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Serotonin: A Mediator of The Brain–Gut Connection
Abstract
The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) provides practical and professional support for clinicians dealing with the gastroenterological disorders seen most often in patients. Published with practicing clinicians in mind, the journal aims to be easily accessible, organizing its content by topic, both online and in print. www.amjgastro.com, *2007 Journal Citation Report (Thomson Reuters, 2008)
... In the brain, the key serotonin hub is the raphe nucleus, but other regions, such as the linear caudal nucleus, oral nucleus pontis centralis, and the postrema region, produce 5-hydroxytryptamine (5-HT). Every group of cell bodies has a distinct connectivity pattern inside the brain [61]. Synthesis of serotonin depends on the bioavailability of its precursor, the amino acid L-Trp, which via the action of 5-Hydroxytryptophan, is converted into serotonin, in a metabolic process involving two enzymes, Trp hydroxylase, and amino acid decarboxylase [62]. ...
Neurotransmitters (NTs) are biologically active chemicals, which mediate the electrochemi-cal transmission between neurons. NTs control numerous organic functions particularly crucial for life, including movement, emotional responses, and the physical ability to feel pleasure and pain. These molecules are synthesized from simple, very common precursors. Many types of NTs have both excitatory and inhibitory effects. Neurotransmitters' imbalance can cause many diseases and disorders , such as Parkinson's disease, depression, insomnia, increased anxiety, memory loss, etc. Natural food sources containing NTs and/or their precursors would be a potential option to help maintain the balance of NTs to prevent brain and psychiatric disorders. The level of NTs could be influenced, therefore, by targeting dietary habits and nutritional regimens. The progressive implementation of nutritional approaches in clinical practice has made it necessary to infer more about some of the nutritional NTs in neuropsychiatry. However, the importance of the intake of nutritional NTs requires further understanding, since there are no prior significant studies about their bioavailability, clinical significance, and effects on nerve cells. Interventional strategies supported by evidence should be encouraged.
... Red and blue colors represent high and low levels of metabolites, respectively tryptophan to be used by the host or intestinal microbes. In addition to nicotinic acid production, tryptophan can also be metabolized into serotonin (5-hydroxyltrptamine) through the serotonin pathway; serotonin is not only a neurotransmitter with multiple functions in the central nervous system but also regulates intestinal movements in the gastrointestinal tract [40]. The majority of serotonin in the host (~95%) is produced by enterochromaffin cells in the gut and is released into the gut lumen in response to various mechanical and chemical stimuli [41]. ...
Background
Public complaints concerning odor emissions from intensive livestock and poultry farms continue to grow, as nauseous odorous compounds have adverse impacts on the environment and human health. Itaconic acid is a metabolite from the citric acid cycle of the host and shows volatile odor-reducing effects during animal production operations. However, the specific role of itaconic acid in decreasing intestinal odorous compound production remains unclear. A total of 360 one-day-old chicks were randomly divided into 6 treatment groups: control group (basal diet) and itaconic acid groups (basal diet + 2, 4, 6, 8 and 10 g/kg itaconic acid). The feeding experiment lasted for 42 d.
Results
Dietary itaconic acid supplementation linearly and quadratically decreased (P < 0.05) the cecal concentrations of indole and skatole but did not affect (P > 0.05) those of lactic, acetic, propionic and butyric acids. The cecal microbial shift was significant in response to 6 g/kg itaconic acid supplementation, in that the abundances of Firmicutes, Ruminococcus and Clostridium were increased (P < 0.05), while those of Bacteroidetes, Escherichia-Shigella and Bacteroides were decreased (P < 0.05), indicative of increased microbial richness and diversity. Furthermore, a total of 35 significantly (P < 0.05) modified metabolites were obtained by metabolomic analysis. Itaconic acid decreased (P < 0.05) the levels of nicotinic acid, nicotinamide, glucose-6-phosphate, fumatic acid and malic acid and increased (P < 0.05) 5-methoxytroptomine, dodecanoic acid and stearic acid, which are connected with the glycolytic pathway, citrate acid cycle and tryptophan metabolism. Correlation analysis indicated significant correlations between the altered cecal microbiota and metabolites; Firmicutes, Ruminococcus and Clostridium were shown to be negatively correlated with indole and skatole production, while Bacteroidetes, Escherichia-Shigella and Bacteroides were positively correlated with indole and skatole production.
