Jujuboside A ameliorates PCPA-induced insomnia and anxiety-like behaviors by enhancing intestinal barrier function and balancing brain neurotransmitter levels in mice

Jujuboside A (JUA) is a saponin abundant in sour jujube seeds ( Ziziphus jujuba var. spinosa ). However, whether JUA improves insomnia and the consequent anxiety-like behaviors remains unclear. In this study, we evaluated the effects of JUA in para-chlorophenylalanine (PCPA)-induced insomnia in mice. JUA administration alleviated sleep disturbances and anxiety-like behaviors in PCPA-treated mice. PCPA reduced tight junction protein expressions, and altered gut microbiota composition, whereas JUA partially reversed these alterations. JUA increased the expression of tight junction proteins, especially claudin-1, providing structural and molecular evidence of preserved intestinal barrier-associated features. It also modulated the gut microbiota, as reflected by increased Bacteroidota and decreased Desulfobacterota . Along with these barrier-associated changes, JUA reduced systemic inflammation and oxidative stress. Furthermore, serum untargeted metabolomics analysis revealed that PCPA disrupted neuroactive metabolite profiles and amino acid metabolism-related pathways, whereas JUA partially reversed these metabolic alterations. Correlation analysis linked JUA-responsive metabolites with sleep parameters and anxiety-like behaviors. JUA corrected PCPA-induced central neurotransmitter imbalance and upregulated the expression of BDNF/TrkB. These findings collectively indicate that JUA has the ability to alleviate insomnia and anxiety-like behaviors induced by PCPA, supporting its potential as a bioactive compound from food sources in the management of sleep disorders and related emotional symptoms in diet.