Stratifying infants with cystic fibrosis for disease severity using intestinal organoid swelling as biomarker of CFTR function

Abstract

Forskolin-induced swelling (FIS) of intestinal organoids from individuals with cystic fibrosis measures function of the cystic fibrosis transmembrane conductance regulator (CFTR), the protein mutated in cystic fibrosis (CF).We investigated whether FIS corresponds with clinical outcome parameters and biomarkers of CFTR function in 34 infants diagnosed with CF. Relations between FIS were studied for indicators of pulmonary and gastro-intestinal disease.Children with low FIS had higher levels of immunoreactive trypsinogen (IRT, p=0.030) and pancreas associated protein (p=0.039), were more often pancreatic insufficient (PI, p<0.001), had more abnormalities at chest computed tomography (p=0.049), and lower z-scores for maximal expiratory flow at functional residual capacity (p=0.033) when compared to children with high FIS values. FIS significantly correlated with sweat chloride concentration (SCC) and intestinal current measurement (ICM), r=-0.82 and 0.70, respectively, both p<0.001. Individual assessment of SCC, ICM and FIS suggested that FIS can help to classify individual disease severity.Thus, stratification by FIS identified subgroups that differed in pulmonary and gastrointestinal outcome parameters. FIS of intestinal organoids correlated well with established CFTR-dependent biomarkers such as SCC and ICM, and performed adequately at group and individual level in this proof-of-concept study.