5-hydroxyindoleacetic Acid Levels Research Articles

The Impact of Antenatal Corticosteroids on the Metabolome of Preterm Newborns: An Untargeted Approach

We analyzed and compared variations in the urinary metabolome, as well as postnatal clinical outcomes among preterm infants, based on the timing of antenatal corticosteroid (ACS) administration in response to preterm labor onset in their mothers. This was a prospective observational study held in the Neonatal Intensive Care Unit, Department of Woman’s and Child’s Health, Padova University Hospital (Italy). A urine sample was obtained from each patient within 24 h of birth; Mass Spectrometry-based untargeted metabolomics analysis was then conducted. We searched for any significant disparities in the metabolomic profile of preterm newborns subjected to antenatal corticosteroid (ACS) treatment at varying timings; their correlation with clinical outcomes were also evaluated. The group receiving ACS within the optimal time window (1–7 days before delivery) exhibited elevated levels of cysteine, N-acetylglutamine, propionyl carnitine and 5-hydroxyindolacetic acid, coupled with a decrease in pipecolic acid. Clinically, this group demonstrated a reduced need for invasive ventilation (p = 0.04). In conclusion, metabolomics analysis identified several metabolites that discriminated preterm infants whose mothers received ACS within the recommended time window. Elevated levels of cysteine and 5-Hydroxyindoleacetic acid, metabolites characterized by antioxidant and anti-inflammatory properties, were observed in these infants. This metabolic profile correlated with improved respiratory outcomes, as evidenced by a reduced necessity for invasive ventilation at birth.

Cannabidiol disrupts tryptophan metabolism in the human term placenta

The increasing use of cannabis during pregnancy raises concerns about its impact on fetal development. While cannabidiol (CBD) shows therapeutic promise, its effects during pregnancy remain uncertain. We investigated CBD's influence on tryptophan (TRP) metabolism in the human placenta. TRP is an essential amino acid that is metabolized via the serotonin and kynurenine (KYN) pathways, which are critical for fetal neurodevelopment. We used human term villous placental explants, an advanced ex vivo model, to study CBD's impact on key TRP metabolic enzymes. In addition, vesicles isolated from the microvillous membrane (MVM) of the human placenta were used to assess CBD’s effect on placental serotonin uptake. Explants were exposed to CBD at therapeutic (0.1, 1, 2.5 μg/ml) and non-therapeutic (20 and 40 μg/ml) concentrations to determine its effects on the gene and protein expression of key enzymes in TRP metabolism and metabolite release. CBD upregulated TRP hydroxylase (TPH) and downregulated monoamine oxidase (MAO-A), resulting in reduced levels of 5-hydroxyindoleacetic acid (HIAA). It also downregulated serotonin transporter expression and inhibited serotonin transport across the MVM by up to 60% while simultaneously enhancing TRP metabolism via the kynurenine pathway by upregulating indoleamine-pyrrole 2,3-dioxygenase (IDO-1). Among kynurenine pathway enzymes, kynurenine 3 monooxygenase (KMO) was upregulated while kynurenine aminotransferase 1 (KAT-1) was downregulated; the former is associated with neurotoxic metabolite production, while the latter is linked to reduced neuroprotective metabolite levels. Overall, these results indicate that CBD modulates TRP catabolism in the human placenta, potentially disrupting the tightly regulated homeostasis of the serotonin and KYN pathways.

Zhumian Granules improves PCPA-induced insomnia by regulating the expression level of neurotransmitters and reducing neuronal apoptosis

