TY - JOUR
T1 - Interplay of metabolome and gut microbiome in individuals with major depressive disorder vs control individuals
AU - Amin, Najaf
AU - Liu, Jun
AU - Bonnechere, Bruno
AU - Mahmoudiandehkordi, Siamak
AU - Arnold, Matthias
AU - Batra, Richa
AU - Chiou, Yu Jie
AU - Fernandes, Marco
AU - Ikram, M. Arfan
AU - Kraaij, Robert
AU - Krumsiek, Jan
AU - Newby, Danielle
AU - Nho, Kwangsik
AU - Radjabzadeh, Djawad
AU - Saykin, Andrew J.
AU - Shi, Liu
AU - Sproviero, William
AU - Winchester, Laura
AU - Yang, Yang
AU - Nevado-Holgado, Alejo J.
AU - Kastenmüller, Gabi
AU - Kaddurah-Daouk, Rima
AU - Van Duijn, Cornelia M.
N1 - Metabolomics data is provided by the Alzheimer’s Disease Metabolomics Consortium (ADMC) and funded wholly or in part by the following grants and supplements thereto: National Institute on Aging R01AG046171, RF1AG051550, RF1AG057452, R01AG059093, RF1AG058942, U01AG061359, and U19AG063744 and Foundation for the National Institutes of Health DAOU16AMPA awarded to Dr. Kaddurah-Daouk at Duke University in partnership with a large number of academic institutions.
PY - 2023/6/7
Y1 - 2023/6/7
N2 - 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 = 500000; 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 = 59851; control individuals = 113154). Summary statistics for the metabolites were obtained from OpenGWAS in MRbase (n = 118000). 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 51446 control individuals and 4370 individuals with recurrent MDD compared with 62508 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.
AB - 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 = 500000; 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 = 59851; control individuals = 113154). Summary statistics for the metabolites were obtained from OpenGWAS in MRbase (n = 118000). 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 51446 control individuals and 4370 individuals with recurrent MDD compared with 62508 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.
UR - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10116384/
U2 - 10.1001/jamapsychiatry.2023.0685
DO - 10.1001/jamapsychiatry.2023.0685
M3 - Article
C2 - 37074710
AN - SCOPUS:85160771344
SN - 2168-622X
VL - 80
SP - 597
EP - 609
JO - JAMA Psychiatry
JF - JAMA Psychiatry
IS - 6
ER -