Microbiota alteration is associated with the development of stress-induced despair behavior

Depressive disorders often run in families, which, in addition to the genetic component, may point to the microbiome as a causative agent. Here, we employed a combination of behavioral, molecular and computational techniques to test the role of the microbiota in mediating despair behavior. In chronically stressed mice displaying despair behavior, we found that the microbiota composition and the metabolic signature dramatically change. Specifically, we observed reduced Lactobacillus and increased circulating kynurenine levels as the most prominent changes in stressed mice. Restoring intestinal Lactobacillus levels was sufficient to improve the metabolic alterations and behavioral abnormalities. Mechanistically, we identified that Lactobacillus-derived reactive oxygen species may suppress host kynurenine metabolism, by inhibiting the expression of the metabolizing enzyme, IDO1, in the intestine. Moreover, maintaining elevated kynurenine levels during Lactobacillus supplementation diminished the treatment benefits. Collectively, our data provide a mechanistic scenario for how a microbiota player (Lactobacillus) may contribute to regulating metabolism and resilience during stress. Mice were either wild type or SCID genotype and were either kept naïve or treated with an EAE or chronic stress protocol as described in doi: 10.1038/srep43859. Fecal samples were taken at multiple time points after commencement of treatment. Sequencing performed at UVa Genome Analysis & Technology Core, Office of Research Core Administration. University of Virginia Health System, P.O. Box 800741, Charlottesville, VA 22908-0741