Ethnopharmacological relevanceSleep problems, according to Traditional Chinese medicine (TCM) philosophy, are attributed to the imbalance between yin and yang. Zhumian Granules, also known as Sleep-aid Granules or ZG, are a traditional Chinese herbal remedy specifically designed to alleviate insomnia. This formula consists of many components, including Wu Wei Zi (Schisandrae Chinensis Fructus), Suan Zao Ren (Ziziphi Spinosae Semen), and other medicinal plants. According to the pharmacology of Traditional Chinese Medicine (TCM), Wu Wei Zi and Suan Zao Ren have the ability to relax the mind and promote sleep. When taken together, they may balance the opposing forces of yin and yang. Therefore, ZG may potentially be used as a therapeutic treatment for insomnia. Aim of the studyThis research was specifically developed to establish a strong empirical basis for the subsequent advancement and utilization of ZG in the management of insomnia. This research aimed to gather empirical data to support the effectiveness of ZG, thereby providing useful insights into its potential therapeutic advantages for persons with insomnia. Materials and methodsThis study utilized Zhumian Granules (ZG), a traditional Chinese herbal decoction, to examine its sedative and hypnotic effects on mice with PCPA-induced insomnia. The effects were assessed using the pentobarbital-induced sleep test (PIST), Morris water maze test (MWM), and autonomic activity test. The levels of neurotransmitters in each group of mice were evaluated using UPLC-QQQ-MS. The impact of ZG on the quantity and structure of hippocampal neurons was seen in brain tissue slices using immunofluorescence labeling. ResultsZG was shown to possess active sedative properties, effectively lowering the distance of movement and lengthening the duration of sleep. ZG mitigated the sleeplessness effects of PCPA by elevating the levels of 5-hydroxytryptamine (5-HT), 4-aminobutyric acid (GABA), and 5-hydroxyindoleacetic acid (5-HIAA), while reducing the levels of dopamine (DA) and norepinephrine (NE), as well as decreasing neuronal death. ConclusionsThis research confirmed the sedative and hypnotic properties of ZG and elucidated its probable mechanism involving neurotransmitters.

The Variability of Tryptophan Metabolism in Patients with Mixed Type of Irritable Bowel Syndrome.

Patients with a mixed type of irritable bowel syndrome (IBS-M) experience constipation and diarrhea, which alternate between weeks or months. The pathogenesis of this syndrome is still little understood. The aim of the study was mainly to evaluate the urinary excretion of selected tryptophan (TRP) metabolites during the constipation and diarrhea periods of this syndrome. In 36 patients with IBS-M and 36 healthy people, serum serotonin level was measured by ELISA and urinary levels of 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN) and indican (3-IS) were determined using the LC-MS/MS method. The levels of all above metabolites were higher in the patient group, and increased significantly during the diarrheal period of IBS-M. In particular, the changes concerned 5-HIAA (3.67 ± 0.86 vs. 4.59 ± 0.95 mg/gCr, p < 0.001) and 3-IS (80.2 ± 17.4 vs. 93.7 ± 25.1 mg/g/Cr, p < 0.001). These changes coexisted with gut microbiome changes, assessed using hydrogen-methane and ammonia breath tests. In conclusion, the variability of TRP metabolism and the gut microbiome may cause the alternation of IBS-M symptoms.

Sophora flavescens alcohol extract ameliorates insomnia and promotes PI3K/AKT/BDNF signaling transduction in insomnia model rats.

Active ingredient of Sophora flavescens is reported to promote non-rapid eye movement (NREM) sleep. However, the role of Sophora flavescens alcohol extract in insomnia is elusive, which is addressed in this study, together with the exploration on its potential mechanism. An insomnia model of rats was established by para-chlorophenylalanine induction and further treated with SFAE or Zaoren Anshen capsule (ZRAS; positive control drug). Sleep quality and sleep architecture of rats were evaluated by the sleep test, electroencephalogram and electromyogram. The levels of monoamine neurotransmitters in rat hypothalamus were determined using ELISA, and the transduction of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/brain-derived neurotrophic factor (BDNF) signaling in the brain tissues of rats was examined by Western blot. SFAE and ZRAS increased the sleeping time and decreased the sleep latency of insomnia rats. SFAE reduced waking time and increased NREM and REM time, while changing power density of wakefulness, NREM sleep, and REM sleep in insomnia rats. SFAE and ZRAS upregulated levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, and downregulated those of norepinephrine and dopamine in insomnia rats. Besides, SFAE and ZRAS elevated BDNF expression as well as the ratios of phosphorylated (p)-PI3K/PI3K and p-AKT/AKT. The role of SFAE in insomnia model rats was similar with that of ZRAS. SFAE reduces insomnia and enhances the PI3K/AKT/BDNF signaling transduction in insomnia model rats, which can function as a drug candidate for insomnia.

