Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin
1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China; Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
Insights
A newly identified metabolite, 2-methylbutyrylcarnitine (2MBC), promotes thrombosis by enhancing platelet activation. Gut microbiota influence 2MBC levels, suggesting a link between dysbiosis and cardiovascular events.
Area of Science:
- Cardiovascular Science
- Metabolomics
- Microbiome Research
Background:
- Thrombosis is a major cause of death and disability, often linked to conditions like COVID-19 and metabolic disorders.
- The precise mechanisms driving heightened thrombotic risk in these conditions are not fully understood.
- Identifying novel molecular pathways is crucial for developing effective anti-thrombotic strategies.
Purpose of the Study:
- To investigate the role of 2-methylbutyrylcarnitine (2MBC) in thrombosis.
- To elucidate the molecular mechanisms by which 2MBC influences platelet function and thrombus formation.
- To explore the contribution of gut microbiota to 2MBC accumulation and its pro-thrombotic effects.
Main Methods:
- Quantification of 2MBC levels in patients with COVID-19 and major adverse cardiovascular events (MACEs).
- In vivo studies in mice to assess the impact of 2MBC on platelet hyperreactivity and thrombus formation.
- Investigating the interaction of 2MBC with platelet receptors, specifically integrin α2β1, and its downstream effects on cPLA2 activation.
- Utilizing genetic depletion and pharmacological inhibition of integrin α2β1 to evaluate its role in 2MBC-induced thrombosis.
- Assessing the influence of gut microbiota, including antibiotic-induced depletion, on plasma 2MBC levels and thrombotic outcomes.
Main Results:
- 2-methylbutyrylcarnitine (2MBC) was found to be elevated in patients with COVID-19 and MACEs.
- Administration of 2MBC increased platelet hyperreactivity and thrombus formation in mice.
- 2MBC directly binds to platelet integrin α2β1, activating cPLA2 and leading to platelet hyperresponsiveness.
- Genetic or pharmacological blockade of integrin α2β1 significantly reduced the pro-thrombotic effects of 2MBC.
- Gut microbiota were shown to be essential for 2MBC generation, and antibiotic treatment diminished plasma 2MBC levels and thrombosis-promoting effects.
Conclusions:
- 2-methylbutyrylcarnitine (2MBC) is a novel metabolite implicated in thrombosis.
- The gut microbiota plays a significant role in regulating 2MBC levels and associated thrombotic risk.
- Targeting the 2MBC-integrin α2β1 pathway presents a potential therapeutic strategy for managing thrombosis, particularly in the context of gut dysbiosis.
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.
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