Anxiolytic activity of nutritional interventions with soybean protein and its derived peptides in mice: from the gut-brain axis to the HPA axis

Anxiety disorders have emerged as global neurological disorders with serious detrimental effects, while dietary supplementation offers new insights for alleviating them. Although bioactive peptides have demonstrated anxiolytic properties, a systematic comparison between low-molecular-weight soybean peptides (SPep) and intact soybean proteins (SPro) through nutritional interventions remains unexplored. This study evaluated the effects of SPro and SPep nutritional interventions on anxiety-like behaviors induced by chronic unpredictable mild stress in mice, exploring their underlying mechanisms. The results revealed that both SPro and SPep nutritional interventions increased glutamate and glutamine levels in mouse brain tissue, but only the SPep diet was effective in alleviating anxiety-like behaviors and reducing c-Fos expression. Distinct alterations in gut microbiota composition were observed for each diet, with the SPep diet notably increasing the relative abundance of Bacteroidales and Lachnospiraceae, and elevating isobutyric acid, valeric acid, and isovaleric acid levels. Additionally, the SPep diet significantly reduced corticosterone levels and specifically modulated the StAR gene, contributing to the normalization of the hypothalamic-pituitary-adrenal (HPA) axis. Importantly, correlation analysis underscored the critical roles of the gut-brain and HPA axes. Collectively, these findings suggest that the SPep diet exerts its anxiolytic effects primarily through the gut-brain axis, with the HPA axis serving as the central regulatory mechanism.