Increased stress vulnerability in the offspring of socially isolated rats: Behavioural, neurochemical and redox dysfunctions

Stressful events during pregnancy impact on the progeny neurodevelopment. However, little is known about preconceptional stress effects. The rat social isolation represents an animal model of chronic stress inducing a variety of dysfunctions. Moreover, social deprivation during adolescence interferes with key neurodevelopmental processes. Here, we investigated the development of behavioural, neurochemical and redox alterations in the male offspring of socially isolated female rats before pregnancy, reared in group (GRP) or in social isolation (ISO) from weaning until young-adulthood. To this aim, females were reared in GRP or in ISO conditions, from PND21 to PND70, when they were mated. Their male offspring was housed in GRP or ISO conditions through adolescence and until PND70, when passive avoidance-PA, novel object recognition-NOR and open field-OF tests were performed. Levels of noradrenaline (NA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), glutamate (GLU) and GABA were assessed in the prefrontal cortex (PFC). Moreover, cortical ROS levels were quantified, as well as NF-kB and the NADPH oxidase NOX2 expression, redox status (expressed as GSH:GSSG ratio) and SOD1 amount.A significant decrease of the latency time in the PA was observed in the offspring of ISO females. In the NOR test, while a significant increase in the exploratory activity towards the novel object was observed in the offspring of GRP females, no significant differences were found in the offspring of ISO females. No significant differences were found in the OF test among experimental groups. Theoffspring of ISO females showed increased NA and 5-HIAA levels, whereas in the offspring persistently housed in isolation condition from weaninguntil adulthood, we detected reduced 5-HT levels and ehnanced 5-HIAA amount. No significant changes in GLU concentrations were detected, while decreased GABA content was observed in the offspring of ISO females exposed to social isolation. Increased ROS levels as well as reduced NF-κB, NOX2 expression were detected in the offspring of ISO females. This was accompanied by reduced redox status and enhanced SOD1 levels.In conclusion, our results suggest that female exposure to chronic social stress before pregnancy might have a profound influence on the offspring neurodevelopment in terms of cognitive, neurochemical and redox-related alterations, identifying this specific time window for possible preventive and therapeutic strategies.

Association between gut microbiome-related metabolites and symptomatic hand osteoarthritis in two independent cohorts

Since gut microbiome dysbiosis can cause inflammatory disorders by affecting host metabolism, we postulate that the gut microbiome and related metabolites could play a role in hand osteoarthritis. We characterised gut microbiome-related metabolites in people with symptomatic hand osteoarthritis (SHOA) in two independent cohorts. Using data collected from a large-sample community-based observational study (discovery cohort), we assessed the relations of the microbial function and plasma key metabolites related to altered microbial function with SHOA. Finally, we verified the relations of plasma metabolites to SHOA in an independent observational study (validation cohort). In the discovery cohort (n=1359), compared to those without SHOA, participants with SHOA had significantly altered microbial functions related to tryptophan metabolism (Q=0.025). Therefore we measured the plasma tryptophan metabolites and found that participants with SHOA had higher levels of 5-hydroxyindoleacetic acid (odds ratio [OR]=1.25, 95% confidence interval [CI]: 1.09-1.42) and 5-hydroxytryptophol (OR=1.13, 95% CI: 1.04-1.23), but lower levels of indole-3-lactic acid (ILA) (OR=0.85, 95% CI: 0.72-1.00), skatole (OR=0.93, 95% CI: 0.88-0.99) and 3-hydroxyanthranilic acid (OR=0.90, 95% CI: 0.85-0.96). Findings from the validation cohort (n=142) verified that lower levels of ILA were related to SHOA (OR=0.70, 95% CI: 0.53-0.92). Alterations of the microbial function of tryptophan biosynthesis and tryptophan metabolites, especially lower levels of ILA, are associated with SHOA. These findings suggest the role of the microbiome and tryptophan metabolites in developing of SHOA and may contribute to future translational opportunities. National Key Research and Development Plan and National Natural Science Foundation of China.

Attenuation of Chronic Stress-Induced Depressive-like Symptoms by Fish Oil via Alleviating Neuroinflammation and Impaired Tryptophan Metabolism in Aging Rats.

