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

Research output: Contribution to journalJournal articlepeer-review

  • Arash Haghikia
  • Friederike Zimmermann
  • Paul Schumann
  • Andrzej Jasina
  • Johann Roessler
  • David Schmidt
  • Philipp Heinze
  • Johannes Kaisler
  • Vanasa Nageswaran
  • Annette Aigner
  • Uta Ceglarek
  • Roodline Cineus
  • Ahmed N. Hegazy
  • Emiel P.C. Van Der Vorst
  • Yvonne Doring
  • Christopher M. Strauch
  • Ina Nemet
  • Valentina Tremaroli
  • Chinmay Dwibedi
  • Nicolle Krankel
  • And 12 others
  • David M. Leistner
  • Markus M. Heimesaat
  • Stefan Bereswill
  • Geraldine Rauch
  • Ute Seeland
  • Oliver Soehnlein
  • Dominik N. Muller
  • Ralf Gold
  • Fredrik Backhed
  • Stanley L. Hazen
  • Aiden Haghikia
  • Ulf Landmesser

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.

Original languageEnglish
JournalEuropean Heart Journal
Issue number6
Pages (from-to)518-533
Number of pages16
Publication statusPublished - 2022

Bibliographical note

Publisher Copyright:
© 2021 Published on behalf of the European Society of Cardiology. All rights reserved.

    Research areas

  • Atherosclerosis, Gut microbiome, Propionic acid

ID: 298645101