Melatonin for immune, gut, and brain health

Posted 10:21 pm by valerielarosa & filed under NEWS.

June 22, 2020

Melatonin, a neurohormone available in supplement form, is best known for its use in initiating sleep. Our own endogenous melatonin plays a key role in regulating our 24-hour sleep-wake cycle. Of course, the body doesn’t usually make a substance to do just one thing. Similar to many plant medicines, substances made in the body can have multiple actions in different places in the body. They can also have a modulating effect, meaning they can exhibit opposite actions depending on what the body needs, for example increasing or decreasing inflammation. Melatonin has been shown to exhibit modulating effects on our immune function in the GI tract, the brain, and elsewhere in the body

WHERE ITS MADE:

We commonly hear that melatonin is made in the pineal gland of the brain in response to changes from light to dark. Its production increases when it is dark outside and gradually declines in the early hours of the morning slowly waking us up for the day. But melatonin is made in other parts of the body as well. More than 400-500 times as much is made in immune cells in the GI tract called enterochromaffin cells. It is reasonable to conclude that the health of our GI tract influences its secretion, including what we eat and what we digest and absorb. Another function of melatonin that has been widely discussed is that it has antioxidant properties. Some research shows that the primary site of melatonin production is in the mitochondria, where its antioxidant capabilities protect the mitochondria.

IMMUNE SYSTEM:

In addition to its circadian rhythm and antioxidant effects, melatonin modulates many immune system responses. It is involved in both T cell and antibody responses. It can be pro-inflammatory against pathogens, disease-causing organisms, by increasing inflammatory cytokines. However, it can also exhibit anti-inflammatory actions in the presence of an over-response to pathogens, as recent studies have shown with COVID-19 and cytokine storm or an overproduction of cytokines. Melatonin is anti-inflammatory in response to slow developing, low grade inflammation such as neurodegeneration seen in normal aging and Alzheimer’s. It is also anti-inflammatory in situations of acute, high grade inflammation such as sepsis and traumatic brain injury.

It’s ability to modulate inflammatory cytokines is also evident in allergic and autoimmune responses. It balances the Th1 and Th2 responses to bacteria/viruses and parasites/allergens, respectively. Studies of people with atopic, or allergic, eczema show that it helps decrease IgE antibody response to allergens. People with allergic rhinitis – seasonal or environmental allergies with primarily nasal symptoms – have lower levels of endogenous melatonin. Melatonin regulates histamine-release from mast cells. Histamine is also involved in our sleep-wake cycle, increasing in the early morning hours when melatonin levels are decreasing. New studies are looking at melatonin as a possible treatment for allergic rhinitis. Melatonin regulates Th17 cells and inhibits TNF alpha that lead to autoimmune tissue destruction. TNF alpha inhibition is the mechanism of action of many pharmaceutical medicines for autoimmune conditions, but these also carry an increased risk of certain infections and cancers. Healthy levels of melatonin in the body may have a preventative effect against development or worsening of allergy, excess histamine, and autoimmunity. It has been widely studied for its benefits in preventing and treating certain cancers, such as colorectal cancers. It can mitigate the side effects of treatments like chemotherapy and radiation and help decrease cancer growth.

GI SYSTEM:

Melatonin has numerous actions in the gastrointestinal tract. Studies of supplemental melatonin’s impact on patients with Irritable Bowel Syndrome (IBS) show that a 3 mg dose has a pain-relieving effect. Visceral abdominal pain is a hallmark symptom of IBS.

Melatonin is thought to play a role in modulating GI motility. Initial research suggests, at low doses it increases intestinal motility, while high doses may decrease gut motility. Melatonin receptors are found in the muscular layers of the intestines, responsible for GI motility. The presence of melatonin in the gut activates these receptors and can have both contractile and relaxing effects on the smooth muscle of the GI tract. It appears to act as a modulator of gut motility in response to an excess or deficient motility response

Melatonin has been studied in patients with GERD, who have lower levels of endogenous melatonin than people without GERD. It again exhibits multiple helpful actions, protecting the esophageal mucosa from stomach acid and also regulating the muscle tone of the lower esophageal sphincter preventing refluxing of stomach acid into the esophagus. One 40-day study compared treatment of GERD with Omeprazole (a commonly prescribed medication for GERD) to a supplement with melatonin, l-tryptophan, methionine (melatonin precursors), vitamin B6, folic acid, vitamin B12 (co-factors to making melatonin), and betaine.

Within 1 week, 99% of patients taking the supplement with melatonin improved, 66% taking Omeprazole improved.
At the end of the 40 days 100% taking the supplement reported no symptoms, 60% taking Omeprazole had no symptoms.
Those with remaining symptoms were given the supplement with melatonin for 40 days and 100% of them had resolution of their symptoms.

