2. Academic Validation
  3. Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism

Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism

  • Eur Heart J. 2022 Feb 10;43(6):518-533. doi: 10.1093/eurheartj/ehab644.
Arash Haghikia 1 2 3,  Friederike Zimmermann 1 2,  Paul Schumann 1 2,  Andrzej Jasina 1,  Johann Roessler 1 2,  David Schmidt 1,  Philipp Heinze 1,  Johannes Kaisler 4,  Vanasa Nageswaran 1,  Annette Aigner 3 5,  Uta Ceglarek 6 7,  Roodline Cineus 8 9,  Ahmed N Hegazy 3 8 9,  Emiel P C van der Vorst 10 11 12 13,  Yvonne Döring 10 11 14,  Christopher M Strauch 15,  Ina Nemet 15,  Valentina Tremaroli 16,  Chinmay Dwibedi 16 17,  Nicolle Kränkel 1 2,  David M Leistner 1 2 3,  Markus M Heimesaat 18,  Stefan Bereswill 18,  Geraldine Rauch 3 5,  Ute Seeland 2 19,  Oliver Soehnlein 10 11 20,  Dominik N Müller 2 3 21 22,  Ralf Gold 4,  Fredrik Bäckhed 16 23 24,  Stanley L Hazen 15 25,  Aiden Haghikia 26,  Ulf Landmesser 1 2 3
Affiliations

Affiliations

  • 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.
PMID: 34597388 DOI: 10.1093/eurheartj/ehab644
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.

Keywords

Atherosclerosis; Gut microbiome; Propionic acid.

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