Roseburia hominis Increases Intestinal Melatonin Level by Activating p-CREB-AANAT Pathway

Intestinal melatonin exerts diverse biological effects on the body. Our previous research showed that the abundance of the butyrate-producing bacteria, Roseburia, is positively related to the expression of colonic mucosal melatonin. However, the detailed relationship is unclear. Therefore, we aimed to explore whether Roseburia regulates intestinal melatonin and its underlying mechanisms. Male Sprague–Dawley germfree rats were orally administered with or without Roseburia hominis. R. hominis treatment significantly increased the intestinal melatonin level. The concentrations of propionate and butyrate in the intestinal contents were significantly elevated after gavage of R. hominis. Propionate or butyrate treatment increased melatonin, 5-hydroxytryptamine (5-HT), arylalkylamine N-acetyltransferase (AANAT), and phosphorylated cAMP-response element-binding protein (p-CREB) levels. When pretreated with telotristat ethyl, the inhibitor of tryptophan hydroxylase (TPH), or siRNA of Aanat, or 666-15, i.e., an inhibitor of CREB, propionate, or butyrate, could not promote melatonin production in the pheochromocytoma cell line BON-1. Metabolomics analysis showed that propionate and butyrate stimulation regulated levels of some metabolites and some metabolic pathways in BON-1 cell supernatants. In conclusion, propionate and butyrate, i.e., metabolites of R. hominis, can promote intestinal melatonin synthesis by increasing 5-HT levels and promoting p-CREB-mediated Aanat transcription, thereby offering a potential target for ameliorating intestinal diseases.

Obstructive sleep apnea syndrome: association of serum melatonin, increased daytime sleepiness, and intermitting night hypoxemia

The relevance of studies related to the features of respiratory disorders during sleep is undeniable due to the steady growth of the worldwide prevalence of apnea syndrome, which leads to a decrease in quality of life, the risk of early cardiovascular diseases together with cerebrovascular, endocrine, and pulmonary disorders.The aim of this study was to determine the relationship between the morning serum melatonin, blood oxygen saturation (SрO2), and increased daytime sleepiness in patients with SOAS, as well as to assess changes in the production of endogenous melatonin after eliminating clinical manifestations of nocturnal hypoxemia, through a 3-month course of non-invasive continuous positive airway pressure (CPAP) therapy. The study enrolled 30 male patients who came to the Federal State Public Scientific Institution “Scientific Centre of Family Health and Human Reproduction Problems” because of snoring, sleep apnea, and increased daytime sleepiness.Methods. Polysomnography, questionnaire, HPLC-MS/MS analysis of serum melatonin levels, CPAP-therapy for the respiratory support at home for 3 months, monitoring of the sleep scores, serum melatonin, and daytime sleepiness after the treatment.Results. A comparative assessment of the sleep scores before and after the respiratory support for 3 months revealed a significant improvement in sleep structure, elimination of the apnea episodes, and restoration of blood SрO2 after the therapy. Analysis of the serum melatonin vales confirmed a statistically significant increase of melatonin level against baseline in patients with SOAS after the treatment. A correlation analysis showed a relationship between the melatonin level, daytime sleepiness, and blood SрO2.Conclusion. The results of this study and the data of other researchers demonstrate that the elimination of intermittent nocturnal hypoxia in patients with SOAS allows reducing the morning serum melatonin level, thereby reducing the daytime sleepiness and subsequently improving the quality of life.

Relationship between pineal gland, sleep and melatonin in fibromyalgia women: a magnetic resonance imaging study

A total of 80% of fibromyalgia (FM) population have reported poor sleep. In this regard, the pineal gland, involved in circadian rhythm processes as a key neuroendocrine organ which mainly synthesises and secretes melatonin, has never been studied before in this population. Therefore, this study aimed to evaluate the parenchyma pineal volume and its relation to sleep hours, sleep quality index and melatonin level at night. A total of 50 participants, 30 women with FM and 20 healthy control women underwent cranial magnetic resonance imaging. The total pineal volume, cyst pineal volume and parenchyma pineal volume were manually calculated in cubic millimetres. Also, the total pineal volume was estimated using Hasehawa method. Parenchyma pineal volume was significantly correlated with sleep hours (p-value = 0.041) and nocturnal melatonin level (p-value = 0.027). Moreover, there was also a non-significant correlation between parenchyma pineal volume and sleep quality index (p-value = 0.055). Furthermore, a mean parenchyma pineal volume of 102.00 (41.46) mm³ was observed, with a prevalence of 29.60% cyst in FM group. This is the first study that has reported pineal gland volumes, cyst prevalence and correlative relationships between parenchyma pineal volume and sleep hours and melatonin levels in women with FM.

