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Gut-Synthesized Melatonin & the Gut Microbiome

Two types of cells are responsible for the production of melatonin: pinealocytes and enterochromaffin cells. Pinealocytes are located in the pineal gland within the brain. Enterochromaffin cells are located on the surface of the entire gastrointestinal (GI) tract, with high concentrations in the mucosal lining of the GI tract. Pinealocytes are affected by light and dark; exposure to light suppresses melatonin production and release from the pinealocytes, while darkness (when registered by the retina) increases melatonin production and release into the bloodstream starting with vessels in the brain. From the blood vessels in the brain, melatonin is carried to other body tissues. It is estimated that the enterochromaffin cells within the gut contain upwards of 400 times the amount of melatonin than what is produced by pinealocytes. Levels of gut melatonin can be anywhere from 10 to 100 times greater than melatonin in blood serum levels (1,2).


Unlike pinealocytes, enterochromaffin cells are not regulated by light and dark but appear affected by food intake and digestion (3,4). Of note, it remains speculative as to how pineal-produced and gut-derived melatonin interrelate, whether there is any gut-pineal axis crosstalk, and how different dietary patterns or even specific foods, fasting regimens, or timing of meals (chrononutrition) may alter systemic melatonin levels or the physiological relevance of any changes. This area of diet and gut-produced melatonin is rich with questions to be answered through research.


The release of melatonin in the gut acts in a paracrine manner to increase activity and circulation in the gastric mucosa and enhances GI motility (5,6). With the increased production of gastrin, melatonin has also been attributed to increasing the tone of the lower esophageal sphincter (7). Further, melatonin has anti-excitatory properties in the gut. It can stimulate the regeneration of epithelial cells (8) and has also been shown to have protective antioxidant effects on the lining of the GI tract (8).


An investigation into gut microbiota has identified microbial influences on the serotonergic and melatonergic systems (9). The established serotonergic and melatonergic systems may be vulnerable before establishing a stable global biota in infancy. Elderly individuals may also be more susceptible to serotonergic and melatonergic system errors due to known lower amounts of biota diversity. Both serotonergic and melatonergic systems are also prone to immune and inflammatory responses, adding to the complexities of the gut-brain axis (10).


It is suspected that the gut-brain axis is a network of complex interactions between the nervous and GI systems with major contributions from intestinal microbiota. Ultimately, the gut microbiota may influence CNS function and, over time, could cause neurological diseases, including Alzheimer’s disease, mood and anxiety disorders, multiple sclerosis (MS), Parkinson’s disease, and migraines. Preliminary animal research indicates a relationship between gut dysbiosis, endogenous melatonin production, and pathological changes associated with Alzheimer’s disease (1). Along these lines of research, melatonin administration in animals helped reduce dysbiosis due to sleep restriction (11,12). In one of the studies, Akkermansia muciniphila and Lactobacilli species were increased in the melatonin-treated animals (13).


Gut Health, Dietary Polyphenols & Melatonin


While still in exploratory phases, there may be eventual complementary action between melatonin and polyphenols. Although not absorbed in the GI tract to a great extent, polyphenols have become highlighted for their impacts on gut health, particularly due to the secondary metabolites that form from their interaction with the microbiota (13). There are initial indications that the antioxidant, and anti-inflammatory actions of melatonin may work together with select polyphenols (e.g., resveratrol, epigallocatechin 3-gallate) for therapeutic indications (14–20).


Authors: Deanna Minich, Ph.D., Melanie Henning, ND, Catherine Darley, ND, Mona Fahoum, ND, Corey B. Schuler, DC, James Frame

Reviewer: Peer-review in Nutrients Journal

Last updated: September 22, 2022





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