Akkermansia muciniphila prevents cold-related atrial fibrillation in rats by modulation of TMAO induced cardiac pyroptosis
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 sequenci...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396422002687 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yingchun Luo |
| collection | DOAJ |
| description | 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). |
| first_indexed | 2024-12-11T04:49:00Z |
| format | Article |
| id | doaj.art-6b37c6156d6c4b98a6e877f380598ac2 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-11T04:49:00Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-6b37c6156d6c4b98a6e877f380598ac22022-12-22T01:20:26ZengElsevierEBioMedicine2352-39642022-08-0182104087Akkermansia muciniphila prevents cold-related atrial fibrillation in rats by modulation of TMAO induced cardiac pyroptosisYingchun Luo0Yun Zhang1Xuejie Han2Yue Yuan3Yun Zhou4Yunlong Gao5Hui Yu6Jiawei Zhang7Yiya Shi8Yu Duan9Xinbo Zhao10Sen Yan11Hongting Hao12Chenguang Dai13Shiqi Zhao14Jing Shi15Wenpeng Li16Song Zhang17Wei Xu18Ning Fang19Yongtai Gong20Yue Li21Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment 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, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, Qingdao Central Hospital, Qingdao, ChinaMicrobiome Medicine Center, Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, ChinaDepartment 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.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).http://www.sciencedirect.com/science/article/pii/S2352396422002687ColdAtrial fibrillationGut microbiotaAkkermansia muciniphilaTMAO |
| spellingShingle | 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 Akkermansia muciniphila prevents cold-related atrial fibrillation in rats by modulation of TMAO induced cardiac pyroptosis EBioMedicine Cold Atrial fibrillation Gut microbiota Akkermansia muciniphila TMAO |
| title | Akkermansia muciniphila prevents cold-related atrial fibrillation in rats by modulation of TMAO induced cardiac pyroptosis |
| title_full | Akkermansia muciniphila prevents cold-related atrial fibrillation in rats by modulation of TMAO induced cardiac pyroptosis |
| title_fullStr | Akkermansia muciniphila prevents cold-related atrial fibrillation in rats by modulation of TMAO induced cardiac pyroptosis |
| title_full_unstemmed | Akkermansia muciniphila prevents cold-related atrial fibrillation in rats by modulation of TMAO induced cardiac pyroptosis |
| title_short | Akkermansia muciniphila prevents cold-related atrial fibrillation in rats by modulation of TMAO induced cardiac pyroptosis |
| title_sort | akkermansia muciniphila prevents cold related atrial fibrillation in rats by modulation of tmao induced cardiac pyroptosis |
| topic | Cold Atrial fibrillation Gut microbiota Akkermansia muciniphila TMAO |
| url | http://www.sciencedirect.com/science/article/pii/S2352396422002687 |
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