Identification of a Signaling Mechanism by Which the Microbiome Regulates Th17 Cell-Mediated Depressive-Like Behaviors in Mice

Eva M Medina-Rodriguez; Derik Madorma; Gregory O'Connor; Brittany L Mason; Dongmei Han; Sapna K Deo; Mark Oppenheimer; Charles B Nemeroff; Madhukar H Trivedi; Sylvia Daunert; Eléonore Beurel

doi:10.1176/appi.ajp.2020.19090960

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Identification of a Signaling Mechanism by Which the Microbiome Regulates Th17 Cell-Mediated Depressive-Like Behaviors in Mice

Journal article

Peer reviewed

Identification of a Signaling Mechanism by Which the Microbiome Regulates Th17 Cell-Mediated Depressive-Like Behaviors in Mice

Eva M Medina-Rodriguez, Derik Madorma, Gregory O'Connor, Brittany L Mason, Dongmei Han, Sapna K Deo, Mark Oppenheimer, Charles B Nemeroff, Madhukar H Trivedi, Sylvia Daunert, …

The American journal of psychiatry, Vol.177(10), pp.974-990

2020-10-01

DOI: https://doi.org/10.1176/appi.ajp.2020.19090960

PMID: 32731813

Abstract

Th17 Cells - physiology

Quorum Sensing

Depressive Disorder, Major - metabolism

Humans

Interleukin-17 - analysis

Mice, Inbred C57BL

Middle Aged

Male

Gastrointestinal Microbiome - physiology

Gastrointestinal Microbiome - genetics

Depression - metabolism

Animals

Feces - chemistry

Flow Cytometry

Th17 Cells - metabolism

RNA, Ribosomal, 16S - genetics

Adult

Female

Mice

Real-Time Polymerase Chain Reaction

Helplessness, Learned

Serum Amyloid A Protein - analysis

Disease Models, Animal

Microbiota dysbiosis has been linked to major depressive disorder, but the mechanisms whereby the microbiota modulates mood remain poorly understood. The authors tested whether specific changes in the microbiome modulate depressive-like behaviors. Stools from learned helpless, non-learned helpless, and non-shocked mice were analyzed by V4 16S RNA sequencing to identify gut bacteria associated with learned helplessness and to quantify the level of the quorum-sensing molecule autoinducer-2 (AI-2). T cells were analyzed by flow cytometry, and serum amyloid proteins (SAA) were analyzed by quantitative real-time polymerase chain reaction. Fecal transfer approach and administration of oleic acid and AI-2 were used to determine the effects of the microbiome and quorum-sensing molecules on depressive-like behaviors. Mice deficient in segmented filamentous bacteria (SFB) were resilient to the induction of depressive-like behavior, and were resensitized when SFB was reintroduced in the gut. SFB produces the quorum-sensing AI-2 and promotes the production of SAA1 and SAA2 by the host, which increases T helper 17 (Th17) cell production. Th17 cells were required to promote depressive-like behaviors by AI-2, as AI-2 administration did not promote susceptibility to depressive-like behaviors or SAA1 and SAA2 production in Th17-deficient mice after stress. Oleic acid, an AI-2 inhibitor, exhibited antidepressant properties, reducing depressive-like behavior, intestinal SAA1 and SAA2 production, and hippocampal Th17 cell accumulation. Stool samples from 10 people with current depressive symptoms and 10 matched healthy control subjects were analyzed as well. Patients with current major depressive disorder exhibited increased fecal interleukin 17A, SAA, and SFB levels. The study results reveal a novel mechanism by which bacteria alter mood.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.120 Inflammatory Bowel Diseases & Infections; 1.120.384 Gut Microbiota
Web Of Science research areas: Psychiatry
ESI research areas: Psychiatry/Psychology

