Whey protein isolate attenuates depression-like behavior developed in a mouse model of breast tumor

Increasing evidence indicates that tryptophan (Trp) metabolism disturbance controls hippocampal 5-hydroxytryptamine (5-HT) and thereby affecting depression-like behavior, in which the gut microbiota (GM) might be involved. This study investigated the effect of Trp-rich whey protein isolate (WPI) on depressive-like behavior in 4T1 tumor-bearing mice. Female BALB/c mice were subcutaneously inoculated with murine 4T1 mammary carcinoma cells and received 2 g/kg of WPI by gavage daily for 21 days. The results showed that WPI exerted no significant effects on tumor weight and volume, but abrogated tumor-induced depression-like behavior, as evidenced by remarkably increased time and distance in the center of the open-field test, decreased immobility time in the tail suspension test, increased time and number of entries to the open arms in the elevated plus maze and sucrose preference. Moreover, WPI promoted the hippocampal Trp, 5-hydroxytryptophan (5-HTP), 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) levels and inhibited kynurenine (Kyn) through up-regulating serotonin transporter (SERT) and down-regulating indoleamine 2, 3-dioxygenase (IDO). WPI showed an enriched microbial diversity indicated by increased Shannon index and decreased Simpson index, reduced the abundances of Proteobacteria, Rikenellaceae_RC9_gut_group, Alloprevotella and Prevotellaceae_UCG-001, and increased the abundance of unclassified_k__norank_d__Bacteria in tumor-bearing mice (P < 0.05). At level 3, WPI enhanced the function of microbial gene related to Trp metabolism in the KEGG pathways (P < 0.05). Our results suggest that WPI exhibits a potent antidepressant-like effect via the regulation of hippocampal Trp metabolism and alteration of GM composition and function, and it may be an effective prevention for cancer-related depression.