Abstract: TH-OR90
Targeted Antibiotic Modulation of the Gut Microbiome Ameliorates Hypertensive Organ Damage
Session Information
- Mechanisms of Hypertension and Cardiorenal Disease: From the Vasculature to the Gut
November 02, 2023 | Location: Room 108, Pennsylvania Convention Center
Abstract Time: 05:51 PM - 06:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Wimmer, Moritz Immanuel, Max Delbruck Centrum fur Molekulare Medizin Experimental and Clinical Research Center, Berlin, Berlin, Germany
- Vecera, Valentin, Max Delbruck Centrum fur Molekulare Medizin Experimental and Clinical Research Center, Berlin, Berlin, Germany
- Anandakumar, Harithaa, Max Delbruck Centrum fur Molekulare Medizin Experimental and Clinical Research Center, Berlin, Berlin, Germany
- Löber, Ulrike, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Buch, Berlin, Germany
- Forslund, Sofia Kirke, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Buch, Berlin, Germany
- Müller, Dominik N., Max Delbruck Centrum fur Molekulare Medizin Experimental and Clinical Research Center, Berlin, Berlin, Germany
- Bartolomaeus, Hendrik, Max Delbruck Centrum fur Molekulare Medizin Experimental and Clinical Research Center, Berlin, Berlin, Germany
- Wilck, Nicola, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
Background
Gut microbiota play an important role in the development of hypertension. To better understand the role of the gut microbiota in modulating hypertensive organ damage, we used narrow-spectrum antibiotics without enteral absorption to specifically deplete gram-negative or -positive bacteria in double transgenic rats (dTGR).
Methods
Four-week-old dTGR (transgenic for human renin and angiotensinogen) were treated with oral Vancomycin (Vanco), Polymyxin B (Poly) or Vehicle (Veh) for 3 weeks. Seven-week-old SD rats were included as healthy controls. Flow cytometry, echocardiography, telemetric blood pressure (BP) measurement, shotgun metagenomic sequencing, clinical chemistry, and gene expression analyses (qPCR & bulk RNAseq) were employed to analyze the microbiome, clinical and immune phenotype.
Results
Hypertensive kidney damage was ameliorated in Vanco treated dTGR, as assessed by renal Lcn2 expression, blood urea nitrogen and albuminuria. Vanco treated dTGR had significantly decreased cardiac hypertrophy. Poly treatment showed no effect. BP levels for both antibiotic treatments were not significantly different from Veh, despite a significantly improved endothelium-dependent and –independent vasorelaxation in isolated mesenteric arteries in both treated groups. Surprisingly, Vanco treatment led to a massive increase of gram-positive Lactobacilli. As the microbiome and immune system are closely connected, we performed in-depth flow cytometry of immune cells isolated from the heart, kidney, blood, spleen, and intestine. We observed a broad shift to pro-inflammatory immune cell subsets in dTGR. Vanco treatment could partially rescue the kidney inflammation as observed by a reduction in Th17 cells, classical dendritic cells and tissue infiltrating monocytes. Poly treatment did not alter the inflammatory signature.
Conclusion
Modulation of the intestinal microbiome by narrow-spectrum antibiotics affects hypertensive organ damage. Depletion of gram-positive intestinal bacteria by oral Vanco ameliorates organ damage independent of BP. Our data underscores the importance of the gut microbiome in modulating hypertensive organ damage and helps to identify potential therapeutic strategies in the microbiome (e.g. Lactobacilli).
Funding
- Government Support – Non-U.S.