The most relevant gut microbiota-derived metabolites along with their suggested AF-promoting mechanisms. Primary BAs (primarily CDCA) activate NADPH oxidase, promoting ROS formation and inducing ATP release, which acts via P2X7 receptors to cause K⁺ efflux, resulting in NLRP3 inflammasome activation. This activates caspase-1, which generates IL-1β, promoting cardiac inflammation and fibrosis. CDCA may also cause myocyte apoptosis via caspase 9 and caspase 3 and decrease cAMP production via muscarinic M₂ receptor activation, altering intracellular Ca²⁺ homeostasis. Indoxyl sulphate also promotes ROS generation and may increase the expression of pro-inflammatory and profibrotic signalling molecules, promoting cardiac inflammation and fibrosis. TMAO up-regulates NF-κB, which increases the abundance of inflammatory cytokines including IL-1β, IL-6, TNFα, and the synthesis of NGF in atrial ganglionated plexi, which activate the cardiac autonomic nervous system. TMAO also causes oxidative stress and activates the NLRP3 inflammatory and TGFβ1/Smad3 signalling pathways. LPS strongly activates the NLRP3 system, increases the expression and lateralization of connexin-43 protein, and down-regulates L-type Ca²⁺ channel expression. Choline activates I_{K, ACh} at high concentrations, which could theoretically cause proarrhythmic action potential shortening. The effects of these microbiota-derived metabolites have the potential to cause atrial electrical, autonomic, structural, and Ca²⁺-handling remodelling that increases the likelihood of AF-promoting ectopic firing and AF-maintaining re-entry, enhancing the susceptibility to AF and its maintenance. Dashed lines indicate potential mechanisms in AF pathogenesis for which there is indirect evidence. Solid lines indicate potential mechanisms in AF pathogenesis for which there is direct evidence. Bold lines indicate mechanisms with evidence for a direct contribution of gut dysbiosis to AF pathogenesis. Further experimental evaluation is needed to confirm or disprove the involvement of all mechanisms except those shown by bold lines. AC, adenylyl cyclase; AF, atrial fibrillation; Apf-1, apoptosis protease-activating factor-1; ATP, adenosine triphosphate; BAs, bile acids; Ca²⁺, calcium; cAMP, cyclic adenosine monophosphate; CDCA, chenodeoxycholic acid; EGFR, epidermal growth factor receptor; IL, interleukin; I_{K, Ach}, acetylcholine-activated potassium channel; K⁺, potassium; LPS, lipopolysaccharide; MPTP, mitochondrial permeability transition pore; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NGF, nerve growth factor; NLRP3, NACHT, LRR, and PYD domains-containing protein-3; P2RX7, P2X purinoceptor 7; PLB, phospholamban; ROS, reactive oxygen species; RyR2, ryanodine receptor 2; SERCA2a, sarcoendoplasmic reticulum Ca²⁺-ATPase; SR, sarcoendoplasmic reticulum; TGFβ1, transforming growth factor β1; TGR5, Takeda G-protein-coupled receptor 5; TMAO, trimethylamine N-oxide; TNFα, tumour necrosis factor α.