Investigators found that MDD had specific metabolic “signatures” consisting of 124 metabolites that spanned energy and lipid pathways, with some involving the tricarboxylic acid cycle in particular. These changes in metabolites were consistent with differences in composition of several gut microbiota.
The researchers found that fatty acids and intermediate and very large lipoproteins changed in association with the depressive disease process. However, high-density lipoproteins and metabolites in the tricarboxylic acid cycle did not.
“As we wait to establish causal influences through clinical trials, clinicians should advise patients suffering from mood disorders to modify their diet by increasing the intake of fresh fruits, vegetables, and whole grains, as these provide the required fuel/fiber to the gut microbiota for their enrichment, and more short-chain fatty acids are produced for the optimal functioning of the body,” study investigator Najaf Amin, PhD, DSc, senior researcher, Nuffield Department of Population Health, Oxford University, England, told this news organization.
“At the same time, patients should be advised to minimize the intake of sugars and processed foods, which are known to have an inverse impact on the gut microbiome and are associated with higher inflammation,” she said.
The study was published online in JAMA Psychiatry.
MDD poorly understood
Although most antidepressants target the monoamine pathway, “evidence is increasing for a more complex interplay of multiple pathways involving a wide range of metabolic alterations spanning energy and lipid metabolism,” the authors wrote.
Previous research using the Nightingale proton nuclear magnetic resonance (NMR) metabolomics platform showed a “shift” toward decreased levels of high-density lipoproteins (HDLs) and increased levels of very low-density lipoproteins (VLDLs) and triglycerides among patients with depression.
The gut microbiome, which is primarily modulated by diet, “has been shown to be a major determinant of circulating lipids, specifically triglycerides and HDLs, and to regulate mitochondrial function,” the investigators noted. Patients with MDD are known to have disruptions in the gut microbiome.
The gut microbiome may “explain part of the shift in VLDL and HDL levels observed in patients with depression and if the metabolic signatures of the disease based on Nightingale metabolites can be used as a tool to infer the association between gut microbiome and depression.”
Dr. Amin called depression “one of the most poorly understood diseases, as underlying mechanisms remain elusive.”
Large-scale genetic studies “have shown that the contribution of genetics to depression is modest,” she continued. On the other hand, initial animal studies suggest the gut microbiome “may potentially have a causal influence on depression.”
Several studies have evaluated the influence of gut microbiome on depression, “but, due to small sample sizes and inadequate control for confounding factors, most of their findings were not reproducible.”
Harnessing the power of the UK Biobank, the investigators studied 58,257 individuals who were between the ages of 37 and 73 years at recruitment. They used data on NMR spectroscopy–based plasma metabolites in depression. Individuals who didn’t report depression at baseline served as controls.
Logistic regression analysis was used to test the association of metabolite levels with depression in four models, each with an increasing number of covariates.
To identify patterns of correlation in the “metabolic signatures of MDD and the human gut biome,” they regressed the metabolic signatures of MDD on the metabolic signatures of the gut microbiota and then regressed the metabolic signature of gut microbiota on the metabolic signatures of MDD.
Bidirectional 2-sample Mendelian randomization was used to ascertain the direction of the association observed between metabolites and MDD.
Individuals with lifetime and recurrent MDD were compared with controls (6,811 vs. 51,446 and 4,370 vs. 62,508, respectively).
Participants with lifetime MDD were significantly younger (median [IQR] age, 56 [49-62] years vs. 58 [51-64] years) and were more likely to be female in comparison with controls (54% vs. 35%).