Topic 1: Genetic Variants, Emotional Epigenomics And Serotonin Levels | Nutrition Genome

When assessing serotonin levels using the Nutrition Genome Report, it is important to combine MAO-A, FUT2 (Digestion Section), COMT (Neurotransmitter Section), SHBG (Hormones) and DI01 and DI02 (Thyroid Section) along with epigenetic factors.

MAO-A: MAO-A (Monoamine oxidase A) is a critical enzyme involved in breaking down important neurotransmitters such as serotonin, estrogen, norepinephrine, and dopamine.

FUT2: Approximately 90 percent of serotonin is made in the digestive tract. Poor gut flora dramatically disrupts serotonin and GABA. A red flag should go up when you see antibiotic use and homozygous FUT2 genes.

COMT: MAO-A and COMT are in the same pathway for estrogen metabolism. Genetic variants and epigenetic factors that slow down both genes, medications, suboptimal co-factors, stress and high estrogen affect serotonin levels.

SHBG: SHBG levels can alter estrogen levels that could affect serotonin, especially if fiber intake is low and sugar/refined carbohydrate intake is high.

DI01 and DI02: Depression and adrenal fatigue can lead to suppressed thyroid function. T3 is found in large amounts in the limbic system (joy, anger, fear) and regulates serotonin, norepinephrine, and GABA levels. Serotonin, T3, T4, and norepinephrine rely on the amino acid tryptophan, while tyrosine is a precursor of T3. Low protein intake, chronic stress and depression can lead to depleted tryptophan and tyrosine, causing a vicious cycle of hypothyroidism and mood dysregulation.






MAO-A Genotypes 

The GG allele genotype is for the high activity of the enzyme, while a TT genotype encodes for slow activity of the enzyme. Looking at serotonin levels from a genetic standpoint requires much more than just MAO-A. As you may have noticed, both the normal and homozygous genotype come up in the Nutrition Genome Report as relevant. The TT genotype is actually believed to help preserve circulating serotonin through the reduced enzyme function, however, there are many factors that easily alter serotonin levels and this gene shouldn’t be assessed on its own.

While the GG genotype has produced mixed results with depression, low estrogen in women combined with the GG genotype may lead to depression and pain from low serotonin, poor sleep from low melatonin and sugar/refined carbohydrate cravings and increased alcohol consumption (the body’s way to temporarily boost serotonin but with bigger drops). However, this can still occur with the TT genotype.

With the TT genotype, constipation and high estrogen cause a very slow MAO-A enzyme, which can increase sensitivity to stress due to high levels of estrogen, serotonin, and poor detoxification. This can be especially true for those with variants in SHBG. Fiber and magnesium are crucial for this genotype.

Serotonin and Mental Health

Approximately 300 million suffer from depression, with more women affected than men. A Mayo Clinic study found that 70% of Americans are prescribed medications and anti-depressants are the second highest prescription given. Only 1/3 of these people are helped by anti-depressantsPrescribed antidepressants target the monoamine (MAO) systems.

Serotonin is a critical modulator of executive function, impulse control, sensory gating, and pro-social behaviorLow brain serotonin is connected to PTSD, Obsessive-Compulsive Disorder (OCD), Turret’s Disorder (TD) Social Anxiety Disorder (SAD), anxiety, depression, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder and schizophrenia.

SSRIs block the reabsorption (reuptake) of serotonin in the brain, making more serotonin available. SSRI’s are one of the main clinical interventions for obsessive-compulsive disorder (OCD). They have been found to be effective in reducing both the thought (obsessions) and behavioral (compulsions) components of OCD. Imaging studies have suggested that individuals with OCD have decreased serotonin transporter availability in the midbrain/brainstem. Altered serotonin transport activity has also been highlighted in research to contribute to serotonin abnormalities in Tourette disorder. Tourette disorder is highly correlated with OCD (60%) and ADHD (40%).

Emotional Epigenomics and Serotonin 

A recent study offered an epigenetic explanation as to why some people are more reactive to stress or more vulnerable to disorders related to stress. A team of researchers at Duke University found that that methylation of a gene called SLC6A4 can affect how an individual reacts to threats or stress. This is not a gene available with traditional SNP testing because it is known as a tri-allele, containing both a short and long allele.

In both college students and individuals aged 11-15 who were shown images of angry or fearful faces, results indicated that the more the serotonin transporter DNA was methylated, the greater the reactivity of the amygdala (limbic system in the brain responsible for responses to threatening or stressful stimuli). For those with variants in SLC6A4, this could help explain a higher stress response and increased reactivity by the amygdala. This higher reactivity contributes to a vulnerability to disorders previously mentioned that are connected to low brain serotonin.

Results were found in subsequent follow-up studies confirming that increased methylation of the serotonin transporter gene (SLC6A4) at a particular location was linked to a decrease in serotonin transporter expression in the amygdala. Children were genotyped for the SLC6A4 polymorphism, and researchers found that the variant alleles were associated with increased vulnerability to depression in response to negative events.

SLC6A4 is the molecular target of the selective serotonin reuptake inhibitors (SSRIs) including fluoxetine, fluvoxamine, sertraline, paroxetine and citalopram.

Estrogen, Serotonin and the Menstrual Cycle

For females, the menstrual cycle gives a rise and fall in estrogen, progesterone, and serotonin. As estrogen rises, so does serotonin. As it goes down, serotonin follows. Estrogen influences pain transmission, headaches, dizziness, nausea, and depression through serotonin signaling. When these swings happen in extremes, the feelings of anxiety and depression can be amplified. While serotonin is mainly thought of as a mood-elevating neurotransmitter of the brain, only 1% of serotonin is found in the central nervous system. The remaining 99% is found in the gut and immune tissues regulating gut motility, vasodilation, clotting, immune cells and uterine contractions.

