Exploring the potential efficacy of Ziziphus spina-christi on restoring steroid sensitivity in severe asthma.

OBJECTIVE

To determine whether Ziziphus spina-christi adjuvant restores steroid hyporesponsiveness in severe asthma by strengthening the gut epithelial barrier and inhibiting the STING sensing pathway.

METHODS

Chemical profiling of Z. spina-christi extract was performed using liquid chromatography mass spectrometry (LC/MS-MS). Steroid-hyporesponsive asthma was induced with house dust mite (HDM) and cyclic-di-GMP (c-di-GMP). Mice were treated with dexamethasone, Z. spina-christi, or combination therapy. The study assessed gut histopathology, epithelial tight junction proteins, lung inflammation, airway hyporesponsiveness, inflammatory phenotypes, STING pathway activation, and glucocorticoid response.

RESULTS

Z. spina-christi exhibited a flavonoid-dominated chemotype enriched in quercetin-related compounds. Severe asthma induction was associated with significant gut epithelial injury, loss of tight junction proteins, and barrier dysfunction. Dexamethasone monotherapy failed to restore gut architecture or tight junction integrity. Conversely, Z. spina-christi markedly improved gut histology and reinstated expression of Claudin-1, Occludin, and ZO-1, with near-complete normalization observed with combination therapy. Restoring the gut barrier was associated with decreased airway inflammation, improved lung function, suppression of the STING pathway, and normalization of the GRα/GRβ ratio.

CONCLUSION

Z. spina-christi enhances steroid sensitivity in severe asthma by restoring the gut epithelial barrier and reducing STING-driven inflammation.