Synergistic effects of Lacticaseibacillus rhamnosus GG, glutamine, and curcumin on chronic unpredictable mild stress-induced depression in a mouse model

The microbiota-gut-brain axis is important in anxiety-depressive disorders. These conditions are associated with dysbiosis of the intestinal microbiota, intestinal hyperpermeability and an increase in circulating markers of inflammation and oxidative stress. They are also associated with a deregulation of the glutamine-glutamate-γ-aminobutyric acid cycle, with impairment of the excitatory/inhibitory balance in the brain. Our aim was to examine the impact of chronic treatment with the probiotic organism Lacticaseibacillus rhamnosus GG, alone or in combination with glutamine and curcumin, in a validated model of anxiety-depressive disorder in mice. Six-month-old mice (n=144) were exposed to chronic unpredictable mild stress (CUMS) stimulation for 3 weeks and emotional disturbances were assessed using two tests assessing anxiety (elevated plus maze test) and depressive-like behaviour (tail suspension test). After discontinuation of CUMS, mice were force-fed once-daily with curcumin, glutamine and probiotic alone or in combination for 21 consecutive days. Emotional reactivity was assessed in two separate behavioural tests: open field test and forced swim test. The outcomes of the interventions were compared with those induced by acute intraperitoneal administration of clomipramine, one of the major tricyclic antidepressants used in humans. Two independent sets of experiment were performed in this study, in order to evaluate the effects of two different formulations based on the utilisation of the probiotic L. rhamnosus GG in its live or inactivated form. CUMS led to an impairment of the emotional state of 6-month-old mice. However, chronic treatment with a combination of glutamine, curcumin and L. rhamnosus GG rescued the anxiety and depressive-like phenotype with an efficiency similar to clomipramine. A synergistic effect of the three compounds was observed, suggesting that simultaneous action on different targets is a relevant approach for the management of anxiety-depressive disorders.