Chronic stress is a critical predisposing factor for neuropsychiatric and metabolic disorders, profoundly affecting both physical health and behavioral performance. Stress induces gut microbiota dysbiosis and disrupts tryptophan metabolism, notably via the kynurenine (KYN) and 5-hydroxytryptamine (5-HT) pathways. Targeted modulation of the gut-brain axis through probiotics and prebiotics has therefore emerged as a promising approach for preventing and alleviating stress-related disorders, yet the efficacy of specific synbiotic combinations remains largely unexplored. This study investigated the effects of feline milk-derived Lactiplantibacillus plantarum MNN, galacto-oligosaccharides (GOS), and their combination on stress-related behavioral abnormalities and tryptophan metabolism in a mouse model of chronic social defeat stress (CSDS). Behavioral outcomes, gut microbial composition, cecal tryptophan metabolites, and molecular markers associated with serotonin (5-HT) synthesis and neuroplasticity were evaluated. Intervention with MNN, GOS, and MNN + GOS attenuated several CSDS-induced behavioral abnormalities and was associated with alterations in gut microbial composition and cecal tryptophan metabolism. In the SIT, the social interaction ratio increased from 0.307 ± 0.089 in CSDS mice to 0.778 ± 0.042 (p = 0.003), 0.826 ± 0.035 (p = 0.001), 1.445 ± 0.114 (p < 0.0001) in the MNN, GOS, and MNN + GOS groups, respectively. Cecal indoxyl sulfate levels decreased from 1.944 ± 0.286 in CSDS mice to 0.206 ± 0.022 (p < 0.0001), 0.231 ± 0.058 (p < 0.0001) and 0.275 ± 0.018 (p < 0.0001) in the MNN, GOS, and MNN + GOS groups, respectively. The interventions also increased intestinal and hippocampal 5-HT signals and partially restored the expression of tryptophan hydroxylases, brain-derived neurotrophic factor (BDNF), and postsynaptic density protein 95 (PSD95). These findings suggest that MNN, GOS, and MNN + GOS interventions may alleviate stress-related abnormalities, potentially through modulation of the microbiota-tryptophan-5-HT axis. However, the causal role of the gut microbiota and the efficacy of these interventions in cats require further investigation.
