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      The Microbiota Promotes Arterial Thrombosis in Low-Density Lipoprotein Receptor-Deficient Mice

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      mBio
      American Society for Microbiology
      gut microbiota, germfree, low-density lipoprotein receptor, arterial thrombosis, atherothrombosis, carotid artery, atherosclerosis, microbiota, platelets, vascular inflammation

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          Abstract

          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.

          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.

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          Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential

          Trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite derived from trimethylamine (TMA)-containing nutrients that are abundant in a Western diet, enhances both platelet responsiveness and in vivo thrombosis potential in animal models and predicts incident atherothrombotic event risks in clinical studies. Here, utilizing a mechanism-based inhibitor approach targeting a major microbial TMA-generating enzyme (CutC/D), we developed potent, time-dependent and irreversible inhibitors that do not affect commensal viability. In animal models, a single oral dose of a CutC/D inhibitor significantly reduced plasma TMAO levels for up to 3 days and rescued diet-induced enhanced platelet responsiveness and thrombus formation, without observable toxicity or increased bleeding risk. The inhibitor selectively accumulated within intestinal microbes to millimolar levels, a concentration over a million-fold higher than needed for a therapeutic effect. These studies reveal that mechanism-based inhibition of gut microbial TMA/TMAO production reduces thrombosis potential, a critical adverse complication in heart disease. They also offer a generalizable approach for the selective non-lethal targeting of gut microbial enzymes linked to host disease, while limiting systemic exposure of the inhibitor in the host.
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            Transmission of atherosclerosis susceptibility with gut microbial transplantation.

            Recent studies indicate both clinical and mechanistic links between atherosclerotic heart disease and intestinal microbial metabolism of certain dietary nutrients producing trimethylamine N-oxide (TMAO). Here we test the hypothesis that gut microbial transplantation can transmit choline diet-induced TMAO production and atherosclerosis susceptibility. First, a strong association was noted between atherosclerotic plaque and plasma TMAO levels in a mouse diversity panel (n = 22 strains, r = 0.38; p = 0.0001). An atherosclerosis-prone and high TMAO-producing strain, C57BL/6J, and an atherosclerosis-resistant and low TMAO-producing strain, NZW/LacJ, were selected as donors for cecal microbial transplantation into apolipoprotein e null mice in which resident intestinal microbes were first suppressed with antibiotics. Trimethylamine (TMA) and TMAO levels were initially higher in recipients on choline diet that received cecal microbes from C57BL/6J inbred mice; however, durability of choline diet-dependent differences in TMA/TMAO levels was not maintained to the end of the study. Mice receiving C57BL/6J cecal microbes demonstrated choline diet-dependent enhancement in atherosclerotic plaque burden as compared with recipients of NZW/LacJ microbes. Microbial DNA analyses in feces and cecum revealed transplantation of donor microbial community features into recipients with differences in taxa proportions between donor strains that were transmissible to recipients and that tended to show coincident proportions with TMAO levels. Proportions of specific taxa were also identified that correlated with plasma TMAO levels in donors and recipients and with atherosclerotic lesion area in recipients. Atherosclerosis susceptibility may be transmitted via transplantation of gut microbiota. Gut microbes may thus represent a novel therapeutic target for modulating atherosclerosis susceptibility.
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              Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways.

              Atherosclerosis, the leading cause of death in developed countries, has been linked to hypercholesterolemia for decades. More recently, atherosclerotic lesion progression has been shown to depend on persistent, chronic inflammation in the artery wall. Although several studies have implicated infectious agents in this process, the role of infection in atherosclerosis remains controversial. Because the involvement of monocytes and macrophages in the pathogenesis of atherosclerosis is well established, we investigated the possibility that macrophage innate immunity signaling pathways normally activated by pathogens might also be activated in response to hyperlipidemia. We examined atherosclerotic lesion development in uninfected, hyperlipidemic mice lacking expression of either lipopolysaccharide (LPS) receptor CD14 or myeloid differentiation protein-88 (MyD88), which transduces cell signaling events downstream of the Toll-like receptors (TLRs), as well as receptors for interleukin-1 (IL-1) and IL-18. Whereas the MyD88-deficient mice evinced a marked reduction in early atherosclerosis, mice deficient in CD14 had no decrease in early lesion development. Inactivation of the MyD88 pathway led to a reduction in atherosclerosis through a decrease in macrophage recruitment to the artery wall that was associated with reduced chemokine levels. These findings link elevated serum lipid levels to a proinflammatory signaling cascade that is also engaged by microbial pathogens.
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                Author and article information

