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Original Investigation
April 19, 2023

Interplay of Metabolome and Gut Microbiome in Individuals With Major Depressive Disorder vs Control Individuals

Author Affiliations
  • 1Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
  • 2REVAL Rehabilitation Research Center, Faculty of Rehabilitation Sciences, Hasselt University, Hasselt, Belgium
  • 3Technology-Supported and Data-Driven Rehabilitation, Data Sciences Institute, Hasselt University, Hasselt, Belgium
  • 4Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina
  • 5Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
  • 6Institute for Computational Biomedicine, Englander Institute for Precision Medicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York
  • 7Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
  • 8Department of Psychiatry, University of Oxford, Oxford, United Kingdom
  • 9Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 10Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 11Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis
  • 12Department of Computer Science and Engineering, Shanghai Jiao Tong University, Shanghai, China
JAMA Psychiatry. 2023;80(6):597-609. doi:10.1001/jamapsychiatry.2023.0685
Key Points

Question  What are the metabolic signatures of major depressive disorder (MDD), what direction do they take, and how does the host gut microbiome contribute to these signatures?

Findings  In this cohort study, metabolites in the energy and lipid metabolism processes were associated with MDD. Changes in lipid metabolism were consistent with the gut dysbiosis observed in individuals with MDD.

Meaning  Energy and lipid metabolism was disrupted in individuals with MDD, the latter of which may be explained by gut dysbiosis observed in individuals with MDD.


Importance  Metabolomics reflect the net effect of genetic and environmental influences and thus provide a comprehensive approach to evaluating the pathogenesis of complex diseases, such as depression.

Objective  To identify the metabolic signatures of major depressive disorder (MDD), elucidate the direction of associations using mendelian randomization, and evaluate the interplay of the human gut microbiome and metabolome in the development of MDD.

Design, Setting and Participants  This cohort study used data from participants in the UK Biobank cohort (n = 500 000; aged 37 to 73 years; recruited from 2006 to 2010) whose blood was profiled for metabolomics. Replication was sought in the PREDICT and BBMRI-NL studies. Publicly available summary statistics from a 2019 genome-wide association study of depression were used for the mendelian randomization (individuals with MDD = 59 851; control individuals = 113 154). Summary statistics for the metabolites were obtained from OpenGWAS in MRbase (n = 118 000). To evaluate the interplay of the metabolome and the gut microbiome in the pathogenesis of depression, metabolic signatures of the gut microbiome were obtained from a 2019 study performed in Dutch cohorts. Data were analyzed from March to December 2021.

Main Outcomes and Measures  Outcomes were lifetime and recurrent MDD, with 249 metabolites profiled with nuclear magnetic resonance spectroscopy with the Nightingale platform.

Results  The study included 6811 individuals with lifetime MDD compared with 51 446 control individuals and 4370 individuals with recurrent MDD compared with 62 508 control individuals. Individuals with lifetime MDD were younger (median [IQR] age, 56 [49-62] years vs 58 [51-64] years) and more often female (4447 [65%] vs 2364 [35%]) than control individuals. Metabolic signatures of MDD consisted of 124 metabolites spanning the energy and lipid metabolism pathways. Novel findings included 49 metabolites, including those involved in the tricarboxylic acid cycle (ie, citrate and pyruvate). Citrate was significantly decreased (β [SE], −0.07 [0.02]; FDR = 4 × 10−04) and pyruvate was significantly increased (β [SE], 0.04 [0.02]; FDR = 0.02) in individuals with MDD. Changes observed in these metabolites, particularly lipoproteins, were consistent with the differential composition of gut microbiota belonging to the order Clostridiales and the phyla Proteobacteria/Pseudomonadota and Bacteroidetes/Bacteroidota. Mendelian randomization suggested that fatty acids and intermediate and very large density lipoproteins changed in association with the disease process but high-density lipoproteins and the metabolites in the tricarboxylic acid cycle did not.

Conclusions and Relevance  The study findings showed that energy metabolism was disturbed in individuals with MDD and that the interplay of the gut microbiome and blood metabolome may play a role in lipid metabolism in individuals with MDD.

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1 Comment for this article
Interplay of Metabolome and Gut Microbiome in Individuals With Major Depressive Disorder
Anne Provet, Post. Doc in Psych/Epi | Private Practice
The authors indicate some interesting associations but nowhere in the design or results are there any indications of causality. Maybe depressed people have worse diets, gain weight, binge eat, have prolonged exposure to stress hormones, neurotransmitter disruptions, drug exposures...and any of these could in turn disrupt their gut. While the authors are careful not to make assumptions of causation, the secondary postings and search driven bites should avoid misleading impressions.