5-HTP (5-Hydroxytryptophan)

Observational studies suggest a link between biological aging and adverse pregnancy outcomes (APOs), but causal relationships remain unclear. This study aimed to investigate the relationship between genetically predicted biological aging traits and APOs. Genetic summary statistics from the genome-wide association study (GWAS) of the IEU open GWAS, FinnGen, and meta-analysis were analyzed using Mendelian randomization (MR) to infer causality. Biological aging indicators included facial aging, frailty index, and epigenetic aging markers. APOs included gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HTP), preterm birth (PTB), and pregnancy loss (PL). The primary MR analyses utilized the inverse variance weighted method, followed by sensitivity analyses. Reverse MR and multivariable MR were employed to explore reverse causality and potential mediating effects. We found that the frailty index was positively associated with GDM (OR = 2.00, 95% CI 1.44-2.77, P = 3.41E - 5), HTP (OR = 2.09, 95% CI 1.33-3.29, P = 0.001), and PL (OR = 1.22, 95% CI 1.03-1.46, P = 0.023) risks. Inverse MR showed that susceptibility to HTP (β = 0.05, 95% CI 0.03-0.07, P = 4.43E - 6) and PL (β = 0.06, 95% CI 0.01-0.11, P = 0.011) was positively correlated with the frailty index, while PTB was positively correlated with PhenoAge (β = 0.24, 95% CI 0.02-0.46, P = 0.035). Our findings suggest a genetic association between the frailty index and susceptibility to GDM, HTP, and PL. Closer monitoring of biological aging indicators during pregnancy may be necessary to prevent APOs. © 2025. The Author(s), under exclusive licence to Springer Nature B.V.

The serotonin syndrome (SS) is a potentially life-threatening disorder in humans which is induced by ingestion of an overdose or by combination of two or more serotonin (5-HT)-enhancing drugs. In animals, acute administration of direct and indirect 5-HT agonists also leads to a set of behavioral and autonomic responses. In the current review, we provide an overview of the existing versions of the animal model of the SS. With a focus on studies in rats and mice, we analyze the frequency of behavioral and autonomic responses following administration of 5-HT-enhancing drugs and direct 5-HT agonists administered alone or in combination, and we briefly discuss the receptor mediation of these responses. Considering species differences, we identify a distinct set of behavioral and autonomic responses that are consistently observed following administration of direct and indirect 5-HT agonists. Finally, we discuss the importance of a standardized assessment of SS responses in rodents and the utility of animal models of the SS in translational studies, and provide suggestions for future research.

OBJECTIVE: To review the literature regarding the effectiveness of 5-hydroxytryptophan (5-HT) and L-tryptophan in the treatment of unipolar depression. METHODS: A systematic review of the literature from 1966 to 2000 using the search terms 'tryptophan', 5-hydroxytryptophan', '5-HTP', '5-HT' and 'depression'. We extracted and grouped data for meta-analysis by pooling odds ratios (OR) and relative risks where possible. RESULTS: One hundred and eight studies were located of which only two studies, one of 5-HT and one of L-tryptophan, with a total of 64 patients met sufficient quality criteria to be included. These studies suggest 5-HT and L-tryptophan are better than placebo at alleviating depression (Peto OR = 4.1, 95% CI = 1.3-13.2). However, the small size of the studies, and the large number of inadmissible, poorly executed studies, casts doubt on the result from potential publication bias, and suggests that they are insufficiently evaluated to assess their effectiveness. CONCLUSION: A large body of evidence was subjected to very basic criteria for assessing reliability and validity, and was found to largely be of insufficient quality to inform clinical practice. More well-designed studies are urgently required to enable an assessment of what may be an effective class of agents.

BACKGROUND: 5 Hydroxytryptophan (5-HTP) and tryptophan are so-called natural alternatives to traditional antidepressants, used to treat unipolar depression and dysthymia. OBJECTIVES: To determine whether 5-HTP and tryptophan are more effective than placebo, and whether they are safe to use to treat depressive disorders in adults. SEARCH STRATEGY: Trials were searched in computerized general (Medline, Psychlit, and Embase) and specialized databases (Cochrane Controlled Clinical Trials Register, Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trial Register); by checking reference lists of relevant articles; by handsearching relevant specialist journals; and by contacting relevant authors where appropriate. Publications in all languages were sought. SELECTION CRITERIA: Trials were included if they were randomized, included patients with unipolar depression or dysthymia, compared preparations of 5-HTP or tryptophan with placebo, and included clinical outcomes assessed by scales assessing depressive symptoms. DATA COLLECTION AND ANALYSIS: Data was extracted independently by the three reviewers, onto data collection forms. Inclusion criteria were applied to all potential studies independently and a coefficient of agreement (Kappa) was calculated for them. Disagreement was resolved by reaching consensus. Trial quality was scored according to risk of bias. Analysis for 5-HTP and tryptophan were combined due to the small number of included trials. MAIN RESULTS: 108 trials were located using the specified search strategy. Of these, only two trials, involving a total of 64 patients, were of sufficient quality to meet inclusion criteria. The available evidence suggests these substances were better than placebo at alleviating depression (Peto Odds Ratio 4.10; 95% confidence interval 1.28-13.15; RD 0.36; NNT 2.78). However, the evidence was of insufficient quality to be conclusive. REVIEWER'S CONCLUSIONS: A large number of studies appear to address the research questions, but few are of sufficient quality to be reliable. Available evidence does suggest these substances are better than placebo at alleviating depression. Further studies are needed to evaluat