Decreased Circulating Melatonin with Loss of Age-Related Biphasic Change in Patients with Oral Squamous Cell Carcinoma

Background: Melatonin, produced by the pineal gland, is known for its antioxidant, oncostatic, and anti-inflammatory properties. However, studies on serum melatonin levels in different cancer types have yielded conflicting results, and little is known about the clinical significance of serum melatonin in oral squamous cell carcinoma (OSCC) in the Southern Asian population. Therefore, we explored its role in OSCC in this study. Methods: A total of 67 male OSCC patients and 78 healthy controls were enrolled in this case–control study. The serum levels of melatonin were determined by enzyme-linked immunosorbent assay (ELISA) and compared between the two groups. Results: The serum melatonin levels were significantly lower in OSCC patients compared with healthy controls (mean ± standard deviation, 15.0 ± 4.6 vs. 18.5 ± 11.8 pg/mL, p = 0.02). In the subgroup of age less than 55 years (mean age of OSCC), OSCC patients had a significantly decreased melatonin level than healthy controls (mean melatonin, 15.7 ± 12.6 vs. 20.8 ± 3.9 pg/mL, p = 0.02). Decreased serum melatonin (odds ratio (OR): 0.95, 95%CI: 0.91–0.99), alcohol consumption (OR: 29.02, 95%CI: 11.68–72.16), betel quid chewing (OR:136.44, 95%CI: 39.17–475.27), and cigarette smoking (OR:29.48, 95%CI: 11.06–78.60) all increased the risk of OSCC under univariate analyses of logistic regression. Betel quid chewing (OR: 45.98, 95%CI: 10.34–204.49) and cigarette smoking (OR:6.94, 95%CI: 1.60–30.16) were the independent risk factors for OSCC in Taiwan. In addition, a negative correlation between age and melatonin level was observed in healthy controls (Pearson r = −0.24, p = 0.03). However, the negative correlation was lost in patients with OSCC. Melatonin concentration had no association with the severity of OSCC. Conclusion: Overall, our study provides evidence that serum melatonin levels decreased in OSCC patients in Taiwan and the decreased level is much significant in young populations and suggests that the decreased melatonin was associated with OSCC, especially in young populations. Further studies are warranted to investigate whether melatonin can be a useful non-invasive screening tool for OSCC.

Melatonin-Mediated Colonic Microbiota Metabolite Butyrate Prevents Acute Sleep Deprivation-Induced Colitis in Mice

Radical cure colitis is a severe public health threat worldwide. Our previous studies have confirmed that melatonin can effectively improve gut microbiota disorder and mucosal injury caused by sleep deprivation (SD). The present study further explored the mechanism whereby exogenous melatonin prevented SD-induced colitis. 16S rRNA high-throughput sequencing and metabolomics analysis were used to explore the correlation between SD-induced colitis and intestinal microbiota and metabolite composition in mice. Fecal microbiota transplantation (FMT) and melatonin or butyrate supplementation tests verified the core role of gut microbiota in melatonin-alleviating SD-induced colitis. Further, in vitro tests studied the modulatory mechanism of metabolite butyrate. The results demonstrated that SD leads to reductions in plasma melatonin levels and colonic Card9 expression and consequent occurrence of colitis and gut microbiota disorder, especially the downregulation of Faecalibacterium and butyrate levels. The FMT from SD-mice to normal mice could restore SD-like colitis, while butyrate supplementation to SD-mice inhibited the occurrence of colitis, but with no change in the plasma melatonin level in both treatments. However, melatonin supplementation reversed all inductions in SD-mice. In intestinal epithelial cells, the inflammatory ameliorative effect of butyrate was blocked with pretreatments of HDAC3 agonist and HIF-1α antagonist but was mimicked by GSK-3β and p-P65 antagonists. Therefore, the administration of MLT may be a better therapy for SD-induced colitis relative to butyrate. A feasible mechanism would involve that melatonin up-regulated the Faecalibacterium population and production of its metabolite butyrate and MCT1 expression and inhibited HDAC3 in the colon, which would allow p-GSK-3β/β-catenin/HIF-1α activation and NF-κB/NLRP3 suppression to up-regulate Card9 expression and suppress inflammation response.

