Fig. 3

Gut-immune-heart axis. The gut microbiome can manipulate the immune system to control risk factors and indirectly induce the pathology of atrial fibrillation (AF) through the gut-immune-heart axis. a In the lesioned heart, monocytes and macrophages undergo phenotypic alterations and are massively recruited to the injury site, impacting the cardiomyocyte action potential by regulating repolarization, conduction velocity, and heterogeneity. b Macrophages can trigger the transformation of cardiac fibroblasts to myofibroblasts by releasing cytokines, leading to collagen deposition and facilitating structural remodeling. c Cytokines emitted by leukocytes can also influence ion channel expression (e.g., sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2a), which leads to abnormal Ca²⁺-handling in cardiomyocytes. d Cytokines released from leukocytes can impede intercellular conduction between cardiomyocytes and non-cardiomyocytes (e.g., leukocytes) by decreasing the expression of connexin (Cx) protein. e Microbiome is an emergent mediator of macrophage function and can influence the generation of pro-inflammatory cytokines by macrophages through metabolites (of which TMAO and LPS are promoters, while SCFAs and indole derivatives are inhibitors). LPS lipopolysaccharides, RyR2 ryanodine receptor 2, SCFAs short-chain fatty acids, SR sarcoplasmic reticulum, TMAO trimethylamine oxide, SERCA2a sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 2a, Cx40 connexin 40, Cx43 connexin 43, IL interleukin, TGF-β transforming growth factor-β