ZHANG Chang, DONG Zhuo-Yue, LU De-Shuang, WANG Xu-Feng, ZHANG Zi-Wen, SUN Jia-Jun, CHENG Hao, LIU Ting, LI Lin
Depression imposes a substantial burden on global health and the economy; however, the extent to which varying degrees of depressive-like behavior influence gut microbiota composition and intestinal barrier function remains poorly understood. This study investigated the effects of depressive-like behaviors of differing severity that were induced by short-term or long-term restraint stress on multiple physiological systems in rats, including the hypothalamic-pituitary-adrenal (HPA) axis, intestinal inflammation, barrier integrity, gut microbiota composition, and short-chain fatty acid (SCFA) metabolism. Twenty-one male Sprague-Dawley rats were randomly assigned to three groups: a non-stressed control group, a short-term stress group (7 days) to model mild depression, and a long-term stress group (28 days) to model severe depression. Both stress-exposed groups exhibited depression-like behaviors, as evidenced by reduced locomotor activity in the open field test, decreased sucrose preference, and prolonged immobility in the forced swimming test, with the long-term stress group displaying significantly more pronounced deficits across all three measures. Stress exposure elevated serum corticosterone (CORT) and corticotropin-releasing hormone (CRH) levels, exacerbated colonic inflammation, and reduced both antioxidant markers (SOD, GSH-Px, T-AOC) and the expression ofintestinal barrier permeability-related proteins (MUC1, Claudin-1, ZO-1 and Occludin). Notably, all these changes were more pronounced in the severe depression group. Gut microbiota showed that mild depression markedly decreased gut microbial α-diversity and altered specific genera (e.g., reduced Holdemanella and Blautia, increased Clostridium_sensu_stricto_1), whereas severe depression further shifted taxa including Lachnospiraceae_NK4A136_group and Treponema_2. The observed microbial shifts correlated significantly with HPA axis activity, inflammation, and oxidative status, and were accompanied by disrupted fecal SCFA levels and receptor expression (GPR41/43/109A). Together, these findings establish depression severity as a key determinant of microbiota-gut-brain axis dysregulation and underscore the importance of timely intervention in stress-related disorders.
