Interplay of Human Metabolome and Gut Microbiome in Major Depression

The pathogenesis of depression is complex involving the interplay of genetic and environmental risk factors including diet, lifestyle and the gut microbiome. Metabolomics studies may shed light on the interplay of these factors. We study over 63,000 individuals including 8462 cases with a lifetime major depression and 5403 cases with recurrent major depression from the UK Biobank profiled for nuclear magnetic resonance (NMR) spectroscopy based metabolites with the Nightingale platform. We identify 124 metabolites that are associated with major depressive disorder (MDD), including 49 novel associations. No differences were seen between the metabolic profiles of lifetime and recurrent MDD. We find that metabolites involved in the tricarboxylic acid (TCA) cycle are significantly altered in patients with MDD. Integrating the metabolic signatures of major depression and the gut microbiome, we find that the gut microbiome might play an important role in the relationship between these metabolites, lipoproteins in particular, and MDD. The order Clostridiales, and the phyla Proteobacteria and Bacteroidetes were the most important taxa, which link the lipoprotein particles to MDD. Our study shows that at the molecular level energy metabolism is disturbed in patients with MDD and that the interplay between the gut microbiome and blood metabolome may play a key role in the pathogenesis of MDD.