Main idea: Unpredictable chronic mild stress, diet, and gut microbiota generate a pathological feed-forward loop that contributes to despair behavior via the central endocannabinoid system.
Depression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota. In a mouse model of depression, mice display phenotypic alterations, which could be transferred from donors to naive recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in endocannabinoid signaling. The adverse effects of unpredictable chronic mild stress-transferred microbiota were alleviated by selectively enhancing the central endocannabinoid or by complementation with a strain of the Lactobacilli genus.