Gut Pathology and Its Rescue by ACE2 (Angiotensin-Converting Enzyme 2) in Hypoxia-Induced Pulmonary Hypertension

Abstract

Therapeutic advances for pulmonary hypertension (PH) have been incremental because of the focus on the pulmonary vasculature in PH pathology. Here, we evaluate the concept that PH is, rather, a systemic disorder involving interplay among multiorgan systems, including brain, gut, and lungs. Therefore, the objective of this study was to evaluate the hypothesis that PH is associated with a dysfunctional brain-gut-lung axis and that global overexpression of ACE2 (angiotensin-converting enzyme 2) rebalances this axis and protects against PH. ACE2 knockin and wild-type (WT; C57BL/6) mice were subjected to chronic hypoxia (10% FIO2) or room air for 4 weeks. Cardiopulmonary hemodynamics, histology, immunohistochemistry, and fecal 16S rRNA microbial gene analyses were evaluated. Hypoxia significantly increased right ventricular systolic pressure, sympathetic activity as well as the number and activation of microglia in the paraventricular nucleus of the hypothalamus in WT mice. This was associated with a significant increase in muscularis layer thickening and decreases in both villi length and goblet cells and altered gut microbiota. Global overexpression of ACE2 prevented changes in hypoxia-induced pulmonary and gut pathophysiology and established distinct microbial communities from WT hypoxia mice. Furthermore, WT mice subjected to fecal matter transfer from ACE2 knockin mice were resistant to hypoxia-induced PH compared with their controls receiving WT fecal matter transfer. These observations demonstrate that ACE2 ameliorates these hypoxia-induced pathologies and attenuates PH. The data implicate dysfunctional brain-gut-lung communication in PH and provide novel avenues for therapeutic interventions.

Pulmonary arterial hypertension-associated changes in gut pathology and microbiota

“…2) We demonstrated the presence of gut dysbiosis and leakiness in patients with PAH [37]. 3) Hypoxia-induced PAH in mice is associated with neuroinflammation, increased sympathetic activity, gut microbial dysbiosis and gut pathology [47]. Therefore, this concept awaits further validation by utilisation of other animal models of PAH.…”

Antihypertensive effects of exercise involve reshaping of gut microbiota and improvement of gut-brain axis in spontaneously hypertensive rat

“…The QIIME 1.9.1 software was employed to process and analyze the paired-sequence data as previously described. 7,29 Briefly, the quality of the reads was determined using chimera-picking and qualityfiltering. Open reference operational taxonomic units (OTU) were picked and taxonomic assignments using the SILVA database 16S rRNA database (Version 138) were performed to generate OTU table.…”

Would Repurposing Minocycline Alleviate Neurologic Manifestations of COVID-19?

“…Regardless of viral expression in brain, acute hypoxic ischemic damage was detected in brains of all 18 patients with SARS-CoV-2 infection (Solomon et al, 2020 ) and may indicate another route to induce neuroinflammation and increase inflammatory cytokines. This resembles the effects of hypoxia in animal models, which are microglia activation, neuroinflammation, autonomic imbalance and increased inflammatory cytokines leading, over time, to pulmonary hypertension (Savale et al, 2009 ; Oliveira et al, 2018 ; Sharma et al, 2020a ).…”