Abstract
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.
Highlights
Depressive disorders often run in families, which, in addition to the genetic component, may point to the microbiome as a causative agent
Microbiota composition is altered by unpredictable chronic mild stress
Our results demonstrate that microbiome homeostasis was robustly altered in animals undergoing unpredictable chronic mild stress (UCMS), with a consistent decrease in Lactobacilli
Summary
Depressive disorders often run in families, which, in addition to the genetic component, may point to the microbiome as a causative agent. In chronically stressed mice displaying despair behavior, we found that the microbiota composition and the metabolic signature dramatically change. While improved diagnosis led to appreciation of the frequency of the disorder, better understanding of the mechanisms leading to depression is needed for the development of new therapeutic approaches for this debilitating disease. Based on both human and animal studies, several hypotheses have been proposed to underlie the etiology of depression, including monoamine deficiency, stress response dysregulation, neuronal plasticity deficits, and inflammation[1,2,3]. Therapeutic administration of L. reuteri to stressed mice improves metabolic homeostasis and corrects stress-induced despair behaviors
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