Highlights d Lactic acid bacteria are enriched in the healthy human nose and nasopharynx d Lactobacillus casei AMBR2 is functionally adapted to the upper respiratory tract d L. casei AMBR2 has antimicrobial and immunomodulatory properties d Live L. casei AMBR2 is safe for intranasal application in healthy humans

Highlights d Lactic acid bacteria are enriched in the healthy human nose and nasopharynx d Lactobacillus casei AMBR2 is functionally adapted to the upper respiratory tract d L. casei AMBR2 has antimicrobial and immunomodulatory properties d Live L. casei AMBR2 is safe for intranasal application in healthy humans

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Purpose A defective epithelial barrier has been demonstrated in chronic rhinosinusitis with nasal polyps (CRSwNP). Lactobacilli are shown to restore epithelial barrier defects in gastrointestinal disorders, but their effect on the airway epithelial barrier is unknown. In this study, hence, we evaluated whether the nasopharyngeal isolates Lacticaseibacillus casei AMBR2 and Latilactobacillus sakei AMBR8 could restore nasal epithelial barrier integrity in CRSwNP. Methods Ex vivo trans-epithelial tissue resistance and fluorescein isothiocyanate-dextran 4 kDa (FD4) permeability of nasal mucosal explants were measured. The relative abundance of lactobacilli in the maxillary sinus of CRSwNP patients was analyzed by amplicon sequencing of the V4 region of the 16S rRNA gene. The effect of spray-dried L. casei AMBR2 and L. sakei AMBR8 on epithelial integrity was investigated in vitro in primary nasal epithelial cells (pNECs) from healthy controls and patients with CRSwNP as well as in vivo in a murine model of interleukin (IL)-4 induced barrier dysfunction. The activation of Toll-like receptor 2 (TLR2) was explored in vitro by using polyclonal antibodies. Results Patients with CRSwNP had a defective epithelial barrier which positively correlated with the relative abundance of lactobacilli-specific amplicons in the maxillary sinus. L. casei AMBR2, but not L. sakei AMBR8, increased the trans-epithelial electrical resistance (TEER) of pNECs from CRSwNP patients in a time-dependent manner. Treatment of epithelial cells with L. casei AMBR2 promoted the tight junction proteins occludin and zonula occludens-1 reorganization. Furthermore, L. casei AMBR2 prevented IL-4-induced nasal permeability in vivo and in vitro. Finally, the beneficial effect of L. casei AMBR2 on nasal epithelial cells in vitro was TLR2-dependent as blocking TLR2 receptors prevented the increase in TEER. Conclusions A defective epithelial barrier in CRSwNP may be associated with a decrease in relative abundance of lactobacilli-specific amplicons. L. casei AMBR2 would restore nasal epithelial integrity and can be a novel therapeutic strategy for CRSwNP.

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