Abstract

Ethnopharmacological relevance Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F.Chow ( Ziziphus jujuba ) has been used in Chinese folk medicine for over 2000 years, with the Shennong Bencao Jing noting that the “main worry is not sleeping.” More than 100 health foods and Chinese patent medicines, feature Ziziphus jujuba as the core ingredient, embodying the traditional concept of “nourishing heart and tranquilizing mind.” Objective This study investigated microbiome-targeted phytotherapeutic strategies for sleep disorders, which are often linked to gut dysbiosis and systemic oxidative stress. Materials and methods Chronic sleep-deprived Drosophila were orally treated with a Ziziphus jujuba alcohol extract (ZJAE). Sleep architecture was recorded using a Drosophila activity monitor. Intestinal microbiota shifts were assessed by gnotobiotic colonization and 16S rRNA sequencing. Quantitative PCR, western blotting, and reactive oxygen species (ROS) imaging assessed intestinal signaling of the Nrf2 homolog cap ‘n’ collar C (CncC) gene, antioxidant gene expression, gut barrier integrity, and systemic ROS. Gut-specific RNA interference was used to targeted the CncC gene. Results ZJAE restored total sleep time and reduced motor hyperactivity, consistent with reduced systemic ROS and restoration of intestinal barrier function. Acetobacter was enriched. Antibiotic-treated flies colonized with acetic acid bacteria and treated with ZJAE showed the highest CncC gene expression. Knockdown of the CncC gene knockdown in intestinal epithelial cells abolished improvements in both sleep parameters and redox status. Conclusion ZJAE recruits commensal Acetobacter to activate an intestinal Nrf2-dependent redox axis, normalizing oxidative stress-linked sleep deficits. These findings provide the first preclinical evidence of a microbiota-dependent mechanism, supporting a rationale for the development of jujube-based functional foods targeting oxidative sleep disorders.