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

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 Döring, Christopher M Strauch, Ina Nemet, Valentina Tremaroli, Chinmay Dwibedi, Nicolle KränkelDavid M Leistner, Markus M Heimesaat, Stefan Bereswill, Geraldine Rauch, Ute Seeland, Oliver Soehnlein, Dominik N Müller, Ralf Gold, Fredrik Bäckhed, Stanley L Hazen, Aiden Haghikia, Ulf Landmesser

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Web of Science)

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.

Original languageEnglish
Pages (from-to)518–533
Number of pages16
JournalEuropean Heart Journal
Volume43
Issue number6
Early online date1 Oct 2021
DOIs
Publication statusPublished - 7 Feb 2022

Keywords

  • Gut microbiome
  • Propionic acid
  • Atherosclerosis
  • TRIMETHYLAMINE-N-OXIDE
  • CHAIN FATTY-ACIDS
  • CARDIOVASCULAR RISK
  • DIETARY FIBER
  • MICROBIOTA
  • PHOSPHATIDYLCHOLINE
  • MORTALITY
  • PROTEIN
  • CELLS

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