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| Item Type: | Article |
|---|---|
| Title: | Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism |
| Creators: |
Haghikia, A.  ORCID: https://orcid.org/0000-0002-5646-3237, Zimmermann, F. ORCID: https://orcid.org/0000-0002-4353-8527, Schumann, P. ORCID: https://orcid.org/0000-0001-7961-0749, Jasina, A., Roessler, J., Schmidt, D. ORCID: https://orcid.org/0000-0002-3779-6765, Heinze, P., Kaisler, J. ORCID: https://orcid.org/0000-0003-1753-700X, Nageswaran, V., Aigner, A. ORCID: https://orcid.org/0000-0003-4891-8921, Ceglarek, U. ORCID: https://orcid.org/0000-0002-4034-5535, Cineus, R. ORCID: https://orcid.org/0000-0003-4393-5757, Hegazy, A.N. ORCID: https://orcid.org/0000-0002-2946-8251, van der Vorst, E.P.C. ORCID: https://orcid.org/0000-0001-5771-6278, Döring, Y., Strauch, C.M. ORCID: https://orcid.org/0000-0002-4766-9604, Nemet, I. ORCID: https://orcid.org/0000-0002-0657-7121, Tremaroli, V., Dwibedi, C., Kränkel, N. ORCID: https://orcid.org/0000-0002-9363-1770, Leistner, D.M. ORCID: https://orcid.org/0000-0002-4351-420X, Heimesaat, M.M. ORCID: https://orcid.org/0000-0001-6399-651X, Bereswill, S., Rauch, G., Seeland, U., Soehnlein, O., Müller, D.N. ORCID: https://orcid.org/0000-0003-3650-5644, Gold, R., Bäckhed, F. ORCID: https://orcid.org/0000-0002-4871-8818, Hazen, S.L. ORCID: https://orcid.org/0000-0001-7124-6639, Haghikia, A. and Landmesser, U. ORCID: https://orcid.org/0000-0002-0214-3203
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| 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 |
| Volume: | 43 |
| Number: | 6 |
| Page Range: | ehab644 |
| Date: | 7 February 2022 |
| Additional Information: | Published on behalf of the European Society of Cardiology. All rights reserved. Copyright © The Author(s) 2021. |
| Official Publication: | https://doi.org/10.1093/eurheartj/ehab644 |
| PubMed: | View item in PubMed |
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