Like us, the microbes in our intestines operate on a 24-hour circadian rhythm of rest and activity, regulated in part by our melatonin secretion. Research on night shift workers and people experiencing jet lag, show that our gut microbes do best when our eating times are more predictable, since they are helping to digest some of our food. Regular mealtimes may help our beneficial microbes to predict their own eating times and can affect their growth and movement. Newer studies show that some types of bacteria show patterns of “swarming” behavior – spread and growth – in response to melatonin levels in the intestines.

Melatonin in GI tract also exerts its antioxidant and microbiome regulation functions in studies of intestinal inflammation. It may have preventative or even treatment effects in GI inflammation.

NEUROINFLAMMATION:

Melatonin’s immune-modulating effects also occur in the brain, regulating the activation of microglia, immune cells in the brain, to protect our neurons from injury and inflammation. Many studies focus on patients with traumatic brain injury and on typically aging brains, as well as the brains of people with Alzheimer’s disease. Our endogenous melatonin levels decrease in later life, possibly contributing to oxidation and other effects in the aging brain.Melatonin’s regulation of our brain’s inflammatory response is also beneficial in people with Autism and PANS/PANDAS. In people with autoimmune reactions, susceptibility to infections, and GI inflammation, it can have numerous benefits. Melatonin has been studied in people with Autism with high levels of oxidative stress and GI symptoms, for its antioxidant and anti-inflammatory properties. People with autism show a genetic tendency toward lower melatonin levels. Many people with Down Syndrome also have lower levels of endogenous serotonin and melatonin with higher levels of kynurenic acid excreted in their urine. Increased levels of this organic acid suggest “tryptophan steal”, a process in which tryptophan is shunted away from making adequate amounts of serotonin and melatonin, to create kynurenic acid. Inflammation and/or infection may underly this process. Melatonin given as an antioxidant nutrient shows benefit for people with autism and Down Syndrome who experience high levels of oxidative stress. As a supplement, it is often used to help with initiation of sleep, but it may improve sleep quality by addressing underlying causes of sleep disruption from abdominal pain to excess inflammation and oxidative stress.

LONG TERM USE:

Systematic reviews of melatonin use in people of various ages from neonates to elders, of different dosages and forms, as well as different lengths of follow up suggest that endogenous melatonin use is not only safe but clearly associated with improved health outcomes. Now that its use has been more widespread over the last several years, most commonly for children with neurodevelopmental conditions involving disturbed sleep, some studies are beginning to examine longer term supplementation. Continued improvements are often seen, even with several years of use. As a clinician, I think it is important to note that my goal for any patient is not to remain on melatonin supplements indefinitely, but to address the underlying causes of their own endogenous melatonin production being disrupted. Because that process can take some time, it is heartening to see studies of melatonin use up to 2-4 years showing a low side effect profile, no tolerance, and good efficacy in promoting better sleep, physical health, behavior, and learning.

In one study of children with autism with sleep disturbances, 2 years of use showed continued favorable results and while a 2-week break showed some decline in sleep quality, during that time their sleep quality was still improved over their baseline before beginning supplementation.

Studies of melatonin use in people with sleep onset delay insomnia (trouble falling asleep) show that long term, regular use of exogenous melatonin supplements affect our own melatonin release by advancing it by as much as 3 hours. The amount of our own melatonin released is not lessened by taking supplemental melatonin. There is some evidence that exogenous melatonin use may increase storage of our endogenous melatonin, making it more available to us.

Because melatonin production is influenced by our morning exposure to light and our evening exposure to darkness, adjustments to our sleep hygiene that create optimal conditions for melatonin production include morning walks or time outside, and evening avoidance of bright light, in particular screens which emit blue light.

Melatonin production is also dependent on availability of its amino acid precursor, tryptophan, as well as many vitamin co-factors. This means our melatonin levels are influenced by our dietary intake, as well as our digestion and absorption of nutrients in the GI tract. Most plant foods contain some amount of melatonin, but foods that have been shown to contain notable amount of melatonin are tomatoes, olives, barley, rice, and walnuts.

In conclusion, improving intake, digestion, and absorption of proteins and vitamins needed to make our own melatonin, along with improving sleep hygiene are essential to supporting the numerous beneficial functions of melatonin in the body. Supplementing while addressing root causes, is not only safe, but can be very effective in helping with better sleep, as well as immune, brain, and GI function. Creating a regular daily rhythm of sleep, wake, and eating patterns is most beneficial to our health.

Research Links:

https://pubmed.ncbi.nlm.nih.gov/27919824/

https://www.nature.com/articles/s41419-019-1556-7

https://onlinelibrary.wiley.com/doi/full/10.1111/jpi.12525

https://www.sciencedirect.com/science/article/abs/pii/S1359610119300449

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159806/

https://www.researchgate.net/publication/339025705_Melatonin_and_Allergic_Rhinitis

https://pubmed.ncbi.nlm.nih.gov/19963060/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949259/

https://pubmed.ncbi.nlm.nih.gov/27919824/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198018/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821302/#B26