                Contributors
                Role: Invited Editor
                Role: Editor
                Journal
                mBio
                MBio
                mbio
                mbio
                mBio
                mBio
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2150-7511
                22 October 2019
                Sep-Oct 2019
                : 10
                : 5
                : e02298-19
                Affiliations
                [a ]Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany
                [b ]German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Mainz, Germany
                [c ]Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
                [d ]Institute of Cardiovascular Prevention, Department of Medicine, Ludwig-Maximilians-University Munich, Munich, Germany
                [e ]German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
                [f ]Institute of Clinical Molecular Biology (IKMB), Kiel University, Kiel, Germany
                [g ]Center for Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany
                [h ]Institute of Developmental Biology and Neurobiology, Johannes Gutenberg University of Mainz, Mainz, Germany
                [i ]Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, Bern, Switzerland
                University of Wisconsin—Madison
                University of Texas at Austin
                Author notes
                Address correspondence to Christoph Reinhardt, Christoph.Reinhardt@ 123456unimedizin-mainz.de .

                K.K., S.J., and G.P. are co-first authors. E.P.C.V.D.V., Y.D., and C.R. are co-senior authors.

                Author information
                https://orcid.org/0000-0002-6545-3487
                https://orcid.org/0000-0002-0696-2636
                Article
                mBio02298-19
                10.1128/mBio.02298-19
                6805995
                31641089
                d62ac44d-9c62-495a-ab3b-29805628b345
                Copyright © 2019 Kiouptsi et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 30 August 2019
                : 17 September 2019
                Page count
                supplementary-material: 9, Figures: 6, Tables: 0, Equations: 0, References: 56, Pages: 16, Words: 10735
                Funding
                Funded by: German Center for Cardiovascular Research (DZHK);
                Award ID: FKZ 81X2210106
                Award Recipient :
                Funded by: European Research Council;
                Award ID: ERC AdG {degree sign}692511
                Award Recipient :
                Funded by: Cardiovascular Center MUMC+ Maastricht;
                Award Recipient :
                Funded by: EMBO Short Term Fellowship;
                Award ID: No. 7605
                Award Recipient :
                Funded by: Inneruniversitäre Forschungsförderung (Stufe 1);
                Award Recipient :
                Funded by: Deutsche Forschungsgemeinschaft (DFG) Major Research Instrumentation Programme;
                Award ID: DFG INST 371/47-1 FUGG
                Award Recipient :
                Funded by: Deutsche Forschungsgemeinschaft (DFG), https://doi.org/10.13039/501100001659;
                Award ID: CRC1182
                Award Recipient :
                Funded by: Deutsche Forschungsgemeinschaft (DFG), https://doi.org/10.13039/501100001659;
                Award ID: ExC306
                Award Recipient :
                Funded by: Deutsche Forschungsgemeinschaft (DFG), https://doi.org/10.13039/501100001659;
                Award ID: RTG 1743/1
                Award Recipient :
                Funded by: Bundesministerium für Bildung und Forschung (BMBF), https://doi.org/10.13039/501100002347;
                Award ID: 01EO1003
                Award Recipient :
                Funded by: Bundesministerium für Bildung und Forschung (BMBF), https://doi.org/10.13039/501100002347;
                Award ID: 01EO1503
                Award Recipient :
                Funded by: Bundesministerium für Bildung und Forschung (BMBF), https://doi.org/10.13039/501100002347;
                Award ID: 01EO1003
                Award Recipient :
                Categories
                Research Article
                Host-Microbe Biology
                Custom metadata
                September/October 2019

                Life sciences
                gut microbiota,germfree,low-density lipoprotein receptor,arterial thrombosis,atherothrombosis,carotid artery,atherosclerosis,microbiota,platelets,vascular inflammation

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