The prevalence of depression is increasing, and geriatric depression, in particular, is difficult to recognize and treat. Depression in older adults is often accompanied by neuroinflammation in the central nervous system (CNS). Neuroinflammation affects the brain's physiological and immune functions through several pathways and induces depressive symptoms. This study investigated the relationship among depression, neuroinflammation, and fish oil supplementation. Thirty-six male Sprague-Dawley rats were used in an aging-related depression animal model to simulate geriatric depression. Cognitive function, depressive-like symptoms, peripheral nervous system and CNS inflammation status, and the tryptophan-related metabolic pathway were analyzed. The geriatric depression animal model was associated with depressive-like behaviors and cognitive impairment. The integrity of the blood-brain barrier was compromised, resulting in increased expression of ionized calcium-binding adapter molecule 1 and the glial fibrillary acidic protein in the brain, indicating increased neuroinflammation. Tryptophan metabolism was also negatively affected. The geriatric-depressive-like rats had high levels of neurotoxic 5-hydroxyindoleacetic acid and kynurenine in their hippocampus. Fish oil intake improved depressive-like symptoms and cognitive impairment, reduced proinflammatory cytokine expression, activated the brain's glial cells, and increased the interleukin-10 level in the prefrontal cortex. Thus, fish oil intervention could ameliorate abnormal neurobehaviors and neuroinflammation and elevate the serotonin level in the hippocampus.

Neurochemical Effects of Methylphenidate and Modafinil in Ameliorating Stress-Induced Cognitive Deficits.

Chronic stressful situations result in altered monoaminergic activity of neurotransmitters, resulting in various conditions characterized by deficits in learning, memory and attention. Stimulant effects can be visualized in terms of increased cognitive abilities through enhancement of dopamine (DA) release. This study examined cognitive responses and brain DA and 5-hydroxytryptamine (5HT) levels after prolonged methylphenidate (MPH) and modafinil administration, to demonstrate their effect on stress-induced cognitive deficits in rats. Effects on cognition were evaluated by passive avoidance and water maze tests. Furthermore brain levels of DA, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 5HT and 5-hydroxyindoleacetic acid (5HIAA) were analyzed by high-performance liquid chromatography coupled with electrochemical detection. We found that both MPH and modafinil improved cognition in both restrained and unrestrained rats, as examined through water maze and passive avoidance tests. Furthermore, these substance were associated with increased brain DA and 5-HT levels. Notabily, we observed decrease in DOPAC and HVA levels, while 5-HIAA levels exhibited a slight increase. The prevention of stress-induced cognitive deficits by MPH and modafinil could be elucidated through the interaction between 5HT and DA in regulating cognitive function.

SEROTONIN IN THE MEDIATION OF BEHAVIORAL EFFECTS OF OMEGA-3 FISH OIL SUPPLEMENTS: A STUDY IN RATS.

Omega-3 polyunsaturated fatty acids (omg-3 PUFAs) are widely prescribed for improving therapeutic strategies in many diseases. There are reports that the use of these supplements can reduce disease-related depression and anxiety in patients taking these supplements. However, pre-clinical research shows mixed results. In view of the role of serotonin (5-hydroxytryptamine, 5-HT) in anxiety and depression, the present study concern effects of omg-3 on anxiety-like behavior and on serotonin metabolism in brain regions known to have a role in anxiety. It was found that administration of omg-3 for 20 days did not alter food intake and body weight. The treatment reduced locomotor activity in an open field arena and enhanced anxiety-like behavior in an elevated plus-maze test. 5-HT concentration increased in the hippocampus (HPC) and midbrain (MB) but decreased in the prefrontal cortex (PFC). Levels of 5-hydroxyindoleacetic acid (5-HIAA) were decreased in these regions. The tryptophan levels were not affected in the PFC but increased in the HPC and MB at a low dose; suggesting that decreases of 5-HT and 5-HIAA were not due to a decrease in the availability of tryptophan. The present study implied that unnecessary use of omg-3 supplements can reduce serotonin neurotransmission via the PFC to predispose to anxiety.

Tryptophan-synthesizing bacteria enhance colonic motility.

An emerging strategy to treat symptoms of gastrointestinal (GI) dysmotility utilizes the administration of isolated bacteria. However, the underlying mechanisms of action of these bacterial agents are not well established. Here, we elucidate a novel approach to promote intestinal motility by exploiting the biochemical capability of specific bacteria to produce the serotonin (5-HT) precursor, tryptophan (Trp). Mice were treated daily for 1 week by oral gavage of Bacillus (B.) subtilis (R0179), heat-inactivated R0179, or a tryptophan synthase-null strain of B. subtilis (1A2). Tissue levels of Trp, 5-HT, and 5-hydroxyindoleacetic acid (5-HIAA) were measured and changes in motility were evaluated. Mice treated with B. subtilis R0179 exhibited greater colonic tissue levels of Trp and the 5-HT breakdown product, 5-HIAA, compared to vehicle-treated mice. Furthermore, B. subtilis treatment accelerated colonic motility in both healthy mice as well as in a mouse model of constipation. These effects were not observed with heat-inactivated R0179 or the live 1A2 strain that does not express tryptophan synthase. Lastly, we found that the prokinetic effects of B. subtilis R0179 were blocked by coadministration of a 5-HT4 receptor (5-HT4 R) antagonist and were absent in 5-HT4 R knockout mice. Taken together, these data demonstrate that intestinal motility can be augmented by treatment with bacteria that synthesize Trp, possibly through increased 5-HT signaling and/or actions of Trp metabolites, and involvement of the 5-HT4 R. Our findings provide mechanistic insight into a transient and predictable bacterial strategy to promote GI motility.