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Title: Identification of a Signaling Mechanism by Which the Microbiome Regulates Th17 Cell-Mediated Depressive-Like Behaviors in Mice
Creators: Eva M Medina-Rodriguez - Department of Psychiatry and Behavioral Sciences (Medina-Rodriguez, Han, Oppenheimer, Beurel), Department of Biochemistry and Molecular Biology (Madorma, O'Connor, Deo, Daunert, Beurel), the Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute (Madorma, O'Connor, Deo, Daunert), and the University of Miami Clinical and Translational Science Institute (Daunert), Miller School of Medicine, University of Miami, Miami; Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas (Mason, Trivedi); and Department of Psychiatry, Mulva Clinic for Neurosciences, University of Texas Dell Medical School in Austin (Nemeroff)
Derik Madorma - Department of Psychiatry and Behavioral Sciences (Medina-Rodriguez, Han, Oppenheimer, Beurel), Department of Biochemistry and Molecular Biology (Madorma, O'Connor, Deo, Daunert, Beurel), the Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute (Madorma, O'Connor, Deo, Daunert), and the University of Miami Clinical and Translational Science Institute (Daunert), Miller School of Medicine, University of Miami, Miami; Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas (Mason, Trivedi); and Department of Psychiatry, Mulva Clinic for Neurosciences, University of Texas Dell Medical School in Austin (Nemeroff)
Gregory O'Connor - Department of Psychiatry and Behavioral Sciences (Medina-Rodriguez, Han, Oppenheimer, Beurel), Department of Biochemistry and Molecular Biology (Madorma, O'Connor, Deo, Daunert, Beurel), the Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute (Madorma, O'Connor, Deo, Daunert), and the University of Miami Clinical and Translational Science Institute (Daunert), Miller School of Medicine, University of Miami, Miami; Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas (Mason, Trivedi); and Department of Psychiatry, Mulva Clinic for Neurosciences, University of Texas Dell Medical School in Austin (Nemeroff)
Brittany L Mason - Department of Psychiatry and Behavioral Sciences (Medina-Rodriguez, Han, Oppenheimer, Beurel), Department of Biochemistry and Molecular Biology (Madorma, O'Connor, Deo, Daunert, Beurel), the Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute (Madorma, O'Connor, Deo, Daunert), and the University of Miami Clinical and Translational Science Institute (Daunert), Miller School of Medicine, University of Miami, Miami; Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas (Mason, Trivedi); and Department of Psychiatry, Mulva Clinic for Neurosciences, University of Texas Dell Medical School in Austin (Nemeroff)
Dongmei Han - Department of Psychiatry and Behavioral Sciences (Medina-Rodriguez, Han, Oppenheimer, Beurel), Department of Biochemistry and Molecular Biology (Madorma, O'Connor, Deo, Daunert, Beurel), the Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute (Madorma, O'Connor, Deo, Daunert), and the University of Miami Clinical and Translational Science Institute (Daunert), Miller School of Medicine, University of Miami, Miami; Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas (Mason, Trivedi); and Department of Psychiatry, Mulva Clinic for Neurosciences, University of Texas Dell Medical School in Austin (Nemeroff)
Sapna K Deo - Department of Psychiatry and Behavioral Sciences (Medina-Rodriguez, Han, Oppenheimer, Beurel), Department of Biochemistry and Molecular Biology (Madorma, O'Connor, Deo, Daunert, Beurel), the Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute (Madorma, O'Connor, Deo, Daunert), and the University of Miami Clinical and Translational Science Institute (Daunert), Miller School of Medicine, University of Miami, Miami; Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas (Mason, Trivedi); and Department of Psychiatry, Mulva Clinic for Neurosciences, University of Texas Dell Medical School in Austin (Nemeroff)
Mark Oppenheimer - Department of Psychiatry and Behavioral Sciences (Medina-Rodriguez, Han, Oppenheimer, Beurel), Department of Biochemistry and Molecular Biology (Madorma, O'Connor, Deo, Daunert, Beurel), the Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute (Madorma, O'Connor, Deo, Daunert), and the University of Miami Clinical and Translational Science Institute (Daunert), Miller School of Medicine, University of Miami, Miami; Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas (Mason, Trivedi); and Department of Psychiatry, Mulva Clinic for Neurosciences, University of Texas Dell Medical School in Austin (Nemeroff)
Charles B Nemeroff - Department of Psychiatry and Behavioral Sciences (Medina-Rodriguez, Han, Oppenheimer, Beurel), Department of Biochemistry and Molecular Biology (Madorma, O'Connor, Deo, Daunert, Beurel), the Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute (Madorma, O'Connor, Deo, Daunert), and the University of Miami Clinical and Translational Science Institute (Daunert), Miller School of Medicine, University of Miami, Miami; Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas (Mason, Trivedi); and Department of Psychiatry, Mulva Clinic for Neurosciences, University of Texas Dell Medical School in Austin (Nemeroff)
Madhukar H Trivedi - Department of Psychiatry and Behavioral Sciences (Medina-Rodriguez, Han, Oppenheimer, Beurel), Department of Biochemistry and Molecular Biology (Madorma, O'Connor, Deo, Daunert, Beurel), the Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute (Madorma, O'Connor, Deo, Daunert), and the University of Miami Clinical and Translational Science Institute (Daunert), Miller School of Medicine, University of Miami, Miami; Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas (Mason, Trivedi); and Department of Psychiatry, Mulva Clinic for Neurosciences, University of Texas Dell Medical School in Austin (Nemeroff)
Sylvia Daunert - Department of Psychiatry and Behavioral Sciences (Medina-Rodriguez, Han, Oppenheimer, Beurel), Department of Biochemistry and Molecular Biology (Madorma, O'Connor, Deo, Daunert, Beurel), the Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute (Madorma, O'Connor, Deo, Daunert), and the University of Miami Clinical and Translational Science Institute (Daunert), Miller School of Medicine, University of Miami, Miami; Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas (Mason, Trivedi); and Department of Psychiatry, Mulva Clinic for Neurosciences, University of Texas Dell Medical School in Austin (Nemeroff)
Eléonore Beurel - Department of Psychiatry and Behavioral Sciences (Medina-Rodriguez, Han, Oppenheimer, Beurel), Department of Biochemistry and Molecular Biology (Madorma, O'Connor, Deo, Daunert, Beurel), the Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute (Madorma, O'Connor, Deo, Daunert), and the University of Miami Clinical and Translational Science Institute (Daunert), Miller School of Medicine, University of Miami, Miami; Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas (Mason, Trivedi); and Department of Psychiatry, Mulva Clinic for Neurosciences, University of Texas Dell Medical School in Austin (Nemeroff)
Publication Details: The American journal of psychiatry, Vol.177(10), pp.974-990
Publisher: United States
Grant note: R01 MH104656 / NIMH NIH HHS R01 GM127706 / NIGMS NIH HHS R01 GM047915 / NIGMS NIH HHS R01 GM114321 / NIGMS NIH HHS R01 MH110415 / NIMH NIH HHS
Academic Unit: Leadership Department; Miller School of Medicine; Biochemistry & Molecular Biology Research; UMMG Dept of Psychiatry & Behavioral Sciences
Language: English
Resource Type: Journal article
PMID: 32731813
Record Identifier: 991031576423602976