Conclusions
Itaconic acid decreased cecal indole and skatole levels and altered the microbiome and metabolome in favor of odorous compound reduction. These findings provide new insight into the role of itaconic acid and expand its application potential in broilers.
... 53 Additionally, the GI tract has high levels of 5-hydroxytryptamine (5-HT), and studies suggest that the epithelial enterochromaffin (ECCs) cells are responsible for 90% of 5-HT secretion, while only 10% remains from the enteric nervous system. 54 Bacteria, such as Escherichia, Streptococcus, Enterococcus, and Candida, are some gut microorganisms capable of producing serotonin. 55 Brain functions can be affected by gut dysbiosis, as intestinal microorganisms influence not only serotonin synthesis/metabolism but also the synthesis of other neurotransmitters. ...
The human gut microbiota is a complex ecosystem made of trillions of microorganisms. The composition can be affected by diet, metabolism, age, geography, stress, seasons, temperature, sleep, and medications. The increasing evidence about the existence of a close and bi-directional correlation between the gut microbiota and the brain indicates that intestinal imbalance may play a vital role in the development, function, and disorders of the central nervous system. The mechanisms of interaction between the gut-microbiota on neuronal activity are widely discussed. Several potential pathways are involved with the brain-gut-microbiota axis, including the vagus nerve, endocrine, immune, and biochemical pathways. Gut dysbiosis has been linked to neurological disorders in different ways that involve activation of the hypothalamic-pituitary-adrenal axis, imbalance in neurotransmitter release, systemic inflammation, and increase in the permeability of the intestinal and the blood-brain barrier. Mental and neurological diseases have become more prevalent during the coronavirus disease 2019pandemic and are an essential issue in public health globally. Understanding the importance of diagnosing, preventing, and treating dysbiosis is critical because gut microbial imbalance is a significant risk factor for these disorders. This review summarizes evidence demonstrating the influence of gut dysbiosis on mental and neurological disorders.
... Serotonin (5-hydroxytryptamine: 5-HT) is one of candidates of responsible transmitters because 5-HT3 receptor antagonist is effective on patients with IBS with predominant diarrhea [18] and ones with migraine [19]. The other receptors including 5-HT1A, 5-HT1B/D, and 5-HT1F receptors have been shown to have a function leading to the reduction of pain [20,21]. Several studies also indicated an abnormally increased activation of N-methyl-D-aspartate (NMDA) receptors in individuals suffering from IBS and migraine [22]. ...
Background
Irritable bowel syndrome (IBS) and migraines are often comorbid each other. These disorders are likely to be bidirectionally linked through the gut-brain axis and share several underlying mechanisms including central nervous system sensitization. However, quantitative analysis of comorbidity was not reported enough. The aim of this systematic review and meta-analysis was to calculate the present degree of comorbidity of these two disorders.
Methods
A literature search was performed searching for articles describing IBS or migraine patients with the same inverse comorbidity. Pooled odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs) were then extracted. The total effect estimates were determined and presented by random effect forest plots for the group of articles with IBS patients with migraine and the group of articles on migraine sufferers with comorbid IBS separately. The average results of these plots were compared.
Results
The literature search resulted in initial 358 articles and final 22 articles for the meta-analysis. The total OR values obtained were 2.09 [1.79 – 2.43] in IBS with comorbid migraine or headache, 2.51 [1.76 – 3.58] for migraineurs with comorbid IBS and an overall HR of 1 .62 [1.29 – 2.03] was found for cohort studies of migraine sufferers with comorbid IBS. A similar expression of a selection of other comorbidities was found in IBS and migraine patients, especially for depression and fibromyalgia a strong similarity was found in their expression rate.
