The advent of CFTR modulators represents a turning point in the history of cystic fibrosis (CF) management, changing profoundly the disease’s clinical course by improving mucosal hydration. Assessing changes in airway and digestive tract microbiomes is of great interest to better understand the mechanisms and to predict disease evolution. Bacterial and fungal dysbiosis have been well documented in patients with CF; yet the impact of CFTR modulators on microbial communities has only been partially deciphered to date. In this review, we aim to summarize the current state of knowledge regarding the impact of CFTR modulators on both pulmonary and digestive microbiomes. Our analysis also covers the inter-organ connections between lung and gut communities, in order to highlight the gut-lung axis involvement in CF pathophysiology and its evolution in the era of novel modulators therapies.

Several predictive models have been proposed to understand the microbial risk factors associated with cystic fibrosis (CF) progression. Very few have integrated fungal airways colonisation, which is increasingly recognized as a key player regarding CF progression. To assess the association between the percent predicted forced expiratory volume in 1 s (ppFEV1) change and the fungi or bacteria identified in the sputum, 299 CF patients from the “MucoFong” project were included and followed-up with over two years. The relationship between the microorganisms identified in the sputum and ppFEV1 course of patients was longitudinally analysed. An adjusted linear mixed model analysis was performed to evaluate the effect of a transient or chronic bacterial and/or fungal colonisation at inclusion on the ppFEV1 change over a two-year period. Pseudomonas aeruginosa, Achromobacter xylosoxidans, Stenotrophomonas maltophilia, and Candida albicans were associated with a significant ppFEV1 decrease. No significant association was found with other fungal colonisations. In addition, the ppFEV1 outcome in our model was 11.26% lower in patients presenting with a transient colonisation with non-pneumoniae Streptococcus species compared to other patients. These results confirm recently published data and provide new insights into bacterial and fungal colonisation as key factors for the assessment of lung function decline in CF patients.

Quantitative PCR (qPCR) is highly sensitive to diagnose Pneumocystis jirovecii (Pj) pneumonia (PCP). However, differentiating PCP and colonization remains difficult. This study aimed to establish the performances of the commercialized qPCR MycoGENIE^® Pj kit (Ademtech) to distinguish PCP and Pj colonization. Patients with a positive Pj qPCR on bronchoalveolar lavage (BAL) or upper respiratory tract (URT) samples were prospectively included between May 2019 and December 2020 at Bordeaux University Hospital. They were classified in “PCP” or “Pj colonization” groups based on the revised EORTC/MSGERC criteria. The two groups’ results were compared; ROC curves were produced to determine the best thresholds. Excluding the low number of HIV-positive subjects, there were 100 PCP (32 BAL, 68 URT) and 70 Pj colonization (34 BAL, 36 URT). Pj loads were significantly higher in PCP compared to Pj colonization group (p ≤ 0.01). The best cut-offs for PCP diagnosis were 31.45 Cq/8275 copies/mL for BAL and 32.33 Cq/8130 copies/mL for URT (sensitivity = 59.4%, 63.3%, specificity = 82.4%, 88.9%, respectively). Fungal load quantification using MycoGENIE^® Pj qPCR helps discriminating PCP from colonization, high fungal loads being indicative of probable PCP. Low load results should be interpreted with caution, in accordance with clinical and radiological signs.

La mucoviscidose est une pathologie multi-organes dont la progression est principalement déterminée par les atteintes respiratoires et digestives. L’avènement des modulateurs de CFTR en a révolutionné le pronostic au cours de la dernière décennie. Les perturbations du microbiote et du mycobiote ont été bien décrites dans la mucoviscidose, ainsi que dans une moindre mesure les connexions inter-organes définissant l’axe intestin-poumon. Cependant les données sont encore lacunaires concernant l’impact des thérapies protéiques sur le myco-microbiote.Le protocole LUM-IVA-BIOTA est une étude nationale multicentrique visant à documenter l’évolution du myco-microbiote et de l’inflammation chez des patients recevant l’association lumacaftor-ivacaftor (LUM/IVA), grâce à des approches de métagénomique ciblée. La première partie du travail portant sur des patients de plus de 12 ans a montré que l’effet de LUM/IVA sur le microbiote pulmonaire dépendait de la colonisation chronique par Pseudomonas aeruginosa. La suite du projet a porté sur une cohorte d’enfants de 2 à 11 ans et a permis de mettre en évidence des améliorations des microbiotes pulmonaire et intestinal sous LUM/IVA avec modification de l’axe intestin-poumon, en confirmant le rôle clé de la colonisation par P. aeruginosa dans l’amélioration du microbiote pulmonaire. Ces résultats soulignent que les thérapies protéiques peuvent améliorer la diversité des flores microbiennes au sein de l’axe intestin-poumon si elles sont initiées précocement, avant le tournant évolutif de la colonisation par P. aeruginosa. Ils seront à confirmer chez des patients recevant les nouvelles générations de modulateurs tels que la trithérapie élexacaftor-tézacaftor-ivacaftor.