Melatonin and Gastrointestinal Disease

May 16, 2009

This newsletter is rather reference dense. Footnotes have been omitted in this version. The web posted version contains abstracts of all citations and can be viewed at: http://denvernaturopathic.com/melatoninandGIT.htm

Modern life exposes us to a degree of nighttime illumination that evolution has ill prepared us for. This 'light at night' suppresses melatonin production. It should come as no surprise then that in modern industrial societies some of our diseases are the result of melatonin deficiency. Melatonin may be useful in treating these conditions. This article focuses on the therapeutic potential of melatonin in treating diseases of the digestive tract.

I've had the odd privilege, over the years, of asking thousands of people about their bowel habits. Until a few months ago, I never noticed something that should have been obvious. Healthy people never wake at night to poop. Granted people will have an occasional episode when they are sick to the stomach, eaten or drunk something they shouldn't have, and this will get them up. A normal person, in good health, never reports, "I wake nightly at 2 AM for a bowel movement."

People tell me they poop according to the clock. They have a typical time of day when the plumbing says go. Time varies person to person. Bowel movements follow a circadian rhythm. I suppose from an evolutionary perspective it makes more sense to have bowel movement during daylight when you are less likely to become prey to tigers and the like

The hormone melatonin is the body's clock; it regulates the circadian rhythms of the body. Melatonin production spikes when it gets dark and decreases when it gets light. This fluctuation in hormone level tells the body what time it is.

It should thus be no surprise that melatonin affects what's going on in the gut and that melatonin has therapeutic value in balancing bowel function. The surprise is the extent it does so.

AB Lerner and co-workers discovered melatonin in the bovine pineal gland back in 1958. Sixteen years later, in 1974, the Russians Raikhlin and Kvetnoi isolated melatonin from the human appendix. In 1977 GA Bubenik and his colleagues at the University of Guelph in Ontario, Canada, detected melatonin in the mucous membrane of the entire gastrointestinal tract (GIT). This fellow Bubenik's name appears a fair percentage of research on melatonin and digestion since that time. Melatonin is made in the GIT by the enteroendocrine cells, what used to be called enterochromaffin cells, that line the digestive tract. How much melatonin is in the gut is not dependent on what the brain makes. In rats, cutting out the pineal gland drastically decreases melatonin levels in the blood but levels the gut levels remain unchanged. One assumes this is true in people as well but nobody is volunteering for such a study.

The fact that the digestive tract produces its own supply of melatonin as well as accumulating melatonin produced by the pineal gland from the circulation initially came as a surprise to me.

Taking oral l-tryptophan increases blood levels of melatonin. The conversion of l-tryptophan to melatonin occurs even in animals that have had their pineal glands removed. This strongly suggests that the l-tryptophan is converted to melatonin in the GIT rather than the brain.

This is confusing. I distinctly recall learning as a student that l-tryptophan is converted to serotonin.

Wikipedia diagram of l-tryptophan conversion pathways: http://upload.wikimedia.org/wikipedia/en/0/0b/Tryptophan_metabolism.png

In this flow chart l-tryptophan can follow one of two pathways. One leads to production of niacin. The second pathway leads to production for first serotonin that can then be converted to melatonin.

Which of these chemical pathways l-tryptophan will move down depends on factors that I suppose we'd better figure out.

Chronic immune activation appears to push tryptophan down the niacin road, to the point that we see low tryptophan serum levels in certain conditions like cancer:

"Low serum/plasma tryptophan concentration is observed in infectious, autoimmune, and malignant diseases and disorders that involve cellular (Th1-type) immune activation as well as during pregnancy due to accelerated tryptophan conversion."

In these chronic states low tryptophan may lead to low serotonin levels and presumably low melatonin levels. This is certainly an argument supporting use of melatonin with cancer but it also suggests other chronic conditions where increasing melatonin directly or through l-tryptophan supplementation should be considered.

