) exacerbates oxidative stress and apoptosis and enhances activation of CaMKII and RyR2 in atrial myocytes by stimulating α2A, α2B and β2-adrenergic receptors (β2aRs). Bile acids (BAs) signaling via farnesoid X receptor (FXR) quench NLRP3 activation, whereas BA-induced Ca²⁺ influx can activate NLRP3 inflammasome. Moreover, discrepancies in levels of upstream factors, including the autonomic nervous system (ANS), systemic inflammation, and reactive oxygen species (ROS), can also interfere with both ectopic firing and re-entry-promoting substrate, thus directly contributing to the onset and evolution of AF. APD action potential duration, CASP1 caspase-1, DAD delayed afterdepolarizations, DAMPs damage-associated molecular patterns, IL interleukin, M2R M2 receptor, NCX Na⁺/Ca²⁺ exchanger, NF-κB nuclear factor-κB, NGF nerve growth factor, SR sarcoendoplasmic reticulum, TLR Toll-like receptor, TMA trimethylamine, FMO flavin-containing monooxygenase, MyD88 myeloid differentiation primary response protein 88, GPR43 G-protein-coupled receptor 43, Kv voltage-gated potassium