Patients with cystic fibrosis (CF) have decreased serum levels of sphingosine and altered ceramide composition, according to a new study published in the Journal of Cystic Fibrosis. Treatment with the triple-combination CF transmembrane conductance regulator (CFTR) modulator (elexacaftor [ELX]/tezacaftor [TEZ]/ivacaftor [IVA]) improved their sphingolipid profiles.

“For the most part, the present study and existing evidence suggest a rebalancing of the ceramide composition in plasma of [people with CF] and in CF bronchial epithelial cells after treatment with ELX/TEZ/IVA,” the authors said. “Nonetheless, depending on the model and the methods used, varying results have been published in the field of ceramide research and further confirmatory studies are needed.”

Patients with CF presented with a marked sphingosine deficiency. Further analysis showed that sphingosine levels might have diagnostic potential in CF, with an area under the curve of 0.95. Moreover, the levels of sphingosine and dihydrosphingosine were found to be weakly correlated with the percent predicted forced expiratory volume in 1 second (negative correlation).

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Although the total amounts of serum ceramide were similar between patients with CF and healthy controls, the authors found slight differences in the expression of certain ceramide subtypes. For instance, they observed increased levels of long-chain ceramides C18Cer and C20Cer and reduced levels of dihydroceramide subspecies C16dhCer, C22dhCer, and C24dhCer in patients with CF.

However, this study did not detect alterations in either C16Cer, the most abundant long-chain ceramide, or the very long-chain ceramide C24Cer, as reported by previous studies. Treatment with ELX/TEZ/IVA decreased the levels of several ceramide species, such as C18Cer, C20Cer, and C16Cer, as well as the ratio C16Cer/C24Cer, while it increased the levels of C24Cer and sphingosine-1-phosphate in patients with CF.

The decrease in C16Cer/C24Cer ratio suggests an improvement in patients’ outcomes, as previous studies linked an elevated ratio to inflammation. In contrast, the levels of sphingosine were not affected by the triple-combination CFTR therapy.

“Strategies for sphingolipid remodeling need to be reassessed and adjusted in the light of highly effective CFTR modulator therapies,” the authors said.


Westhölter D, Schumacher F, Wülfinghoff N, et al. CFTR modulator therapy alters plasma sphingolipid profiles in people with cystic fibrosis. J Cyst Fibros. Published online February 12, 2022. doi:10.1016/j.jcf.2022.02.005