Pulmonary Arterial Hypertension Affects the Rat Gut Microbiome

María Callejo,Bianca Barreira,Daniel Morales-Cano,Juan Duarte,Gema Mondejar-Parreño,Francisco Perez-Vizcaino,José L Izquierdo-Garcia,Laura Moreno,Sergio Esquivel-Ruiz,Ángel Cogolludo

doi:10.1038/s41598-018-27682-w

Abstract

We have analysed whether pulmonary arterial hypertension (PAH) alters the rat faecal microbiota. Wistar rats were injected with the VEGF receptor antagonist SU5416 (20 mg/kg s.c.) and followed for 2 weeks kept in hypoxia (10% O2, PAH) or injected with vehicle and kept in normoxia (controls). Faecal samples were obtained and microbiome composition was determined by 16S rRNA gene sequencing and bioinformatic analysis. No effect of PAH on the global microbiome was found (α- or β-diversity). However, PAH-exposed rats showed gut dysbiosis as indicated by a taxonomy-based analysis. Specifically, PAH rats had a three-fold increase in Firmicutes-to-Bacteroidetes ratio. Within the Firmicutes phylum, there were no large changes in the relative abundance of the bacterial families in PAH. Among Bacteroidetes, all families were less abundant in PAH. A clear separation was observed between the control and PAH clusters based on short chain fatty acid producing bacterial genera. Moreover, acetate was reduced in the serum of PAH rats. In conclusion, faecal microbiota composition is altered as a result of PAH. This misbalanced bacterial ecosystem might in turn play a pathophysiological role in PAH by altering the immunologic, hormonal and metabolic homeostasis.

Highlights

Pulmonary arterial hypertension (PAH) is a progressive disease affecting the lung vasculature that is characterized by sustained vasoconstriction, vascular remodelling and in situ thrombosis[1]
We performed a tridimensional principal component analysis (PCA) of the bacterial community, which measures microorganism diversity between samples, i.e. β-diversity, at the level of the different taxa, in an unsupervised manner. This analysis showed no perfect clustering of the animals into the control and pulmonary arterial hypertension (PAH) groups; e.g. Fig. 2C shows the analysis at the species level
We present the first evidence of changes in the microbiota in a small sample of rats during the early phases of PAH

Summary

Introduction

Pulmonary arterial hypertension (PAH) is a progressive disease affecting the lung vasculature that is characterized by sustained vasoconstriction, vascular remodelling and in situ thrombosis[1]. Metabolic and respiratory diseases such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, type 2 diabetes mellitus and sleep apnoea have been linked to gut dysbiosis[12,13,14,15]. This is characterized by a microbial flora that is less diverse and less rich with an increased Firmicutes to Bacteroidetes ratio (F/B)[6,16]. We report that PAH is associated to gut dysbiosis, namely an increased F/B ratio This represents the first, but still preliminary, evidence suggesting a possible pathophysiological role of intestinal bacteria in the disease

Methods

Results

Conclusion