Localization, Physiological Significance and Possible Clinical Implication of Gastrointestinal Melatonin

Abstract

The gastrointestinal tract (GIT) is a major source of extrapineal melatonin. In some animals, tissue concentrations of melatonin in the GIT surpass blood levels by 10–100 times and the digestive tract contributes significantly to melatonin concentrations in the peripheral blood, particularly during the day. Some melatonin found in the GIT may originate from the pineal gland, as the organs of the digestive system contain binding sites, which in some species exhibit circadian variation. Unlike the production of pineal melatonin, which is under the photoperiodic control, release of GI melatonin seems to be related to periodicity of food intake. Melatonin and melatonin binding sites were localized in all GI tissues of mammalian and avian embryos. Postnatally, melatonin was localized in the GIT of newborn mice and rats. Phylogenetically, melatonin and melatonin binding sites were detected in GIT of numerous mammals, birds and lower vertebrates. Melatonin is probably produced in the serotonin-rich enterochromaffin cells (EC) of the GI mucosa and can be released into the portal vein postprandially. In addition, melatonin can act as an autocrine or a paracrine hormone affecting the function of GI epithelium, lymphatic tissues of the immune system and the smooth muscles of the digestive tube. Finally, melatonin may act as a luminal hormone, synchronizing the sequential digestive processes. Higher peripheral and tissue levels of melatonin were observed not only after food intake but also after a long-term food deprivation. Such melatonin release may have a direct effect on the various GI tissues but may also act indirectly via the CNS; such action might be mediated by sympathetic or parasympathetic nerves. Melatonin can protect GI mucosa from ulceration by its antioxidant action, stimulation of the immune system and by fostering microcirculation and epithelial regeneration. Melatonin may reduce the secretion of pepsin and the hydrochloric acid and influence the activity of the myoelectric complexes of the gut via its action in the CNS. Tissue or blood levels of melatonin may serve as a marker of GI lesions or tumors. Clinically, melatonin has a potential for a prevention or treatment of colorectal cancer, ulcerative colitis, irritable bowel syndrome, children colic and diarrhea.

Chronomics affirm extending scope of lead in phase of duodenal vs. pineal circadian melatonin rhythms

“…In fact, already early investigations indicated the possibility of such rhythms in the digestive tract of rats [3] and pigeons [30]. But the extent of variation was consistently much lower in the gut than the pineal gland or the peripheral circulation [4,23], and sometimes rhythmicity was not readily detectable but see [30]. Since the amounts of total gastrointestinal melatonin are up to orders of magnitude higher than those found in the pineal [4][5][6]12,15], the contribution of this extrapineal source to the levels of circulating melatonin is of conside-rable interest.…”

“…[8][9][10]) is here applied to melatonin, usually regarded as the hormone of the pineal gland, but also synthesized by various extrapineal tissues [12,15,23,25,26]. Among those, the digestive tract represents a system which contains by far the highest amount of this indoleamine [4][5][6]15,23]. Melatonin has properties of an antiinflammatory and antioxidant agent and is a modulator of the immune system, acid secretion and smooth muscle tone.…”

“…Melatonin has properties of an antiinflammatory and antioxidant agent and is a modulator of the immune system, acid secretion and smooth muscle tone. Hence, gastrointestinal melatonin has a potential as a clinically relevant agent [4,5]. With regard to the pronounced circadian rhythmicity of melatonin released into the blood by the pineal, it also seemed worthwhile to consider the circadian aspect of secretion of gastrointestinal melatonin.…”

“…But the extent of variation was consistently much lower in the gut than the pineal gland or the peripheral circulation [4,23], and sometimes rhythmicity was not readily detectable but see [30]. Since the amounts of total gastrointestinal melatonin are up to orders of magnitude higher than those found in the pineal [4][5][6]12,15], the contribution of this extrapineal source to the levels of circulating melatonin is of conside-rable interest. This question cannot be definitely solved by pinealectomy, since any persisting rhythms may be attributed to other extrapineal sources, such as the retina, bone marrow, pituitary and hypothalamus [10,31] oras assumed in the pigeon [29]-the Harderian gland.…”

A protective effect of melatonin on intestinal permeability is induced by diclofenac via regulation of mitochondrial function in mice

“…Melatonin plays a fundamental role in the neuroimmunoendocrine system [7] . The levels of melatonin and melatonin receptors are highly concentrated in the intestine [8] ; melatonin concentrations in the gut are 10-100 times greater than those found in the plasma [9] . Moreover, it has been suggested that the intestine is the major site for extra-pineal melatonin production [10] .…”