Introduction: Gut microbiota play an important role in the development of hypertension. While overuse of broad-spectrum antibiotics leads to dysbiosis, targeted use of narrow-spectrum antibiotics could provide important insights into host-microbiome interactions. Targeted antibiotic treatment could impact the disease process by eradicating potentially harmful bacteria or positively influencing protective bacteria and their metabolites. To better understand the role of the gut microbiota in hypertensive double transgenic rats (dTGR), we used narrow-spectrum antibiotics without enteral absorption to specifically deplete gram-negative or gram-positive bacteria.

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. Untreated seven-week-old SD rats were included as healthy controls. Flow cytometry, conventional and strain echocardiography, radiotelemetric blood pressure measurement, clinical chemistry and gene expression analyses were employed to analyze the clinical and immune phenotype.

Results: Vanco treatment led to an increase in cecum weight, comparable to ceca observed in germ-free animals. Interestingly, Poly treated animals did not show any gross morphological changes in the intestine. Vanco treated dTGR had significantly lower normalized heart weights (heart weight-to-tibia length), indicating decreased cardiac hypertrophy. Longitudinal conventional echocardiography analysis was able to demonstrate that the anti-hypertrophic effect occurred during the treatment period. Intriguingly, blood pressures for both antibiotic treatments were not significantly different from Veh, despite a significantly improved endothelium-dependent and –independent vasorelaxation of mesenteric arteries in both treated groups. Hypertensive kidney damage was ameliorated in Vanco treated dTGR, as assessed by albuminuria measurements and renal Lcn2 expression. Gram-negative depletion by Poly did not affect the renal or cardiac phenotype. As the microbiome and immune system are closely connected, we performed in-depth flow cytometry of immune cells isolated from the heart, the kidney, the blood, the spleen and the intestine. Interestingly, first preliminary immune analyses revealed an organ-specific immune cell signature with broad shifts to pro-inflammatory immune cell subsets such as macrophages and effector T cell subsets in dTGR without prominent antibiotic treatment effects.

Conclusion: Selective 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 blood pressure. Using metagenomic sequencing, we aim to identify potential mediators of these effects. Our data underscores the importance of the gut microbiome in modulating hypertensive organ damage.