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

Item Type:Article
Title:Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism
Creators Name:Haghikia, A. and Zimmermann, F. and Schumann, P. and Jasina, A. and Roessler, J. and Schmidt, D. and Heinze, P. and Kaisler, J. and Nageswaran, V. and Aigner, A. and Ceglarek, U. and Cineus, R. and Hegazy, A.N. and van der Vorst, E.P.C. and Döring, Y. and Strauch, C.M. and Nemet, I. and Tremaroli, V. and Dwibedi, C. and Kränkel, N. and Leistner, D.M. and Heimesaat, M.M. and Bereswill, S. and Rauch, G. and Seeland, U. and Soehnlein, O. and Müller, D.N. and Gold, R. and Bäckhed, F. and Hazen, S.L. and Haghikia, A. and Landmesser, U.
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:Gut Microbiome, Propionic Acid, Atherosclerosis, Low-Density Lipoproteins, LDL Cholesterol Lipoproteins, Signal Transduction, Cholesterol, Homeostasis, Apolipoprotein E, Interleukin-10, Intestines, Membrane Transport Proteins, Propionates, Propionic Acid, Regulatory T-Lymphocytes, Cholesterol Metabolism, Cholesterol Absorption, Metabolites, Microbiome, NPC1L1 Gene, Diet, High-Fat, Animals, Mice
Source:European Heart Journal
ISSN:0195-668X
Publisher:Oxford University Press
Page Range:ehab644
Date:1 October 2021
Official Publication:https://doi.org/10.1093/eurheartj/ehab644
PubMed:View item in PubMed

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