BACKGROUND: 5 Hydroxytryptophan (5-HTP) and tryptophan are so-called natural alternatives to traditional antidepressants, used to treat unipolar depression and dysthymia. OBJECTIVES: To determine whether 5-HTP and tryptophan are more effective than placebo, and whether they are safe to use to treat depressive disorders in adults. SEARCH STRATEGY: Trials were searched in computerized general (Medline, Psychlit, and Embase) and specialized databases (Cochrane Controlled Clinical Trials Register, Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trial Register); by checking reference lists of relevant articles; by handsearching relevant specialist journals; and by contacting relevant authors where appropriate. Publications in all languages were sought. SELECTION CRITERIA: Trials were included if they were randomized, included patients with unipolar depression or dysthymia, compared preparations of 5-HTP or tryptophan with placebo, and included clinical outcomes assessed by scales assessing depressive symptoms. DATA COLLECTION AND ANALYSIS: Data was extracted independently by the three reviewers, onto data collection forms. Inclusion criteria were applied to all potential studies independently and a coefficient of agreement (Kappa) was calculated for them. Disagreement was resolved by reaching consensus. Trial quality was scored according to risk of bias. Analysis for 5-HTP and tryptophan were combined due to the small number of included trials. MAIN RESULTS: 108 trials were located using the specified search strategy. Of these, only two trials, involving a total of 64 patients, were of sufficient quality to meet inclusion criteria. The available evidence suggests these substances were better than placebo at alleviating depression (Peto Odds Ratio 4.10; 95% confidence interval 1.28-13.15; RD 0.36; NNT 2.78). However, the evidence was of insufficient quality to be conclusive. REVIEWER'S CONCLUSIONS: A large number of studies appear to address the research questions, but few are of sufficient quality to be reliable. Available evidence does suggest these substances are better than placebo at alleviating depression. Further studies are needed to evaluat

Objectives: Concurrent with global aging epidemics, cognitive decline has become an increasing public health concern. Dietary supplementation may offer neuroprotective benefits, and 5-hydroxytryptophan (5-HTP) has gained interest due to its role in serotonin synthesis, thereby regulating cognitive function and mood. However, there is limited evidence on its effect on cognitive function, especially among older Asian adults. Therefore, the study aimed to investigate the effects of 5-HTP supplementation on cognitive function and mood in Singaporean older adults. Methods: This was a single-blinded, 12-week randomized controlled trial, and 30 participants (66 ± 3 years) were randomly assigned to consume 100 mg of 5-HTP daily or not consume it. Cognitive function and mood were assessed via the Montreal Cognitive Assessment (MoCA), Geriatric Anxiety Inventory (GAI), and Geriatric Depression Scale (GDS). Cognitive function-related blood biomarkers, including amyloid beta (Aβ)40, Aβ42, gamma-aminobutyric acid, and serotonin, were also determined. Results: A significant time effect was observed in the MoCA score, which was mainly explained by a significant increase in the 5-HTP group (week 0 vs. week 12: 26.6 ± 1.4 a.u. vs. 27.6 ± 1.4 a.u., p < 0.05). Moreover, the 5-HTP group showed a significant increase in serum serotonin levels. Additionally, the GDS score improved in the 5-HTP group (week 0 vs. week 8: 1.2 ± 1.7 a.u. vs. 0.7 ± 1.2 a.u., p < 0.05). However, no effects on GAI and other biomarkers were observed. Conclusions: 5-HTP supplementation can enhance cognitive performance and reduce symptoms of depression in Singaporean older adults, potentially through serotonergic modulation. However, given the relatively small sample size (n = 30) and short-term (12-week) intervention, these findings should be interpreted cautiously, and further long-term studies with a larger sample size are warranted to confirm these preliminary results.

Comment in Clin Nutr. 2024 Jun;43(6):1597-1598. doi: 10.1016/j.clnu.2024.05.010. BACKGROUND & AIMS: Sleep quality is a pivotal part of health and there is growing evidence on the association between gut microbiota composition and sleep quality. 5-Hydroxytryptophan (5-HTP) is known as a precursor of the sleep regulating neurotransmitter and hormone. However, efficacy of 5-HTP supplementation for improving sleep quality in older adults is unclear. Hence, the aim of this study is to assess the impact of 5-HTP supplementation on sleep quality and gut microbiota composition in older adults. METHODS: This is a single-blinded, 12-week parallel randomized controlled trial. Thirty older adults (66 ± 3 years) in Singapore were randomly assigned to either consume or not consume 100 mg 5-HTP daily. Every 4 weeks, sleep quality was assessed via both subjective (Pittsburg Sleep Quality Index) and objective (actigraphy watch) measures. A global sleep score (GSS) was obtained from the PSQI, where a GSS>5 defines as poor sleeper while a GSS≤5 defines as good sleeper. Blood serotonin level, urine melatonin concentration, gut microbiota composition and stool short chain fatty acids (SCFA) content were assessed at week 0 and 12. This study was registered in clinicaltrials.gov as NCT04078724 (https://clinicaltrials.gov/ct2/show/NCT04078724). RESULTS: 5-HTP supplementation showed an overall favorable effect on certain sleep quality components and an increase in serum serotonin concentration. In particular, at week 12, not good sleepers but poor sleepers with 5-HTP supplementation were able to significantly improve subjective GSS (ΔSL5-HTP: -2.80 ± 1.10 min, p-value = 0.005). In addition, they showed an increase in microbiota diversity (Simpson5-HTP vs. SimpsonControl: 0.037 ± 0.032 a.u. vs. -0.007 ± 0.022 a.u.; pinteraction: 0.013) and relative abundance of SCFA producing bacteria in the gut. CONCLUSIONS: 5-HTP supplementation can improve certain sleep quality components in older adults and this benefit was more prominently observed in poor sleepers. 5-HTP was also able to improve the gut microbiota composition in poor sleepers.

