Gut microbiota-atrium axis: Microbiota metabolite-mediated regulation of the NLRP3 inflammasome in atrial fibrillation-pathophysiological roles and therapeutic perspectives.

The NLR family pyrin domain containing 3 (NLRP3) inflammasome has been increasingly implicated in the pathophysiology of atrial fibrillation, whereas gut microbial metabolites contribute to systemic inflammatory signaling. This review proposes a mechanistic framework linking microbiota-derived metabolites to NLRP3 activation, with the recognition that much of the evidence derives from immune or noncardiac models rather than atrial tissue. We organize the discussion across the stages of NLRP3 activation-priming, assembly, and downstream signaling-and summarize how key metabolites may differentially modulate these processes. Lipopolysaccharide and indoxyl sulfate have been associated with enhanced inflammasome activation, whereas short-chain fatty acids and selected bile acids exhibit inhibitory or regulatory effects. Trimethylamine N-oxide has been implicated in oxidative stress-related pathways, although direct atrial evidence remains limited. Based on these insights, we present a 4-tier conceptual framework to highlight potential intervention strategies while acknowledging the predominantly preclinical nature of the current evidence.