Gut microbiota dysbiosis promotes chronic kidney disease-associated atrial fibrillation through activation of the NLRP3 inflammasome.

CKD rats induced by an adenine-enriched diet exhibited gut microbiota dysbiosis and significantly increased susceptibility to atrial fibrillation.

• A rat model of CKD was induced by an adenine-enriched diet.
• 16S rRNA sequencing was used to characterize gut microbiota alterations in CKD rats.
• CKD rats showed both structural gut microbiota changes and elevated AF inducibility compared to controls.

Faecal microbiota transplantation (FMT) from CKD rats transferred heightened AF susceptibility to healthy recipient rats.

• FMT was used to causally link gut microbiota dysbiosis to AF susceptibility.
• Healthy recipient rats receiving FMT from CKD donors developed increased AF susceptibility.
• The transferred AF susceptibility was linked to activation of the NLRP3 inflammasome in recipient rats.

Gut dysbiosis in CKD led to elevated indoxyl sulphate (IS) levels, which caused gut barrier dysfunction and increased circulating lipopolysaccharide (LPS).

• IS is a uremic toxin produced by gut bacteria from dietary tryptophan.
• Elevated IS was mechanistically linked to impaired gut barrier integrity in CKD.
• Gut barrier dysfunction resulted in translocation of LPS into systemic circulation.
• AST-120 (an IS scavenger) and gut barrier protectants were used to confirm this mechanistic pathway.

Elevated circulating LPS activated atrial Toll-like receptor 4 (TLR4), triggering NLRP3 inflammasome activation and contributing to AF pathogenesis.

• LPS-TLR4 signaling in atrial tissue was identified as the link between gut dysbiosis and cardiac arrhythmia.
• NLRP3 inflammasome activation downstream of TLR4 was demonstrated in atrial tissue.
• This pathway constitutes the mechanistic bridge between gut-derived endotoxemia and AF susceptibility.

Treatment with the IS scavenger AST-120 or gut barrier protectants successfully prevented CKD-associated AF.

• AST-120 is an oral spherical carbon adsorbent that sequesters IS in the gut.
• Gut barrier protectants were administered to reduce LPS translocation.
• Both interventions reduced AF susceptibility in CKD rats, supporting the IS-LPS-TLR4-NLRP3 mechanistic axis.

Supplementation with Lactobacillus gasseri reduced circulating IS levels and mitigated AF susceptibility in CKD rats.

• Mono-colonization experiments with Lactobacillus gasseri were performed in CKD rats.
• Lactobacillus gasseri supplementation resulted in decreased circulating IS levels.
• Reduced IS levels following Lactobacillus gasseri treatment were associated with decreased AF inducibility.
• This finding identifies a specific probiotic species as a potential therapeutic agent for CKD-associated AF.