Melatonin in Health and Disease and its Metabolism by the GutMicrobes: Implications for Deuterium Homeostasis?

Deuterium (2H), a heavy isotope of protium (1H), is a naturally occurring element with a significant impact on human metabolism. Despite its natural presence, deuterium can impair mitochondrial function by damaging ATPase pumps; consequently, biological organisms have evolved sophisticated strategies to mitigate the risks of deuterium overload and protect mitochondrial integrity. Multiple enzymes have evolved to prefer hydrogen over deuterium in their reactions to protect these pumps. One class of enzymes is the cytochrome P450 (CYP) enzymes, which oxidize many substrates, mainly in the Endoplasmic Reticulum (ER), often producing water as a by-product. Furthermore, hydrogen peroxide (H2O2), produced in the ER by ERO1, can travel via the cytoplasm to the mitochondria, where it is reduced to two molecules of water via glutathione peroxidase. Melatonin is an ancient antioxidant molecule that first appeared in photosynthetic bacteria billions of years ago to protect against oxygen produced by respiration. In this paper, we present a hypothesis that melatonin metabolism in the gut provides deuterium- depleted protons to the enterocyte mitochondria. Few are aware that melatonin, known mainly as the hormone produced by the pineal gland to regulate circadian rhythms, is produced in the gut at 400 times the amount produced by the pineal gland. In the gut lining, melatonin is synthesized from N-acetylserotonin through the addition of a methyl group from S-adenosylmethionine. This methyl group, which we argue is severely deuterium-depleted due to its gut microbial source, is then fully metabolized by CYP2C19 in the ER of enterocytes in the small intestine, producing four molecules of water, which we argue would also be depleted in deuterium. Melatonin is recycled from the gut to the liver multiple times via the bile acids, and it is repeatedly converted back to N-acetylserotonin and regenerated, each time producing four water molecules derived from its methyl group. Butyrate, another nutrient supplied by gut microbes, stimulates the synthesis of serotonin and melatonin from tryptophan in the gut. Melatonin is a powerful antioxidant in mitochondria and promotes a healthy microbiome. Melatonin deficiency is associated with the severity of long COVID, and melatonin supplementation can help minimize side effects.