TY - JOUR
T1 - Identification of a signaling mechanism by which the microbiome regulates Th17 cell-mediated depressive-like behaviors in mice
AU - Medina-Rodriguez, Eva M.
AU - Madorma, Derik
AU - O'Connor, Gregory
AU - Mason, Brittany L.
AU - Han, Dongmei
AU - Deo, Sapna K.
AU - Oppenheimer, Mark
AU - Nemeroff, Charles B.
AU - Trivedi, Madhukar H.
AU - Daunert, Sylvia
AU - Beurel, Eléonore
N1 - Funding Information:
The authors thank Dr. Richard Jope for his constructive comments on the manuscript, Dr. Sue Michalek for her valuable help, and Dr. Elson for providing the SFB monocolonized feces. Dr. Nemeroff has received grants or research support from NIH and the Stanley Medical Research Institute; he has served as a consultant for Acadia Pharmaceuticals, Bracket (Clintara), EMA Wellness, Fortress Biotech, Gerson Lehrman Group, Intra-Cellular Therapies, Janssen Research and Development, Magstim, Navitor Pharmaceuticals, Signant Health, Sumitomo Dainippon Pharma, Sunovion Pharmaceuticals, Taisho Pharmaceutical, Takeda, TC MSO, and Xhale; he is a stockholder in AbbVie, Antares, Celgene, Corcept Therapeutics, BI Gen Holdings, EMA Wellness, OPKO Health, Seattle Genetics, TC MSO, Trends in Pharma Development, and Xhale; he has served on scientific advisory boards for the Anxiety Disorders Association of America (ADAA), the American Foundation for Suicide Prevention (AFSP), Bracket (Clintara), the Brain and Behavior Research Foundation, the Laureate Institute for Brain Research, Signant Health, Skyland Trail, and Xhale and on boards of directors for the ADAA, the AFSP, Gratitude America, and Xhale Smart, Inc.; he has income sources or equity of $10,000 or more from American Psychiatric Publishing, Bracket (Clintara), CME Outfitters, EMA Wellness, Intra-Cellular Therapies, Magstim, Signant Health, Takeda, and Xhale; and he has patents on a method and devices for transdermal delivery of lithium (US 6,375,990B1), a method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2), and compounds, compositions, methods of synthesis, and methods of treatment (CRF receptor binding ligand) (US 8,551, 996 B2). Dr. Trivedi has served as a consultant or on advisory boards for AcademyHealth, Alkermes, Akili Interactive, Allergan Pharmaceuticals, Arcadia Pharmaceuticals, ACI Clinical, Alto Neuroscience, Axsome Therapeutics, the American Society of Clinical Psychopharmacology (speaking fees and reimbursement), the American Psychiatric Association (Deputy Editor for the American Journal of Psychiatry), Avanir Pharmaceuticals, Boehringer Ingelheim, Janssen Pharmaceutical, Jazz Pharmaceutical, Johnson & Johnson Pharmaceutical Research and Development, Lundbeck Research USA, Medscape, Navitor, Otsuka America Pharmaceutical, Perception Neuroscience Holdings, Pharmerit International, Sage Therapeutics, and Takeda Global Research; he has received grants from the Cancer Prevention and Research Institute of Texas, NIDA, NIH, Johnson & Johnson, Janssen Research and Development, and the Patient-Centered Outcomes Research Institute; and he has received editorial compensation from Healthcare Global Village, Engage Health Media, and Oxford University Press. The other authors report no financial relationships with commercial interests. Received September 19, 2019; revisions received January 8, February 21, and April 1, 2020; accepted April 3, 2020; published online July 31, 2020.
Funding Information:
SupportedbyNIHgrantsMH104656andMH110415.Drs.DeoandDaunert thank the National Institute of General Medical Sciences (grants R01GM047915 and R01GM127706) and the National Science Foundation (grants CHE-1506740 and ECC-08017788) for funding support. Dr. Daunert acknowledges support from the Lucille P. Markey Chair of the University of Miami. Dr. Trivedi acknowledges support from the Hersh Foundation and the Betty Jo Hay Distinguished Chair in Mental Health at UT Southwestern Medical Center.
Funding Information:
Supported by NIH grants MH104656 and MH110415. Drs. Deo and Daunert thank the National Institute of General Medical Sciences (grants R01GM047915 and R01GM127706) and the National Science Foundation (grants CHE-1506740 and ECC-08017788) for funding support. Dr. Daunert acknowledges support from the Lucille P. Markey Chair of the University of Miami. Dr. Trivedi acknowledges support from the Hersh Foundation and the Betty Jo Hay Distinguished Chair in Mental Health at UT Southwestern Medical Center.
PY - 2020/10
Y1 - 2020/10
N2 - Objective: 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. Methods: 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. Results: 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. Conclusions: The study results reveal a novel mechanism by which bacteria alter mood.
AB - Objective: 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. Methods: 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. Results: 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. Conclusions: The study results reveal a novel mechanism by which bacteria alter mood.
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U2 - 10.1176/appi.ajp.2020.19090960
DO - 10.1176/appi.ajp.2020.19090960
M3 - Article
C2 - 32731813
AN - SCOPUS:85092271026
VL - 177
SP - 974
EP - 990
JO - American Journal of Psychiatry
JF - American Journal of Psychiatry
SN - 0002-953X
IS - 10
ER -