A Walnut-Derived Peptide WSPSGR Alleviates Depressive-Like Behaviors in Mice via IDO1 Inhibition and Gut Microbiota–Tryptophan Axis Modulation

Depression is a complex psychiatric disorder with increasing global impact. This study explored the antidepressant mechanisms of Trp-Ser-Pro-Ser-Gly-Arg (WSPSGR), a walnut-derived peptide with indoleamine 2,3-dioxygenase 1 (IDO1) inhibitory activity. In a chronic unpredictable mild stress (CUMS)-induced mouse model, WSPSGR ameliorated depressive-like behaviors by restoring tryptophan (Trp) metabolic balance and reshaping gut microbiota composition. Notably, it reduced IDO1-mediated kynurenine (Kyn) pathway activation and corrected gut dysbiosis, including a decreased <i>Firmicutes</i>/<i>Bacteroidota</i> ratio. These effects collectively re-established microbiota-gut-brain axis homeostasis. These findings identify IDO1 as a key target of WSPSGR and suggest that peptide-based modulation of Trp metabolism and gut microbiota may be a promising strategy for depression therapy.