Pulmonary Arterial Hypertension Affects the Rat Gut Microbiome

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.This study is supported by grants from Mineco (SAF2014-55399-R, SAF2014-55523-R, SAF2016-77222 and SAF2017-84494-C2-1R), Instituto de Salud Carlos III (PI15/01100), with funds from the European Union (Fondo Europeo de Desarrollo Regional FEDER). M.C., G.M-P. and S.E-R. are funded by Universidad Complutense, Fondo de Garantía Juvenil (Comunidad de Madrid) and Ciberes grant with funds from Fundación Contra la Hipertensión Pulmonar, a FPU grant from Ministerio de Educación, respectively. J.L.I.G is a CNIC IPP COFUND Fellow and has received funding from the People Programme (Marie Curie Actions) of the FP7/2007-2013 under REA grant agreement n° 600396. The CNIC is supported by MEIC-AEI and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505)