Nutrient‐Synbiotic Complex Ameliorates LPS‐Induced Depressive‐Like Behavior via Modulation of Gut Microbiota and Tryptophan Metabolism in Mice

ABSTRACT The conventional antidepressant treatments are ineffective, having undesirable side effects and relapse susceptibility. Nutrient and probiotics supplementation may have adjuvant antidepressant effects. This study aims to develop and assess the antidepressant properties of a nutrient‐synbiotic complex and investigate the underlying mechanisms. We randomly divided into control, model, and four complex groups (nutrient, prebiotic, probiotic and united all components, respectively). We used lipopolysaccharide (LPS) to establish the depression model and assessed depressive‐like behaviors using various behavioral tests, neuroplasticity, tryptophan pathway metabolites, and brain‐derived neurotrophic factor (BDNF) in serum and prefrontal cortex (PFC). Intestinal microbiome analysis was performed using 16S rRNA gene sequencing. The nutrient‐synbiotic complex presented beneficial effects against the depression‐like behaviors induced by LPS, mitigated the increased level of kynurenine, and decreased levels of 5‐hydroxytryptamine and BDNF both in serum and PFC ( p < 0.05). It also reduced neuronal damage in PFC after LPS exposure ( p < 0.05). Additionally, the nutrient‐synbiotic complex effectively prevented the disturbance in abundance and diversity of the intestinal flora induced by LPS (Chao1: p = 0.013, ACE: p = 0.006, PCoA: R 2 = 0.25, p = 0.003). A total of nine bacterial genera were negatively associated with depression, while eight were positively associated with depression. Among them, g__Family_XIII_UCG_001 , g__Clostridia_vadinBB60_group , and g__Lactobacillus showed significant intergroup differences ( p < 0.05). This is the first study to demonstrate that a combined nutrient‐synbiotic complex can prevent depressive‐like behavioral changes induced by LPS. The underlying mechanisms may be associated with modifying the composition of the gut microbial community and improving the tryptophan metabolic homeostasis.