Pulmonary Arterial Hypertension Affects the Rat Gut Microbiome

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.

Impact of Nutrition on Pulmonary Arterial Hypertension

“…In a rat model of PAH induced by a single dose of Sugen5416 plus chronic hypoxia for two weeks, we found two main hallmarks of gut dysbiosis: a three-fold increase in F/B ratio, driven by a decrease in all Bacteroidetes families in PAH animals (2-10-fold decrease) and no changes in Firmicutes abundance. Furthermore, feces from PAH rats present a decreased in acetate-producing bacteria, accompanied by a reduced serum acetate, without changes in butyrate and lactate producing bacteria [130]. In contrast, we did not find global differences in microbial diversity and richness, as happened in other diseases [124].…”

“…However, it could be speculated that part of the effects of the dietary factors mentioned above in PAH might be due to changes in the microbiota. We demonstrated for the first time that there are several changes in the gut microbiota in PAH [130]. In a rat model of PAH induced by a single dose of Sugen5416 plus chronic hypoxia for two weeks, we found two main hallmarks of gut dysbiosis: a three-fold increase in F/B ratio, driven by a decrease in all Bacteroidetes families in PAH animals (2-10-fold decrease) and no changes in Firmicutes abundance.…”

“…Gut dysbiosis is typically characterized by a lower diversity and richness of the microbial communities, an increase in Firmicutes to Bacteroidetes ratio (F/B), and altered short chain fatty acids (SCFA) producing bacteria, with an increase in lactate-producing bacteria and a decrease in acetateand butyrate-producing bacteria [123,124]. In recent years, a growing body of evidence points to a relationship between gut dysbiosis and many diseases, including essential hypertension [124,125], obesity [126,127], inflammation [128] neurologic disorders [129], and pulmonary hypertension [130].…”

Gut microbiota modification suppresses the development of pulmonary arterial hypertension in an SU5416/hypoxia rat model

“…Several other studies have described the relationship between cardiovascular diseases and dysbiosis. 20,21,23,28 For example, Yang et al have demonstrated that F/B ratios are higher in two different animal models of systemic hypertension than in control rats. 28 They have also shown that patients with systemic hypertension have distinct gut microbiota compositions from those of healthy control subjects.…”

Resveratrol and the Interaction between Gut Microbiota and Arterial Remodelling

“…IL-12 is shown to be associated with arterial stiffness in healthy individuals [117]. Interestingly, induced pulmonary arterial hypertension in rats also leads to a greater Firmicutes to Bacteroidetes ratio in the gut microbiota [118]. The gut dysbiosis might play a pathophysiological role in pulmonary arterial hypertension by altering the host immunologic, hormonal and metabolic homeostasis.…”