Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1

Kan Huang; Zilun Li; Xi He; Jun Dai; Bingding Huang; Yongxia Shi; Dongxiao Fan; Zefeng Zhang; Yunchong Liu; Na Li; Zhongyu Zhang; Jiangyun Peng; Chenshu Liu; Renli Zeng; Zhipeng Cen; Tengyao Wang; Wenchao Yang; Meifeng Cen; Jingyu Li; Shuai Yuan; Lu Zhang; Dandan Hu; Shuxiang Huang; Pin Chen; Peilong Lai; Liyan Lin; Jielu Wen; Zhengde Zhao; Xiuyi Huang; Lining Yuan; Lifang Zhou; Haoliang Wu; Lihua Huang; Kai Feng; Jian Wang; Baolin Liao; Weiping Cai; Xilong Deng; Yueping Li; Jianping Li; Zhongwei Hu; Li Yang; Jiaojiao Li; Youguang Zhuo; Fuchun Zhang; Lin Lin; Yifeng Luo; Wei Zhang; Qianlin Ni; Xiqiang Hong; Guangqi Chang; Yang Zhang; Dongxian Guan; Weikang Cai; Yutong Lu; Fang Li; Li Yan; Meng Ren; Linghua Li; Sifan Chen

doi:10.1016/j.cmet.2024.01.014

Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1

Kan Huang, Zilun Li, Xi He, Jun Dai, Bingding Huang, Yongxia Shi, Dongxiao Fan, Zefeng Zhang, Yunchong Liu, Na Li, Zhongyu Zhang, Jiangyun Peng, Chenshu Liu, Renli Zeng, Zhipeng Cen, Tengyao Wang, Wenchao Yang, Meifeng Cen, Jingyu Li, Shuai YuanLu Zhang, Dandan Hu, Shuxiang Huang, Pin Chen, Peilong Lai, Liyan Lin, Jielu Wen, Zhengde Zhao, Xiuyi Huang, Lining Yuan, Lifang Zhou, Haoliang Wu, Lihua Huang, Kai Feng, Jian Wang, Baolin Liao, Weiping Cai, Xilong Deng, Yueping Li, Jianping Li, Zhongwei Hu, Li Yang, Jiaojiao Li, Youguang Zhuo, Fuchun Zhang, Lin Lin, Yifeng Luo, Wei Zhang, Qianlin Ni, Xiqiang Hong, Guangqi Chang, Yang Zhang, Dongxian Guan, Weikang Cai, Yutong Lu, Fang Li, Li Yan, Meng Ren, Linghua Li, Sifan Chen

Molecular and Cellular Biochemistry

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2β1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2β1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.

Original language	English
Pages (from-to)	598-616.e9
Journal	Cell Metabolism
Volume	36
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2024.01.014
State	Published - Mar 5 2024

Bibliographical note

Publisher Copyright:
© 2024 Elsevier Inc.

Keywords

2-methylbutyrylcarnitine
BTT 3033
gut microbial metabolite
integrin α2β1
platelet hyperreactivity
thrombosis

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2024.01.014

Cite this

Huang, K., Li, Z., He, X., Dai, J., Huang, B., Shi, Y., Fan, D., Zhang, Z., Liu, Y., Li, N., Zhang, Z., Peng, J., Liu, C., Zeng, R., Cen, Z., Wang, T., Yang, W., Cen, M., Li, J., ... Chen, S. (2024). Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1. Cell Metabolism, 36(3), 598-616.e9. https://doi.org/10.1016/j.cmet.2024.01.014

@article{e67cc013ecf94210bfae42fb14884289,

title = "Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1",

abstract = "Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2β1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2β1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.",

keywords = "2-methylbutyrylcarnitine, BTT 3033, gut microbial metabolite, integrin α2β1, platelet hyperreactivity, thrombosis",

author = "Kan Huang and Zilun Li and Xi He and Jun Dai and Bingding Huang and Yongxia Shi and Dongxiao Fan and Zefeng Zhang and Yunchong Liu and Na Li and Zhongyu Zhang and Jiangyun Peng and Chenshu Liu and Renli Zeng and Zhipeng Cen and Tengyao Wang and Wenchao Yang and Meifeng Cen and Jingyu Li and Shuai Yuan and Lu Zhang and Dandan Hu and Shuxiang Huang and Pin Chen and Peilong Lai and Liyan Lin and Jielu Wen and Zhengde Zhao and Xiuyi Huang and Lining Yuan and Lifang Zhou and Haoliang Wu and Lihua Huang and Kai Feng and Jian Wang and Baolin Liao and Weiping Cai and Xilong Deng and Yueping Li and Jianping Li and Zhongwei Hu and Li Yang and Jiaojiao Li and Youguang Zhuo and Fuchun Zhang and Lin Lin and Yifeng Luo and Wei Zhang and Qianlin Ni and Xiqiang Hong and Guangqi Chang and Yang Zhang and Dongxian Guan and Weikang Cai and Yutong Lu and Fang Li and Li Yan and Meng Ren and Linghua Li and Sifan Chen",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Inc.",