Several insecticides have been shown to increase melatonin production including, parathion, carbaryl, and lindane. Mild stress also increases melatonin production. In this study the stress was restraint alone (no waterboarding) for 2 hours. They classified the stress as mild because the subjects did not develop bleeding ulcers. Thus it looks as if this pathway from l-tryptophan to serotonin and then to melatonin is fraught with bumps in the road. Stress, disease, malignancy, active immune activity and pesticides all create road blocks. Perhaps actual melatonin supplementation will prove more reliable than either giving l-tryptophan or attempting to increase serotonin.

Eating food triggers melatonin production in the GIT some of which enters the blood stream. This postprandial melatonin spike may be responsible for the after eating drowsiness we have long attributed to the 'alkaline wave' resulting from neutralization of stomach acid as it reaches the duodenum.

At night more of the melatonin in circulation is made in the pineal gland but during the day, it is the gut that makes the baseline levels of melatonin in circulation. Gut or GIT, I find I use the terms somewhat interchangeably. Technically I suppose guts refer to intestines and GIT is tongue to anus. A bit of a side tangent here on the word git.

The slang term 'git' shows up in the Harry Potter book, The Goblet of Fire, when Harry says, "You're a right foul git, you know that?" This was new language for most American readers.

"From before 1300 a 'get' was what had been begotten, a child or offspring. But by about 1500 it had started to be used in Scotland and northern England in the sense of misbegotten, a bastard; from there it became a general term of abuse for a fool or idiot. By about 1700 get seems to have lapsed into slang or dialect, only to reappear in the wider language in the 1940s with a different spelling and lacking the associations with illegitimacy. James Joyce uses the older spelling (and meaning) in Ulysses in 1922: "The bloody thicklugged sons of whores' gets!" These days, it's a widely known and used term of abuse in Britain for somebody regarded as totally worthless or useless."

Once I saw this abbreviation, GIT, used for gastrointestinal tract, I can't keep the two meanings separate in my mind. So excuse me if I sometimes refer to the GIT as the gut.

Anyway, there is a lot more melatonin in the guts or GIT than in the blood. Melatonin concentrations in the GIT tissues are 10 to 100 times higher than in blood. In 1994 Huether made the calculations and figured out that the GIT contains 400 to 500 times more melatonin than the pineal gland.

For the purpose of organization in describing melatonin's action, let me divide the digestive tract into upper and lower realms. In the upper digestive tract, melatonin does a lot of things; it sets the circadian rhythm, scavenges free radicals, protects mucosa against various irritants, tightens the lower esophageal sphincter and heals intestinal lesions like those from stomatitis, esophagitis, gastritis and peptic ulcer.

In the lower gastrointestinal tract melatonin helps regulate peristalsis. It cancels out serotonin's spasmodic effect and restores peristalsis. Pretreatment with melatonin prevents serotonin induced spasm. This shows up when measuring bowel transit times (BTT). Serotonin speeds things up, that is shortens BTT. Adding melatonin slows things back down, lengthening BTT. Small doses of melatonin though relax serotonin spasm and aid motility and again speed transit up. If you want some big words you could call this melatonin a peristaltic modulator. These properties lead to the suggestion to use melatonin to treat irritable bowel syndrome. As already mentioned low doses of melatonin, improves, that is speeds up, slow transit times and larger doses slow down and delay fast transit times.

The first clear glimmer I noticed about melatonin being useful for reflux disease was Pereira and de Souza's article published in the Journal of Pineal Research in May 2006. They told the story of a 64 year old woman whose GERD symptoms responded favorably to a formula containing 6 mg of melatonin plus several amino acids and vitamins. That October, the same journal published a paper by Pereira comparing the action of the same melatonin combination formula against omeprazole. Pereira gave the melatonin containing supplement to 176 patients and 20 mg doses of omeprazole to another 175 patients. All 176 patients who received the melatonin supplements "reported a complete regression of symptoms after 40 days of treatment." Only 115 subjects (65.7%) of the omeprazole patients reported similar improvement. Part of the explanation for this effect is that melatonin, by inhibiting nitric oxide production, prevents relaxation of the lower esophageal sphincter. The lower esophageal sphincter is that valve on top of the stomach that holds your food down, preventing reflux.

