Commensal microbe-derived SCFA alleviates atrial fibrillation via GPR43/NLRP3 signaling.
Commensal microbe-derived SCFA alleviates atrial fibrillation via GPR43/NLRP3 signaling.
复制标题
DOI：
10.7150/ijbs.70644
复制
发表时间：
2022
影响因子：
9.2
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Zuo K;Fang C;Liu Z;Fu Y;Liu Y;Liu L;Wang Y;Yin X;Liu X;Li J;Zhong J;Chen M;Xu L;Yang X
原理：肠道微生物群（GM）和NLRP 3炎性小体是房颤（AF）的促发因素。在此，转基因发酵膳食纤维产生的短链脂肪酸（SCFA）是否作为不可见的介质还不清楚。因此，目前的研究旨在确定SCFA是否从NLRP 3信号介导的心房重构中缓解，从而保护AF的发展。研究方法：首先，进行了一项基于GC-MS代谢组学的横断面研究，以探讨粪便SCFA水平与48名个体组成的队列中AF性状之间的关联。然后，建立了一个完善的小鼠模型，喂养缺乏或富含膳食纤维的饮食，以阐明SCFA参与AF易感性，心房重构和G蛋白偶联受体43（GPR 43）/NLRP 3信号转导的病理生理作用。最后，在HL-1细胞上验证了SCFA的作用。结果如下：粪便SCFA水平显着降低AF患者的下降趋势，从阵发性到持续性AF。延长P波持续时间的基础上，表面心电图和增加左心房直径获得超声心动图确定在低纤维饮食小鼠，但失去了SCFA补充组。短阵快速起搏时，缺乏膳食纤维会增加房颤的易感性，而SCFA可能具有保护作用。补充SCFA可防止膳食纤维缺乏上调的钙调蛋白依赖性蛋白激酶II和ryanodine受体2磷酸化、心房组织中的无序纤维化、胶原蛋白表达和NLRP 3炎性小体激活。最后，通过在HL-1细胞中通过GPR 43敲低GPR 43介导的NLRP 3失活来鉴定SCFA的AF保护作用。结论：肠溶菌发酵膳食纤维产生的SCFA通过GPR 43/NLRP 3信号通路抑制AF的发生。
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.
登录
查看更多内容
影响因子：
7.3
作者：
Matt SM;Allen JM;Lawson MA;Mailing LJ;Woods JA;Johnson RW
通讯作者：
Johnson RW
影响因子：
64.5
作者：
Duscha, Alexander;Gisevius, Barbara;Haghikia, Aiden
通讯作者：
Haghikia, Aiden
影响因子：
37.8
作者：
Kaye, David M.;Shihata, Waled A.;Marques, Francine Z.
通讯作者：
Marques, Francine Z.
影响因子：
2.1
作者：
Ruan, Jianjun;Meng, Heyu;Meng, Fanbo
通讯作者：
Meng, Fanbo
影响因子：
37.8
作者：
Bartolomaeus, Hendrik;Balogh, Andras;Wilck, Nicola
通讯作者：
Wilck, Nicola