Citrus p-synephrine Ameliorates Metabolic and Cognitive Deficits in a Mouse Model of Circadian Rhythm Disruption

• P-synephrine improves lipid metabolism and rhythm disturbance induced by CRD. • P-synephrine increases the abundance of beneficial bacteria in intestinal flora. • Serotonin may mediate the cognitive rescue effect of p-synephrine. • P-synephrine reduces food intake in CRD mice. p-synephrine is an alkaloid found naturally in citrus fruit. However, its effect on circadian rhythm disruption (CRD) remains unclear. This study established a CRD model in mice to systematically evaluate the effects of p-synephrine intervention. The findings revealed that p-synephrine intervention not only effectively alleviated CRD-induced metabolic syndrome phenotypes, including increased body weight, fat accumulation, and dyslipidemia, but also significantly improved anxiety-like behaviors and cognitive deficits. We observed that p-synephrine produced positive effects at multiple systemic levels: first, it remodeled the dysregulated gut microbiota structure, notably increasing the relative abundance of beneficial Akkermansia and decreasing levels of genera like Rikenellaceae_RC9_gut_group; second, it increased serotonin levels in the duodenum and hypothalamus; and third, it regulated the expression of genes in the liver related to lipid metabolism and circadian rhythm. In summary, p-synephrine may improve the complex pathological state caused by CRD through multi-target, multi-system integrated pathways. These findings provide a new scientific basis for the use of p-synephrine as a functional component to combat health problems related to rhythm disorders. Citrus p-synephrine improves metabolic and cognitive impairments caused by circadian rhythm disturbances, which appear to be related to gut-brain axis-mediated serotonin secretion.