Akkermansia muciniphila prevents cold-related atrial fibrillation in rats by modulation of TMAO induced cardiac pyroptosis
Yingchun Luo,
Yun Zhang,
Xuejie Han,
Yue Yuan,
Yun Zhou,
Yunlong Gao,
Hui Yu,
Jiawei Zhang,
Yiya Shi,
Yu Duan,
Xinbo Zhao,
Sen Yan,
Hongting Hao,
Chenguang Dai,
Shiqi Zhao,
Jing Shi,
Wenpeng Li,
Song Zhang,
Wei Xu,
Ning Fang,
Yongtai Gong,
Yue Li
Affiliations
Yingchun Luo
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Yun Zhang
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China; Microbiome Medicine Center, Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
Xuejie Han
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Yue Yuan
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Yun Zhou
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Yunlong Gao
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Hui Yu
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Jiawei Zhang
Department of Cardiology, Qingdao Central Hospital, Qingdao, China
Yiya Shi
Microbiome Medicine Center, Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
Yu Duan
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Xinbo Zhao
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Sen Yan
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Hongting Hao
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Chenguang Dai
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Shiqi Zhao
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Jing Shi
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Wenpeng Li
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Song Zhang
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Wei Xu
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Ning Fang
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Yongtai Gong
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China; Address for correspondence: Yue Li and Yongtai Gong, Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Youzheng Street 23#, Nangang District, Harbin 150001, China. Tel: +86 451 85555673, Fax: +86 451 53675733.
Yue Li
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China; NHC Key Laboratory of Cell Translation, Harbin Medical University, Heilongjiang 150001, China; Key Laboratory of Hepatosplenic Surgery, Harbin Medical University, Ministry of Education, Harbin 150001, China; Key Laboratory of Cardiac Diseases and Heart Failure, Harbin Medical University, Harbin 150001, China; Heilongjiang Key Laboratory for Metabolic Disorder & Cancer Related Cardiovascular Diseases, Harbin 150081, China; Address for correspondence: Yue Li and Yongtai Gong, Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Youzheng Street 23#, Nangang District, Harbin 150001, China. Tel: +86 451 85555673, Fax: +86 451 53675733.
Summary: Background: Cold exposure is one of the most important risk factors for atrial fibrillation (AF), and closely related to the poor prognosis of AF patients. However, the mechanisms underlying cold-related AF are poorly understood. Methods: Various techniques including 16S rRNA gene sequencing, fecal microbiota transplantation, and electrophysiological examination were used to determine whether gut microbiota dysbiosis promotes cold-related AF. Metabonomics were performed to investigate changes in fecal trimethylamine (TMA) and plasma trimethylamine N-oxide (TMAO) during cold exposure. The detailed mechanism underlying cold-related AF were examined in vitro. Transgenic mice were constructed to explore the role of pyroptosis in cold-related AF. The human cohort was used to evaluate the correlation between A. muciniphila and cold-related AF. Findings: We found that cold exposure caused elevated susceptibility to AF and reduced abundance of Akkermansia muciniphila (A. muciniphila) in rats. Intriguingly, oral supplementation of A. muciniphila ameliorated the pro-AF property induced by cold exposure. Mechanistically, cold exposure disrupted the A. muciniphila, by which elevated the level of trimethylamine N-oxide (TMAO) through modulation of the microbial enzymes involved in trimethylamine (TMA) synthesis. Correspondingly, progressively increased plasma TMAO levels were validated in human subjects during cold weather. Raised TMAO enhanced the infiltration of M1 macrophages in atria and increased the expression of Casp1-p20 and cleaved-GSDMD, ultimately causing atrial structural remodeling. Furthermore, the mice with conditional deletion of caspase1 exhibited resistance to cold-related AF. More importantly, a cross-sectional clinical study revealed that the reduction of A. muciniphila abundance was an independent risk factor for cold-related AF in human subjects. Interpretation: Our findings revealed a novel causal role of aberrant gut microbiota and metabolites in pathogenesis of cold-related AF, which raises the possibility of selectively targeting microbiota and microbial metabolites as a potential therapeutic strategy for cold-related AF. Funding: This work was supported by grants from the State Key Program of National Natural Science Foundation of China (No.81830012), and National Natural Science Foundation of China (No.82070336, No.81974024), Youth Program of the National Natural Science Foundation of China (No.81900374, No.81900302), and Excellent Young Medical Talents supporting project in the First Affiliated Hospital of Harbin Medical University (No. HYD2020YQ0001).
