Depression: could the microbiota-metabolism axis be involved?

Major depressive disorder (MDD) is not limited to affective and cognitive symptoms; it is also associated with substantial disturbances in energy metabolism, including blood glucose dysregulation, mitochondrial dysfunction, and alterations in key metabolic pathways such as glycolysis, the Krebs cycle, and amino acid metabolism. At the same time, gut dysbiosis is frequently observed in patients with MDD, with alterations in specific bacterial species, including Faecalibacterium prausnitzii and Escherichia coli, that may indirectly influence host metabolic pathways. This led the researchers¹ to ask: could the gut microbiota influence the host’s energy homeostasis and in turn, alleviate depression? 

A microbiota-metabolites-depressive phenotype axis

Analysis of serum and fecal samples from 100 patients with depression and 68 healthy controls revealed significant disruptions in key energy metabolism pathways in individuals with depression: 14 metabolites were significantly altered, including lower serum levels of glucose, ornithine, AMP, and cyclic AMP, and higher levels of lactate, glutamate, arginine, citrulline, and isocitrate. Several of these metabolites were also associated with measures of depression, anxiety, and cognitive function, suggesting a potential link between these metabolic alterations and the severity of depressive symptoms.

Most importantly, the authors identified 92 bacterial species that differed significantly in individuals with depression, including 50 that were overrepresented and 42 that were underrepresented, particularly within the Firmicutes phylum. The researchers also identified 36 bacterial species whose abundance was potentially associated with mitochondrial fatty acid synthesis, ketogenesis, and amino acid metabolism. Among these, 28 species appeared to be involved in the relationship between the gut microbiota, energy metabolites, and mood, cognitive function, and anxiety. These findings thus point to a potential “gut microbiota–metabolites–depressive phenotype” axis, in which certain bacterial metabolites act as mediators.

Preclinical evidence supporting a causal role for the gut microbiota

As is often the case in microbiota research, an important question remained: were these findings simply correlational, or could the gut microbiota play a causal role? To investigate this, the researchers first collected samples of the gut microbiota from mice and then subjected them to 14 days of chronic stress, which induced depressive-like behaviors (including reduced sucrose preference and increased immobility) as well as impaired memory. An autologous fecal microbiota transplantation (FMT) was performed after each episode of stress. FMT reduced depressive-like behaviors and improved memory, while also restoring the composition and function of the gut microbiota. However, the intestinal barrier remained impaired. Most importantly, FMT corrected several metabolic disturbances—including alterations in glucose, lactate, glutamate, and the ornithine cycle—and restored mitochondrial structural integrity in the prefrontal cortex and hippocampus of the mice. According to the authors, these findings highlight the role of the gut microbiota in regulating energy metabolism in depressive disorders. 
Although the experiment has so far been conducted only in mice, they raise an intriguing question: could early autologous FMT one day become a therapeutic approach for depression in humans? This remains an important avenue for future research.

In the meantime, maintaining a balanced diet that includes some citrus fruits and engaging in regular physical activity such as running, may be beneficial.