The Intricate Biological Proximity of Vitamin D and Brain Serotonin

Background: The purpose of this article is to extend and elaborate on our current understanding of Calcitriol and Brain Serotonin synthesis; particularly on how the two may be related. Methods: Using a 2014 study involving clinical trials to extend this hypothesis. Results: Vitamin D (Calcitriol) activated the gene that codes for Tryptophan Hydroxylase 2, which synthesizes Brain Serotonin. It also inhibits Tryptophan Hydroxylase 1, which makes serotonin in the gut. Conclusion: Vitamin D is closely related to the synthesis of Brain Serotonin. If furthered, it may be used as a treatment for the Serotonin Anomaly in Autistic Children. Keywords: 1. Biochemistry 2. Genetics 3. Neuroscience 4. Physiology

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.

Night-Restricted Feeding Improves Gut Health by Synchronizing Microbe-Driven Serotonin Rhythm and Eating Activity-Driven Body Temperature Oscillations in Growing Rabbits

The circadian misalignment of the gut microbiota caused by unusual eating times in adult animals is related to disease development. However, whether the composition and diurnal rhythm of gut microbiota can be optimized by synchronizing the window period of eating with natural eating habits to reduce the risk of diarrhea remains unclear, especially in growing animals. In this study, 108 5-week-old weaned rabbits (nocturnal animals) were randomly subjected to daytime feeding (DF) and night-restricted feeding (NRF). At age 12 weeks, six rabbits were selected from each group, and caecum and cecal contents, as well as serum samples were collected at 4-h intervals during 24 h. Overall, NRF was found to reduce the risk of diarrhea in growing rabbits, improved the diurnal rhythm and abundance of beneficial microorganisms, along with the production of beneficial metabolites, whereas reduced the abundance of potential pathogens (Synergistes, Desulfovibrio, and Alistipes). Moreover, NRF improved diurnal rhythm of tryptophan hydroxylase isoform 1 and serotonin. Furthermore, NRF strengthened the diurnal amplitude of body core temperature, and promoted the diurnal expression of intestinal clock genes (BMAL1, CLOCK, REV-ERBα, and PER1), and genes related to the regulation of the intestinal barrier (CLAUDIN-1), and intestinal epithelial cell self-proliferation and renewal (BMI1). In vitro simulation experiments further revealed that synchronization of microbial-driven serotonin rhythm and eating activity-driven body temperature oscillations, which are important zeitgebers, could promote the diurnal expression of clock genes and CLAUDIN-1 in rabbit intestinal epithelial cells (RIEC), and enhance RIEC proliferation. This is the first study to reveal that NRF reprograms the diurnal rhythm of the gut microbiome, promotes the diurnal expression of clock genes and tight junction genes via synchronization of microbial-driven serotonin rhythm and eating activity-driven body temperature oscillations, thereby improving intestinal health and reducing the risk of diarrhea in growing rabbits. Collectively, these results provide a new perspective for the healthy feeding and management of growing animals.

The Combined Effects of Amyloidosis and Serotonin Deficiency by Tryptophan Hydroxylase-2 Knockout Impacts Viability of the APP/PS1 Mouse Model of Alzheimer’s Disease

Background: A decline of brain serotonin (5-HT) is held responsible for the changes in mood that can be observed in Alzheimer’s disease (AD). However, 5-HT’ergic signaling is also suggested to reduce the production of pathogenic amyloid-4β (Aβ). Objective: To investigate the effect of targeted inactivation of tryptophan hydroxylase-2 (Tph2), which is essential for neuronal 5-HT synthesis, on amyloidosis in amyloid precursor protein (APP)swe/presenilin 1 (PS1) ΔE9 transgenic mice. Methods: Triple-transgenic (3xTg) APP/PS1 mice with partial (+/-) or complete Tph2 knockout (–/–) were allowed to survive until 6 months old with APP/PS1, Tph2–/–, and wildtype mice. Survival and weight were recorded. Levels of Aβ 42/40/38, soluble APPα (sAβPPα) and sAβPPβ, and cytokines were analyzed by mesoscale, neurotransmitters by mass spectrometry, and gene expression by quantitative PCR. Tph2, microglia, and Aβ were visualized histologically. Results: Tph2 inactivation in APP/PS1 mice significantly reduced viability, without impacting soluble and insoluble Aβ 42 and Aβ 40 in neocortex and hippocampus, and with only mild changes of soluble Aβ 42/Aβ 40. However, sAβPPα and sAβPPβ in hippocampus and Aβ 38 and Aβ 40 in cerebrospinal fluid were reduced. 3xTg–/–mice were devoid of Tph2 immunopositive fibers and 5-HT. Cytokines were unaffected by genotype, as were neocortical TNF, HTR2a and HTR2b mRNA levels in Tph2–/– mice. Microglia clustered around Aβ plaques regardless of genotype. Conclusion: The results suggest that Tph2 inactivation influences AβPP processing, at least in the hippocampus, although levels of Aβ are unchanged. The reduced viability of 3xTg–/–mice could indicate that 5-HT protects against the seizures that can impact the viability of APP/PS1 mice.

Is sleep bruxism related to the levels of enzymes involved in the serotonin synthesis pathway?

