Commensal microbe-derived SCFA alleviates atrial fibrillation via GPR43/NLRP3 signaling

Abstract

Rationale: Dysbiotic gut microbiota (GM) and NLRP3 inflammasome are proarrhythmic factors in atrial fibrillation (AF). Herein, whether short-chain fatty acid (SCFA) produced from GM fermentation of dietary fiber serving as invisible mediators is yet unclear. Thus, the current study aimed to determine whether SCFA alleviated from NLRP3 signaling-mediated atrial remodeling protects AF development. Methods: First, a cross-sectional study based on the GC-MS metabolomics was performed to explore the association between fecal SCFA levels and AF traits in a cohort consisted of 48 individuals. Then, a well-established mice model fed diet deficient or enriched in dietary fiber was established to elucidate the pathophysiological role of SCFA involved in AF susceptibility, atrial remodeling, and G-protein-coupled receptor 43 (GPR43)/NLRP3 signaling. Finally, the effects of SCFA were verified on HL-1 cells. Results: Fecal SCFA levels were remarkably reduced in AF patients with a declining trend from paroxysmal to persistent AF. Prolonged P wave duration based on surface ECG and increased left atrial diameter gained from echocardiography was identified in low-fiber diet mice but lost in SCFA-supplemented group. Lack of dietary fiber enhanced susceptibility to AF under burst pacing, whereas SCFA might exert a protective effect. The supplementation of SCFA prevented dietary fiber deficiency-upregulated phosphorylation of calmodulin-dependent protein kinase II and ryanodine receptor 2, the disarray fibrosis, collagen expression, and NLRP3 inflammasome activation in atrial tissue. Finally, the AF protective roles of SCFA were identified through GPR43 mediated deactivation of NLRP3 by GPR43 knockdown in HL-1 cells. Conclusions: SCFA derived from dietary fiber fermentation by gut commensals alleviates AF development via GPR43/NLRP3 signaling.

Association of gut microbiome dysbiosis with the progression of atrial fibrillation: A systematic review

“…| 7 of 10 Zuo et al, 2020Zuo et al, , 2022. Our major findings indicated that there is a significant association between dysbiosis in the gut microbiome with AF.…”

“…One human study demonstrated that increased TMAO synthesis can increase platelet hyperactivity, resulting in a high risk of AF after ablation procedures . Similarly, one other study found increased levels of TMAO after 12-18 months of AF catheter ablation (Zuo et al, 2022). However, the clinical data evaluating the correlation of TMAO with AF is inconclusive in many other studies (Papandreou et al, 2021).…”

Gut microbiota dysbiosis in polycystic ovary syndrome: Mechanisms of progression and clinical applications

“…Intestinal bacteria can produce SCFA, which is involved in the secretion of brain gut peptides by intestinal endocrine cells, such as glucagon like peptide 1, growth hormone releasing peptide (Ghrelin) and YY peptide. SCFA activates mammalian rapamycin target protein/signal transduction and transcriptional activator signal pathway through G-protein coupled receptor 43 and regulates the expression of brain gut peptide (Zuo et al, 2022). Brain gut peptide (such as Ghrelin) can participate in regulating hypothalamic regulatory nucleus and luteinizing hormone secretion.…”

Crosstalk between gut microbiota and renal ischemia/reperfusion injury

“…Dietary fiber is a source of carbohydrates for the microbiota ( Coker et al., 2021 ; Zuo et al., 2022 ). The composition of the colonic microbiota is significantly influenced by diet and its assimilation in the small intestine ( Murga-Garrido et al., 2021 ).…”