Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism
| العنوان: | Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism |
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| المؤلفون: | Chinmay Kumar Dwibedi, Ahmed N. Hegazy, Johannes Kaisler, David M. Leistner, Annette Aigner, Aiden Haghikia, Stanley L. Hazen, Yvonne Döring, Valentina Tremaroli, Arash Haghikia, Nicolle Kränkel, David Schmidt, Markus M. Heimesaat, Paul Schumann, Christopher M. Strauch, Andrzej Jasina, Stefan Bereswill, Philipp Heinze, Ute Seeland, Dominik N. Müller, Geraldine Rauch, Ina Nemet, Fredrik Bäckhed, Johann Roessler, Uta Ceglarek, Oliver Soehnlein, Ralf Gold, Emiel P. C. van der Vorst, Ulf Landmesser, Friederike Zimmermann, Roodline Cineus, Vanasa Nageswaran |
| المساهمون: | Pathologie, RS: Carim - B07 The vulnerable plaque: makers and markers |
| المصدر: | European Heart Journal, 43(6). Oxford University Press |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Apolipoprotein E, medicine.medical_specialty, DIETARY FIBER, Metabolite, PROTEIN, Placebo, Lesion, Mice, chemistry.chemical_compound, Apolipoproteins E, Immune system, Internal medicine, PHOSPHATIDYLCHOLINE, medicine, Animals, Humans, Mice, Knockout, Gut microbiome, business.industry, Cholesterol, CARDIOVASCULAR RISK, MORTALITY, Interleukin, Cholesterol, LDL, Atherosclerosis, Propionic acid, MICROBIOTA, Mice, Inbred C57BL, Endocrinology, CHAIN FATTY-ACIDS, Intestinal Absorption, chemistry, Cardiovascular and Metabolic Diseases, CELLS, Intestinal cholesterol absorption, lipids (amino acids, peptides, and proteins), Propionates, medicine.symptom, Cardiology and Cardiovascular Medicine, business, 610 Medizin und Gesundheit, TRIMETHYLAMINE-N-OXIDE |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0195-668X 0359-0496 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ce082ae98013c4c937e3c28c224c445aTest https://doi.org/10.1093/eurheartj/ehab644Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ce082ae98013c4c937e3c28c224c445a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 0195668X 03590496 |
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