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
1. Zhang B, Chen T, Cao M, Yuan C, Reiter RJ, Zhao Z, et al. Gut Microbiota Dysbiosis Induced by Decreasing Endogenous Melatonin Mediates the Pathogenesis of Alzheimer’s Disease and Obesity. Front Immunol. 2022 May 10;13.
2. Laborda-Illanes A, Sánchez-Alcoholado L, Boutriq S, Plaza-Andrades I, Peralta-Linero J, Alba E, et al. A new paradigm in the relationship between melatonin and breast cancer: Gut microbiota identified as a potential regulatory agent. Vol. 13, Cancers. 2021.
3. Rezzani R, Franco C, Franceschetti L, Gianò M, Favero G. A Focus on Enterochromaffin Cells among the Enteroendocrine Cells: Localization, Morphology, and Role. Vol. 23, International Journal of Molecular Sciences. 2022.
4. Yasmin F, Sutradhar S, Das P, Mukherjee S. Gut melatonin: A potent candidate in the diversified journey of melatonin research. Vol. 303, General and Comparative Endocrinology. 2021.
5. Fowler S, Hoedt EC, Talley NJ, Keely S, Burns GL. Circadian Rhythms and Melatonin Metabolism in Patients With Disorders of Gut-Brain Interactions. Vol. 16, Frontiers in Neuroscience. 2022.
6. Chen CQ, Fichna J, Bashashati M, Li YY, Storr M. Distribution, function and physiological role of melatonin in the lower gut. Vol. 17, World Journal of Gastroenterology. 2011.
7. Majka J, Wierdak M, Brzozowska I, Magierowski M, Szlachcic A, Wojcik D, et al. Melatonin in prevention of the sequence from reflux esophagitis to barrett’s esophagus and esophageal adenocarcinoma: Experimental and clinical perspectives. Vol. 19, International Journal of Molecular Sciences. 2018.
8. Kanova M, Kohout P. Tryptophan: A unique role in the critically ill. Vol. 22, International Journal of Molecular Sciences. 2021.
9. Tan DX, Manchester LC, Esteban-Zubero E, Zhou Z, Reiter RJ. Melatonin as a potent and inducible endogenous antioxidant: Synthesis and metabolism. Molecules. 2015.
10. Bantounou M, Plascevic J, Galley HF. Melatonin and Related Compounds: Antioxidant and Anti-Inflammatory Actions. Antioxidants. 2022 Mar 10;11(3):532.
11. Wang T, Wang Z, Cao J, Dong Y, Chen Y. Melatonin prevents the dysbiosis of intestinal microbiota in sleep-restricted mice by improving oxidative stress and inhibiting inflammation. Saudi Journal of Gastroenterology. 2022;28(3).
12. Park YS, Kim SH, Park JW, Kho Y, Seok PR, Shin JH, et al. Melatonin in the colon modulates intestinal microbiota in response to stress and sleep deprivation. Intest Res. 2020;18(3).
13. Scott MB, Styring AK, McCullagh JSO. Polyphenols: Bioavailability, Microbiome Interactions and Cellular Effects on Health in Humans and Animals. Pathogens. 2022 Jul 5;11(7):770.
14. Aliyev AT, Panieri E, Stepanić V, Gurer-Orhan H, Saso L. Involvement of NRF2 in breast cancer and possible therapeutical role of polyphenols and melatonin. Vol. 26, Molecules. 2021.
15. Labban S, Alghamdi BS, Alshehri FS, Kurdi M. Effects of melatonin and resveratrol on recognition memory and passive avoidance performance in a mouse model of Alzheimer’s disease. Behavioural Brain Research. 2021;402.
16. Marhuenda J, Medina S, Martínez-Hernández P, Arina S, Zafrilla P, Mulero J, et al. Effect of the dietary intake of melatonin- and hydroxytyrosol-rich wines by healthy female volunteers on the systemic lipidomic-related oxylipins. Food Funct. 2017;8(10).
17. Seoane-Viaño I, Gómez-Lado N, Lázare-Iglesias H, Rey-Bretal D, Lamela-Gómez I, Otero-Espinar FJ, et al. Evaluation of the therapeutic activity of melatonin and resveratrol in Inflammatory Bowel Disease: A longitudinal PET/CT study in an animal model. Int J Pharm. 2019;572.
18. Elbe H, Esrefoglu M, Vardi N, Taslidere E, Ozerol E, Tanbek K. Melatonin, quercetin and resveratrol attenuates oxidative hepatocellular injury in streptozotocin-induced diabetic rats. Hum Exp Toxicol. 2015;34(9).
19. Zhang L, He Y, Wu X, Zhao G, Zhang K, Yang CS, et al. Melatonin and (−)-epigallocatechin-3-gallate: Partners in fighting cancer. Cells. 2019;8(7).
20. Chattree V, Singh K, Singh K, Goel A, Maity A, Lone A. A comprehensive review on modulation of <scp>SIRT1</scp> signaling pathways in the immune system of <scp>COVID</scp> ‐19 patients by phytotherapeutic melatonin and epigallocatechin‐3‐gallate. J Food Biochem. 2022 Jun 3;