Lactiplantibacillus plantarum KLDS1.0344 ameliorates depressive-like behavior in CUMS mice: integrative multi-omics evidence linking gut microbiota alterations to sphingolipid and glycerophospholipid metabolic pathways

Abstract

Depression is a common and debilitating psychiatric disorder, and current pharmacotherapies are often limited by delayed onset, variable efficacy, and adverse effects. Therefore, safer and more effective adjunctive or alternative strategies are needed. In the present study, a chronic unpredictable mild stress - induced murine model was used to evaluate the antidepressant potential of Lactiplantibacillus plantarum KLDS1.0344 by integrating behavioral assessments, neurochemical analyses, 16S rRNA sequencing, and untargeted metabolomics of intestinal contents. KLDS1.0344 significantly ameliorated depressive-like behaviors in the open field, tail suspension, forced swim, and sucrose preference tests, with the most pronounced effects observed at the high dose. These behavioral improvements were accompanied by reduced HPA-axis hormones (Corticotropin-Releasing Hormone, Adrenocorticotropic Hormone, and Corticosterone) and partial restoration of monoamine neurotransmitters (Dopamine, Norepinephrine, and 5-Hydroxytryptamine) and Brain-Derived Neurotrophic Factor. Multi-omics analyses further showed that high-dose KLDS1.0344 was associated with remodeling of the gut microbiota, particularly the restoration of Lactobacillus and alterations in other key taxa, together with marked changes in sphingolipid- and glycerophospholipid-related metabolic profiles. Correlation analysis suggested coordinated associations between microbial shifts and intestinal lipid metabolic features, supporting a candidate microbiota-metabolite framework related to the psychobiotic effects of KLDS1.0344. Overall, this study provides evidence supporting the psychobiotic potential of KLDS1.0344 and its possible application in functional foods for depression-related intervention.