The purpose of this investigation was to determine the effects of supplementing with 100 mg daily of 5-Hydroxytryptophan (5-HTP) on indices of body composition in exercise-trained men and women. Sixty-one subjects volunteered for this investigation. Forty-eight subjects were randomized into a treatment (n = 31, 12 male/19 female; 100 mg 5-HTP daily; CLEANMOOD™) or a placebo (n = 17, six male/11 female; maltodextrin). Body composition was assessed pre- and post-treatment after eight weeks via a multi-frequency bioelectrical impedance device (InBody® 270). Subjects were instructed to not change their training or eating habits; moreover, they were instructed to track their diet ∼2-3 days per week using a mobile app (MyFitnessPal). There were no changes in food intake (i.e. total energy intake or grams of macronutrients) between or within groups. Lean body mass, total body water, and % body fat did not change significantly in either group. Fat mass decreased significantly post versus pre in the 5-HTP group (p = 0.02) but did not change in the placebo group (p = 0.58). Moreover, changes in fat mass were significantly different between the 5-HTP and placebo group (p = 0.048). Based on the limited data from this investigation, daily supplementation with 100 mg of 5-HTP may affect body composition.

Understanding of emotions and intentions are key processes in social cognition at which serotonin is an important neuromodulator. Its precursor is the essential amino acid tryptophan (TRP). Reduced TRP availability leads to weaker impulse control ability and higher aggression, while TRP supplementation promotes confidence. In a double-blind placebo-controlled fMRI study with 77 healthy adults, we investigated the influence of a 4 week TRP enriched diet and an acute 5-hydroxytryptophan (5-HTP) intake on two social-cognitive tasks, a moral evaluation and an emotion recognition task. With 5-HTP, immoral behavior without negative consequences was rated as more reprehensible. Additionally, during story reading, activation in insula and supramarginal gyrus was increased after TRP intake. No significant effects of TRP on emotion recognition were identified for the whole sample. Importantly, emotion recognition ability decreased with age which was for positive emotions compensated by TRP. Since the supramarginal gyrus is associated with empathy, pain and related information integration results could be interpreted as reflecting stricter evaluation of negative behavior due to better integration of information. Improved recognition of positive emotions with TRP in older participants supports the use of a TRP-rich diet to compensate for age related decline in social-cognitive processes. © 2021. The Author(s).

PURPOSE: Altered serotonergic neurotransmission may contribute to the non-motor features commonly associated with Parkinson's disease (PD) such as sleep disorders. The 5-hydroxytryptophan (5-HTP) is the intermediate metabolite of L-tryptophan in the production of serotonin and melatonin. The purpose of this study was to compare the effects of 5-HTP to placebo on REM sleep behavior disorder (RBD) status in patients with PD. METHODS: A single-center, randomized, double-blind placebo-controlled crossover trial was performed in a selected population of 18 patients with PD and RBD. The patients received a placebo and 50 mg of 5-HTP daily in a crossover design over a period of 4 weeks. RESULTS: 5-HTP produced an increase in the total percentage of stage REM sleep without a related increase of RBD episodes, as well as a marginal, non-significant reduction in both arousal index and wake after sleep onset. The self-reported RBD frequency and clinical global impression (CGI) were improved during 5-HTP and placebo treatment in comparison to baseline. 5-HTP significantly improved our patients' motor experiences of daily living as rated by the Unified Parkinson's Disease Rating Scale (UPDRS) part II. CONCLUSIONS: This study provides evidence that 5-HTP is safe and effective in improving sleep stability in PD, contributing to ameliorate patients' global sleep quality. Larger studies with higher doses and longer treatment duration are needed to corroborate these preliminary findings. © 2021. The Author(s).

Microbial conversion of dietary or drug substrates into small bioactive molecules represents a regulatory mechanism by which the gut microbiota alters intestinal physiology. Here, we show that a wide variety of gut bacteria can metabolize the dietary supplement and antidepressant 5-hydroxytryptophan (5-HTP) to 5-hydroxyindole (5-HI) via the tryptophanase (TnaA) enzyme. Oral administration of 5-HTP results in detection of 5-HI in fecal samples of healthy volunteers with interindividual variation. The production of 5-HI is inhibited upon pH reduction in in vitro studies. When administered orally in rats, 5-HI significantly accelerates the total gut transit time (TGTT). Deciphering the underlying mechanisms of action reveals that 5-HI accelerates gut contractility via activation of L-type calcium channels located on the colonic smooth muscle cells. Moreover, 5-HI stimulation of a cell line model of intestinal enterochromaffin cells results in significant increase in serotonin production. Together, our findings support a role for bacterial metabolism in altering gut motility and lay the foundation for microbiota-targeted interventions.

