Cystic Fibrosis research has been focused primarily on the lung but this approach results in a lack of in-depth understanding of disease pathogenesis. With this project, the researchers adopt an innovative strategy to examine CF pathogenesis, thus exploring the involvement of other organs apart from the lung. Emerging data link gut microbiology and immunology to respiratory outcomes, although at present, gut/lung cross-talk mechanisms in CF are largely ignored. In addition and prior to any pulmonary pathology, people with cystic fibrosis (pwCF) experience gastrointestinal complications that influence the quality of life and long-term outcomes. Whether, how and to what extent the early and severe gut pathology influences lung disease is still not clear. This project aims to establish the existence of a gut-lung axis by providing evidence that the microbiological and immunological status of the gut affects lung biology and function. A newly-established CF preclinical mouse model and models of gut Pseudomonas aeruginosa infection will be exploited. The researchers will establish whether severe gut disease and functional loss of gut

barrier integrity lead to: 1) microbial translocation within-host from the gut to the lung and/or vice-versa 2) an inflammatory response and, if so, how this process occurs. These data will be translated into cohorts of pwCF. Longitudinal bacterial strains from gut and lung in pwCF with first infection and under Trikafta/Kaftrio treatment will be collected and subjected to genotypic and phenotypic characterization. In pwCF, the researchers expect to establish whether gut and lung share identical pathogens for CF and whether bacteria in the gut may represent a continuous source of infection and/or inflammatory stimulation for the lung. All together, the results will unravel a much-needed novel mechanism of CF disease and the cause of infection and inflammation. This may orient future diagnoses and therapeutic strategies to improve current protocols for all pwCF management.