Atrial fibrillation reduces the quality of life and increases mortality from cardiovascular disease. The prevention of AF is of major health importance because the incidence, prevalence, and lifetime risk of AF are increasing globally. However, the number of studies directed at the primary or secondary prevention of AF is limited. Recent evidence suggests the association of inflammation with the incidence and progression of AF. NLRP3 inflammasome is central to the innate immune system. Although several studies suggest the association of NLRP3 with AF, the precise mechanism linking activated NLRP3 to AF remains to be elucidated. Gut-derived metabolites, such as lipopolysaccharides and trimethylamine N-oxide (TMAO), have been shown to play a role in AF susceptibility. Lipopolysaccharides are derived from gut microbiota and may enter the circulation through the gut mucosa. TMAO is produced in the liver by oxidation of trimethylamine, which is derived from dietary choline and L-carnitine. Although these gut-derived metabolites have been shown to increase AF susceptibility, it is unclear as to how lipopolysaccharides and TMAO increase the risk of AF and whether lowering circulating levels of lipopolysaccharides and TMAO lead to the prevention of AF. This presentation will discuss the association of inflammation with AF and the potential of drug discovery to prevent AF by focusing on the involvement of gut-derived metabolites in inflammation.