#5040 UNTARGETED METABOLOMIC ANALYSIS IDENTIFIES A SPECIFIC METABOLOMIC PROFILE IN PATIENTS WITH EARLY CHRONIC KIDNEY DISEASE

Abstract Background and Aims Chronic kidney disease (CKD) has become one of the most challenging diseases of the twenty-first century and is characterized by increased mortality and morbidity. The pathogenesis of CKD is heterogeneous and the evaluation of renal function is performed with biomarkers such as serum creatinine and blood urea, which have low specificity and sensitivity. Metabolomics, one of the omics sciences, has become of interest in the nephrology field of research. Metabolic pathways can impact both glomerular and tubular structures and can offer a better understanding of the pathogenic mechanisms of CKD. Also, metabolomics provides more sensitive biomarkers for an early detection of CKD. The aim of this study was to perform metabolomic profiling of serum and urine in CKD patients by means of untargeted metabolomics in relation with the glomerular filtration rate (eGFR) and to identify potential serum and urinary biomarkers of early CKD. Method In this cross-sectional study were included 99 patients with CKD, staged by eGFR in six subgroups, according to the KDIGO Guidelines and 20 healthy control subjects. Serum and urinary metabolomic profiling were performed by using ultra-high-performance liquid chromatography coupled with electrospray ionization-quadrupole-time of flight-mass spectrometry. Blood and urine samples were evaluated by multivariate analysis, followed by univariate analysis. First, the PLSDA score plot and VIP score were applied. By using the cross-validation algorithm for the first 4 molecules identified, a high accuracy, high R² values, and a significant Q2 value were obtained. Therefore, the model could be considered predictive. Biomarker analysis and prediction by Random Forest analysis was performed. The specificity and sensibility of the molecules identified as potential biomarkers were evaluated by applying the Receiver Operating Characteristic (ROC) curve and the area under the curve (AUC). Results Significant direct correlations with eGFR were demonstrated for serum levels of Oleoyl glycine (p &amp;lt; 0.05, Log2 = 0.773), alpha-lipoic acid (p &amp;lt; 0.05), Propylthiouracil (p&amp;lt; 0.05), and L-cysteine (p&amp;lt; 0.05, Log2 = 0.363). Interestingly, serum levels of 5-Hydroxyindoleacetic acid, Phenylalanine, Pyridoxamine, Cysteinylglycine, Propenoylcarnitine, and Uridine increased gradually from C group to subgroups G5. Also, 5-Hydroxyindoleacetic acid, Phenylalanine, Pyridoxamine, Cysteinylglycine, Propenoylcarnitine, Uridine, and All-trans retinoic acid levels correlated negatively with eGFR (p&amp;lt; 0.05). Moreover, in urine samples the majority of molecules were increased in group G4 and G5 versus G1-G3b and C groups, respectively. Urinary levels of Indoxyl sulfate, Glycylprolylarginine, and Butenoylcarnitine correlated negatively with eGFR (p &amp;lt; 0.05). Conclusion Amino acids, antioxidants, uremic toxins, and acylcarnitines are increased in all CKD stages. The impact of this metabolites on the glomerular and tubular structures, even in the early stages of CKD, can be explained by their dual serum and urinary variation. The study provided a particular metabolomic profile that can offer new biomarkers useful for the evaluation of early CKD and its progression, as well as potential therapeutic targets.