Conclusions
This systematic review with meta-analysis was the first to combine data on IBS patients with comorbid migraine and migraineurs with comorbid IBS. The fact that closely related existential rates were observed between these two groups should be used as motivation for future research to further investigate these disorders for why this similarity occurs. Mechanisms involved in central hypersensitivity such as genetic risk factors, mitochondrial dysfunction and microbiota are particularly good candidates. Experimental designs in which therapeutic methods for these conditions can be exchanged or combined may also lead to the discovery of more efficient treatment methods.
Aim : to assess the level of stress hormones (cortisol in saliva), neurotransmitters (serotonin in blood serum, dopamine in blood plasma) in relation to eating habits, anxiety and depression levels in patients with IBS.
Materials and methods . An open cohort prospective study was conducted with the inclusion of 263 patients with an established diagnosis of IBS, among them 189 (71.9 %) women and 74 (28.1 %) men. The average age of patients with IBS was 29 [25; 35] years. The control group included 40 healthy volunteers. All individuals included in the study were assessed for diet and eating habits using the WHO CINDI program questionnaire, “Information on Nutrition and Eating Behavior”, the severity of anxiety and depression according to the HADS questionnaire, the level of specific anxiety in relation to gastrointestinal symptoms according to the VSI questionnaire, quality of life according to the IBS-QoL questionnaire. In addition, the enzyme immunoassay method was used to assess the levels of cortisol in the morning and evening portions of saliva, serotonin in the blood serum and dopamine in the blood plasma.
Results . Among patients with IBS there is a statistically significantly higher level of cortisol in the morning and evening portions of saliva ( U = 19.5, p < 0.001 and U = 111.5, p < 0.001, respectively), serotonin in blood serum ( U = 269.0, p = 0.042) and lower plasma dopamine levels ( U = 93.5, p = 0.0002) compared with controls. The mean salivary cortisol level among patients with IBS was 45.39 [29.86; 70.10] ng/ml in the morning and 19.21 [13.98; 23.50] ng/ml in the evening, while in the group of healthy individuals it was 19.0 [16.5; 21.7] and 9.7 [8.5; 10.5] ng/ml, respectively. The average content of serotonin in blood serum in patients with IBS was 188.78 [150.41; 230.32] ng/ml, among healthy individuals — 142.80 [130.52; 154.15] ng/ml. The average content of dopamine in blood plasma in patients with IBS was 28.83 [20.08; 41.54] ng/ml, in healthy individuals — 58.20 [48.15; 66.62] ng/ml.
Conclusion . In patients with IBS the secretion of the stress hormone (cortisol) and neurotransmitters (serotonin, dopamine) is closely related to the nature of nutrition, the level of anxiety and depression, and is also associated with the clinical variant and severity of the course of the disease.
Neuronal circuits in the brain that utilize the neurotransmitter serotonin are essential to the regulation of mood and emotional expression. Disruptions in serotonin signaling underlie neuropsychiatric conditions such as depression and anxiety. However, the cellular mechanisms that regulate serotonergic signaling in the brain in healthy and diseased states remain to be better understood. In particular, as more is learned about serotonin in the brain, we recognize an urgent need to develop techniques capable of mapping its complex spatiotemporal dynamics in awake, behaving animals. Notably, analytical methods to detect serotonin in situ, including tomography, are widely used but still recognized as limited in terms of their spatiotemporal resolution, their methodological caveats, and their technical limitations when cross-referenced with behavioral studies. To overcome such limitations, genetically encoded serotonin indicators were developed, leading to the introduction of novel imaging modalities that enable researchers to achieve remarkable spatiotemporal resolution in the study of serotonergic circuits in preclinical models of neuropsychiatric disorders. These novel approaches, while remarkably powerful, are also not without limitations. Here, we review the current techniques for detecting and quantifying serotonin in vivo within the brain and discuss how novel approaches such as genetically encoded serotonin indicators will lead to new insights into the roles of serotonergic circuits in health and disease.
