Lung Microbiome-Estrogen Interaction May Explain Why Women Are More Susceptible to Genetic Pulmonary Hypertension
A new preprint study proposes that a microbiome-estrogen-immune signaling pathway may help explain why women with BMPR2 mutations are more likely to develop pulmonary arterial hypertension than men. Researchers used genetically modified mice to show that females develop a distinct lung microbiome profile that, combined with an estrogen metabolite, drives macrophages into a hyperactivated state that secretes a potent vasoconstrictor. The findings could open new therapeutic avenues targeting the microbiome or immune response in a disease with poorly understood sex disparities.
Pulmonary arterial hypertension (PAH) linked to BMPR2 mutations disproportionately affects females, yet the biological reasons for this sex bias have remained unclear. Researchers studying humanized Bmpr2+/R899X mice found that females develop a distinct lung microbiome characterized by elevated microbial-derived lipopolysaccharide (LPS). This LPS, in combination with the estrogen metabolite 16-hydroxyestrone (16-OHE), appears to push macrophages into a hyperactivated state marked by increased phagocytosis and elevated secretion of endothelin-1 (ET-1), a potent vasoconstrictor implicated in PAH. Tissue-level analyses confirmed immune cell infiltration spatially associated with elevated ET-1 in affected lung tissue. The study integrates lung metagenomics with immune profiling to propose a previously unrecognized 'estrobolome' axis — the lung microbiome's role in estrogen metabolism — as a contributor to disease penetrance. The work is currently a preprint on bioRxiv and has not yet undergone peer review. If validated, the findings could suggest microbiome modulation or targeted immune intervention as strategies to reduce PAH risk in genetically susceptible women.
What's missing
The study is a preprint and has not yet been peer-reviewed, which limits confidence in its conclusions. The mouse model (Bmpr2+/R899X) may not fully recapitulate human PAH pathophysiology. The causal direction of the microbiome changes — whether dysbiosis drives PAH or results from it — is not firmly established. The study does not address whether the identified microbiome-estrogen-immune axis is also present or relevant in human PAH patients, nor does it test therapeutic interventions targeting this pathway.
What different sources said
- bioRxivCenter
Sex-linked Lung Estrobolome May Contribute to Pulmonary Hypertension Penetrance of Bmpr2 R899X Mutation via an ET-1high Endoregulatory Macrophage Phenotype
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