English

The objective of this study is to study the sedative and hypnotic effects of the compatibility of Schisandra chinensis (SC) and Polygala tenuifolia (PT) on insomnia mice and its mechanisms. The 160 SPF KM mice were divided into 8 groups with 20 each group (10 female and 10 male mice), including control, model, estazolam, SC, PT, SC-PT 1:1, SC-PT 1:2, and SC-PT 2:1 group. Insomnia mice model was established with intraperitoneal injection of P-chlorophenylalanine (PCPA) for 3 days. The mice were investigated by the sleep time of mice induced by pentobarbital sodium, the levels of GABA, DA, 5-HT and 5-HIAA in hypothalamus by enzyme-linked immunosorbent assay, and the GABA&alpha;1 and DRD2 mRNA expression in hypothalamus by quantitative real-time polymerase chain reaction (RT-qPCR). SC-PT reduced the sleep latency of insomnia mice and prolonged the Pentobarbital-sodium induced sleep time than model group. SC-PT 2:1 group increased the levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), &gamma;-Aminobutyric acid (GABA) and the expression of GABAAR&alpha;1 and decreased the levels of dopamine (DA) and the expression of DRD2 in the hypothalamus of insomnia mice. The compatibility of SC and PT can enhance the function of sedation and hypnosis than single group. This study provides a basis for the compatibility of SC and PT in the insomnia treatment. Key words: Schisandra chinensis, Polygala tenuifolia, mice, sedative, hypnotic, &gamma;-Aminobutyric acid, dopamine.

Levels of biogenic amines in lung tissues of patients with non-small cell lung cancer after COVID-19 of various severity

Purpose of the study. Was to analyze levels of biogenic amines (serotonin and its metabolite 5-HIAA, dopamine, norepinephrine and histamine) in lung tissues of patients with lung cancer with previous COVID-19 infection.Patients and methods. The study was carried out on samples of intact lung tissues, tumor tissues and peritumoral lung tissues obtained during open biopsy while performing radical surgery from patients with morphologically verified non-small cell lung cancer (NSCLC), stage I–IIIA (cT1–3NХM0). The main group included 30 NSCLC patients (15 men and 15 women) after severe or moderate to severe COVID-19 who required hospitalization. The control group included 15 men and 15 women with NSCLC after asymptomatic or mild SARS-CoV-2 infection. The mean age of patients was 59.11 ± 2.9 years. Levels of dopamine, norepinephrine, serotonin, 5-hydroxyindoleacetic acid (5-HIAA) and histamine were measured by ELISA (IBL, Germany).Results. All studied lung tissue samples from men and women of the main group, compared to the control group, showed deficiency of catecholamines with their ratio unchanged, and changes in serotonin metabolism to ensure its stable level. Thus, levels of dopamine in samples of patients of the main group were lower on average by 1.3 times, norepinephrine by 1.3–3.3 times, serotonin by 1.6 times, and 5-HIAA by 1.8–4 times. At the same time, sex differences were observed in histamine levels. Regardless of the COVID-19 severity, levels of diamine in women were lower in the resection line tissue by an average of 2.4 times, and in the peritumoral tissue by 1.6 times, compared with men, but there were no sex differences in the tumor tissue. Conclusion. Apparently, changes in the levels of dopamine, norepinephrine, and serotonin in lung tissues could be associated with the severity of SARS-CoV-2 infection. Since dopamine is involved in counteracting the carcinogenic action of the adrenergic system and in the regulation of various immunocompetent cells in the tumor microenvironment, such changes in the biogenic status in the lungs of patients of the main group could lead to a more severe tumor course.

Surfactin Mitigates Dextran Sodium Sulfate-Induced Colitis and Behavioral Disorders in Mice by Mediating Gut-Brain-Axis Balance.

Ulcerative colitis (UC) is associated with brain neurotransmitter disorders and intestinal dysbiosis. Bacillus amyloliquefaciens fmb50 produces the lipopeptide surfactin, which has a wide range of biological activities. However, the effects of surfactin on DSS-induced colitis have not been reported. In the present study, oral surfactin significantly ameliorated colitis in a mouse model and reduced depression-like behavior, such as slowed walking speed, shortened movement distance in the open field test, and weakened exploration ability in the light-dark shuttle test. Surfactin noticeably improved gut microbial dysbiosis, intestinal barrier dysfunction in the colon, and blood-brain barrier dysfunction in the brain. Furthermore, the colon levels of occludin were upregulated by 68.51%, and the brain levels of occludin and ZO-1 were upregulated by 77.81% and 36.42%, respectively. Surfactin supplementation also inhibited inflammatory responses by inactivating the tumor necrosis factor-α (TNF-α), nuclear factor kappa-B (NF-κB), and NLRP3 signaling pathways in the colon and brain. Thus, we believe that surfactin improved the behavioral disorders by upregulating the levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine (NE), and brain-derived neurotrophic factor (BDNF), suppressing the inflammatory responses, and improving the blood-brain barrier dysfunction. Surfactin also reduced the abundances of gut microbes that are related to colitis, especially targeting facultative anaerobes of the phylum Proteobacteria, and it increased the abundance of beneficial bacteria such as Lactobacillus and unidentified Prevotella. Combined with its nontoxic nature observed in this long-term study in mice, oral surfactin might be a promising intervention strategy for preventing colitis by acting on the microbiota-gut-brain axis.

