Altered Microbiota Composition Mediates Depressive Behavior During Chronic Stress

Depressive disorders often run in families. In addition to the genetic component, this may point to the microbiome as a causative agent. In my thesis work, I employed a combination of behavioral, molecular and computational techniques to test the role of the microbiota in mediating stress-induced despair behavior, as an animal model for depression. 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.