Effects of Duodenal 5-Hydroxytryptophan Perfusion on Melatonin Synthesis in GI Tract of Sheep

The purpose of this study is to investigate the potential effects of 5-hydroxytryptophan (5-HTP) duodenal perfusion on melatonin (MT) synthesis in the gastrointestinal (GI) tract of sheep. 5-hydroxytryptophan is a precursor in the melatonin synthetic pathway. The results showed that this method significantly increased melatonin production in the mucosa of all segments in GI tract including duodenum, jejunum, ileum, cecum and colon. The highest melatonin level was identified in the colon and this indicates that the microbiota located in the colon may also participate in the melatonin production. In addition, portion of the melatonin generated by the GI tract can pass the liver metabolism and enters the circulation via portal vein. The current study provides further evidence to support that GI tract is the major site for melatonin synthesis and the GI melatonin also contributes to the circulatory melatonin level since plasma melatonin concentrations in 5-HTP treated groups were significantly higher than those in the control group. In conclusion, the results show that 10–50 mg of 5-HTP flowing into the duodenum within 6 h effectively improve the production of melatonin in the GI tract and melatonin concentration in sheep blood circulation during the day.

The promising oncostatic effects of melatonin against ovarian cancer

Melatonin is a pineal hormone, secreted at the subjective night. It is involved in the regulation of many physiological functions, including the sleep-wake cycle, gonadal activity, free radical scavenging, immunomodulation, neuro-protection, and cancer progression. Melatonin acts through cell surface receptors (MT1 and MT2) as well as nuclear receptors. Circadian dysfunction can alter the secretion of melatonin. Inappropriate melatonin level promotes the initiation of many pathologies including cancer. Ovarian cancer is a common form of gynecological disease. Several studies indicate the profound link between impaired melatonin secretion and the progression of ovarian cancer. Melatonin exerts oncostatic effects in multiple ways; it acts as a potent antioxidant, induces apoptosis, and regulates metabolism, and chronic inflammatory response in ovarian cancer cells. Moreover, melatonin improves the efficacy of the current treatment regimen of ovarian cancer and can be used as an adjuvant.

A Genome-Wide Association Study for Melatonin Secretion

SummaryPurpose: Melatonin exerts a wide range of effects among various tissues and organs. However, there is currently no study to investigate the genetic determinants of melatonin secretion. Here, we conducted a genome-wide association study (GWAS) for melatonin secretion using morning urine 6-hydroxymelatonin sulfate-to-creatinine ratio (UMCR). Methods: We initially enrolled 5,000 participants from Taiwan Biobank in this study. After excluding individuals that did not have their urine collected in the morning and those who failed to pass quality control, association of single nucleotide polymorphisms with log-transformed UMCR adjusted for age, sex and principal components of ancestry were analyzed. A second model additionally adjusted for estimated glomerular filtration rate (eGFR). Results: A total of 2,504 participants underwent the genome-wide analysis. Six candidate loci associated with log UMCR (P value ranging from 7.54 x 10-7 to 4.65 x 10-6) encompassing GALNT15, ZFHX3, NKAIN2, MME and NBPF22P were identified. Similar results were yielded with further adjustment for eGFR. Interestingly, the identified genes are associated with central nervous system function and clinical condition such as Alzheimer's disease or sleep disorders.Conclusions: We conducted the first GWAS for melatonin secretion and identified six candidate genetic loci associated with melatonin level. Replication and functional studies are needed in the future.