I'd always assumed that people get heart burn in bed at night because they are horizontal and gravity no longer keeps the food down. It may be that activities prior to bed with a bright light that lower melatonin, loosening the stomach valve and that this causes heart burn.

It's not just gut smooth muscles that are affected by melatonin. Research dating back to the 1960s and 1970 report that melatonin relaxes smooth muscles in the reproductive tract . Melatonin has a synergistic effect with oxytocin in triggering more coordinated and more forceful uterine contractions and so may be of use in labor and delivery. Melatonin also appears to moderate placental function for the better. Because melatonin relaxes smooth muscles in the GIT and increases mucosal blood flow, it's been suggested that this is how melatonin heals gastric and intestinal ulcers. A 2008 report using a rat model of ulcerative colitis reported that melatonin treatment prevented the translocation of bacteria from the gut into circulation. With this in mind it is no surprise that a review published in January 2009 suggests using melatonin in treating ulcerative colitis.

Melatonin is often referred to as an antioxidant and indeed this is true. Melatonin is reported to be twice as effective as vitamin E. There are loads of interesting papers on how melatonin's antioxidant activity can protect the brain from injury, but this isn't the focus of this discussion and I'm going to skip them. Rather I want to focus on GIT and the role melatonin may have in treating GIT pathology.

Melatonin prevents the damage caused by ischemia and reperfusion of gut mucosa but not the kind of irritant damage caused by 100% ethanol. It increases the number of Peyer's patches but I've lost the reference for this.

Melatonin has been tested as an intervention for all sorts of diseases of the digestive tract. Working our way down, top to bottom, a number of diseases of the oral cavity may respond to melatonin because of the properties already mentioned but also because it stimulates synthesis of type I collagen fibers and promotes bone formation. Melatonin may by of therapeutic benefit, "… in the oral cavity damage of mechanical, bacterial, fungal or viral origin, in post-surgical wounds caused by tooth extractions and other oral surgeries and, in helping bone formation in various auto-immunological disorders such as Sjorgen syndrome, in periodontal diseases, and in oral cancers." Up until reading this, few would have put melatonin on a list of treatments for periodontal disease. It should be on our list now.

Melatonin protects against esophageal lesions. I got interested in this melatonin and GIT business after reading the papers on melatonin and reflux disease.

Melatonin stimulates amylase secretion by the pancreas. It protects the pancreas from damage; these "… beneficial effects of melatonin … on acute pancreatitis could be related to the ability of melatonin to scavenge the free radicals, to activate antioxidative enzymes and to modulate the cytokine production." In animal models of pancreatitis, melatonin not only protects against damage but also moderates the effects of the disease. In a rat study, "… melatonin is potentially capable of reducing pancreatic damage by decreasing serum TNF-alpha levels in … acute pancreatitis in rats. This result supports the idea that melatonin might be beneficial in ameliorating the severity of acute pancreatitis."

Melatonin appears to moderate bowel transit time and may be useful for treating irritable bowel disease. In a small clinical trial of 18 patients in 2007, each patient received either 3 mg of melatonin or a placebo for 8 weeks. Those receiving melatonin significantly improved overall IBS score (45% vs. 16.66%). The overall improvement in Quality of Life score was 43.63% in melatonin group and 14.64% in placebo group. Though a small group to gather data from, the improvements are significant.

Whether melatonin might be a useful treatment for ulcerative colitis was raised in a 2003 paper in the American Journal of Gastroenterology. A 2007 paper that measured the urine metabolites of melatonin in 24 people with ulcerative colitis found that they were significantly higher than in healthy controls. Higher levels of the metabolite were correlated with milder disease. This led the researchers to conclude, "Melatonin seems to be a part of anti-inflammatory response and its high level may appease the course of UC." An October 2008 case report on using melatonin to treat ulcerative colitis described positive effect. A January 2009 review concluded melatonin may be useful to treat ulcerative colitis.

