TY - JOUR

T1 - Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism

AU - Haghikia, Arash

AU - Zimmermann, Friederike

AU - Schumann, Paul

AU - Jasina, Andrzej

AU - Roessler, Johann

AU - Schmidt, David

AU - Heinze, Philipp

AU - Kaisler, Johannes

AU - Nageswaran, Vanasa

AU - Aigner, Annette

AU - Ceglarek, Uta

AU - Cineus, Roodline

AU - Hegazy, Ahmed N.

AU - Van Der Vorst, Emiel P.C.

AU - Doring, Yvonne

AU - Strauch, Christopher M.

AU - Nemet, Ina

AU - Tremaroli, Valentina

AU - Dwibedi, Chinmay

AU - Krankel, Nicolle

AU - Leistner, David M.

AU - Heimesaat, Markus M.

AU - Bereswill, Stefan

AU - Rauch, Geraldine

AU - Seeland, Ute

AU - Soehnlein, Oliver

AU - Muller, Dominik N.

AU - Gold, Ralf

AU - Backhed, Fredrik

AU - Hazen, Stanley L.

AU - Haghikia, Aiden

AU - Landmesser, Ulf

N1 - Publisher Copyright: © 2021 Published on behalf of the European Society of Cardiology. All rights reserved.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Gut microbiome

KW - Propionic acid

U2 - 10.1093/eurheartj/ehab644

DO - 10.1093/eurheartj/ehab644

M3 - Journal article

C2 - 34597388

AN - SCOPUS:85125083329

VL - 43

SP - 518

EP - 533

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

IS - 6

ER -