Arash Haghikia1,2,3, Friederike Zimmermann1,2, Paul Schumann1,2, Andrzej Jasina1, Johann Roessler1,2, David Schmidt1, Philipp Heinze1, Johannes Kaisler4, Vanasa Nageswaran1, Annette Aigner3,5, Uta Ceglarek6,7, Roodline Cineus8,9, Ahmed N Hegazy3,8,9, Emiel P C van der Vorst10,11,12,13, Yvonne Döring10,11,14, Christopher M Strauch15, Ina Nemet15, Valentina Tremaroli16, Chinmay Dwibedi16,17, Nicolle Kränkel1,2, David M Leistner1,2,3, Markus M Heimesaat18, Stefan Bereswill18, Geraldine Rauch3,5, Ute Seeland2,19, Oliver Soehnlein10,11,20, Dominik N Müller2,3,21,22, Ralf Gold4, Fredrik Bäckhed16,23,24, Stanley L Hazen15,25, Aiden Haghikia26, Ulf Landmesser1,2,3. 1. Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany. 2. German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany. 3. Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Straβe 2, Berlin 10178, Germany. 4. Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany. 5. Institute of Biometry and Clinical Epidemiology, Charité-Universitätsmedizin Berlin, Berlin, Germany. 6. Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Paul-List-Str. 13-15, Leipzig 04103, Germany. 7. LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany. 8. Department of Gastroenterology, Infectiology, and Rheumatology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany. 9. Deutsches Rheumaforschungszentrum Berlin (DRFZ), An Institute of the Leibniz Association, Berlin, Germany. 10. Institute for Cardiovascular Prevention (IPEK), LMU München, Munich, Germany. 11. German Center for Cardiovascular Research (DZHK), Partner Site Munich, Heart Alliance Munich, Munich, Germany. 12. Interdisciplinary Center for Clinical Research (IZKF), Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Pauwelsstraße 30, Aachen 52074, Germany. 13. Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Universiteitssingel 50, Maastricht 6200 MD, the Netherlands. 14. Departement of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 35, Bern CH-3008, Switzerland. 15. Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA. 16. The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Bruna Stråket 16, Gothenburg SE-413 45, Sweden. 17. Institute of Neuroscience and Physiology, University of Gothenburg, Box 430, Gothenburg 405 30, Sweden. 18. Insitute of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, Berlin 12203, Germany. 19. Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Social Medicine, Epidemiology and Health Economics, Campus Charité Mitte Luisenstraße 57, Berlin 10117, Germany. 20. Institute for Experimental Pathology (ExPat), Center for Molecular Biology of Inflammation (ZMBE), Von-Esmarch-Straße 56, WWU Münster 48149, Germany. 21. Experimental and Clinical Research Center, a joint cooperation of Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany. 22. Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Str. 10, Berlin 13092, Germany. 23. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen DK-2200, Denmark. 24. Department of Clinical Physiology, Region Västra Götaland, Sahlgrenska University Hospital, Box 430, Gothenburg 405 30, Sweden. 25. Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Ave., NC-10 Cleveland 44195, OH, USA. 26. Department of Neurology, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120, Germany.
Abstract
AIMS: Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism. METHODS AND RESULTS: Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe-/- mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels. CONCLUSION: Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism. METHODS AND RESULTS: Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe-/- mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels. CONCLUSION: Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs. Published on behalf of the European Society of Cardiology. All rights reserved.
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