Unlocking the AhR Therapeutic Potential for Cystic Fibrosis With an Integrated Mucosal Platform for Drug Screening

Abstract

Bacterial-derived molecules are at the basis of bacteria–bacteria and bacteria–host communication. In the context of cystic fibrosis (CF), they are considered possible therapeutic molecules for their natural binding capability on the immunomodulatory cytoplasmic aryl hydrocarbon receptor (AhR). An exponentially growing number of bacteria-derived molecules are identified as AhR activators, highlighting the need for systems to screen possible lead candidates. This challenge is addressed by applying an in vitro tool mimicking the two main barriers that potential AhR-targeting drugs must overcome: the cytoplasmic membrane and the CF pathological mucus. A small dataset of AhR ligands with potential therapeutic applications is selected. The apparent permeability of bacterial-derived molecules across a cellular membrane model is quantified and molecules capable of reaching the cytoplasmic target (AhR) are identified. In a second step, a CF in vitro mucus model is integrated with the phospholipid membrane and the impact of mucus on permeability is assessed. Overall, this study proposes an integrated mucosal platform as a suitable tool in the emerging field of postbiotics as a therapeutic strategy for CF. The mucosal platform can enable the rapid identification of molecules compatible with cytoplasmic targeting of AhR among candidate-drug representatives.