Serotonin- for those who want some more information about serotonin and why you may be feeling the blues…read on. I put together a brief tutorial on this very important neurotransmitter that is produced both in your brain and your gut….
Physiology Review
Serotonin (SERT), is an abundant neurotransmitter that regulates emotional status and mood. It is often called the “happy hormone”, and thought to play a key role in appetite, emotions, motor, cognitive and autonomic functions (McIntosh, 2018). Low metabolism of hippocampal SERT leads to abnormalities in brain regions associated with learning, memory, and emotion. It is found in the central and peripheral nervous systems, especially the enteric nervous system, and plays crucial roles in both mood regulation and gastrointestinal function (Lu, Wang, Liu, & Wang, 2017).
Serotonin is a monoamine transmitter derived solely from the amino acid tryptophan (Trp), one of the nine essential amino acids and also the least abundant of all 21 dietary amino acids in human beings (Mehraj & Routy, 2015). Tryptophan cannot be synthesized in humans and must be obtained through dietary intake from amino acid intake or released during protein turnover. Tryptophan requires an insulin dependent active transport mechanism to cross the blood brain barrier to enter the neuronal environment (Noseworthy, n.d.), and this mechanism is insulin dependent.
Tryptophan is converted to SERT via the kynurenine biosynthetic pathway (KP), the main Trp catabolizing pathway. Trp metabolism is regulated in human beings by three distinct enzymes: indoleamine-2,3-dioxygenase (IDO) 1 and 2 and tryptophan 2,3-dioxygenase (TDO) which is found primarily in the liver (Mehraj & Routy, 2015). TDO is the main enzyme that degrades Trp, particularly during normal physiological conditions (Mehraj & Routy, 2015). The synthesis of kynurenine accounts for approximately 90% of tryptophan metabolism (Jenkins, Nguyen, Polglaze, & Bertrand, 2016).
Another enzyme involved is tryptophan hydroxylase that converts Trp to 5HTP, and this is dependent on 3 cofactors: iron, oxygen, and tetrahydrobiopterin. 5HTP is then converted to SERT using the aromatic amino acid decarboxylase enzyme that is heavily dependent on Vitamin B6. It also relies on niacinamide, methylcobalamin, folate and magnesium (Noseworthy, n.d.).
Aside from regulating mood, SERT is also an important neurotransmitter in the enteric nervous system and also functions to regulate intestinal secretion and motility (Lu et al., 2017). Interestingly, central serotonin production represents just 5% of total serotonin synthesis (Jenkins et al., 2016). Peripheral synthesis, which accounts for the other 95% of serotonin synthesis, occurs mostly in the gastrointestinal epithelium (in the enterochromaffin cells), but also in other tissues such as bone, mammary glands, and the pancreas. SERT is present in the wall of the gut and acts to tie the two ends of the gut-brain axis. The serotonin in the digestive system is primarily involved in regulating movement (motility) of the gut, but also modulates intestinal fluid secretion and gastrointestinal sensation (Wang et al., 2015).
Presenting symptoms
Neurological conditions associated with serotonin imbalance in the brain (Vlainic, & Vukorep, 2016).:
- Depression
- Fatigue/ loss of energy
- Irritable
- Changes in appetite
- Loss of joy
- Sleep disturbances
- Feeling worthless, sad, anxious
- Excessive guilt
- Diminished ability to concentrate, memory problems or inability to make decisions
- Suicidal thoughts
Gastrointestinal conditions associated with downregulation of SERT in the GI-tract (Lu et al., 2017):
- IBS
- IBD such as Crohn’s disease and Ulcerative Colitis
- Motility dysfunction and constipation (Yano et al., 2015).
- Inflammatory conditions of the GI tract
Mechanisms that cause dysfunction
- Iron deficiency (Noseworthy, n.d.)
- Dysglycemia (Noseworthy, n.d.)
- Inadequate co-factors (iron, oxygen, vitamin B6, methylcobalamin, folate, magnesium) (Noseworthy, n.d.)
- Reduced perfusion (Noseworthy, n.d.)
- Pathogenic bacteria- can interfere with the synthesis and regulation of SERT, contributing to anxiety and depression through mechanisms involving the vagus nerve (Zhou & Foster, 2015).
- Inflammatory cytokines- It has been observed that individuals with major depression have significantly higher concentrations of a pro-inflammatory cytokine, IL-6, in comparison with controls as seen in a meta-analysis of 16 studies (Latalova, Hajda, & Prasko, 2017).