Background: Public complaints concerning odor emissions from intensive livestock and poultry farms continue to grow, as nauseous odorous compounds have adverse impacts on the environment and human health. Itaconic acid is a metabolite from the citric acid cycle of the host and shows volatile odor-reducing effects during animal production operations. However, the specific role of itaconic acid in decreasing intestinal odorous compound production remains unclear. A total of 360 one-day-old chicks were randomly divided into 6 treatments: control group (basal diet) and itaconic acid groups (basal diet + 2, 4, 6, 8 and 10 g/kg itaconic acid, respectively). The feeding experiment lasted for 42 d.
Results: Dietary itaconic acid supplementation linearly and quadratically decreased (P < 0.05) the cecal concentrations of indole and skatole but did not affect (P> 0.05) those of lactic, acetic, propionic and butyric acids. The cecal microbial shift was significant in response to 6 g/kg itaconic acid supplementation, in that the abundances of Firmicutes, Ruminococcus and Clostridiumwas increased (P < 0.05), while that of Bacteroidetes, Escherichia-Shigella and Bacteroides were decreased (P < 0.05), indicative of increased microbial richness and diversity. Furthermore, a total of 35 significantly (P < 0.05) modified metabolites were obtained by metabolomic analysis. Itaconic acid decreased (P < 0.05) the levels of nicotinic acid, nicotinamide, glucose-6-phosphate, fumatic acid and malic acid and increased (P< 0.05) 5-methoxytroptomine, dodecanoic acid and stearic acid, which are connected with the glycolytic pathway, citrate acid cycle and tryptophan metabolism. Correlation analysis indicated significant correlations between the altered cecal microbiota and metabolites; Firmicutes, Ruminococcus and Clostridiumwere shown to be negatively correlated with indole and skatole production, while Bacteroidetes, Escherichia-Shigellaand Bacteroides were positively correlated with indole and skatole production.
Conclusions: Itaconic acid decreased cecal indole and skatole levels and altered the microbiome and metabolome in favor of odorous compound reduction. These findings provide new insight into the role of itaconic acid and expand its application potential in broilers.
A brief review is given of the distribution of serotonin in tissues. The enzymatic steps in the biosynthesis and metabolism of serotonin are described, and factors involved in the regulation of the in vivo metabolism of serotonin are reviewed.
Synopsis
Tamsulosin is the first subtype-selective (α1A) α1 adrenoceptor antagonist with specificity for prostatic α1 adrenoceptors (α1A adrenoceptors are thought to be involved in prostatic smooth muscle contraction) to become available for the treatment of patients with symptomatic benign prostatic hyperplasia (BPH).
With tamsulosin, the incidence of adverse events commonly associated with α1 adrenoceptor antagonism is similar to that with placebo (except for ejaculation disorders) and alfuzosin. The incidence of other adverse events is similar with tamsulosin and placebo. Furthermore, blood pressure and heart rate are not significantly affected by tamsulosin in patients with symptomatic BPH. In contrast, blood pressure is significantly reduced by alfuzosin compared with tamsulosin.
Tamsulosin is available as a controlled release formulation suitable for once-daily administration; dose titration is not required. The overall efficacy of this agent administered at a dosage of 0.1 to 0.4 mg/day in Japan, 0.4 mg/day in Europe and 0.4 to 0.8 mg/day in the US to patients with symptomatic BPH is greater than that of placebo and was similar to that of alfuzosin or prazosin in the 2 available studies. Efficacy was primarily assessed by changes in maximum and average urinary flow rates, residual urinary volume and total symptom scores. Improvements in these parameters in short term trials (≤13 weeks) appear to be maintained in the longer term (≤60 weeks). Quality-of-life effects also appear to be similar with tamsulosin and alfuzosin.