The cravings for sugar and carbohydrates right before a period is the digestive brain’s attempt to bring serotonin levels back up. Add poor gut flora to the equation, and estrogen can become deconjugated, reabsorbed and reactivated in the blood leading to estrogen dominance and wide swings in serotonin. Fibromyalgia is a condition believed to be linked to estrogen and serotonin levels due to altered tryptophan metabolism (precursor to serotonin) and is observed in more females than males.

Advanced Serotonin and Digestive Health Research 

Approximately 90 percent of serotonin is made in the digestive tract by microbes that can make it on their own and stimulate intestinal cells to produce it. Altered levels of this peripheral serotonin have been linked to diseases such as irritable bowel syndrome, cardiovascular disease, and osteoporosis.

After serotonin is released into the gut and initiates an intestinal reflex, it is taken out of the bowel by a serotonin transporter found in the cells that line the gut wall. Some people have lower functioning serotonin transport function, which can increase the sensitivity to stress and therefore gut function.

Studies have demonstrated that patients with IBS have low serotonin concentrations. Impaired small intestinal motor function may be a consequence of too low serotonin levels within the intestinal wall, leading to an increased production of interferon gamma (INFγ). This causes immunoactivation, increasing Indolamine dioxygenase (IDO) activity.

IDO is the key enzyme involved in the conversion of tryptophan in the intestine. This conversion creates oxidative stress and is linked to cognitive impairment, allergies, and autoimmune disorders. While the reactive oxygen products have an antimicrobial effect, they may also harm mitochondria and lead to increased production of inflammatory cytokines (TNF-α, IL-6) and are related to fatigue and pain hypersensitivity like fibromyalgia. Vitamin C, polyphenols, carotenoids, sauerkraut, and flavonoids offset this oxidative stress. 

Local tryptophan depletion in and around infected mucosal cells may impair microbial growth. An excessively high fructose level in the colon may reduce the availability of tryptophan for the production of serotonin, and that serotonin deficiency and depression may be associated with fructose malabsorption. Patients with IBS and chronic fatigue often have signs of low-grade malabsorption with deficiencies of iron, vitamin B12, folate and vitamin D. About 30% of IBS patients have fat malabsorption.

The probiotics Lactobacillus reuteri in the intestine and L. acidophilus in the vagina consume tryptophan as a source of energy, which curbs the growth of Candida albicans and boosts the growth of lactic acid bacteria. Given the choice – like many humans – bacteria prefer sugar rather than amino acids. But without tryptophan in their ‘diet,’ there is fewer lactobacilli, less digestive barrier protection, and more Candida, which is typical of IBS. IBS, therefore, may be related to dysbiosis from a diet too high in sugar and carbohydrates and disrupted tryptophan metabolism with increased oxidative stress and deficiencies of tryptophan. The artificial sweetener aspartame inhibits the carbohydrate-induced production of serotonin, creating higher cravings. When serotonin levels are optimal, sugar and carbohydrate cravings go down.

Nutrigenomics and Modulating Serotonin 

Research has found that sunlight, vitamin D, dark chocolate, fish oil, running, biking or yoga, adequate protein intake, B2, B6, folate, B12 and massage all modulate serotonin levels. Patients with serotonin imbalances are going to be more sensitive to sugar, stress, antibiotics, oral contraceptives (those who react poorly typically have wider swings of estrogen/serotonin levels) and refined carbohydrates.

Curcumin may be effective for depression cases that are linked to low serotonin, disrupted gut flora and inflammation. Curcumin is a natural MAO-A inhibitor, increasing the concentration of serotonin, dopamine, and epinephrine in the synapse and thus prolonging their action (similar mechanism to SSRI drugs). This is an important point to note if a patient is already taking an MAO inhibitor because you want to be careful not to cause serotonin syndrome (high levels of serotonin that causes extreme panic and anxiety). Research indicates that turmeric may provide benefit for depression by acting on gut microbiota, but there is currently limited evidence to support this hypothesis. Chronic exposure to elevated inflammatory cytokines alters the neurotransmitters, which can lead to neuropsychiatric disorders and depression.

A 2017 meta-analysis of 6 clinical trials with a total of 377 patients comparing the active ingredient curcumin to a placebo found significant clinical efficacy of curcumin in ameliorating depressive symptoms and anxiety in 3 of the trials. There were also zero reports of adverse events in any of the trials. Since turmeric has a notoriously poor absorption profile, a fat carrier, and black pepper is necessary to increase absorption.

Researchers from UCSF found that the omega-3 fatty acid EPA increases serotonin release from presynaptic neurons by reducing inflammatory signaling molecules in the brain, which inhibit serotonin release and suggests how inflammation may negatively impact serotonin in the brain. DHA was also found to influences the action of various serotonin receptors by making them more accessible to serotonin by increasing cell membrane fluidity in postsynaptic neurons. Vitamin D has a synergy with omega-3’s with serotonin, with low levels of vitamin D affecting serotonin metabolism.


The Nutrition Genome Report gives in-depth insight into the many ways serotonin levels are linked to digestive and mental health. A full analysis of MAO-A, FUT2, COMT, SHBG, DI01, and DI02 can help you formulate explanations of how estrogen, serotonin and thyroid hormone dysregulation may be causing certain health issues.