BACKGROUND AND PURPOSE: Several studies have indicated that altered serotonergic neurotransmission may contribute to the motor features commonly associated with Parkinson's disease (PD) drug treatment such as levodopa-induced dyskinesias (LIDs). 5-Hydroxytryptophan (5-HTP) is the immediate precursor of serotonin. We have recently demonstrated that 5-HTP produces significant antidyskinetic effects in a rat model of PD. To date, there has been inconsistent research on the use of 5-HTP in PD. The purpose of this study was to compare the effects of 5-HTP versus placebo on levodopa-induced motor complications in PD patients. MATERIAL AND METHODS: A single-center, randomized, double-blind placebo-controlled cross-over study was performed. A total of 12 PD patients were diagnosed with LIDs and motor fluctuactions and subsequently were randomized to intervention; 11 subjects completed the entire 16-week protocol. Patients received placebo or 50 mg of 5-HTP daily in a cross-over design over a period of 4 weeks. For the assessment of efficacy on the motor functions and motor complications, the UPDRS (parts III and IV), Unified Dyskinesia Rating Scale (UDysRS), Wearing-Off Questionnaire (WOQ-19) and the self-reported 24-h home dyskinesia diaries were obtained at baseline and weeks 4, 8, 12 and 16 (T-end). RESULTS: Repeated measures analysis revealed a significant improvement of LIDs during the 50 mg 5-HTP treatment as assessed by the UDysRS and UPDRS-IV scores. CONCLUSIONS: This study provides preliminary evidence of clinical benefit of 5-HTP against LIDs in PD. Larger studies with a longer treatment duration and a wider range of doses are warranted to corroborate these findings.

This research was planned to build a Pharmacokinetic/Pharmacodynamic (PK/PD) model of 5-hydroxytryptophan (5-HTP) challenge study including a circadian rhythm component of cortisol and to predict serum cortisol based on saliva cortisol. Data from three 5-HTP challenge studies in healthy volunteers were collected. Serum 5-HTP, saliva, and serum cortisol were sampled as PK and PD marker. The population PK/PD modeling approach was applied. A baseline model of serum cortisol was built to assess the circadian rhythm before a pharmacodynamic model was used to evaluate the drug effect of the 5-HTP on cortisol. Finally, linear and power function relationships were tested to predict serum cortisol based on saliva cortisol. The PK of 5-HTP could be described using a one-compartment model with a transit compartment. The typical value for clearance was 20.40 L h-1 and showed inter-study variability. A cosine function was chosen and properly described the circadian rhythm of serum cortisol. A linear approximation model was applied to fit the 5-HTP PD effect on cortisol data with a slope of 4.16 ng mL-1 h. A power function provided a better description than a linear function to relate the saliva and serum cortisol. In conclusion, a circadian rhythm component was built in the PK/PD model of the 5-HTP challenge test which could better improve the understanding of the stimulating effect on HPA with cortisol change. After the 5-HTP challenge, saliva cortisol correlated well with serum cortisol and was predictable by a population PK-PD model. © 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

BACKGROUND AND PURPOSE: Several studies have indicated that altered serotonergic neurotransmission may contribute to non-motor features commonly associated with Parkinson's disease (PD) such as apathy and depression. 5-hydroxytryptophan (5-HTP) is the intermediate metabolite of L-tryptophan in the production of serotonin. To date, there has been inconsistent research on the use of 5-HTP in PD. The purpose of this study was to compare the effects of 5-HTP with those of placebo on apathy and depressive symptoms in patients with PD. METHODS: A single-center, randomized, double-blind placebo-controlled cross-over trial was employed; 25 individuals were subsequently enrolled into the study. Patients received placebo and 50 mg of 5-HTP daily over a period of 4 weeks. For the assessment of efficacy on depressive and apathy symptoms the Beck Depression Inventory-II (BDI-II), Hamilton Depression Rating Scale (HDRS) and Apathy Scale (AS) were respectively administered at screening, baseline and weeks 4, 8, 12 and 16. Primary efficacy outcomes were the comparison of 5-HTP to placebo in mean change from baseline to weeks 4, 8, 12 and 16 in total score on the AS, BDI-II and HDRS. RESULTS: Repeated-measures analysis revealed a significant improvement of depressive symptoms during the 50-mg 5-HTP treatment compared with placebo as assessed by the HDRS. No effect of 5-HTP was seen on apathy symptoms assessed by the AS. CONCLUSIONS: This study provides preliminary evidence of clinical benefit of 5-HTP for treating depressive symptoms in PD. Larger studies with a longer treatment duration are needed to corroborate these early findings. © 2020 European Academy of Neurology.

PURPOSE: Depression clinical trials are increasingly studying biomarkers to predict and monitor response to treatment. Assessment of biomarkers may reveal subsets of patients who are responsive to nutraceutical treatment, which may facilitate a personalized approach to treating depression. METHODS: This is a post hoc analysis of an 8-week, double-blind, randomized, controlled trial (n = 158) investigating a combination nutraceutical comprising Omega-3 (EPA 1 g/DHA 656 mg), SAMe, zinc, 5-HTP, folinic acid, and co-factors versus placebo for the treatment of Major Depressive Disorder. The study explored levels of polyunsaturated fatty acids, folate, vitamin B12, zinc, homocysteine, and BDNF as possible predictors and correlates of response to nutraceutical supplementation. RESULTS: Concentrations of EPA and DHA in red cell membranes increased in response to treatment and were significantly correlated with a decrease in depressive symptoms during active treatment (p = 0.003 and p = 0.029; respectively). Higher baseline levels of omega-6 fatty acid also correlated with depression reduction in the active treatment group ( p = 0.011). No other biomarkers were associated with a lessening of depressive symptoms. CONCLUSION: Changes in fatty acid levels resulting from a nutraceutical combination containing EPA and DHA provide a response biomarker in treating depression.