Objectives This exploratory research aimed to evaluate the levels of tryptophan hydroxylase 1 (TPH1) and aromatic l-amino acid decarboxylase (DDC), which play an important role in the serotonin synthesis pathway, in individuals with sleep bruxism (SB) diagnosed using audio–video polysomnography (vPSG) and compare them with that of individuals not presenting with SB. Materials and methods The study included adult patients hospitalized in the Department and Clinic of Internal Medicine, Occupational Diseases, Hypertension and Clinical Oncology at the Wroclaw Medical University. The participants underwent a single-night vPSG for the evaluation of the SB parameters. Peripheral blood samples were also collected from them for estimating the serum levels of TPH1 and DDC. Results A total of 105 patients (80 women and 25 men) were included in the study. All the patients were Caucasians and aged 18–63 years (mean age: 33.43 ± 10.8 years). Seventy-five patients (71.43%) presented with SB, of which 50 (47.62%) had severe SB, while the remaining 30 patients (28.57%) did not. No statistically significant differences in TPH1 and DDC levels were observed between the individuals with SB and without SB. A significant negative correlation was found between tonic SB episodes and DDC levels (p = 0.0012). Other correlations between the SB parameters and the levels of the studied enzymes were statistically insignificant (p > 0.05 for all comparisons). Conclusions The levels of the enzymes that are crucial for serotonin synthesis (TPH1 and DDC) did not seem to influence SB. Clinical relevance This study provides important insights for further research on the relationship between the serotonin pathway and SB, which should take into account not only the process of serotonin synthesis but also the effect of serotonin-dependent neurotransmission on SB.

Paeoniflorin Improved Constipation in the Loperamide-Induced Rat Model via TGR5/TRPA1 Signaling-Mediated 5-Hydroxytryptamine Secretion

Slow transit constipation (STC) is a common type of constipation with a high incidence rate and a large number of patients. We aimed to investigate the therapeutic effects and potential mechanism of paeoniflorin (PAE) on loperamide-induced Sprague Dawley (SD) rat constipation models. Rats with loperamide-induced constipation were orally administered different concentrations of PAE (10, 20, or 40 mg/kg). In vitro, enterochromaffin (EC)-like RIN-14B cells were treated with 20, 40, or 80 μg/ml PAE. We found that PAE treatment significantly improved the symptoms of constipation and increased the intestinal transit rate. Hematoxylin and eosin (H&E) staining showed that PAE alleviated colonic tissue pathological damage. Besides, our results implied that PAE concentration-dependently promoted the content of 5-hydroxytryptamine (5-HT) catalyzed by tryptophan hydroxylase (Tph)-1 in the serum of loperamide-induced rats and in RIN-14B cells. Western blot and immunofluorescence (IF) stain indicated that PAE also promoted the expression of G protein-coupled BA receptor 1 (TGR5), transient receptor potential ankyrin 1 (TRPA1), phospholipase C (PLC)-γ1, and phosphatidylinositol 4,5-bisphosphate (PIP2) in vivo and in vitro. RIN-14B cells were cotreated with a TGR5 inhibitor (SBI-115) to explore the mechanism of PAE in regulating the 5-HT secretion. We observed inhibition of TGR5 reversed the increase of 5-HT secretion induced by PAE in RIN-14B cells. We provided evidence that PAE could promote 5-HT release from EC cells and improve constipation by activating the TRPA1 channel and PLC-γ1/PIP2 signaling. Thus, PAE may provide therapeutic effects for patients with STC.

Treating Depression and other Serotonin Deficiency Brain Disorders with Tryptophan

: Deficits of brain serotonin (5-hydroxytryptamine; 5-HT) are implicated in a number of psychiatric illnesses including depression. Treatment efficacy of this highly prevalent brain disorder is not adequate largely because serotonin stores are depleted. Tryptophan an essential amino acid is the sole precursor of serotonin; its systemic or oral administration increases serotonin synthesis because tryptophan hydroxylase, the rate limiting enzyme of 5-HT biosynthesis, is physiologically unsaturated with its substrate. The present article targets importance of tryptophan supplementation in treating serotonin deficiency and improving therapeutic intervention in depression and other serotonin deficiency brain disorders.

Tryptophan Hydroxylase 2 Deficiency Modifies the Effects of Fluoxetine and Pargyline on the Behavior, 5-HT- and BDNF-Systems in the Brain of Zebrafish (Danio rerio)

The mechanisms of resistance to antidepressant drugs is a key and still unresolved problem of psychopharmacology. Serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) play a key role in the therapeutic effect of many antidepressants. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in 5-HT synthesis in the brain. We used zebrafish (Danio rerio) as a promising model organism in order to elucidate the effect of TPH2 deficiency caused by p-chlorophenylalanine (pCPA) on the alterations in behavior and expression of 5-HT-related (Tph2, Slc6a4b, Mao, Htr1aa, Htr2aa) and BDNF-related (Creb, Bdnf, Ntrk2a, Ngfra) genes in the brain after prolonged treatment with two antidepressants, inhibitors of 5-HT reuptake (fluoxetine) and oxidation (pargyline). In one experiment, zebrafish were treated for 72 h with 0.2 mg/L fluoxetine, 2 mg/L pCPA, or the drugs combination. In another experiment, zebrafish were treated for 72 h with 0.5 mg/L pargyline, 2 mg/L pCPA, or the drugs combination. Behavior was studied in the novel tank diving test, mRNA levels were assayed by qPCR, 5-HT and its metabolite concentrations were measured by HPLC. The effects of interaction between pCPA and the drugs on zebrafish behavior were observed: pCPA attenuated “surface dwelling” induced by the drugs. Fluoxetine decreased mRNA levels of Tph2 and Htr2aa genes, while pargyline decreased mRNA levels of Slc6a4b and Htr1aa genes. Pargyline reduced Creb, Bdnf and Ntrk2a genes mRNA concentration only in the zebrafish treated with pCPA. The results show that the disruption of the TPH2 function can cause a refractory to antidepressant treatment.