Abstract

ABSTRACT Chronic stress is a major contributor to mood disturbances through dysregulation of the gut–brain axis and neuroinflammatory responses. Lilium davidii var. unicolor (Lanzhou lily), a traditional medicinal and edible plant, contains bioactive compounds with anti‐inflammatory potential. This study investigated the effects of Lanzhou lily extract (LLE) on chronic restraint stress (CRS)‐induced behavioral and physiological changes in mice. LLE improved CRS‐induced anxiety‐ and depression‐like behaviors, reduced microglial activation in the hippocampus, and suppressed TLR4/MyD88/NF‐κB signaling and downstream cytokine release (TNF‐α, IL‐6, IL‐1β). LLE also restored intestinal barrier integrity, decreased serum LPS levels, and modulated gut microbiota composition by enriching Ligilactobacillus murinus and Muribaculum intestinale while reducing Prevotella abundance. Correlation analysis linked microbial restoration with barrier protection and reduced neuroinflammation. UHPLC‐Q‐Exactive Orbitrap‐MS/MS analysis tentatively identified multiple constituents of LLE, including dioscin, matrine, timosaponin AIII, and catechin. Previous studies have suggested that some of these compounds may possess neuroprotective or antidepressant‐related activities. These findings suggest that Lanzhou lily extract may modulate the gut‐brain axis and exert antidepressant‐like effects in a preclinical stress model, warranting further investigation in clinical studies.