Background: Pneumonia is the leading cause of communicable diseases and the second cause of disability-adjusted life-years in the world. Pneumonia can be acquired in the community or during hospitalization. Severe pneumonia frequently evolves towards acute respiratory distress syndrome, and we observed that current therapies do not produce the expected favorable outcome for 25 to 35% of patients. Our team developed a reappraisal of the pathophysiology of pneumonia, proposing restoration of normal host-microbiome interactions as a primary therapeutical target. We hypothesis that the restoration of normal respiratory microbiome composition and functions has the potential to restore lung homeostasis and enhance the treatment of pneumonia. Objectives: Our main objectives are to define at specie levels a commensal consortium whose elimination is associated with pneumonia severity, to describe the metabolite and peptide productions of this bacterial consortium, to test the effects of a probiotic composed of this lung specific consortium on pathogen multiplication and microbiome composition (inter-species communication) and on lung mucosal immunity (host-microbiome interactions). Methods: Using multi-omics data integration, we will define consortia composed of bacterial species, metabolites, and peptides which will be associated with pneumonia severity and treatment failure. We will then investigate in vitro and in murine models their effects in modulating interspecies bacterial cooperation mechanisms and inhibiting the pathogen’s growth, and on host immune defenses. Perspectives: The SYMBIOLUNG project will help define the commensal bacterial mediators involved in lung homeostasis, thus filling a significant knowledge gap essential for developing lung-specific microbiome-targeted approaches. Thus, if our hypothesis is demonstrated, the impact of our work will be tremendous for patients with pneumonia and for healthcare workers, considering the number of target patients.