So melatonin has been added to my list of therapy options for ulcerative colitis disease. What else might it be useful for? An old paper, from way back in 1979 suggests that melatonin may be useful in treating diseases that cause liver fibrosis. Removing the pineal gland from a lab animal precipitates the formation of fibrosis in the intestinal cavity and especially the liver. They go so far as to suggest, "primary biliary cirrhosis may be a pineal deficiency disease." It's an old paper but worth keeping in mind.

I've only one paper found that addresses whether melatonin might be useful for treating Crohn's disease. No abstract is available but the title, it's not encouraging; "Melatonin triggers Crohn's disease symptoms." For now, avoid giving Crohn's patients melatonin.

A young woman came into see me the other day complaining of chronic reflux disease. She is three months pregnant. It's not clear whether we should avoid or encourage melatonin use during pregnancy. The standard reference books and general websites say melatonin's contraindicated but a PubMed search turns up several recent reviews that suggest melatonin may actually be beneficial during pregnancy and to prevent post partum depression.

Let's step back for a second. If melatonin is good for all this stuff, one would expect these sorts of diseases to be more common in people with low melatonin or less common in people with high melatonin. The main factor that we know that suppresses melatonin is night time exposure to lights. There is that Israeli study that correlates breast cancer incidence with night time out door lighting intensity. That study judged exposure to light at night by examining satellite photos taken by NASA. The same group published another study in 2009, this time looking at prostate cancer. Rather than using night time photos they came up with a system for estimating night time light exposure by combining factors like electricity consumption, per capita income and degree of urbanization. Their calculations could predict slight increases in prostate cancer risk associated with greater calculated night time lighting.

There is certainly information suggesting gastrointestinal disease fluctuates with night time light or melatonin levels.

Women who work night shifts make less melatonin. People with shift work sleep disorder (SWSD), the diagnostic name complaints that stem from working either night shifts or swing shifts, have a higher than average incidence of gastrointestinal disorders. The strongest correlation is with peptic ulcer disease.

If you waterboard a rat, or to use the euphemism employed in the abstracts, stress a restrained rat by water immersion, the poor thing develops gastric ulcerations. Again to use simple English, the rat gets bleeding ulcers. These ulcers bleed more during the daytime and start to heal at night. If you destroy the rat's pineal gland so it can't make melatonin, the ulcers get a lot worse and won't heal even at night. We will choose not to digress from our discussion to consider the ethical concerns of having performed similar experiments on people. It's not only ulcers that heal faster when there's more melatonin, surgical incisions also heal faster.

Recall that night shift workers make less melatonin. A 2003 study analyzed data from the nurse's health study and looked at risk for colon cancer in relation to frequency of working night shifts. The study concluded, "… working a rotating night shift at least three nights per month for 15 or more years may increase the risk of colorectal cancer in women."

It would seem that our modern illuminated lifestyle has inadvertently caused a hormone deficiency that has long term health implications.

This information is changing the way I treat a number of conditions. I now consider using melatonin for a long list of gastrointestinal conditions, pretty much everything except Crohn's Disease. It looks as if l-tryptophan, because it is a precursor to melatonin, might also be useful. If a patient complains of both digestive tract irritations and insomnia, melatonin moves to the top of my list of considerations.

Unlike in cancer treatment, moderate doses of melatonin still seem indicated for GIT conditions. The GERD studies suggest 6 mg doses. The UC studies suggest doses of 3 mg. L-tryptophan, after a long and questionable hiatus, is again easily available as a supplement. No specific l-tryptophan dose suggestions for have emerged from my reading. Whether plain, sustained release or enteric coated melatonin products will prove to be more beneficial remains to be determined.

Other articles on melatonin:

Melatonin and GERD December 2008 http://denvernaturopathic.com/MelatoninandGERD.htm

Blue Light and Melatonin April 2008 http://denvernaturopathic.com/bluelightandmelatonin.htm

Light at Night and Breast Cancer Risk February 2008 http://denvernaturopathic.com/lightatnight.htm

Melatonin, Estrogen and Breast Cancer September 2007 http://denvernaturopathic.com/news/MelatoninandBreastCancer.html

Ruminations on vitamin D and melatonin http://denvernaturopathic.com/news/soltriol.html