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

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.