Active vs passive novelty-related strategies: Sex differences in exploratory behaviour and monoaminergic systems

Sex differences are apparent in numerous behavioural characteristics. In order to compare and characterise male and female variability of exploratory behaviour, 365 male and 401 female rats were assessed in a task where a bimodal response distribution had previously been established in males. Female rats had significantly higher exploratory activity, and presented normal distribution of the behaviour, very differently from the bimodal distribution of males. No major effect of litter or oestrous cycle was detected. Several differences between male and female rats were found in monoamine metabolism measured ex vivo. Male rats had lower levels of dopamine (DA) in frontal cortex, and higher levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in raphe area; higher levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in dorsal striatum but lower levels of 5-HT and 5-HIAA in locus coeruleus area, 5-HIAA levels were also lower in hippocampus as compared to females. Males had higher noradrenaline (NA) levels in hippocampus and lower normetanephrine (NMN) levels in striatum, in both brain regions male animals had lower NMN/NA ratio. No sex difference was found in accumbens. The only brain region with an interaction between sex and the expression of exploratory activity was raphe: Here 5-HT levels were lower, and DOPAC levels and DOPAC/DA and 5-HIAA/5-HT ratios higher in low exploring male but not female rats. Conclusively, female rats not only display higher levels of exploration but the population distribution of this behaviour is distinct; this may be related to differences in the monoaminergic systems between female and male animals.

Investigation of the Relationship of Serotonin, Dopamine and Their Metabolites with α -Synuclein in Obsessive Compulsive Disorder

Objectives: Obsessive compulsive disorder (OCD) is a mental disorder characterized by obsessions and/or compulsions. Impulsive features play a role in the etiology, symptomatology and clinical presentation of OCD. α-synuclein which plays a role in dopaminergic and serotonergic neurotransmission has been shown to be effective in impulse control. The aim of this study is to examine the levels of α-synuclein, serotonin (5-hydroxytryptamine; 5-HT), dopamine, dopamine β-hydroxylase (DBH), 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and heat shock protein 70 (HSP70) in OCD. Methods: Twenty-six OCD patients and age-gender matched 23 healthy volunteers were included in this study. Biochemical parameters were analyzed by enzyme-linked immunosorbent assay method. Patients were evaluated with Barratt Impulsivity Scale (BIS) and Dimensional Obsession Compulsion Scale (DOCS). Results: Compared with the controls, significant reduction of 5-HT, dopamine and DBH levels while significant increase of α-synuclein, HVA and HSP70 levels was found in patients with OCD. Moreover, α-synuclein levels were significantly negatively correlated with 5-HT, dopamine and DBH, while significantly positively correlated with HVA, 5-HIAA and HSP70. HTR and dopamine levels were found to be associated with the subscale of BIS. Dopamine and DBH levels were found to be associated with the subscale of DOCS. Conclusions: It may be suggested that α-synuclein is associated with dopaminergic and serotinergic pathways, and may provide important contributions for elucidating the etiology of OCD. It can be suggested that the effect of dopamine is more than 5-HT, based on the fact that not only dopamine but also DBH is correlated with OCD symptoms.

Long-term neurological and psychiatric outcomes in patients with aromatic l-amino acid decarboxylase deficiency