The effects of berberine (BBR) on intestinal health suffering from soybean meal (SBM)-induced enteritis (SBMIE) in hybrid yellow catfish (Pelteobagrus fulvidraco ♀ × Pelteobagrus vachelli ♂) were investigated in this study, focusing specifically on oxidant-antioxidant capacity, intestinal morphology, microbiota homeostasis and tryptophan catabolites. A total of 270 individuals with the initial body weight (IBW) of 23.27 ± 0.60 g were randomly divided into 9 tanks at the density of 30 fish per tank. Three diets, the SBM diet (75% of fish meal substituted by SBM, SBM), BBR1 (75 mg/kg BBR was added to the SBM diet, BBR1) and BBR2 diet (150 mg/kg BBR was added to the SBM diet, BBR2), were used to feed fish for 42 d. The results indicated that the final body weight (FBW), weight gain rate (WGR) and specific growth rate (SGR) were all significantly increased in BBR2 group compared with SBM group (P < 0.05). Intestinal barrier proteins and genes (ZO-1 and occludin) expression (P < 0.05) and intestinal interleukin-10 (IL-10) content (P = 0.001) were all greatly improved with BBR administration, especially in the BBR2 group. The apoptosis related genes (caspase 3 and caspase 9) (P < 0.05) of intestinal epithelium cells were also significantly reduced by dietary BBR compared with SBM group. Comparative analysis of intestinal microbial composition and tryptophan catabolites between the SBM group and BBR2 group revealed that BBR significantly ameliorated the imbalance of intestinal microbiota and improved the intestinal tryptophan catabolites, especially reflected in the relative abundance of Romboutsia and the levels of L-5-hydroxytryptophan (L-5-HTP), indole-3-acetic acid (IAA) and kynurenine (KYN) in intestinal contents (P < 0.05). As a result, the aryl hydrocarbon receptor (AhR) signaling was then activated. Correlation analyses showed that the relative abundance of Romboutsia was positively correlated with IAA and KYN levels in the intestinal contents (P < 0.05), and negatively correlated with interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) levels in hindgut (P < 0.01). The levels of L-5-HTP, IAA, and KYN in intestinal contents were positively correlated with key f

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia integrifolia Linn. (Chinese name: Liuhao, LH) is a traditional Chinese medicine commonly employed for managing diabetes. However, its pharmacological effects on diabetic nephropathy (DN) remain unclear. AIM OF THE STUDY: This study aimed to investigate the effects and underlying mechanisms of LH on DN. MATERIALS AND METHODS: A DN rat model was established by combining of streptozotocin (STZ) injection with a high-fat and high-sugar (HFHS) diet. Subsequently, the rats were administered LH at doses of 90 and 180 mg/kg/d 15 days. Fasting blood glucose (FBG), body weight, renal and hepatic function, blood lipid levels, renal and pancreas histopathological changes, and insulin levels were assessed. Network pharmacology, untargeted and targeted tryptophan metabolomics of renal, were integrated to explore the mechanism of LH in treating DN. Subsequent validation experiments were performed to measure inflammation markers and oxidative stress levels in serum and kidney tissues, along with the expression of key genes and proteins in the Keap1/Nrf2/HO-1 pathway. RESULTS: LH treatment increased the body weight, reduced FBG and insulin levels, ameliorated pathological and functional damage in the kidneys, liver and pancreas, and regulated blood lipid profiles. Network pharmacology analysis indicated that inflammatory factors and oxidative stress pathways are involved in the pharmacological actions of LH. Renal untargeted metabolomics identified 21 differential metabolites and 6 relevant metabolic pathways that nay contribute to the therapeutic effects of LH. Targeted tryptophan metabolomics found that LH increased the contents of L-tryptophan (Trp) and 5-hydroxytryptophan (5-HTP), decreased the content of serotonin (Ser) in renal. Furthermore, LH alleviated inflammatory and oxidative stress via upregulating the expression of Nrf2 and HO-1, and downregulating Keap1 in the kidney. CONCLUSIONS: LH might attenuate renal inflammation and oxidative stress-induced injury in DN by regulating the Keap1/Nrf2/HO-1 signaling pathway and modulating renal metabolism.

BACKGROUND: Elevating brain extracellular (active) serotonin has broad-spectrum therapeutic efficacy across multiple psychiatric indications, with relatively good safety, tolerability, and scalability. The main drugs used are the serotonin reuptake inhibitors (SRIs), originally tricyclic antidepressants (TCAs), and later mainly selective-serotonin reuptake inhibitors (SSRIs). METHODS: This article reviews key clinical and ancillary animal evidence supporting that serotonin synthesis amplification adjunctive therapy can safety augments SRI clinical efficacy when SRI monotherapy is insufficient. RESULTS: SRIs work by blocking the serotonin transporter. This causes a net shift of serotonin to the extracellular space and increased serotonin neurotransmission, which mediates the therapeutic efficacy. However, SRI efficacy is modest, inconsistent, and with a delayed onset. Conversely, SRIs seem to elevate forebrain extracellular serotonin only modestly, inconsistently, and with a delay. Clinical trials spanning 6 decades report that SRI efficacy can be augmented by adjunctive therapy with a compound that amplifies brain serotonin synthesis, presumably acting by elevating brain extracellular serotonin beyond the SRI effect. SRI adjunctive therapy with the serotonin precursors 5-hydroxytryptophan (5-HTP) and tryptophan has been used in practice and in trials, but both compounds have poor drug properties. Adjunctive therapy with methylfolate and lithium likewise seems to augment SRI clinical efficacy at least partly through serotonin synthesis amplification. CONCLUSIONS: Despite this encouraging evidence, no SRI adjunctive FDA-approved drug product uses a serotonin synthesis amplification pharmacology. Such a drug could exhibit general SRI-augmentation therapeutic potential and be scalable across clinical scenarios.

