In a recent study published in Molecular Psychiatry, researchers used ultra-high-performance liquid chromatography (UHPLC) and mass spectrometry-based Metabolon platform to identify and characterize circulating metabolites associated with depression.

Study: Circulating metabolites modulated by diet are associated with depression. Image Credits: ArtemisDiana/Shutterstock.com

Background

Circulating metabolites might be involved in depression as they are involved in the gut-brain axis, the bi-directional signaling between the gut microbiome and the brain. As the prevalence of depression surges worldwide, more insights into its pathogenesis are needed. Also, there is a need for more effective drugs to treat depression.

Since the metabolome captures the downstream effects of genes, lifestyle factors, and medication use, it might be a valuable tool to uncover biological mechanisms underlying this complex disease.

About the study

In the present study, researchers used the Metabolon platform to simultaneously test 806 metabolites encompassing biochemical processes involving lipid, amino-acid, glucose, and vitamin metabolism for their association with depression.

The team built a conservative model adjusted for all well-recognized confounders, such as lifestyle factors and cardiovascular and antidepressant medication use.

This metabolome-wide association analysis of depression-related metabolites was performed in 13,596 individuals from five European cohorts, namely - the Rotterdam Study, the Cooperative Health Research in the Region of Augsburg (KORA) study, the Study of Health in Pomerania (SHIP-TREND), the Netherlands Epidemiology of Obesity (NEO) study, and the European Prospective Investigation into Cancer (EPIC)-Norfolk Study.

Further, the team used Mendelian Randomization (MR) to infer causal associations using the NIHR BioResource (NBR) and summary statistics of the genome-wide association study (GWAS) of depression, NBR – Rare Disease Study. This multi-center study was a whole-exome and whole-genome sequencing study covering as many as 13,600 patients.

Furthermore, the team elucidated causal relationships to identify possible drug targets for depression, examined the association of dietary sources of the metabolites associated with depression, and examined the impact of different antidepressant therapies on depression-related metabolites.

Finally, they attempted to identify the gut microbiota involved in the metabolism of all identified metabolites.

Results

The authors identified new associations with depression for six metabolites, as follows: i) retinol (vitamin A); ii) 4-hydroxycoumarin; iii) 2-amino octanoate (a lipid); iv) 10-undecenoate (11:1n1) [a lipid]; v) 1-palmitoyl-2-palmitoleoyl-GPC (16:0/16:1), also known as lecithin (a lipid); and vi) 1-linoleoyl-GPA (18:2).

Furthermore, they confirmed the association of depressive symptoms with two already known metabolites, hippurate and mannitol/sorbitol (sugar alcohols). Notably, the association of depression was the most robust for xenobiotics, hippurate, and 4-hydroxycoumarin.

Intriguingly, retinol (an active form of vitamin A) and its lipid-soluble derivatives, retinoids, can penetrate the blood-brain barrier (BBB). They are essential for brain development and functioning. However, its excess is neurotoxic and may result in shrinkage of brain areas relevant to stress and depression. 

In the current study, the authors found a link between depression and higher levels of retinol in blood in a cohort of depressed people in the general population, highlighting the need for intervention studies prospectively evaluating how vitamin A reduction affects patients with depression.

There have been case reports of the resolution of depressive symptoms with discontinuation of vitamin A, implying that depression might be a side effect of vitamin A intake.

Next, the authors noted an association of depression with 4-hydroxycoumarin, a fungal derivative of coumarin found naturally in plants and spices. It converts into dicoumarol (warfarin), which inhibits vitamin K synthesis in the human body. Studies have shown that antidepressants interact with warfarin, which depletes circulating 4-hydroxycoumarin, causing thromboembolism. 

In the brain, cellular membranes of glial and neuronal cells have high concentrations of sphingolipids, for which vitamin K is a precursor. Although the authors did not see an association of circulating sphingolipids present on the Metabolon platform with depressive symptoms, 4-hydroxycoumarin in the blood might be affecting the sphingolipid metabolism in the brain.

Further, the current study platform also identified an association of depression with high circulating levels of lecithin in depressed individuals from the general population, which may cause depression by increasing the production of acetylcholine in the brain. The other three lipids, 2-amino octanoate, 10-undecenoate (11:1n1), and 1-linoleoyl-GPA (18:2), were also associated with depression but had a negative correlation.

Hippurate, a benzoate and polyphenol derivative, is a metabolomic marker of gut microbiome diversity. Fruits, vegetables, nuts, and legumes are good dietary sources of hippurate. The Metabolome platform identified the decreased levels of hippurate in depressed individuals tested in this study. In addition, adequate consumption of foods rich in hippurate significantly reduced inflammation among the study population. Yet, future studies should evaluate whether hippurate mediates this reduction. These findings are consistent with the observations made in the United Kingdom BioBank study, which showed that decreased fresh fruit intake resulted in depression. 

Furthermore, MR analysis suggested that low hippurate levels might be involved in the causal pathway leading towards depression, highlighting putative actionable targets for depression prevention that are easily modifiable through diet interventions. However, these findings require further evaluation in a clinical trial. 

Interestingly, several previous studies have associated several species of Bacteroides, Lactobacillus, Alistipes, and Bifidobacterium with depression. Thus, more work on the role of the gut microbiome, circulating mannitol, and depression are urgently needed.

Conclusion

To summarize, the researchers analyzed 806 circulating metabolites in this study using an untargeted metabolomics platform in 13,596 individuals and identified six new metabolites associated with depression. As most of these metabolites are diet supplemented, altering a patient's diet could be an effective therapeutic option for patients with depression.

Furthermore, the study findings pointed to associations of depression with metabolites from the amino-acid pathways, including serotonin, leucine, kynurenate, and glutamate, all related to antidepressant medication use.

Journal reference:

• van der Spek A, Stewart ID, Kühnel B, et al. (2023). Circulating metabolites modulated by diet are associated with depression. Mol Psychiatry. doi: 10.1038/s41380-023-02180-2. https://www.nature.com/articles/s41380-023-02180-2