Your Mood Is Influenced by What You Feed Your Microbiome

Depression is one of the most common psychiatric disorders. Probably everyone knows someone who suffers from depressive symptoms. In addition, the recent COVID-19 pandemic made depression more common worldwide. Despite its prevalence, the neurochemical mechanisms underlying depression remain unknown. This may explain why our current treatment options are so ineffective for most patients. The heritability of depression is estimated to be around 40 percent, yet the specific genetic variants responsible have not been identified. Some environmental risk factors have also been identified, including low education level (because of depression), smoking (as a form of self-medication), and diet.

The evidence that diet influences mood has become compelling with recent studies showing the role of the gut microbiome. Whatever improves gut health decreases the risk of depression. Our gut microbiome makes us happy when we consume fresh fruits, vegetables, whole grains, fish, and antioxidant-rich foods. In contrast, consumption of red or processed meat, refined grains, sweets, artificial sweeteners, and high-fat foods leads to an increased risk of depression. Many large clinical trials have shown that dietary interventions significantly reduce the risk of depression, especially in women.

The challenge is to understand the mechanistic link between what we eat and how the microbiome responds. We know that the microbiome communicates with the brain to influence mood and mental health and that this communication is bi-directional. Unfortunately, a full understanding of the nature of this communication remains elusive.

Some studies suggest that depression is associated with increased plasma levels of glutamate, lactate, and a few other amino acids often derived from red meat. Other studies have reported that decreased levels of certain amino acids, kynurenine (a metabolite of serotonin), hippurate, and the neurotransmitter GABA are associated with depression. The challenge is knowing whether the complex multitude of changes are causal or a consequence of the depression.

One recent study examined fluctuations in over 800 chemicals in the blood of almost 14,000 people. The authors looked for causal relationships and the dietary sources of those metabolites that correlated with depression. To delineate causality, the authors examined the impact of different types of antidepressant therapy on the levels of these dietary metabolites. Finally, they identified the gut microbiota most likely responsible for the changes in the identified metabolites.

The results of this massive undertaking were the identification of a novel association between depression and five microbiome metabolites, including 4-hydroxycoumarin, 2-amino octanoate, 10-undecenoate (11:1n1), 1-palmitoyl-2-palmitoleoyl-GPC (16:0/16:1), 1-linoleoyl-GPA (18:2). They confirmed the strongest association of two metabolites, hippurate and mannitol, with depression symptoms.

The authors concluded that decreased hippurate levels cause depression. Decreased urine and plasma levels of hippurate have consistently been associated with unipolar and bipolar depression in several studies. Hippurate is derived from the combination of benzoate and polyphenols and is a marker of gut microbiome diversity, fruit and vegetable intake, and diet quality. These results are consistent with previous reports that high consumption of fruits, vegetables, nuts, and legumes is associated with a reduced risk of depression. Most importantly, the authors confirmed that hippurate levels can be increased by treatment with the antidepressant escitalopram.

The consumption of dietary sources of retinol (aka, Vitamin A), and 1-palmitoyl-2-palmitoleoylGPC (often a sign of a fatty liver and predictive of ischemic stroke) was significantly associated with higher depressive symptoms and elevated levels of inflammatory markers in the blood. The connection with vitamin A is interesting since vitamin A intoxication is associated with symptoms of depression. Depressive symptoms resolved upon discontinuation of vitamin A, implying that depression may be a side effect of increased dietary intake of vitamin A. Many vitamins have bi-directional, direct, or indirect effects on the gut microbiome.

The study also discovered that increased levels of mannitol or sorbitol (common artificial sweeteners) were associated with depression. Higher levels of sorbitol in plasma and urine have previously been consistently reported in patients with unipolar and bipolar depression and have been suggested as a diagnostic biomarker of depression. Mannitol is mainly secreted by several species of Bacteroides, Lactobacillus, Fructobacillus, Alistipes, and Bifidobacterium. Interestingly, all genera, except for Fructobacillus have previously been associated with depression.

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In summary, this study identified many new associations of diet-sourced microbiome metabolites with depression including vitamin A, hippurate, sorbitol, mannitol, and four common lipids. These findings suggest that preventive dietary changes might reduce some depressive symptoms. The offending molecules are food-derived and thus can be altered in patients by modifying their diet.