Impact of LUng MIcrobiota in vascular remodeling and pulmonary arterial hypertension: potential for innovative biotherapeutic target – LUMI

Pulmonary Arterial Hypertension (PAH) is a rare, incurable and deadly disease of the pulmonary vessel. It is defined by an elevation of pulmonary arterial pressure, due to progressive and obstructive remodeling of small pulmonary arteries, leading to right heart failure. Existing treatments target vasoconstriction, are not curative and it remains an unmet need for anti-remodeling strategy. The only outcome is lung transplantation, with a survival of 50% at 5 years. A new player related to respiratory diseases, the pulmonary microbiota, is not yet taken into account in PAH. Asthma, COPD, idopathic fibrosis, cystic fibrosis are related to a pulmonary pathobiome with a decrease in diversity promoting progression of the disease, acute exacerbations and mortality, thus opening the way to new therapeutic avenues.

LUMI aims to explore the pulmonary microbiota as a new actor directly impacting vascular remodeling and the progression of PAH, via its metabolites. The specific objectives are: a/ to determine the physiological impact of the microbiota on the architecture of the developing pulmonary vascular tree, b/ to translationally characterize the pulmonary microbiota in experimental and human PAH and c/ to evaluate the physiopathological and therapeutic consequences of this microbiota and its metabolites on vascular remodeling leading to PAH in a pre-clinical model. One of the challenges will be to demonstrate the link between pulmonary bacterial species, their metabolites and pulmonary vascular remodeling. The other challenge is how to ensure the translation of the initial observations on the pulmonary microbiome composition in PAH patients to pre-clinical models of PAH.

Thus LUMI has emerged as a multidisciplinary consortium that brings together 3 complementary expert partners P1 (INSERM UMR_S 999, Paris Sud University/Paris Saclay University), P2 (MICALIS-INRA), and P3 (INSERM UMR_S 1078, UBO), respectively in the fields of Biology/Medicine (Pathophysiology of PAH and Therapeutic Innovation), Functional Metagenomics (METAFUN), and Lung Ecosystem (16S Metagenetics / Metatranscriptomics and MUCOBIOME Bioinformatics pipeline). LUMI has designed a research strategy focused directly on these metabolites, through both a targeted and comprehensive approach, to address these challenges with the unique opportunity of access to explanted lung tissue from PAH patients in relation to the National Reference Center hosted by P1. We believe that whatever the mechanisms leading to altered composition of the pulmonary microbiota – disruption of pulmonary homeostasis, bacterial translocation from intestine along the gut-lung axis, or migration of oropharyngeal bacteria – changes in the structure and diversity of the pulmonary microbiota, its composition and function may have direct effects on pulmonary vascular remodeling leading to PAH, through microbial metabolites produced in the pulmonary microenvironment. Our preliminary results indicate the role of certain targeted metabolites as negative or positive modulators of pulmonary vascular cell proliferation.

The expected results of LUMI are: a) to contribute to new knowledge on the role of the microbiota in respiratory diseases, b) to open up and feed a new field of knowledge on pulmonary vascular development, vascular remodeling and pathophysology of PAH c) to lead to a breakthrough in our vision of the pathophysiology and management of PAH patients. LUMI will provide a first knowledge on the pathobiome diversity and the pulmonary microbiota signature of PAH, as a basis for identifying new biotherapeutic approaches, as well as PAH biomarkers based on identified circulating metabolites. The final products that could emerge from LUMI for further development could be based on bacteria or their metabolites. As new therapeutic agents, they could be used in add-on therapy to existing treatments, to restore lung bacterial homeostasis and reverse lung vascular remodeling.