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

Haghikia, Arash; Zimmermann, Friederike; Schumann, Paul; Jasina, Andrzej; Roessler, Johann; Schmidt, David; Heinze, Philipp; Kaisler, Johannes; Nageswaran, Vanasa; Aigner, Annette; Ceglarek, Uta; Cineus, Roodline; Hegazy, Ahmed N; van der Vorst, Emiel P C; Döring, Yvonne; Strauch, Christopher M; Nemet, Ina; Tremaroli, Valentina; Dwibedi, Chinmay; Kränkel, Nicolle; ... (2022). Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism. European Heart Journal, 43(6), pp. 518-533. Oxford University Press 10.1093/eurheartj/ehab644

[img] Text
HaghikiaA_PropionateAttenuatesAtherosclerosisByImmdepRegOfIntestinalCholMetabolism_EurHeart_2021.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (2MB) | Request a copy

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Angiology

UniBE Contributor:

Döring, Yvonne

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0195-668X

Publisher:

Oxford University Press

Language:

English

Submitter:

Rebecca Scheidegger

Date Deposited:

03 Nov 2021 12:30

Last Modified:

12 Feb 2022 00:11

Publisher DOI:

10.1093/eurheartj/ehab644

PubMed ID:

34597388

Uncontrolled Keywords:

Atherosclerosis Gut microbiome Propionic acid

BORIS DOI:

10.48350/159929

URI:

https://boris.unibe.ch/id/eprint/159929

Actions (login required)

Edit item Edit item
Provide Feedback