Clin Res Cardiol (2021) DOI DOI https://doi.org/10.1007/s00392-021-01843-w

Atheroprotective effects of gut microbiota related metabolite propionate by immune-dependent regulation of intestinal cholesterol metabolism

F. L. Zimmermann1, P. Schumann1, A. Jasina1, J. Rößler1, D. Schmidt1, V. Nageswaran1, U. Ceglarek2, R. Cineus3, A. Hegazy3, E. Van der Vorst4, Y. Döring4, I. Nemet5, V. Tremaroli6, N. Kränkel1, D. Leistner1, M. Heimesaat7, S. Bereswill7, O. Söhnlein4, D. N. Müller8, F. Bäckhed6, S. L. Hazen5, A. Haghikia9, U. Landmesser1, A. Haghikia1

1CC 11: Med. Klinik für Kardiologie, Charité - Universitätsmedizin Berlin, Berlin; 2Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik, Universitätsklinikum Leipzig, Leipzig; 3Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité - Universitätsmedizin Berlin, Berlin; 4Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, LMU Klinikum der Universität München, München; 5Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, US; 6Department of Molecular and Clinical Medicine, University of Gothenburg, Göteborg, SE; 7Institut für Mikrobiologie und Infektionsmedizin, Charité Universitätsmedizin Berlin, Berlin; 8Max-Delbrück-Centrum für Molekulare Medizin, Berlin; 9Forschungszentrum Neuroimmunologie ZKF - Zentrum für klinische Forschung 1, Ruhr-Universität Bochum, Bochum;

Background and Aims Increased low-density lipoprotein (LDL) cholesterol is a causal factor in atherosclerotic cardiovascular disease. Accumulating evidence suggest a crucial role of the gut microbiome in cardiovascular disease development. Here, we examined the effect of the gut microbiota-derived metabolite propionic acid (PA), a short-chain fatty acid, on cholesterol metabolism and investigated its interaction with the intestinal immune system. Methods To investigate the effect of PA on cholesterol metabolism and atherosclerosis, apolipoprotein E -/- (Apoe-/-) mice were fed either a standard chow diet or a high-fat diet (HFD) for a total of 6 weeks. After two weeks mice received either PA (150 mM) or control vehicle administered daily via oral gavage. Lipoprotein fractions and atherosclerotic lesions were investigated by fast-performance liquid chromatography and histology. Modulation of immune mechanisms by PA was examined using flow cytometry and cytometric bead assay. Anti-interleukin (IL)-10 receptor monoclonal antibody was used for in-vivo blockage of IL-10 signaling. PA-related mechanisms of intestinal lipid control were further studied using a mouse intestinal epithelial organoid culture system. Results Treatment with PA reduced blood total cholesterol (TC) and LDL cholesterol levels (TC: HFD vs. HFD+PA: 451 ± 119 mg/dl vs. 309 ± 70 mg/dl, n=10-13, p<0.001) (LDL: HFD vs. HFD+PA: 184 ± 53.5 mg/dl vs. 113 ± 37.2 mg/dl, n=10-13, p<0.001), intestinal cholesterol absorption and aortic atherosclerotic lesion area in Apoe-/- mice fed a HFD (HFD vs. HFD+PA: 12.2 ± 2.5 % of aortic root area vs. 6.6 ± 2.1% of aortic root area, n=8-11, p<0.001). Further, PA increased regulatory T cell numbers and IL-10 levels in the intestinal microenvironment. In intestinal organoids, treatment with recombinant mouse IL-10 induced dose-dependent downregulation of Niemann-Pick C1-like 1, a major intestinal cholesterol transporter. Blockage of IL-10 receptor signaling attenuated PA-related reduction in total (HFD+PA vs. HFD+PA +anti-IL-10R: 309 ± 70 mg/dl vs. 410 ± 50.1 mg/dl, n= 8-13, p=0.002) and LDL cholesterol (HFD+PA vs. HFD+PA +anti-IL-10R: 113 ± 37.2 mg/dl vs. 182 ± 23.3 mg/dl, n= 8-13, p<0.001) and augmented atherosclerotic lesion severity in HFD-fed Apoe-/- mice (HFD+PA vs. HFD+PA +anti-IL-10R: 6.6 ± 2.1% of aortic root area vs. 16.4 ± 5.5% of aortic root area, n=7-11, p<0.001). Conclusion Oral supplementation of gut microbiota-derived metabolite PA reduced LDL levels and aortic atherosclerotic lesion size in HFD fed hypercholesterolemic mice. Our findings reveal a novel regulatory mechanism that links PA with intestinal cholesterol homeostasis and highlight the gut immune system as potential therapeutic target to control dyslipidemia and prevent atherosclerosis.

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