肠道菌群代谢产物SCFAs通过GPR41/43抑制心房肌细胞NLRP3炎症小体活性保护心房颤动发病的机制研究

心房颤动（房颤）患者存在肠道菌群紊乱，但其中作用机制尚不明确；既往研究表明肠道细菌发酵膳食纤维产物短链脂肪酸（SCFAs）可调控炎症反应，缺乏膳食纤维致高血压易感表型可经肠道菌群传递。我们前期研究发现：房颤患者肠道菌群SCFAs合成功能减低，低膳食纤维饮食使小鼠房颤诱发率升高，SCFAs感受器GPR41/43在心房肌细胞表达，SCFAs可增加GPR43表达并抑制IL-1β分泌。据此我们提出假说，SCFAs经心房肌细胞GPR41/43，通过磷酸化及泛素化修饰促进与心房重构密切关联的NLRP3自噬降解，从而对房颤发病起保护作用。本研究拟比较不同膳食纤维含量饮食喂养小鼠心房重构指标，确证SCFAs可保护房颤发病；在体外试验中分析GPR41/43敲减及SCFAs干预等对NLRP3磷酸化与泛素化修饰水平的影响，以阐明SCFAs抑制NLRP3活性保护房颤发病的机制。为干预肠道菌群改善房颤进程提供证据。

Disordered gut microbiota (GM) and alterations in metabolic patterns have been characterized in patients with atrial fibrillation (AF). However, the impact of GM shift and the associated mechanisms that contribute to the progression of AF remain largely unknown. A growing body of evidence suggests that gut metabolites called short-chain fatty acids (SCFAs), produced from the fermentation of prebiotic fibre by the GM, are a key modulator of inflammatory disorders and can protect against the development of hypertension in a pre-clinical model. Furthermore, lack of prebiotic dietary fibre leads to the development of hypertensinogenic GM and hypertension. Our previous study revealed decreased function of SCFA synthesis in AF patients. Notably, we found that a diet deficient in prebiotic fibre predisposed mice to a higher AF susceptibility. Moreover, the expression of G-protein coupled-receptors (GPR) 41/43, which sense SCFAs, has been discovered in HL-1 cells. SCFA could increase the expression of GPR43 and suppress the secretion of IL-1β in HL-1 cell. Therefore, we hypothesized that the AF-protective effects of SCFAs were mediated via the cognate SCFAs receptors GPR41/GPR43 in atrial cardiomyocytes, which could further promote the phosphorylation and ubiquitination of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and subsequently induce NLRP3 inflammasome degradation through autophagy. This would ultimately inhibit the NLRP3 inflammasome signaling whose pathophysiological role has been established as a mechanistic link to the atrial remodeling of AF. The current study illuminated the beneficial modulatory role of SCFAs during the development of AF by comparing the difference of atrial remodeling in mice lacking prebiotic fibre with or without intervention of water containing SCFAs and in mice with sufficient prebiotic fibre diet. Furthermore, the effect of SCFA-mediated NLRP3 inflammasome attenuation was illustrated by GPR41/43 knockdown and SCFAs stimulated in vitro by detecting the phosphorylation and ubiquitination levels of NLRP3. The current research aimed to provide evidence for the intervention of intestinal flora to improve AF and emphasized that maintaining a healthy, SCFA-producing microbiome is important for cardiovascular health.