Long-lasting Depressive Behavior of Adolescent Chronically Stressed Mice is Mediated by Gut Microbiota Dysbiosis

Depression is one of the most common mental disorders worldwide, and its prevalence sharply rises during adolescence. Adolescence is a particularly sensitive period to the effects of environmental stressors, which can cause persistent depressive behavior extending into adulthood. However, the studies assessing if changes in gut microbiota could be one of the mediators of long-term effects of adolescent stress are scarce. In the present study, we examined enduring effects of adolescent chronic unpredictable stress (CUS) on mice behavior along with alterations in their gut microbiome, by using 16 s rRNA gene sequencing and fecal microbiota transplantation (FMT). CUS mice, as well as naïve mice receiving FMT from stressed animals, showed long-lasting anxiety and depressive-like behavior extending into adulthood. The microbiota dysbiosis in adolescence was characterized by higher abundance of Alloprevotella and lower abundance of Paraprevotella, Parasutterella, Parabacteroides, and undefined genus Rikenellaceae_RC9_gut_group. On the contrary, microbiota dysbiosis in adulthood was characterized by higher abundance of Bacteroides, Enterorhabdus, Marvinbriantia, and Parabacteroides and lower abundance of Akkermansia, Odoribacter, and Rikenella. In particular, depressive-like behavior in adolescence was negatively correlated with Paraprevotella, while depressive-like behavior in adulthood was negatively correlated with Rikenella abundance, in both CUS and FMT mice. Therefore, the transfer of microbiota from mice stressed in adolescence is able to induce long-lasting depressive-like behavior in naïve mice, clearly showing the importance of gut microbiota dysbiosis in adolescence in shaping enduring depressive behavior. Moreover, our results indicate that changes in specific but different bacteria are related to depressive behavior in adolescence and in adulthood.