Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9 |
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Gut microbiota-dependent metabolite propionate mediates atheroprotective effects by immune-dependent modulation of intestinal cholesterol absorption | ||
J. Rößler1, F. L. Zimmermann1, P. Schumann1, A. Jasina1, D. Schmidt1, V. Nageswaran1, U. Ceglarek2, R. Cineus3, A. N. Hegazy3, E. Van der Vorst4, Y. Döring5, N. Kränkel1, D. Leistner1, M. M. Heimesaat6, S. Bereswill6, O. Söhnlein7, D. N. Müller8, 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; 3CBF: Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin; 4Institut für Molekulare Herz-Kreislaufforschung (IMCAR), Uniklinik RWTH Aachen, Aachen; 5Inselspital - Universitätsspital Bern, Bern, CH; 6Charité - Universitätsmedizin Berlin, Berlin; 7Kardiologie, LMU Klinikum der Universität München, München; 8Max-Delbrück-Centrum für Molekulare Medizin, Berlin; 9Universitätsklinik für Neurologie, Otto von Guericke - Universität Magdeburg, Magdeburg; | ||
Background and Aims Elevated low-density lipoprotein (LDL) cholesterol is a causal factor for atherosclerotic cardiovascular disease. Growing evidence suggests a crucial role for the gut microbiome in cholesterol metabolism and cardiovascular health. Here, we examined the influence of the gut microbiota-dependent metabolite proprionic acid (PA) on cholesterol metabolism and its interaction with the intestinal immune system.
Methods and Results Apolipoprotein E-/- (ApoE-/-) mice were fed either a standard chow diet (SCD, n=12) or a high fat diet (HFD, n=23) for 6 weeks. After two weeks mice were treated with either PA (150mM) or control vehicle via daily oral gavage. Assessment of lipoprotein fractions in plasma using fast-performance liquid chromatography revealed reduced total cholesterol (TC) (TC: HFD vs. HFD+PA: 451 ± 119mg/dl vs. 309 ± 70mg/dl, n=10-13, p<0.001) and LDL (LDL: HFD vs. HFD+PA: 184 ± 53.5mg/dl vs. 113 ± 37.2mg/dl, n=10-13, p<0.001) upon PA-treatment. Using qRT-PCR altered gene expression of cholesterol regulating genes (Srebp-2, Npc1l1) in PA-treated mice was observed. Histological staining of the aortic root displayed reduced atherosclerotic lesions upon PA-treatment (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). Furthermore, flow cytometry and cytometric bead assay indicated increased regulatory T-cell numbers and IL-10 levels within the intestinal microenvironment by PA-treatment. Subsequent in vivo blockade of IL-10 receptor signaling by intraperitoneal injection of anti-IL-10 receptor monoclonal antibody in ApoE-/- mice (n=8) reversed PA-mediated reduction of TC (HFD+PA vs. HFD+PA +anti-IL-10R: 309 ± 70mg/dl vs. 410 ± 50.1mg/dl, n= 8-13, p=0.002) and LDL (HFD+PA vs. HFD+PA + anti-IL-10R: 113 ± 37.2mg/dl vs. 182 ± 23.3mg/dl, n=8-13, p<0.001) in plasma and increased atherosclerotic lesion size in HFD fed 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). Additionally, incubation of intestinal epithelial organoids of murine origin with recombinant mouse IL-10 illustrated a dose-dependent downregulation of Npc1l1, a major intestinal cholesterol transporter.
Conclusion Oral administration of PA reduces LDL levels and atherosclerotic lesion size in hypercholesterolemic (ApoE-/-) mice. Our findings reveal a regulatory role of PA on intestinal cholesterol absorption via modulation of the intestinal immune system representing a novel concept to treat dyslipidemia and prevent atherosclerotic cardiovascular disease. |
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https://dgk.org/kongress_programme/ht2021/BS894.htm |