Natural Remedies:
- L-Tryptophan supplementation-To support the conversion to SERT through the 2-step process that uses 5HTP as an intermediate.
- 5-HTP supplementation– To bypass the conversion of tryptophan to serotonin, that requires key cofactors, you can also supplement with 5-HTP. 5HTP is well-absorbed and crosses the BBB when it gets converted to SERT, and often believed (Cooley, 2018).
- SAM-e- Is produced from the amino acid methionine, and is also required for the synthesis of serotonin. It is an endogenous, intracellular amino acid metabolite and enzyme co-substrate involved in multiple crucial biochemical pathways, including biosynthesis of hormones and neurotransmitters (Sharma et al, 2017). SAMe deficiency in CSF has been reported in patients with rare inherited defects in folate and methionine metabolism, as well as common depressive disorders. “Deficiencies of folate and vitamin B12, necessary co-factors in the synthesis of SAMe, may account for decreased SAMe levels, especially in patients with depression and dementia” (Sharma et al, 2017). Several double-blind, randomized controlled trials (RCTs) compared SAMe to other antidepressants: tricyclic antidepressants (TCAs), and early RCT’s demonstrated that 150-400mg of SAMe to be as effective or superior to TCA’s with fewer side effects (Sharma et al, 2017). SAMe also has some promise as working synergistically with antidepressants to alleviate some of the side effects associated with the use such as sexual dysfunction.
- St. John’s Wort– This plant is known for being able to inhibit the reuptake of serotonin and well as norepinephrine and dopamine, making more of these neurotransmitters available in the brain (Cooley, 2018). “For people suffering from mild to moderate depression, studies show that St. John’s wort extracts are significantly more effective than placebo” (Cooley, 2018). “In a 26-week clinical trial with 124 participants, St. John’s wort, a standard antidepressant (sertraline, an SSRI), and a placebo were similarly effective in treating major depression of moderate severity. NCCIH and NIMH funded this 2012 analysis of data collected in 2002” (NIH, n.d). Care should be taken with people who have bipolar disorder or schizophrenia. There are some side effects associated with St. John’s wort that should be educated such as agitation, high blood pressure, rapid heartbeat, upset stomach, fatigue, dizziness, sexual dysfunction. It can also weaken many prescription medications such as antidepressants, birth control, pain medications and cancer drugs.
- Check for and correct any nutritional imbalances such as iron, B6, methylcobalamin (B12), folate, magnesium
- Improve oxygenation through optimizing iron status, exercise, or supplements that can improve blood flow such as Gingko Biloba, nattokinase (that can prevent fibrin buildup that impedes blood flow) and L-arginine (can promote NO production), Acetyl L-carnitine (can increase blood flow to brain, oxygenation to heart and improve blood flow to vascular tissues). Foods that can help improve blood flow include ginger (anti-inflammatory), green tea extract (can promote NO production). Other nutrients such as magnesium blend that contains magnesium glycinate, malate and citrate; Vitamin K2-7 can pull calcium out of blood stream and deliver directly to bones; Vitamin D3 that can prevent arterial hardening of the arterial walls; Vitamin E it can thin the blood and improve viscosity.
- Probiotic supplementation-Probiotic administration can influences the availability of tryptophan, the serotonin precursor. For example, infantis can affect metabolites of 5-HT with subsequent anti-inflammatory effects and normalization of depression-like behavior. A study by Cao et. al revealed that L. acidophilus and B. longum could increase the expression of serotonin in intestinal epithelial cells. According to Wang et. al, L. rhamnosus is one of the best-studied Lactobacillus strains in clinical trials, and has the ability to increase expression of serotonin, inducing remission and preventing recurrence of IBD. L. helveticus was administered during periods of stress and demonstrated the ability to reduce cortisol levels and increase IL-10, hippocampal BDNF mRNA, noradrenaline and SERT (Sarkar et al., 2016). B. infantis and Lactobacillus GG have also been shown to enhance concentrations of IL-10, which may be able to reduce the access of pro-inflammatory cytokines from accessing the CNS, and may be able to restore inflammation-induced permeability of the blood brain barrier (BBB). Probiotics such as L. rhamnosus can ameliorate gut barrier dysfunction by inhibiting the signaling potential of pro-inflammatory cytokines such as TNF-a.