year = "2024",

month = mar,

day = "5",

doi = "10.1016/j.cmet.2024.01.014",

language = "English",

volume = "36",

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Huang, K, Li, Z, He, X, Dai, J, Huang, B, Shi, Y, Fan, D, Zhang, Z, Liu, Y, Li, N, Zhang, Z, Peng, J, Liu, C, Zeng, R, Cen, Z, Wang, T, Yang, W, Cen, M, Li, J, Yuan, S, Zhang, L, Hu, D, Huang, S, Chen, P, Lai, P, Lin, L, Wen, J, Zhao, Z, Huang, X, Yuan, L, Zhou, L, Wu, H, Huang, L, Feng, K, Wang, J, Liao, B, Cai, W, Deng, X, Li, Y, Li, J, Hu, Z, Yang, L, Li, J, Zhuo, Y, Zhang, F, Lin, L, Luo, Y, Zhang, W, Ni, Q, Hong, X, Chang, G, Zhang, Y, Guan, D, Cai, W, Lu, Y, Li, F, Yan, L, Ren, M, Li, L & Chen, S 2024, 'Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1', Cell Metabolism, vol. 36, no. 3, pp. 598-616.e9. https://doi.org/10.1016/j.cmet.2024.01.014

TY - JOUR

T1 - Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1

AU - Huang, Kan

AU - Li, Zilun

AU - He, Xi

AU - Dai, Jun

AU - Huang, Bingding

AU - Shi, Yongxia

AU - Fan, Dongxiao

AU - Zhang, Zefeng

AU - Liu, Yunchong

AU - Li, Na

AU - Zhang, Zhongyu

AU - Peng, Jiangyun

AU - Liu, Chenshu

AU - Zeng, Renli

AU - Cen, Zhipeng

AU - Wang, Tengyao

AU - Yang, Wenchao

AU - Cen, Meifeng

AU - Li, Jingyu

AU - Yuan, Shuai

AU - Zhang, Lu

AU - Hu, Dandan

AU - Huang, Shuxiang

AU - Chen, Pin

AU - Lai, Peilong

AU - Lin, Liyan

AU - Wen, Jielu

AU - Zhao, Zhengde

AU - Huang, Xiuyi

AU - Yuan, Lining

AU - Zhou, Lifang

AU - Wu, Haoliang

AU - Huang, Lihua

AU - Feng, Kai

AU - Wang, Jian

AU - Liao, Baolin

AU - Cai, Weiping

AU - Deng, Xilong

AU - Li, Yueping

AU - Li, Jianping

AU - Hu, Zhongwei

AU - Yang, Li

AU - Li, Jiaojiao

AU - Zhuo, Youguang

AU - Zhang, Fuchun

AU - Lin, Lin

AU - Luo, Yifeng

AU - Zhang, Wei

AU - Ni, Qianlin

AU - Hong, Xiqiang

AU - Chang, Guangqi

AU - Zhang, Yang

AU - Guan, Dongxian

AU - Cai, Weikang

AU - Lu, Yutong

AU - Li, Fang

AU - Yan, Li

AU - Ren, Meng

AU - Li, Linghua

AU - Chen, Sifan

PY - 2024/3/5

Y1 - 2024/3/5

N2 - Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2β1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2β1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.

AB - Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2β1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2β1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.

KW - 2-methylbutyrylcarnitine

KW - BTT 3033

KW - gut microbial metabolite

KW - integrin α2β1

KW - platelet hyperreactivity

KW - thrombosis

UR - http://www.scopus.com/inward/record.url?scp=85186519735&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85186519735&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2024.01.014

DO - 10.1016/j.cmet.2024.01.014

M3 - Article

C2 - 38401546

AN - SCOPUS:85186519735

SN - 1550-4131

VL - 36

SP - 598-616.e9

JO - Cell Metabolism

JF - Cell Metabolism

IS - 3

ER -

Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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