Gut Microbiota Has a Crucial Role in the Development of Hypertension and Vascular Dysfunction in Toll-like Receptor 7-Driven Lupus Autoimmunity.

Néstor De La Visitación,Cristina González-Correa,Iñaki Robles-Vera,Manuel Gómez-Guzmán,Juan Duarte,Rosario Jiménez,Natividad Martin-Morales,Manuel Sánchez,Nazaret Aguilera-Sánchez,Marta Toral,Javier Moleón,Miguel Romero,Francisco O’Valle

doi:10.3390/antiox10091426

Abstract

Our group has investigated the involvement of gut microbiota in hypertension in a murine model of systemic lupus erythematosus induced by Toll-like receptor (TLR)-7 activation. Female BALB/c mice were randomly assigned to four experimental groups: an untreated control (CTR), a group treated with the TLR7 agonist imiquimod (IMQ), IMQ-treated with vancomycin, and IMQ-treated with a cocktail of broad-spectrum antibiotics. We carried out faecal microbiota transplant (FMT) from donor CTR or IMQ mice to recipient IMQ or CTR animals, respectively. Vancomycin inhibited the increase in blood pressure; improved kidney injury, endothelial function, and oxidative stress; and reduced T helper (Th)17 infiltration in aortas from IMQ-treated mice. The rise in blood pressure and vascular complications present in IMQ mice were also observed in the CTR mice recipients of IMQ microbiota. Reduced relative populations of Sutterella and Anaerovibrio were associated with high blood pressure in our animals, which were increased after stool transplantation of healthy microbiota to IMQ mice. The reduced endothelium-dependent vasodilator responses to acetylcholine induced by IMQ microbiota were normalized after interleukin-17 neutralization. In conclusion, gut microbiota plays a role in the TLR7-driven increase in Th17 cell, endothelial dysfunction, vascular inflammation, and hypertension. The vascular changes induced by IMQ microbiota were initiated by Th17 infiltrating the vasculature.

Highlights

Taken account that IL-17a is a key factor contributing to endothelial dysfunction in this TLR7-driven lupus autoimmunity model [13], we examined the changes brought by the antibiotics on the observed Systemic lupus erythematosus (SLE)-linked endothelial dysfunction
We subsequently examined whether the enriched gut bacterial communities partake in Th17 polarization in mesenteric lymph nodes (MLNs) and high blood pressure (BP)-associated with Toll-like receptor (TLR)-7 activation
These experiments show that: (1) there are differences between gut microbiota from hypertensive IMQ-treated mice and their appropriate controls, (2) this gut microbiota triggers changes in BP regulation, as proved by reduced BP induced by vancomycin treatment and stool transplantation from control mice, and (3) this can be linked to the activation of pro-inflammatory Th17 lymphocytes

Summary

Introduction

Systemic lupus erythematosus (SLE) is among the most deleterious autoimmune inflammatory diseases, in which the synthesis of autoantibodies is promoted, forming immune complexes, that in turn deposit in target organs, causing damage to the tissues. SLE is related to an increased risk of renal and cardiovascular disease development [1], the most important cause of mortality in SLE patients [2]. It mainly affects young women of child-bearing age. This disease is linked to an elevated incidence of hypertension [3]. This disease is linked to an elevated incidence of hypertension [3]. 4.0/).

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