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. 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.
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.
How does gut microbiome affect depression?
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.
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.
This cohort study used data from participants in the UK Biobank cohort on over 500 000 participants; 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.
Outcomes were lifetime and recurrent MDD, with 249 metabolites profiled with nuclear magnetic resonance spectroscopy with the Nightingale platform.
How do you fix gut microbiome depression?
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.
After characterizing microbial community membership and dynamics, it is critical to understand the functional activities that ultimately affect host physiology. Gut microbiota are integral to host digestion and nutrition, and they can generate nutrients from substrates that are otherwise indigestible by the host. For instance, xyloglucans are commonly found in dietary vegetables such as lettuce and onions, and the capacity for microbial digestion of xyloglucans was recently mapped to a single locus in a certain species of Bacteroides. The ability to digest xyloglucans was shown to be a relatively rare trait in members of the phylum Bacteroidetes, and the importance of this capability to the human host was demonstrated by analysis of a public metagenome database showing that 92% of individuals contained at least one of these rare Bacteroides species capable of digesting xyloglucans. These findings illustrate how humans have cultivated mutually beneficial relationships with gut microbiota with implications for diet and nutrition.
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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Amin N, Liu J, Bonnechere B, et al. Interplay of Metabolome and Gut Microbiome in Individuals With Major Depressive Disorder vs Control Individuals. JAMA Psychiatry. Published online April 19, 2023. doi:10.1001/jamapsychiatry.2023.0685