Pulmonary arterial hypertension-associated changes in gut pathology and microbiota

Abstract

Emerging evidence implicates an interplay among multiple organs such as brain, vasculature, gut and lung in the development of established pulmonary arterial hypertension (PAH). This has led us to propose that activated microglia mediated-enhanced sympathetic activation contributes to PAH pathophysiology. Since enhanced sympathetic activity is observed in human PAH and the gut is highly innervated by sympathetic nerves that regulate its physiological functions, we hypothesized that PAH would be associated with gut pathophysiology.A monocrotaline rat model of PAH was utilized to investigate the link between gut pathology and PAH. Haemodynamics, histology, immunocytochemistry and 16S RNA gene sequencing were used to assess cardiopulmonary functions, gut pathology and gut microbial communities respectively.Monocrotaline treatment caused increased right ventricular systolic pressure, haemodynamics and pathological changes associated with PAH. PAH animals also showed profound gut pathology that included increased intestinal permeability, increased muscularis layer, decreased villi length and goblet cells. These changes in gut pathology were associated with alterations in microbial communities, some unique to PAH animals. Furthermore, enhanced gut–neural communication involving the paraventricular nucleus of the hypothalamus and increased sympathetic drive were observed.In conclusion, our data show the presence of gut pathology and distinct changes in gut microbiota and increased sympathetic activity in PAH. They suggest that dysfunctional gut–brain crosstalk could be critical in PAH and considered a future therapeutic target for PAH.

MSCs Therapy Reverse the Gut Microbiota in Hypoxia-Induced Pulmonary Hypertension Mice

“…An imbalanced F/B ratio is associated with various disease processes ( Liu et al, 2016 ). MCT-induced PH rats showed an increased F/B ratio, suggesting that the F/B ratio can serve as an indicator of PH ( Sharma et al, 2020 ). Our results also showed that the ratio of Firmicutes/Bacteroidetes was increased in hypoxia-induced PH mice and that MSC treatment reversed this imbalance, which indicated the correlation between MSC treatment and the gut microbiota ( Figure 3B ).…”

“…The intestinal microbial community is changed and loses its balance in iPAH patients ( Kim et al, 2020 ). Monocrotaline (MCT)-induced rat PH showed a profound gut pathology, which was associated with alterations in microbial communities, some of which were unique to PH animals ( Sharma et al, 2020 ). Alternative gut microbes were also observed in hypoxia/Sugen 5416-induced PH rats ( Callejo et al, 2018 ).…”

Preventive effects of nitrate-rich beetroot juice supplementation on monocrotaline-induced pulmonary hypertension in rats

“…Although nitrite and NO, reduction products of nitrate, have pulmonary arterial dilating, anti-proliferative, and anti-inflammatory effects [ 31 , 45 , 46 ], it remains unclear whether BJ-derived nitrate improves PH symptom through one or combinations of these effects. Interestingly, it has been demonstrated that PH is affected by the intestinal environment [ 47 , 48 ]. BJ ingestion and dietary nitrate have been demonstrated to modulate the gut microflora and its metabolic activity [ 49 , 50 ].…”

Angiotensin-converting enzyme 2 and COVID-19 in cardiorenal diseases

“…The transporter activity of B0AT1 in the gut is dramatically augmented by ACE2 co-expression [ 1 , 31 ]. ACE2 in the gut also functions as a key regulator of innate immunity, gut microbial ecology and expression of antimicrobial peptides [ 29 , 32 , 33 ]. High expression of ACE2 throughout the luminal surface of the GI tract, particularly in enterocytes, suggests that the gut could serve as a secondary site for SARS-CoV-2 infection.…”