Limosilactobacillus fermentum WIS32 alleviates LPS-induced depression-like behavior via the microbiota-gut-brain axis

Introduction In recent years, the global incidence of depression has continued to rise, posing a severe threat to physical and mental health as well as overall quality of life. While Lactobacillus , as a significant probiotic, has demonstrated remarkable potential in alleviating depressive symptoms, the specific mechanisms of Limosilactobacillus fermentum in depression have not been fully elucidated. This study aimed to evaluate the antidepressant effects of L. fermentum WIS32 and explore its underlying mechanisms via the microbiota-gut-brain axis (MGBA). Methods A cross-cohort meta-analysis was initially conducted to assess the abundance of L. fermentum in the gut microbiota of patients with depression. Subsequently, in vitro experiments were performed to evaluate the gastrointestinal tolerance, antioxidant capacity, and antibacterial properties of WIS32 compared to a control strain, LFG89. In vivo, a lipopolysaccharide (LPS)-induced mouse model of depression was established to assess the effects of WIS32 intervention on behavioral phenotypes, hippocampal neurochemicals (5-HT and BDNF), and serum pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Finally, full-length 16S rRNA sequencing and correlation analyses were utilized to examine the remodeling of the gut microbiota structure. Results The meta-analysis revealed a significant reduction in the abundance of L. fermentum in patients with depression. In vitro assessments demonstrated that WIS32 exhibited superior gastrointestinal tolerance, antioxidant capacity, and antibacterial properties compared to LFG89. In vivo, WIS32 intervention significantly ameliorated LPS-induced depressive-like behaviors, upregulated 5-HT and BDNF levels in the hippocampus, and inhibited serum pro-inflammatory cytokines. Furthermore, 16S rRNA sequencing indicated that WIS32 significantly remodeled the gut microbiota by promoting beneficial taxa, such as Bacteroides stercorirosoris and Massilimaliae timonensis , while inhibiting pro-inflammatory pathogens like Streptococcus —effects that were more pronounced than those of LFG89. Correlation analysis confirmed that these microbial shifts were strongly associated with reduced inflammation and enhanced neuroplasticity. Discussion These findings demonstrate that L. fermentum WIS32 effectively alleviates depressive symptoms by modulating key taxa within the gut microbiota to suppress inflammation and promote neuroplasticity. Therefore, L. fermentum WIS32 holds significant promise as a potential psychobiotic for the treatment and management of depression.