Disordered gut microbiota promotes atrial fibrillation by aggravated conduction disturbance and unbalanced linoleic acid/SIRT1 signaling
Disordered gut microbiota promotes atrial fibrillation by aggravated conduction disturbance and unbalanced linoleic acid/SIRT1 signaling
复制标题
DOI：
10.1016/j.bcp.2023.115599
复制
发表时间：
2023-05-25
影响因子：
5.8
通讯作者：
Yang, Xinchun
中科院分区：
文献类型：
--
作者：
Fang, Chen;Zuo, Kun;Yang, Xinchun
新出现的证据表明，肠道微生物区系失调(GM)与房颤(AF)有关。目前的研究旨在确定异常GM是否促进房颤的发生。一种粪便微生物区系移植(FMT)小鼠模型表明，通过经食道爆发起搏评估，反生菌GM足以增强房颤的易感性。与移植健康人GM的受者(FMT-CH)相比，移植AFGM(FMT-AF)的受者左心房P波时限延长，有增大的趋势。同时，FMT-AF大鼠心房间隙连接蛋白43和N-钙粘蛋白定位紊乱，磷酸化CaMKII和磷酸化RyR2表达增强，提示肠道菌群改变加重了心房电重构。具体地说，严重的纤维化紊乱、胶原沉积、α-SMA表达和心房炎症也被证实是可由GM传播的。此外，FMT-AF小鼠的肠道上皮屏障和肠道通透性恶化，并伴有粪便和血浆代谢紊乱，尤其是亚油酸(LA)的降低。随后，在用内毒素/黑素、LA和SIRT1基因敲除的小鼠HL-1细胞中，证实了LA在FMT-AF心房中发现的不平衡SIRT1信号中的抗炎作用。本研究初步探讨了异常GM在房颤的病理生理学中的作用，提示GM-肠屏障-心房轴可能参与了房颤发生的易损底物，GM可作为房颤治疗的环境靶点。
Emerging evidence suggests an association of dysbiotic gut microbiota (GM) with atrial fibrillation (AF). The current study aimed to determine whether aberrant GM promotes AF development. A fecal microbiota trans-plantation (FMT) mouse model demonstrated that dysbiotic GM is sufficient to enhance AF susceptibility assessed by transesophageal burst pacing. Compared with recipients transplanted with GM obtained from healthy subjects (FMT-CH), the prolonged P wave duration and an enlarging tendency for the left atrium were detected in recipients transplanted with AF GM (FMT-AF). Meanwhile, the disrupted localizations of connexin 43 and N-cadherin and increased expression levels of phospho-CaMKII and phospho-RyR2, were observed in the atrium of FMT-AF, which indicated aggravated electrical remodeling caused by the altered gut flora. Specifically, exac-erbated fibrosis disarray, collagen deposition, & alpha;-SMA expression, and inflammation in the atrium were also confirmed to be transmissible by the GM. Furthermore, deteriorated intestinal epithelial barrier and intestinal permeability, accompanied by disturbing metabolomic features in both feces and plasma, especially decreased linoleic acid (LA), were identified in FMT-AF mice. Subsequently, the anti-inflammatory role of LA among the imbalanced SIRT1 signaling discovered in the atrium of FMT-AF was confirmed in mouse HL-1 cells treated with LPS/nigericin, LA, and SIRT1 knockdown. This study provides preliminary insights into the causal role of aberrant GM in the pathophysiology of AF, suggesting the GM-intestinal barrier-atrium axis might participate in the vulnerable substrates for AF development, and the GM could be utilized as an environmental target in AF management.