title: Microbiota alteration is associated with the development of stress-induced despair behavior.
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.
authors.affiliation: Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA, 22904, USA.|Department of Neuroscience, University of Virginia, Charlottesville, VA, 22904, USA.|Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
authors.forename: Ioana A
authors.initials: IA
authors.lastname: Marin
authors.affiliation: Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA, 22904, USA.|Department of Neuroscience, University of Virginia, Charlottesville, VA, 22904, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Goertz
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA, 22904, USA.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Ren
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908, USA.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Farber
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA, 22904, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Wu
authors.affiliation: Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA, 22904, USA.|Department of Neuroscience, University of Virginia, Charlottesville, VA, 22904, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Overall
authors.affiliation: Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA, 22904, USA.|Department of Neuroscience, University of Virginia, Charlottesville, VA, 22904, USA.|Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kipnis
authors.affiliation: Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA, 22904, USA.|Department of Neuroscience, University of Virginia, Charlottesville, VA, 22904, USA.|Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
authors.forename: Alban
authors.initials: A
authors.lastname: Gaultier
mesh_terms: D000818:Animals; D003866:Depressive Disorder / Q000503:physiopathology* / Q000523:psychology; D000069196:Gastrointestinal Microbiome / Q000235:genetics / Q000502:physiology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000382:microbiology; D007737:Kynurenine / Q000097:blood / Q000378:metabolism; D007778:Lactobacillus / Q000145:classification / Q000235:genetics / Q000502:physiology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011157:Population Dynamics; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D017422:Sequence Analysis, DNA; D013315:Stress, Psychological / Q000503:physiopathology* / Q000523:psychology
chemical_list: C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012336:RNA, Ribosomal, 16S; D007737:Kynurenine