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Propionate attenuat...
Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism
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Haghikia, A. (author)
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Zimmermann, F. (author)
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Schumann, P. (author)
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Jasina, A. (author)
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Roessler, J. (author)
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Schmidt, D. (author)
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Heinze, P. (author)
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Kaisler, J. (author)
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Nageswaran, V. (author)
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Aigner, A. (author)
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Ceglarek, U. (author)
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Cineus, R. (author)
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Hegazy, A. N. (author)
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van der Vorst, E. P. C. (author)
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Doring, Y. (author)
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Strauch, C. M. (author)
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Nemet, I. (author)
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- Tremaroli, Valentina, 1978 (author)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Dwibedi, Chinmay, 1987 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberglaboratoriet,Institute of Medicine, Department of Molecular and Clinical Medicine,Wallenberg Laboratory
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Krankel, N. (author)
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Leistner, D. M. (author)
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Heimesaat, M. M. (author)
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Bereswill, S. (author)
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Rauch, G. (author)
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Seeland, U. (author)
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- Soehnlein, O. (author)
- Karolinska Institutet
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Muller, D. N. (author)
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Gold, R. (author)
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- Bäckhed, Fredrik, 1973 (author)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine
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Hazen, S. L. (author)
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Haghikia, A. (author)
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Landmesser, U. (author)
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(creator_code:org_t)
- 2021-10-01
- 2022
- English.
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 43:6, s. 518-533
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https://doi.org/10.1...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Keyword
- Gut microbiome
- Propionic acid
- Atherosclerosis
- trimethylamine-n-oxide
- chain fatty-acids
- cardiovascular risk
- dietary
- fiber
- microbiota
- phosphatidylcholine
- mortality
- protein
- cells
- Cardiovascular System & Cardiology
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Haghikia, A.
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Zimmermann, F.
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Schumann, P.
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Jasina, A.
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Roessler, J.
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Schmidt, D.
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show more...
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Heinze, P.
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Kaisler, J.
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Nageswaran, V.
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Aigner, A.
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Ceglarek, U.
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Cineus, R.
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Hegazy, A. N.
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van der Vorst, E ...
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Doring, Y.
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Strauch, C. M.
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Nemet, I.
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Tremaroli, Valen ...
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Dwibedi, Chinmay ...
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Krankel, N.
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Leistner, D. M.
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Heimesaat, M. M.
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Bereswill, S.
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Rauch, G.
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Seeland, U.
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Soehnlein, O.
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Muller, D. N.
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Gold, R.
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Bäckhed, Fredrik ...
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Hazen, S. L.
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Landmesser, U.
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cardiac and Card ...
- Articles in the publication
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European Heart J ...
- By the university
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University of Gothenburg
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Karolinska Institutet