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

Arash Haghikia; Friederike Zimmermann; Paul Schumann; Andrzej Jasina; Johann Roessler; David Schmidt; Philipp Heinze; Johannes Kaisler; Vanasa Nageswaran; Annette Aigner; Uta Ceglarek; Roodline Cineus; Ahmed N Hegazy; Emiel P C van der Vorst; Yvonne Döring; Christopher M Strauch; Ina Nemet; Valentina Tremaroli; Chinmay Dwibedi; Nicolle Kränkel; David M Leistner; Markus M Heimesaat; Stefan Bereswill; Geraldine Rauch; Ute Seeland; Oliver Soehnlein; Dominik N Müller; Ralf Gold; Fredrik Bäckhed; Stanley L Hazen; Aiden Haghikia; Ulf Landmesser

doi:10.1093/eurheartj/ehab644

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

Arash Haghikia^*, Friederike Zimmermann, Paul Schumann, Andrzej Jasina, Johann Roessler, David Schmidt, Philipp Heinze, Johannes Kaisler, Vanasa Nageswaran, Annette Aigner, Uta Ceglarek, Roodline Cineus, Ahmed N Hegazy, Emiel P C van der Vorst, Yvonne Döring, Christopher M Strauch, Ina Nemet, Valentina Tremaroli, Chinmay Dwibedi, Nicolle KränkelDavid M Leistner, Markus M Heimesaat, Stefan Bereswill, Geraldine Rauch, Ute Seeland, Oliver Soehnlein, Dominik N Müller, Ralf Gold, Fredrik Bäckhed, Stanley L Hazen, Aiden Haghikia, Ulf Landmesser

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	518–533
Number of pages	16
Journal	European Heart Journal
Volume	43
Issue number	6
Early online date	1 Oct 2021
DOIs	https://doi.org/10.1093/eurheartj/ehab644
Publication status	Published - 7 Feb 2022

Keywords

Gut microbiome
Propionic acid
Atherosclerosis
TRIMETHYLAMINE-N-OXIDE
CHAIN FATTY-ACIDS
CARDIOVASCULAR RISK
DIETARY FIBER
MICROBIOTA
PHOSPHATIDYLCHOLINE
MORTALITY
PROTEIN
CELLS

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10.1093/eurheartj/ehab644

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Haghikia, A., Zimmermann, F., Schumann, P., Jasina, A., Roessler, J., Schmidt, D., Heinze, P., Kaisler, J., Nageswaran, V., Aigner, A., Ceglarek, U., Cineus, R., Hegazy, A. N., van der Vorst, E. P. C., Döring, Y., Strauch, C. M., Nemet, I., Tremaroli, V., Dwibedi, C., ... Landmesser, U. (2022). Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism. European Heart Journal, 43(6), 518–533. https://doi.org/10.1093/eurheartj/ehab644

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title = "Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism",

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, TRIMETHYLAMINE-N-OXIDE, CHAIN FATTY-ACIDS, CARDIOVASCULAR RISK, DIETARY FIBER, MICROBIOTA, PHOSPHATIDYLCHOLINE, MORTALITY, PROTEIN, CELLS",

author = "Arash Haghikia and Friederike Zimmermann and Paul Schumann and Andrzej Jasina and Johann Roessler and David Schmidt and Philipp Heinze and Johannes Kaisler and Vanasa Nageswaran and Annette Aigner and Uta Ceglarek and Roodline Cineus and Hegazy, {Ahmed N} and {van der Vorst}, {Emiel P C} and Yvonne D{\"o}ring and Strauch, {Christopher M} and Ina Nemet and Valentina Tremaroli and Chinmay Dwibedi and Nicolle Kr{\"a}nkel and Leistner, {David M} and Heimesaat, {Markus M} and Stefan Bereswill and Geraldine Rauch and Ute Seeland and Oliver Soehnlein and M{\"u}ller, {Dominik N} and Ralf Gold and Fredrik B{\"a}ckhed and Hazen, {Stanley L} and Aiden Haghikia and Ulf Landmesser",

year = "2022",

month = feb,

day = "7",

doi = "10.1093/eurheartj/ehab644",

language = "English",

volume = "43",

pages = "518–533",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "6",

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Haghikia, A, Zimmermann, F, Schumann, P, Jasina, A, Roessler, J, Schmidt, D, Heinze, P, Kaisler, J, Nageswaran, V, Aigner, A, Ceglarek, U, Cineus, R, Hegazy, AN, van der Vorst, EPC, Döring, Y, Strauch, CM, Nemet, I, Tremaroli, V, Dwibedi, C, Kränkel, N, Leistner, DM, Heimesaat, MM, Bereswill, S, Rauch, G, Seeland, U, Soehnlein, O, Müller, DN, Gold, R, Bäckhed, F, Hazen, SL, Haghikia, A & Landmesser, U 2022, 'Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism', European Heart Journal, vol. 43, no. 6, pp. 518–533. https://doi.org/10.1093/eurheartj/ehab644

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 - Döring, Yvonne

AU - Strauch, Christopher M

AU - Nemet, Ina

AU - Tremaroli, Valentina

AU - Dwibedi, Chinmay

AU - Kränkel, Nicolle

AU - Leistner, David M

AU - Heimesaat, Markus M

AU - Bereswill, Stefan

AU - Rauch, Geraldine

AU - Seeland, Ute

AU - Soehnlein, Oliver

AU - Müller, Dominik N

AU - Gold, Ralf

AU - Bäckhed, Fredrik

AU - Hazen, Stanley L

AU - Haghikia, Aiden

AU - Landmesser, Ulf

PY - 2022/2/7

Y1 - 2022/2/7

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 - Gut microbiome

KW - Propionic acid

KW - Atherosclerosis

KW - TRIMETHYLAMINE-N-OXIDE

KW - CHAIN FATTY-ACIDS

KW - CARDIOVASCULAR RISK

KW - DIETARY FIBER

KW - MICROBIOTA

KW - PHOSPHATIDYLCHOLINE

KW - MORTALITY

KW - PROTEIN

KW - CELLS

U2 - 10.1093/eurheartj/ehab644

DO - 10.1093/eurheartj/ehab644

M3 - Article

C2 - 34597388

SN - 0195-668X

VL - 43

SP - 518

EP - 533

JO - European Heart Journal

JF - European Heart Journal

IS - 6

ER -

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

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Keywords

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