- Prebiotics – Gut bacteria produce a range of neurotransmitters through the metabolism of indigestible fibers. These include dopamine and noradrenaline by members of the Bacillus family, GABA by the Bifidobacteria family, serotonin by the Enterococcus and Streptococcus families, noradrenaline and serotonin by the Escherichia family, and GABA and acetylcholine by the Lactobacilli family. The metabolism of fibers produce short chain fatty acids (SCFA’s) such as butyrate, lactate and propionate. In one example, systemic sodium butyrate injections in rats produced antidepressant effects and increased serotonin neurotransmission and BDNF expression (Sarkar et al., 2016). SCFA’s can also stimulate the HPA axis and have direct effects on the mucosal immune system, which can indirectly affect central neurotransmission. “There is also evidence of direct interaction between oligosaccharides and the epithelium, independent of gut bacteria, with substantial reductions in pro-inflammatory cytokines” (Sarkar et al., 2016). The reduction in cytokines can have psychobiotic effects, since pro-inflammatory cytokines can increase the permeability of the blood brain barrier (BBB), permitting access to potential pathogenic entities. Cytokines can alter concentrations of several NT’s that regulate communication in the brain, such as serotonin, dopamine, and glutamate, and can stimulate secretion of pro-inflammatory substances such as prostaglandins, that can promote further inflammation. “There is also emerging evidence of a lymphatic drainage system subserving the brain, which we speculate may allow cytokines to interact with neural tissue” (Sarkar et al., 2016).
References
Jenkins, T. A., Nguyen, J. C., Polglaze, K. E., & Bertrand, P. P. (2016). Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients, 8(1). doi:10.3390/nu8010056
Cooley, J. (2018). Serotonin Supplements to Treat Depression, Anxiety, and Insomnia Yourself. Retrieved (2018, November 12) from https://universityhealthnews.com/daily/depression/serotonin-supplements-to-treat-depression-anxiety-insomnia-yourself/
Latalova, K., Hajda, M., & Prasko, J. (2017). Can gut microbes play a role in mental disorders and their treatment? Psychiatr Danub, 29(1), 28-30.
Lu, X., Wang, Y., Liu, C., & Wang, Y. (2017). Depressive disorder and gastrointestinal dysfunction after myocardial infarct are associated with abnormal tryptophan-5-hydroxytryptamine metabolism in rats. PLoS ONE, 12(2), e0172339. doi:10.1371/journal.pone.0172339
McIntosh, Janes. (2018, February 2). What is serotonin and what does it do? Retrieved from https://www.medicalnewstoday.com/kc/serotonin-facts-232248
Mehraj, V., & Routy, J. P. (2015). Tryptophan Catabolism in Chronic Viral Infections: Handling Uninvited Guests. Int J Tryptophan Res, 8, 41-48. doi:10.4137/ijtr.S26862
National Institute of Health (n.d.) St. John’s Wort and Depression: In Depth. Retrieved (2018, November 11) from https://nccih.nih.gov/health/stjohnswort/sjw-and-depression.htm
Noseworthy, S. (n.d.). Understanding Neurotransmitters. [Presentation] Retrieved (2018, Nov 12) from https://learn.muih.edu/courses/7566/pages/week-11-resources-understanding-neurotransmitters?module_item_id=202245
Sarkar, A., Lehto, S. M., Harty, S., Dinan, T. G., Cryan, J. F., & Burnet, P. W. J. (2016). Psychobiotics and the Manipulation of Bacteria-Gut-Brain Signals. Trends Neurosci, 39(11), 763-781. doi:10.1016/j.tins.2016.09.002
Sharma, A., Gerbarg, P., Bottiglieri, T., Massoumi, L., Carpenter, L. L., Lavretsky, H., . . . Mischoulon, D. (2017). S-Adenosylmethionine (SAMe) for Neuropsychiatric Disorders: A Clinician-Oriented Review of Research. J Clin Psychiatry, 78(6), e656-e667. doi:10.4088/JCP.16r11113
Vlainic, J. V., Suran, J., Vlainic, T., & Vukorep, A. L. (2016). Probiotics as an Adjuvant Therapy in Major Depressive Disorder. Curr Neuropharmacol, 14(8), 952-958.
Yano, J. M., Yu, K., Donaldson, G. P., Shastri, G. G., Ann, P., Ma, L., . . . Hsiao, E. Y. (2015). Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell, 161(2), 264-276. doi:10.1016/j.cell.2015.02.047
