Abstract
AIMS: Chronic kidney disease (CKD) significantly increases the risk of atrial fibrillation (AF). Although alterations in the gut microbiota have been linked to CKD progression, its exact involvement in CKD-associated AF remains unclear. We aim to investigate the role of gut microbiota in the development of CKD-associated AF and to uncover potential mechanisms that could serve as effective targets for prevention and treatment. METHODS AND RESULTS: A rat model of CKD was induced by an adenine-enriched diet. 16S rRNA sequencing and faecal microbiota transplantation (FMT) were utilized to study the involvement of gut microbiota. AST-120, gut barrier protectants, and mono-colonization experiments were performed to investigate potential mechanism. CKD rats exhibited gut microbiota dysbiosis and a significantly increased susceptibility to AF. FMT from CKD rats transferred this heightened AF susceptibility to healthy recipient rats, linked to the activation of the NLRP3 inflammasome. Mechanistically, gut dysbiosis in CKD patients leads to elevated indoxyl sulphate (IS) levels, causing gut barrier dysfunction and increased circulating lipopolysaccharide (LPS). Elevated LPS activates atrial Toll-like receptor 4 (TLR4) receptors, triggering NLRP3 inflammasome activation, which contributes to AF pathogenesis. Treatment with the IS scavenger AST-120 or gut barrier protectants successfully prevented CKD-associated AF. Furthermore, supplementation with Lactobacillus gasseri reduced circulating IS levels and mitigated AF susceptibility in CKD rats. CONCLUSION: This study demonstrates that gut dysbiosis-driven elevation of IS and subsequent activation of the atrial NLRP3 inflammasome are key mechanisms in CKD-associated AF. Modulating the gut microbiota could provide a new therapeutic strategy for CKD-associated AF.