The gut microbiota impacts arterial thrombosis under hyperlipidemic conditions

Introduction The gut microbiota is a central regulator of lipid metabolism and platelet reactivity, shaping the risk of atherothrombosis. While severe hyperlipidemia is known to drive platelet hyperreactivity and thrombosis, emerging evidence indicates that even mild hyperlipidemia can prime platelets toward a pro-thrombotic state. In hyperlipidemic low-density lipoprotein receptor-deficient ( Ldlr– / –) mice on normal chow diet, modest cholesterol elevations increase thrombus and fibrin formation, underscoring the lipid milieu as an early determinant of platelet activity. Simultaneously, the gut microbiota and its metabolites, as well as pattern recognition signaling, also modulate platelet adhesion and aggregation. Notably, germ-free (GF) mice display reduced platelet activation compared to their conventionally raised (CONV-R) counterparts. However, the combined influence of gut microbial colonization and mild hyperlipidemia on platelet function remains unclear. Method We investigated microbiota-dependent differences in platelet deposition using GF and CONV-R mice. In vivo thrombosis was assessed by high-speed fluorescence intravital microscopy (IVM) after carotid artery ligation in mildly hyperlipidemic Ldlr– / – and normolipidemic WT controls. To further investigate the microbial effect on hyperlipidemia and thrombosis, WT mice received high-fat diet (HFD) and broad-spectrum antibiotics followed by IVM. Serum samples from Ldlr– / – and WT mice were analyzed by OLINK proteomics to identify changes in inflammatory protein levels. Results IVM revealed increased platelet deposition to the vascular injury site in mildly hyperlipidemic Ldlr– / – mice under GF and CONV-R conditions as compared to normolipidemic controls, suggesting that mild hyperlipidemia attenuates microbiota-dependent modulation and promotes a prothrombotic phenotype. In WT mice, HFD enhanced platelet adhesion. Interestingly, this effect was abolished by antibiotic microbiota depletion. Interestingly, antibiotics alone increased platelet adhesion after carotid ligation. Proteomic profiling revealed distinct inflammatory protein expression patterns across groups, highlighting microbiota- and lipid-dependent regulation of this thromboinflammatory phenotype. Conclusion Our findings demonstrate that mild hyperlipidemia and gut microbial colonization jointly shape thrombotic platelet responses. While hyperlipidemia enhances platelet deposition and diminishes microbiota-dependent modulation, microbiota depletion produces context-dependent effects, either promoting or suppressing thrombosis depending on the dietary status. These results underscore the complex interplay between gut microbiota and lipid environment in regulating atherothrombosis. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany