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Lactobacillus fermentum Improves Tacrolimus‐Induced Hypertension by Restoring Vascular Redox State and Improving eNOS Coupling

  • 2018-06-28
  • Molecular Nutrition & Food Research 62(14)
    • M. Toral
    • M. Romero
    • A. Rodríguez‐Nogales
    • R. Jiménez
    • Iñaki Robles‐Vera
    • F. Algieri
    • N. Chueca-Porcuna
    • M. Sánchez
    • Néstor de la Visitación
    • M. Olivares
    • Federico García
    • F. Pérez-Vizcaino
    • J. Gálvez
    • J. Duarte

Abstract

Scope: The aim is to analyze whether the probiotic Lactobacillus fermentum CECT5716 (LC40) can prevent endothelial dysfunction and hypertension induced by tacrolimus in mice.

Methods and results: Tacrolimus increases systolic blood pressure (SBP) and impairs endothelium-dependent relaxation to acetylcholine and these effects are partially prevented by LC40. Endothelial dysfunction induced by tacrolimus is related to both increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) and uncoupled endothelial nitric oxide synthase (eNOS)-driven superoxide production and Rho-kinase-mediated eNOS inhibition. LC40 treatment prevents all the aortic changes induced by tacrolimus. LC40 restores the imbalance between T-helper 17 (Th17)/regulatory T (Treg) cells induced by tacrolimus in mesenteric lymph nodes and the spleen. Tacrolimus-induced gut dysbiosis, that is, it decreases microbial diversity, increases the Firmicutes/Bacteroidetes (F/B) ratio and decreases acetate- and butyrate-producing bacteria, and these effects are prevented by LC40. Fecal microbiota transplantation (FMT) from LC40-treated mice to control mice prevents the increase in SBP and the impaired relaxation to acetylcholine induced by tacrolimus.

Conclusion: LC40 treatment prevents hypertension and endothelial dysfunction induced by tacrolimus by inhibiting gut dysbiosis. These effects are associated with a reduction in vascular oxidative stress, mainly through NOX2 downregulation and prevention of eNOS uncoupling, and inflammation possibly because of decreased Th17 and increased Treg cells polarization in mesenteric lymph nodes.

Keywords: T cells; endothelial dysfunction; gut dysbiosis; probiotics; tacrolimus.

Research Insights

SupplementHealth OutcomeEffect TypeEffect Size
Lactobacillus fermentum CECT5716Improved Gut Microbiome CompositionBeneficial
Moderate
Lactobacillus fermentum CECT5716Improved Microbial DiversityBeneficial
Moderate
Lactobacillus fermentum CECT5716Improved Vascular Endothelial FunctionBeneficial
Moderate
Lactobacillus fermentum CECT5716Reduced HypertensionBeneficial
Moderate
Lactobacillus fermentum CECT5716Reduced InflammationBeneficial
Moderate
Lactobacillus fermentum CECT5716Reduced Oxidative StressBeneficial
Moderate
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