PURPOSE: Chromone-containing allylmorpholines (CCAMs) are a promising class of compounds that have been shown to have a dose-dependent inhibition effect on locomotion in zebrafish (Danio rerio). However, experiments using behavioural tests on mice have not yet allowed us to fully understand the specificity of their action. In this study, we conducted a pharmacoencephalographic evaluation of the psychotropic effects of CCAM 33a on rats using a Naïve Bayes classifier (NBC) combined with the principal component analysis (PCA). METHODS: The ECoG experiments were conducted on white outbred rats. The training set, which was used as a reference for determining the pharmacological effects of each dose of the compound under study, included matrices of effects from 9 agents with different mechanisms of action. Amplitude-spectral analysis using PCA resulted in 6 new principal components that accounted for 83.57% of the variance. Classification of the effects of compound 33a was performed using NBC. To validate the classification results, additional experiments were conducted including the 5-hydroxytryptophan (5-HTP)-induced head twitch test and apomorphine-induced climbing in mice, as well as the 'presynaptic' low-dose apomorphine-induced yawning test in rats. RESULTS: CCAM 33a at doses of 100 and 300 mg/kg shows similar effects to hydroxyzine and sulpiride. In mouse experiments, CCAM 33a reduced the number of head twitches induced by 5-HTP administration at a dose of 20 mg/kg, and inhibited apomorphine-induced climbing at a dose of 300 mg/kg. In rats, the substance at a dose of 100 mg/kg reduced the number of yawns caused by apomorphine administration at a dose of 0.032 mg/kg. CONCLUSION: The data obtained confirm the effectiveness of the combined use of NBC and PCA for classification tasks. The effects of the different doses of compound 33a on ECoG, as well as the abolition of the effects of apomorphine and 5-HTP in mice and rats, suggest a dopamine- and 5-HT2-blocking action of the molecule under study. © 2025 The Author (s).

BACKGROUND: Major depressive disorder (MDD) is a common and heterogeneous mental illness with an unclear pathogenesis and often suboptimal treatment outcomes. Astragalus polysaccharide (APS) has shown potential antidepressant effects and may serve as a functional food; however, its impact on the gut microbiota and metabolome in MDD remains unexplored. METHODS: Using an in vitro fermentation model coupled with 16S rRNA sequencing and targeted metabolomics, we characterized the gut microbial composition and neurotransmitter metabolites in fecal samples from 15 MDD patients and 15 healthy subjects. RESULTS: MDD samples exhibited elevated Fusobacteriaecae and Eggerthellaceae, reduced levels of Eubacterium hallii, Faecalibacterium, and Ruminococcus, and higher concentrations of glutamine (Gln) and glutamate (Glu). APS fermentation significantly increased Bifidobacterium and Lactobacillus while decreasing Eubacterium hallii and Bilophila, without increasing the total gas volume, CO2, and H2S production. Additionally, beneficial metabolites were elevated in MDD samples after APS addition, including glutamine (Gln), γ-aminobutyric acid (GABA), dopamine (DA), and 5-hydroxytryptophan (5-HTP). The increase in GABA among healthy subjects was more significant. CONCLUSIONS: These findings indicate that MDD is associated with disruptions in gut microbiota and Glu/GABA metabolism. When APS are applied directly to the colon, they may mitigate these disruptions by modulating microbial composition and key neuroactive metabolites, thereby influencing the central nervous system via the gut-brain axis. This effect appears to be more pronounced in healthy individuals. CLINICAL TRIAL REGISTRATION: https://www.medicalresearch.org.cn, identifier MR-33-25-010733.

Age-related hearing loss (ARHL) is a prevalent sensory disorder lacking disease-modifying interventions. The biological drivers, particularly the contribution of the gut microbiota and gut-inner ear crosstalk, remain poorly defined. Here, we utilize germ-free (GF) mice and fecal microbiota transplantation (FMT) to isolate microbiota-dependent effects on ARHL progression. Through integrated metagenomic, metabolomic, and proteomic profiling, we map molecular signatures of auditory aging and uncover functional gut-inner ear network, prioritizing 5-hydroxytryptophan (5-HTP) as a key intermediate metabolite within this network. Furthermore, in an aging-like House Ear Institute-Organ of Corti 1 (HEI-OC1) model, 5-HTP exhibits protective effects, potentially mediated through the PI3K/Akt-antioxidant signaling axis. Collectively, this study provides a valuable multi-omics resource and highlights microbiota-derived metabolic regulation as a promising avenue for biomarker discovery and therapeutic development in ARHL. © 2026 The Author(s). Advanced Science published by Wiley‐VCH GmbH.

