In a recent publication in the Journal of the American Medical Association Psychiatry, researchers conducted a cohort study that sought to find the metabolic signatures of MDD, use Mendelian randomization to clarify the direction of correlations, and assess the interaction between the human gut microbiome and metabolome in the pathogenesis of MDD.

To examine the interaction of the metabolome and the gut microbiome in the pathogenesis of depression, metabolic signatures of the gut microbiome were acquired from a 2019 study performed in Dutch cohorts, and the researchers examined data from March 2021 to December 2021.

The primary outcomes and measures included lifetime MDD and recurrent MDD with 249 metabolites profiled with nuclear magnetic resonance spectroscopy with the Nightingale platform.

The study involved 6,811 individuals diagnosed with lifetime MDD compared with 51,446 control individuals and 4,370 individuals diagnosed with recurrent MDD compared with 62,508 individuals in the control group.

The results revealed that individuals with lifetime MDD were younger (median [interquartile range] age 56 [49-62] years vs. 58 [51-64] years), and 65% were female 4,447 vs. 2,364 [35%]) compared with those in the control group, were more likely to smoke, had a higher level of education, had a higher BMI, were more likely to be sedentary, consumed less alcohol, and were more likely to have a black or mixed racial or ethnic background compared with control individuals. Additionally, of participants with a history of depression, 1,312 (19%) were using antidepressants at the time of evaluation, and individuals with depression more often utilized medication related to gastric diseases, pain, and addiction.

The authors indicated that the metabolic signatures of MDD comprised 124 metabolites spanning the energy and lipid metabolism pathways. The novel findings included 49 metabolites, including those involved in the tricarboxylic acid cycle (i.e., citrate and pyruvate).

The authors indicated that in those with MDD, levels of citrate were significantly diminished (beta [SE], –0.07 [0.02]; FDR = 4 x 10-4), and pyruvate was augmented considerably (beta [SE], 0.04 [0.02]; FDR = 0.02). Moreover, alterations detected in these metabolites, particularly lipoproteins, were consistent with the differential composition of gut microbiota that are species of the order Clostridiales and the phyla Proteobacteria/Pseudomonadota and Bacteroidetes/Bacteroidota. They noted that the microbes involved in such processes are also involved in preserving levels of butyrate, glutamate, serotonin, and gamma-aminobutyric acid, which have all been correlated with long-term depression.

Based on their findings, the authors wrote, “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.”

The authors also indicated that their findings demonstrate that in individuals with MDD, energy metabolism was disrupted and that the interaction of the gut microbiome and blood metabolome may play a part in lipid metabolism in this patient population.

In conclusion, the authors wrote, “This cohort study identified that the metabolites involved in the tricarboxylic acid cycle/energy metabolism were significantly altered in individuals with MDD compared to control individuals. We further showed that the metabolic shift observed in individuals with MDD was consistent with the gut dysbiosis observed in this group, suggesting an interplay of the host gut microbiome and the blood metabolome in individuals with MDD.”

Lastly, they added that additional experimental studies and trials are necessary to determine whether metabolic profiles in patients enhance after intervention with respect to their gut microbiomes.

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