Introductionl-amino acid decarboxylase deficiency (AADCD) is an ultrarare autosomal recessive defect of biogenic amine synthesis that presents with early-onset encephalopathy progressing to severe neurological impairment and intellectual disability. We aimed to explore neurocognitive and behavioral profiles associated with AADCD and possible factors predicting outcome in more detail. MethodsNine AADCD patients (23.2 ± 10.3 years; range 8–40) underwent systematic clinical and neuropsychological assessment. Diagnostic levels of CSF 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA), and DDC genotype (as ascertained by American College of Medical Genetics and Genomics grading) were included in the data analysis. ResultsAll AADCD patients were affected by intellectual disability and psychiatric disorders. Movement disorders included parkinsonism-dystonia, dysarthria, and oculogyric crises. CSF 5-HIAA and HVA levels at diagnosis had a significant influence on adaptive behavior and executive function performance. Patients homozygous for DDC pathogenetic variants showed lower CSF 5-HIAA and HVA levels and higher Unified Parkinson's Disease Rating Scale scores. The disease showed a self-limiting clinical course with partial improvement under pharmacological treatment (B6 and dopamine mimetic drugs). ConclusionsPatients with AADCD suffer from neuropsychological and psychopathological impairment, which may be improved but not reversed under the present therapeutic approach. However, cognitive functioning should be specifically examined in order to avoid its underestimation on the basis of movement disorder severity. Genotype and biogenic amine level at diagnosis have an important prognostic value.

Repeated early-life exposure to anaesthesia and surgery causes subsequent anxiety-like behaviour and gut microbiota dysbiosis in juvenile rats

BackgroundEarly exposure to general anaesthetics for multiple surgeries or procedures might negatively affect brain development. Recent studies indicate the importance of microbiota in the development of stress-related behaviours. We determined whether repeated anaesthesia and surgery in early life cause gut microbiota dysbiosis and anxiety-like behaviours in rats. MethodsSprague Dawley rats received skin incisions under sevoflurane 2.3 vol% three times during the first week of life. After 4 weeks, gut microbiota, anxiety-related behaviours, hippocampal serotonergic activity, and plasma stress hormones were tested. Subsequently, we explored the effect of faecal microbiota transplantation from multiple anaesthesia/surgery exposed rats after administration of a cocktail of antibiotics on anxiety-related behaviours. ResultsAnxiety-like behaviours were observed in rats with repeated anaesthesia/surgery exposures: In the OF test, multiple anaesthesia/surgery exposures induced a decrease in the time spent in the centre compared to the Control group (P<0.05, t=3.05, df=16, Cohen’s d=1.44, effect size=0.58). In the EPM test, rats in Multiple AS group travelled less (P<0.05, t=5.09, df=16, Cohen’s d=2.40, effective size=0.77) and spent less time (P<0.05, t=3.58, df=16, Cohen’s d=1.69, effect size=0.65) in the open arms when compared to the Control group. Repeated exposure caused severe gut microbiota dysbiosis, with exaggerated stress response (P<0.01, t=4.048, df=16, Cohen's d=−1.91, effect size=−0.69), a significant increase in the hippocampal concentration of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) (P<0.05; for 5-HT: t=3.33, df=18, Cohen’s d=−1.49, effect size=−0.60; for 5-HIAA: t=3.12, df=18, Cohen’s d=−1.40, effect size=−0.57), and changes in gene expression of serotonergic receptors later in life (for Htr1a: P<0.001, t=4.49, df=16, Cohen’s d=2.24, effect size=0.75; for Htr2c: P<0.01, t=3.72, df=16, Cohen’s d=1.86, effect size=0.68; for Htr6: P<0.001, t=7.76, df=16, Cohen’s d=3.88, effect size=0.89). Faecal microbiota transplantation led to similar anxiety-like behaviours and changes in the levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. ConclusionsGut microbiota dysbiosis caused by early repeated exposure to anaesthesia and surgery affects long-term anxiety emotion behaviours in rats.

The effects of biogenic amines in Chinese Huangjiu on the behavior of mice and hangover headache-related indices.

Huangjiu (Chinese rice wine) is a popular and traditional alcoholic beverage in China; however, the consumption of Huangjiu readily results in hangover symptoms. The aim of this study was to identify the main components associated with behavioral inhibition, headache, and the relevant mechanisms by using a mice hangover model. The results of an open-field experiment revealed that the key biogenic amine associated with mice behavior was histamine, which inhibited the behavior activity of mice in a dose-dependent manner. Moreover, histamine treatment decreased the levels of serotonin (5-HT) and 5-hydroxyindole acetic acid. In addition, the levels of dopamine and nitric oxide, which are associated with migraine, increased in the brain tissue of mice. In addition, the expression of receptor genes of 5-HT, including Htr1a, Htr1f, and Htr2c, is essential in regulating various behaviors and mental activities. In conclusion, the present study demonstrated that histamine is a key component in Huangjiu, and it is related to hangover symptoms by affecting the level of 5-HT and its receptors.