Chitooligosaccharide ameliorates depression in CUMS mice by regulating gut serotonin metabolism

The objective of this study was to investigate the interventional role and underlying mechanisms of chitooligosaccharide (COS) in a mouse model of depression induced by Chronic Unpredictable Mild Stress (CUMS). Mice subjected to CUMS were orally administered with COS2, and its effects were evaluated using a comprehensive approach encompassing behavioral assessments, neurobiological analyses, immunological profiling, and metabolic evaluations. Our findings demonstrated that COS2 significantly reduced the hyperactivation of the Hypothalamic-Pituitary-Adrenal (HPA) axis, mitigated inflammatory responses in both brain and colonic tissues, and alleviated CUMS-induced anxiety- and depression-like behaviors. Notably, COS2 upregulated the expression of Tryptophan Hydroxylase 1 (Tph1), a key enzyme in the serotonin metabolic pathway within the colon, leading to increased peripheral levels of 5-hydroxytryptophan (5-HTP). This elevation in 5-HTP facilitated its transport across the blood-brain barrier, maintaining stable serotonin (5-hydroxytryptamine, 5-HT) levels in the brain. Simultaneously, COS2 reduced the production of metabolic byproducts, including kynurenine and indole derivatives, favoring the preferential conversion of tryptophan (Trp) to serotonin. This process facilitated the preferential conversion of Trp to 5-HT. To further confirm the regulatory effects of COS2 on Tph1, an <em>in vitro</em> model using RIN-14B cells in the presence of a Tph1 inhibitor was employed. Results showed that COS2 modulates Tph1 activity to serotonin metabolism, primarily through the Tph1-mediated 5-HT metabolic signal transduction axis. Collectively, these findings highlight the critical role of COS2 in mitigating depressive states induced by CUMS through the Tph1-mediated 5-HT metabolic transduction signal axis. This study provides valuable insights into the therapeutic potential of food-derived compounds, like COS for managing stress-related depressive and anxiety disorders that result from chronic stress through Gut-Brain Axis (GBA) modulation.