Melatonin used to promote sleep may worsen IBD gut inflammation

• Inflammatory bowel disease (IBD) is associated with changes in gut microbiota composition and intestinal inflammation.
• Melatonin is a hormone synthesized in the brain that regulates the circadian rhythm and is used as a supplement to promote sleep.
• Melatonin is also produced in the intestine, where it can modulate the gut immune system, suggesting this hormone may have potential as a therapeutic for IBD.
• A new study in a mouse model of IBD now shows that melatonin caused changes in the gut microbiota composition, resulting in increased disease severity and delayed recovery from IBD.

Although biologics and immunosuppressive drugs can be effective against inflammatory bowel disease (IBD), some individuals do not respond to these treatments and require surgery.

The hormone melatonin, which regulates the sleep-wake cycle, is also produced in the intestines, where it can modulate immune response.

These properties of melatonin have led to an interest in utilizing this hormone for the treatment of IBD. However, studies examining the ability of melatonin to treat IBD have produced contradictory results.

A recent study published in the journal Microorganisms now suggests that melatonin worsened gut inflammation in a mouse model of IBD and, during remission, delayed recovery. Notably, these effects of melatonin on gut inflammation were mediated by changes in the gut microbiota composition.

“[Melatonin is] generally thought to be harmless. After all, it’s a hormone and can help regulate sleep. However, our study shows that people should be careful about taking hormone supplements and that the ingestion of melatonin as a supplement can have adverse effects on health,” Dr. Cristina Ribeiro de Barros Cardoso, a study author and a professor at the University of Sao Paulo in Brazil, said in a press release.

“We should take great care with medications, hormone supplements, or hormones offered as food supplements,” she added. “You buy a ‘food supplement’ in a pharmacy and think it’s not a drug, it won’t alter anything in your body, it will only do good because, after all, it’s sold as a food supplement, but it’s not really that at all. It’s a hormone and regulation of the interaction between all hormones and the immune system is very delicate.”

Dr. Shilpa Ravella, a gastroenterologist at Columbia University Medical Center in New York and the author of “A Silent Fire: The Story of Inflammation, Diet, and Disease,” said, “The study prompts us to use caution when administering long-term supplements for chronic diseases. Supplements, even seemingly harmless ones, are generally not well-regulated and may have effects that we don’t yet understand.”

Role of gut microbiota

Inflammatory bowel disease is characterized by the chronic inflammation of the gastrointestinal tract. Inflammatory bowel disease collectively refers to Crohn’s disease and ulcerative colitis. The focus of IBD treatment is to control symptoms during active flares and to induce remission, a period in which an individual does not have any symptoms.

Individuals with IBD show alterations in the abundance and composition of the gut microbes, including a decline in the diversity of gut bacteria. Specifically, studies have shown an increase in the proportion of harmful or pathogenic microorganisms and a decrease in the proportion of beneficial ones in IBD.

The gut microbiota play a critical role in the development of the intestinal immune system and maintaining its function. Consistent with this, the alteration in the gut microbiota composition in IBD is associated with the dysregulation of the immune system, leading to a proinflammatory environment in the digestive system and tissue damage.

Treatments for IBD include immunosuppressive drugs and antibodies that help to reduce inflammation. However, some individuals with moderate or severe IBD do not respond to these therapeutics. Surgery can be necessary in this subset of people. As such, there is a need for additional treatment options that are more conservative.

Due to the ability of melatonin to modulate the immune response, scientists have examined its potential to ameliorate IBD symptoms. Melatonin is synthesized in the pineal gland in the brain and helps regulate the circadian rhythm. Melatonin is released at night and is used as a supplement to induce sleep.

Moreover, melatonin is also produced by specific groups of cells in the intestine, such as the enterochromaffin cells. The levels of melatonin in the intestine are much higher than in the pineal gland, indicating an important role for melatonin in the digestive tract.

Evidence from a few preliminary studies suggests that the use of melatonin at low doses or for a short duration may have beneficial effects in IBD patients. However, there is also evidence indicating that the chronic use of melatonin may worsen inflammation.

Impact of melatonin in a mouse model of IBD

To further examine the impact of melatonin on the course of IBD and remission periods, the researchers induced colitis in mice using the chemical agent dextran sulfate sodium (DSS).

Administration of melatonin over the duration of DSS treatment increased the severity of colitis and the levels of inflammatory markers in the blood and the intestine. Continuing melatonin treatment after the end of DSS exposure also prolonged recovery from colitis, accompanied by greater levels of systemic and gut inflammation.

Previous studies have shown that individuals with IBD show an increase in bacterial species belonging to Proteobacteria and Actinobacteria phyla while showing a decline in those belonging to the Firmicutes and Bacteriodetes. Treatment of chemically induced colitis with melatonin during the recovery phase resulted in an increase in Actinobacteria species and a reduction in Bacteriodetes species.

In addition, there was an increase in strains belonging to the Verrucomicrobia phyla. Some of the species belonging to this phyla can break down mucin, the protein that constitutes the layer of mucus lining the wall of the intestine. Mucin helps protect the gastrointestinal tract from infection and inflammation, and changes in mucins are also observed in IBD. Thus increase in species that degrade mucins may increase the risk of gastrointestinal inflammation.

The researchers then examined the role of gut microbiota in mediating these adverse effects of melatonin administration. The depletion of gut microbiota using antibiotics before the onset of DSS treatment resulted in more rapid remission from IBD and reduced systemic and gut inflammation.

The induction of colitis after gut microbiota depletion also led to an increase in bacterial species belonging to the Bacteriodetes phylum while reducing the abundance of those belonging to the Actinobacteria and Verrucomicrobia phyla. These findings suggest that gut microbiota may mediate these effects of melatonin on gut inflammation.

“It’s important to remember that this is an animal study and what happens in animals may not happen in humans, so we cannot state that these findings are definitively relevant to humans,” Ravella told Medical News Today. “And this study does differ from previous literature, which has suggested that melatonin may actually help to treat inflammation and intestinal diseases. In addition, melatonin is generally used to regulate sleep, and we know that sleep loss is tied to increased inflammation.”

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