A sharp difference in the structure and composition of airway microbiota between S (Stable) and SD (Severe Decline) patients was found, especially in patients with severe lung disease, where Pseudomonas represented the most abundant genus. A co-occurrence network analysis showed that microbial communities were less complex in SD patients than in S ones. Moreover, an inverse relationship between bacterial community diversity and disease severity was found. Additionally, significant differences in antibiotic resistance genes and metabolic pathways of the microbiome between normal/ mild and severe lung disease FEV1 groups were found. The analysis of the meta-community dynamics can give us a set of tools to unlock the potential of microbiome-based personalized medicine in major disease areas including CF.