In conclusion, the pharmacodynamic properties of this agent appear to translate into tolerability and administration advantages over other α1 adrenoceptor antagonists. If future investigations confirm its promising efficacy and tolerability, tamsulosin will be ideally placed as a valuable therapeutic option for patients with symptomatic BPH and in patients awaiting surgery or in those unable to undergo surgery.
Pharmacodynamic Properties
The α adrenoceptor antagonist activity of tamsulosin has been demonstrated in vitro (human prostatic tissue) and in vivo. The antagonistic activity of tamsulosin against epinephrine-induced contraction of the canine prostate was greater than that of terazosin and at least the same as with prazosin.
In contrast to other clinically available α1 adrenoceptor antagonists, tamsulosin has greater affinity (7- to 38-fold) for α1A adrenoceptors than for α1B adrenoceptors, α1A Adrenoceptors are thought to be the predominant α1 adrenoceptor in the prostate and to mediate prostatic smooth muscle contraction; α1B adrenoceptors are also found in the prostate. Evidence suggests that am and α1D adrenoceptors are involved in vascular smooth muscle contraction.
Tamsulosin has greater affinity for α1 adrenoceptors in the prostate than in the vasculature. The affinity of tamsulosin for [ 3H]prazosin binding sites was approximately 12 times greater in human prostatic than aortic tissue. Tamsulosin was approximately 6 times more potent than prazosin in prostatic tissue in this study. Results of 4 of 5 in vivo animal studies have shown tamsulosin to have a greater effect on intraurethral pressure than blood pressure; the remaining study showed tamsulosin to have similar effects on these 2 parameters.
Blood pressure and heart rate were not significantly changed from baseline by multiple doses of tamsulosin 0.4mg in 10 healthy volunteers. The effects of tamsulosin on finger skin and dorsal hand vein constrictor responses to appropriate stimuli were similar to those with placebo and less than those with doxazosin.
A significant reduction in maximum urinary flow rate (Qmax) compared with placebo has been observed after one dose of tamsulosin 0.4mg in patients with symptomatic benign prostatic hyperplasia (BPH). No single-dose studies addressing the effects of tamsulosin on other urodynamic parameters in humans have been reported.
Pharmacokinetic Properties
Tamsulosin is available as a controlled release (modified release) once-daily oral formulation with almost 100% bioavailability. The extent and rate of absorption of this agent are reduced when it is given with food.
Steady-state plasma concentrations of tamsulosin are achieved by day 5 of multiple dose (0.4mg once daily) administration. Mean maximum plasma concentration was 17 μ/L after a mean time of approximately 6 hours and elimination half-life was about 13 hours in elderly patients (aged >65 years) with symptomatic BPH who received tamsulosin 0.4mg once daily for 8 days.
Tamsulosin is approximately 99% protein bound and has a small volume of distribution (approximately 0.2 L/kg). The drug undergoes hepatic metabolism, with most of the parent drug and metabolites excreted in the urine; up to 14% is excreted as unchanged drug.
In general, the pharmacokinetic profile of tamsulosin is not significantly altered in patients with renal impairment or mild to moderate hepatic impairment. There are no pharmacokinetic data on the drug in patients with severe hepatic impairment or in those with a creatinine clearance of <10 ml/min (0.6 L/h).
Therapeutic Efficacy
The overall efficacy of short term (≤13 weeks) controlled release tamsulosin 0.1 to 0.4 mg/day in Japanese, 0.4 mg/day in European and 0.4 to 0.8 mg/day in US patients with symptomatic BPH is greater than that of placebo. Efficacy was primarily assessed by changes in Qmax, average urinary flow rate (Qave), residual urinary volume and total symptom scores from baseline. In a meta-analysis of 2 trials involving >500 patients with symptomatic BPH, a clinically significant response (≥30% increase in Qmax or ≥25% decrease in total Boyarsky symptom score) occurred in significantly more tamsulosin than placebo recipients (32 vs 20% and 66 vs 49%, respectively). Improvements in efficacy parameters with tamsulosin in short term trials appear to be maintained with longer term therapy (≤60 weeks).
