# Pulmonary hypertension: Genetic, Microbiome and Environmental Determinants

> **NIH NIH P01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $444,087

## Abstract

Pulmonary hypertension (PH) encompasses a diverse group of diseases marked by vascular injury and
increased pulmonary artery pressures. Many sub-phenotypes of PH share a common link to the metabolic
syndrome (systemic hypertension, obesity, glucose intolerance). For example, obesity, hyperlipidemia, and
systemic hypertension are common risk factors for Group I pulmonary arterial hypertension (PAH) as well as
for a subset of Group II (PH-heart failure with preserved ejection fraction, HF-pEF). The microbiome is
important in development of obesity and the metabolic syndrome and is altered by high fat diet (HFD),
suggesting that it may also play a role in PH. In Phase I of the tPPG, we tested 36 mouse strains and
discovered that a 60% HFD led to PH HF-pEF, but only in certain strains. In our preliminary data, mice that
developed PH on HFD had an increased ratio of gut Firmicutes to Bacteroidetes, similar to changes in obese
humans with metabolic syndrome. In contrast, mice that did not develop PH on a high fat diet had a stable ratio.
When commensal bacteria were decreased by treating mice with broad-spectrum antibiotics during HFD, the
Firmicutes to Bacteroidetes ratio increased further, and manifestations of PH worsened. Despite a growing
literature implicating the microbiome in a wide range of diseases, these studies are the first to support a critical
protective role of bacteria in PH. Oral bacteria are also crucial, given that they are required for enterosalivary
conversion of dietary nitrate to nitrite. Lack of these bacteria could result in decreased nitrite availability and
resultant loss of downstream reactions in the host such as generation of nitric oxide and lipid signaling
mediators such as electrophilic nitro-fatty acid (NO2-FA), leading to vasoconstriction and vascular proliferation.
Abolishing oral microbes leads to systemic hypertension, but effects on the pulmonary vasculature are
unknown. Thus, the goal of Project 3 is to define the relationships between PH, high fat diet, the oral and gut
microbiome, and the metabolism of nitrogen oxide signaling mediators that may regulate the development and
severity of PH. Our overall hypothesis is that the commensal microbiome is beneficial in PH because of its
function in bioactivation of the nitrate-nitrite-NO-NO2-FA pathway. This hypothesis will be tested in murine
models and in PH patients with the following specific aims: Aim 1. Bench To test the hypothesis that bacteria
are essential for nitrate (NO3-) reduction and NOx metabolism in animal models of PH. Aim 2. Bedside To
determine epidemiological relationships of oral and gut microbial structure and function to PH in humans and
test the specific hypothesis that the oral microbiome is critical for protective nitrate bioactivation and improves
pulmonary hemodynamics. Successful completion will profoundly shift the current paradigm of PH and yield
novel avenues for therapy. This innovative proposal will leverage resources established duri...

## Key facts

- **NIH application ID:** 9939668
- **Project number:** 5P01HL103455-10
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Alison Morris
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $444,087
- **Award type:** 5
- **Project period:** 2011-06-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939668

## Citation

> US National Institutes of Health, RePORTER application 9939668, Pulmonary hypertension: Genetic, Microbiome and Environmental Determinants (5P01HL103455-10). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9939668. Licensed CC0.

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