ETHNOPHARMACOLOGICAL RELEVANCE: Sleep deprivation is a growing public health burden linked to neuroinflammation, oxidative stress, and neurodegeneration. While conventional hypnotics provide transient relief, their long-term use is limited by tolerance and adverse effects. Guhan Yangsheng Jing (GHYSJ), a classical multi-herbal prescription from traditional Chinese medicine, has been clinically used to relieve insomnia and fatigue, yet its neuroprotective mechanisms remain unclear. OBJECTIVE: This study aimed to elucidate the protective effects and molecular mechanisms of GHYSJ against sleep-deprivation-induced neuronal injury, focusing on neurotransmitter balance, mitochondrial function, and pyroptosis regulation. METHODS: A PCPA-induced mouse model of sleep deprivation was established. Behavioral assays (righting-reflex and open-field tests), histological analyses, and ELISA quantifications of neurotransmitters and cytokines were performed. Integrative serum metabolomics and hippocampal transcriptomics were conducted to identify molecular pathways, and pyroptosis-related proteins were validated by immunohistochemistry, immunoblotting, and immunofluorescence. LPS/nigericin-induced pyroptosis in HT-22 neurons was used for in vitro validation. RESULTS: GHYSJ significantly shortened sleep latency, prolonged sleep duration, and restored locomotor activity. It rebalanced hippocampal 5-HTP, 5-HT, GABA, and Glu levels, preserved neuronal cytoarchitecture, and reduced degenerative signals. Multi-omics profiling revealed that GHYSJ modulated pathways related to the TCA cycle, lipid peroxidation, and innate immunity, reversing the aberrant expression of key genes such as Hspa1a, Plin4, Nod2, and Nkx2-4. GHYSJ suppressed hippocampal NLRP3, ASC, HMGB1, cleaved caspase-1, and GSDMD-N expression, decreased IL-1β/IL-18 release, and ameliorated mitochondrial swelling and cristae disruption. In HT-22 cells, GHYSJ-containing serum restored cell viability, alleviated G1/S arrest, stabilized mitochondrial membrane potential, increased ATP levels, and reduced pyroptosis-related membrane rupture. CONCLUSION: GHYSJ exerts multi-target neuroprotection through integrated neurotransmitte

BACKGROUND: Parkinson's disease (PD) exhibits a distinct gut microbiota and microbial metabolites, with specific enterotypes potentially influencing disease susceptibility. Current research lacks systematic comparisons of different enterotypes in PD susceptibility and targeted intervention efficacy. This study identifies their gut microbiota-metabolite biomarkers and validates a "probiotic plus herbal medicine" intervention in vitro to explore enterotype-stratified precision strategies for PD prevention and treatment. PURPOSE: This study aimed to identify a high-risk enterotype for PD and its associated microbial and metabolic signatures using public metagenomic data. Furthermore, we evaluated the therapeutic efficacy of a combination therapy, comprising Patrinia scabiosaefolia Fisch (Herba Patriniae; HP) extract and the probiotics, Faecalibacterium prausnitzii and Lactiplantibacillus plantarum (F.l-HP), in a PD-relevant in vitro model. METHODS: Public metagenomic data from PD patients and healthy controls (HC) were analyzed to characterize enterotypes. An in vitro gut-brain axis (GBA) model was established by co-culturing PC12 neuronal cells and Caco-2 intestinal epithelial cells to validate the pathogenic role of Escherichia fergusonii. The effects of the F.l-HP combination therapy were then assessed on bacterial growth, key metabolites (5-hydroxytryptophan (5-HTP), trimethylamine N-oxide (TMAO), butyrate), neuroinflammation, oxidative stress, mitochondrial function, and gut barrier integrity, with a focus on the underlying p-Akt and p-AMPKα signaling pathways. RESULTS: The Bacteroidaceae enterotype (ET-B) was identified as a high-risk enterotype for PD, characterized by an enrichment of E. fergusonii. This bacterium was associated with the consumption of neuroprotective 5-HTP and the production of pro-inflammatory TMAO. The F.l-HP combination therapy significantly suppressed the growth of E. fergusonii while promoting the proliferation of beneficial probiotics. This intervention restored metabolic balance by reducing 5-HTP consumption and TMAO production and increasing butyrate levels. Consequently, F.l-HP treatment alleviated neuroinflammation and oxidative

The mortality of hepatocellular carcinoma (HCC) is high. Plant-derived bioactive compounds have emerged as potential therapies for HCC. Procyanidin (PAC) has been shown to possess immune-modulating and anti-tumor properties. However, the role and mechanism of total PAC in treating HCC remain unclear. We established subcutaneous and orthotopic HCC mouse models to assess the effect of PAC on tumor growth. Multi-omics analyses and in vitro experiments were conducted to investigate the changes in the gut microbiota, related-metabolites, and the tumor microenvironment (TME). 16S rDNA sequencing revealed that PAC could reshape the gut microbiota, notably increasing Lactobacillus murinus abundance. Furthermore, transplantation of Lactobacillus murinus reduced tumor volumes in mice. Single-cell RNA sequencing showed upregulation of the MAPK pathway in B cells within the TME. Metabolomic analysis suggests that 5-Hydroxytryptophan (5-HTP) derived from Lactobacillus murinus was significantly increased in B cells from mesenteric lymph nodes (MLNs) in the PAC-treated group. In vitro experiments revealed that 5-HTP could significantly upregulate the MAPK pathway in B cells. Additionally, 5-HTP-educated B cells could activate IFN-γ+CD8+T cells through B cell-T cell interactions, indicating that 5-HTP is a key metabolite in the therapeutic effect of PAC. Finally, feeding 5-HTP to HCC mice reduced tumor volume, upregulated the MAPK pathway in B cells from MLNs, and activated IFN-γ+CD8+T cells in the TME. PAC reshapes the gut microbiota and metabolites, upregulates the MAPK pathway in B cells from MLNs, and activates CD8+T cells in the TME through the gut-liver axis, thereby inhibiting HCC progression. © The author(s).