Overall efficacy of tamsulosin was similar to that of alfuzosin or prazosin in the 2 studies currently available. However, based on Qmax values, there was a tendency for tamsulosin to have a faster onset of effect than alfuzosin; this is likely to be a direct effect of the lack of need for dose titration with tamsulosin. Trials comparing tamsulosin with other long-acting α1 adrenoceptor antagonists or other pharmacological treatment options (e.g. finasteride) are awaited.
According to the Life Style Quality-of-Life questionnaire, the overall quality of life of patients with symptomatic BPH was significantly improved from baseline with tamsulosin but not with placebo. These improvements were maintained for ≤60 weeks. According to the same questionnaire, quality-of-life effects of tamsulosin and alfuzosin appear to be similar.
Tolerability
With the exception of ejaculation disorders, the incidence of adverse events with tamsulosin up to 0.4mg once daily in patients with symptomatic BPH is similar to that with placebo. In particular, tamsulosin does not affect blood pressure or heart rate to a clinically significant extent. The incidence of postural hypotension with this drug was similar to that with placebo in controlled trials of patients with symptomatic BPH. The most common adverse events with tamsulosin in European patients are abnormal (retrograde) ejaculation or decreased volume of ejaculate (4.5%), dizziness (3.4%), infection (3.1%), headache (2.1%) and flu-like symptoms (1.6%); the incidence of the above ejaculation problems was significantly greater than with placebo (1%). Similar results were seen when treatment was continued for ≤60 weeks.
In the 1 available comparative study, the incidence of adverse events associated with α1 adrenoceptor blockade (including dizziness, postural hypotension, headache and palpitation/tachycardia) was similar with tamsulosin and alfuzosin (9.2 vs 10.5%); abnormal ejaculation occurred in 1 and 0 patients, respectively. Tamsulosin had no significant effects on blood pressure or heart rate, whereas alfuzosin significantly reduced blood pressure compared with baseline and tamsulosin.
Dosage and Administration
In clinical trials of patients with symptomatic BPH, controlled release tamsulosin dosages of 0.1 to 0.4 mg/day in Japan, 0.4 mg/day in Europe and 0.4 to 0.8 mg/day in the US have been used. The recommended dosage in Europe is 0.4mg once daily after breakfast and the recommended dosage in Japan is 0.2mg once daily. Dosage adjustments are not required in patients with mild to moderate hepatic impairment or renal dysfunction; however, there are no available data specifically in patients with a creatinine clearance of <10 ml/min (<0.6 L/h). In Europe, tamsulosin is contraindicated in patients with severe hepatic impairment because of a lack of available data in this patient group.
Some of the mystery surrounding serotonin has been unraveled recently after the development of a means of selectively depriving the organism of this amine. Key aspects of recent advances include biochemical characterization of the first enzymatic step in tissue serotonin biosynthesis, that of tryptophan 5-hydroxylation; discovery of an inhibitor (para-chlorophenylalanine (PCPA)) of the reaction; and observations on the effects of serotonin deprival as produced by PCPA in man and animals. Control of diarrhea in the carcinoid syndrome by PCPA treatment indicates that the major target organ of circulating serotonin is the intestinal tract. Induction of psychiatric effects with high doses of PCPA, along with other evidence, is compatible with a serotonin-deficiency hypothesis of affective illness. Serotonin plays a role in sleep mechanisms, with PCPA suppressing and 5-hydroxytryptophan (serotonin precursor) restoring rapid eye movement sleep in man. Finally, animal data raise exciting possibilities of the involvement of brain serotonin in control of sexual behavior. The serotonin-deprival approach has only begun to be explored in clinical pathophysiologic states.