Chronically socially isolated mice exhibit depressive-like behavior regulated by the gut microbiota.

Objectives: Chronic loneliness is a widespread issue, and the gut-brain axis is known to be crucial in facilitating communication between the gut and brain. However, the precise mechanism by which chronic loneliness affects the gut-brain axis remains uncertain. Methods: Fourteen 55-week-old Balb/c mice were used in the experiment, with seven mice being randomly assigned to the chronic social isolation (CSI) group. The CSI group mice underwent 12 weeks of isolation to simulate the psychiatric state of a population in prolonged social isolation. The mental state of the CSI mice was assessed through animal behavior analysis, while plasma cytokines were measured using ELISA. Additionally, the composition of the gut microbiota was analyzed using 16S rRNA sequencing, and the metabolite composition of the intestinal contents was examined using nontargeted metabolomics. The Student-T test was used to determine significant mean differences. Results: Mice that were exposed to the CSI exhibited increased immobility time lengths in forced swimming and hanging tail experiments, and decreased movement lengths and number of times traversing the intermediate region, compared to control mice. Additionally, CSI decreased the abundance of the probiotics Ruminococcaceae, Akkermansiaceae, and Christensenellaceae. Additionally, CSI reduced the production of the metabolites oleamide and tryptophan. Furthermore, IL-1β, IL-4, and IL-6 were significantly increased, while TNF-α was significantly decreased. Conclusion: CSI induces a dysbiotic gut microbiota and the production of neurorelated metabolites, which in turn increase inflammatory responses and result in depressive behaviors in CSI mice. Therefore, these findings suggest that the gut microbiota may serve as a target for the treatment of long-term social isolation-induced mental disorders.