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

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.

• Authors: 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 Kränkel, David 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
• Journal: European heart journal (Eur Heart J) Vol. 43 Issue 6 Pg. 518-533 (02 10 2022) ISSN: 1522-9645 [Electronic] England
• PMID: 34597388 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected].

Chemical References

• Apolipoproteins E
• Cholesterol, LDL
• Propionates
• Cholesterol

Topics

• Animals
• Apolipoproteins E (metabolism)
• Atherosclerosis (etiology)
• Cholesterol (metabolism)
• Cholesterol, LDL (metabolism)
• Humans
• Intestinal Absorption
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Propionates (pharmacology, therapeutic use)