Abstract
Atherosclerotic plaque development depends on chronic inflammation of the arterial wall. A dysbiotic gut microbiota can cause low-grade inflammation, and microbiota composition was linked to cardiovascular disease risk. However, the role of this environmental factor in atherothrombosis remains undefined. To analyze the impact of gut microbiota on atherothrombosis, we rederived low-density lipoprotein receptor-deficient (Ldlr-/- ) mice as germfree (GF) and kept these mice for 16 weeks on an atherogenic high-fat Western diet (HFD) under GF isolator conditions and under conventionally raised specific-pathogen-free conditions (CONV-R). In spite of reduced diversity of the cecal gut microbiome, caused by atherogenic HFD, GF Ldlr-/- mice and CONV-R Ldlr-/- mice exhibited atherosclerotic lesions of comparable sizes in the common carotid artery. In contrast to HFD-fed mice, showing no difference in total cholesterol levels, CONV-R Ldlr-/- mice fed control diet (CD) had significantly reduced total plasma cholesterol, very-low-density lipoprotein (VLDL), and LDL levels compared with GF Ldlr-/- mice. Myeloid cell counts in blood as well as leukocyte adhesion to the vessel wall at the common carotid artery of GF Ldlr-/- mice on HFD were diminished compared to CONV-R Ldlr-/- controls. Plasma cytokine profiling revealed reduced levels of the proinflammatory chemokines CCL7 and CXCL1 in GF Ldlr-/- mice, whereas the T-cell-related interleukin 9 (IL-9) and IL-27 were elevated. In the atherothrombosis model of ultrasound-induced rupture of the common carotid artery plaque, thrombus area was significantly reduced in GF Ldlr-/- mice relative to CONV-R Ldlr-/- mice. Ex vivo, this atherothrombotic phenotype was explained by decreased adhesion-dependent platelet activation and thrombus growth of HFD-fed GF Ldlr-/- mice on type III collagen.IMPORTANCE Our results demonstrate a functional role for the commensal microbiota in atherothrombosis. In a ferric chloride injury model of the carotid artery, GF C57BL/6J mice had increased occlusion times compared to colonized controls. Interestingly, in late atherosclerosis, HFD-fed GF Ldlr-/- mice had reduced plaque rupture-induced thrombus growth in the carotid artery and diminished ex vivo thrombus formation under arterial flow conditions.
Highlights
Atherosclerotic plaque development depends on chronic inflammation of the arterial wall
Since the role of commensal microbiota on hypercholesterolemia and atherothrombosis is unresolved [19, 28], we rederived conventionally raised (CONV-R) LdlrϪ/Ϫ mice as GF and kept this mouse line on a sterile gammairradiated high-fat Western diet (HFD) at GF isolator conditions for 16 weeks to compare them with CONV-R LdlrϪ/Ϫ control mice
HFD feeding was previously associated with dysbiosis that is characterized by a reduced diversity of the gut microbiota [29, 30], resulting in decreased intestinal barrier function and in the onset of a low-grade inflammatory state [20, 31]
Summary
Atherosclerotic plaque development depends on chronic inflammation of the arterial wall. In the atherothrombosis model of ultrasound-induced rupture of the common carotid artery plaque, thrombus area was significantly reduced in GF LdlrϪ/Ϫ mice relative to CONV-R LdlrϪ/Ϫ mice Ex vivo, this atherothrombotic phenotype was explained by decreased adhesion-dependent platelet activation and thrombus growth of HFD-fed GF LdlrϪ/Ϫ mice on type III collagen. The commensal microbiota composition has emerged as a risk factor for cardiometabolic disease [26], it remains controversial how the gut metagenome contributes to the development of atherosclerosis [7, 18,19,20] and in particular how the gut microbiota influences atherothrombotic processes, i.e., the rupture of an atherosclerotic plaque at the carotid artery, with subsequent thrombus formation
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