Background: Lung infections play a critical role in cystic fibrosis (CF) pathogenesis. While CF respiratory tract is now considered as a polymicrobial niche, advances in high-throughput sequencing (NGS) have paved the way to microbiota and mycobiota analysis. However, none of these NGS studies have characterized both communities during CF pulmonary exacerbation (CFPE). Methods: Using NGS, thirty-three sputa isolated from patients with and without CFPE were successfully sequenced targeting 16S and ITS2 regions of bacterial and fungal rRNA. We built inter-kingdom network and adapted Phy-Lasso method to detect significant correlations in compositional data. Findings: We confirmed that respiratory function decline was significantly associated with a decrease in bacterial diversity. The inter-kingdom network revealed three main clusters organized around Aspergillus, Candida and Scedosporium genera. Using Phy-Lasso method, we identified Aspergillus and Malassezia as significantly associated with CFPE, and Scedosporium plus Pseudomonas with a decline in lung function. We corroborated in vitro the cross-domain interactions between Aspergillus and Streptococcus predicted by our correlation network. Interpretation: For the first time, we proposed a version of the ecological Climax/Attack model that includes documented mycobiome data. Such combinations of omics and ecological approaches will help us to understand better the physiopathology of CF lung disease, and to improve therapeutic management of this critical clinical state.- Funding Statement: LD has received a research grant from Vaincre La Mucoviscidose (RF20160501626); LEV's salary was provided by Genoscreen Company. All these funders had no role in article design, decision to publish, or preparation of the manuscript. Declaration of Interests: The authors declared no conflict of interest. Ethics Approval Statement: MucoFong study was approved by the institutional ethics committees of Lille University Hospital (Reference Number: CPP-06/84), and a written informed consent was provided by all participants.