Phototaxis, the movement toward or away from light, is a fundamental behavior with ecological and evolutionary relevance. In Drosophila melanogaster, phototactic choice shows individual variability and has been linked to serotonergic signaling. Using a high-throughput FlyVac assay to test single flies in parallel, we reared w1118 flies on (1) standard food (Control), (2) aMW (a serotonin-synthesis inhibitor), (3) 5-HTP (a serotonin precursor), or (4) escitalopram (a selective serotonin reuptake inhibitor, SSRI). Light-choice probability (LCP) did not differ between Control and aMW. LCP was lower in 5-HTP and escitalopram than in Control and aMW, and lower with escitalopram than with 5-HTP. Between-fly variability (MADn) differed across treatments: escitalopram exhibited higher dispersion than Control and aMW, whereas 5-HTP did not differ reliably from Control. These findings support the hypothesis that serotonin modulates behavioral predictability and mean choice bias; variability effects were compound-specific (escitalopram modestly increased MADn, whereas 5-HTP did not differ from Control). Given the rising costs and ethical constraints of vertebrate models, our results highlight Drosophila and FlyVac as a powerful, cost-effective system for investigating SSRI effects on decision phenotypes.

STUDY OBJECTIVES: Circadian disruption is a common phenomenon that can cause various physiological and psychological problems, including cognitive impairment. The tryptophan-5-HT pathway, a crucial neurotransmitter system, plays a vital role in regulating circadian rhythms and cognitive functions. However, whether it mediates the cognitive impairment induced by circadian disruption remains unclear. METHODS: In this study, C57BL/6 mice were exposed to irregular light-dark (LD) cycles for 15 weeks in a rhythmic box. Cognitive behavioral and histopathological assessments were conducted to evaluate the impact on cognitive function, while metabolomics was used to explore the underlying mechanisms. RESULTS: The results revealed that circadian disruption impaired spatial exploration, novel object recognition (NOR), and spatial memory in mice and caused pathological damage to the dentate gyrus region of the hippocampus. Metabolomic analysis revealed 787 differentially abundant metabolites in serum and 349 in hippocampal tissue, highlighting the dysregulation of tryptophan metabolism. Targeted tryptophan metabolomics revealed a decrease in the activity of the tryptophan metabolism 5-hydroxytryptamine (5-HT) pathway. Further tests confirmed that circadian rhythm disorder reduced the expression levels of tryptophan hydroxylase 1 (TPH1) and tryptophan hydroxylase 2 (TPH2), key rate-limiting enzymes of the 5-HT pathway, in the mouse hippocampus. Furthermore, supplementation with a 5-HT precursor (5-HTP) improved the NOR ability of the alternating LD cycle (LD-DL) group. CONCLUSIONS: Circadian disruption downregulated key rate-limiting enzymes in the tryptophan metabolism 5-HT pathway, decreasing 5-HT levels and leading to cognitive impairment. These findings offer new insights into the understanding of cognitive impairment caused by circadian disruption and its metabolic mechanisms in mice. Statement of Significance This study is significant because it simulates the circadian disruption induced by chronic irregular light exposure. A comprehensive evaluation of the impact of circadian disruption on cognitive function was conducted, and metabolomics technology was used to eluc

Circadian rhythm disorder (CRD) is a risk factor for cognitive deficits, yet its mechanisms remain unclear. We previously found CRD model mice developed cognitive impairment mediated through gut microbiota disturbance, intestinal barrier damage, and microglia activation, but the signaling pathway was undefined. Here, we show CRD induces cognitive deficits and gut microbiota disturbance in mice. Fecal microbiota transplantation (FMT) from CRD mice to normal mice reproduced intestinal barrier damage, microglia activation, neuronal damage, and cognitive deficits. Notably, gut metabolite analysis revealed significant alterations, with tryptophan metabolism being particularly affected: tryptophan decreased by 26.9 % and 5-hydroxytryptophan (5-HTP) by 30.7 % (both P < 0.05). Dietary tryptophan supplementation restored serum tryptophan and 5-HTP levels, ameliorating the neuronal damage and cognitive deficits caused by CRD gut microbiota. Collectively, these findings indicate that disturbances in gut microbiota and metabolites play a key role in CRD-induced neurological damage in mice, suggesting targeting the gut microbiota or tryptophan metabolism may prevent CRD-induced cognitive dysfunction.

This study aimed to investigate the impact of dietary supplementation with RPT 5-HTP and MT on the meat quality and shelf life of Hu sheep. Thirty 4-month-old male Hu sheep with similar body weights (30.84 ± 1.16 kg) were randomly allocated into three groups (one sheep per replicate): a control group (fed a basal diet), a RPT 5-HTP group (basal diet + 222 mg/kg BW RPT 5-HTP), and an MT group (basal diet + 4 mg/d MT). The experimental period lasted 37 days, including a 7-day adaptation phase and a 30-day formal trial. The results show that supplementation with RPT 5-HTP and MT significantly increased MT levels in the longissimus dorsi muscle of Hu sheep (p < 0.05). Compared to the control group, the malondialdehyde (MDA) content in the longissimus dorsi muscle was significantly reduced in the MT and RPT 5-HTP groups (p < 0.05), while catalase (CAT) activity was significantly increased in the MT group (p < 0.05). The drip loss of the longissimus dorsi muscle in Hu sheep was significantly reduced after supplementation with RPT 5-HTP and MT (p < 0.05). Essential amino acids, non-essential amino acids, sweet-tasting amino acids, and umami amino acids in the longissimus dorsi muscle of supplemented groups were significantly elevated (p < 0.05). Both 5-HTP and MT extended the shelf life of mutton; compared to the control, the shelf life was prolonged by 22.08 h in the RPT 5-HTP group and by 45.36 h in the MT group. In conclusion, it was found that 5-HTP and MT had a certain effect on improving the antioxidant capacity of Hu sheep, thereby enhancing the meat quality of mutton and extending its shelf life, with the amino acid content in mutton being increased to improve its umami and flavor.

BACKGROUND: 2'-Fucosyllactose (2'-FL) is one of the major oligosaccharides found in human breast milk, with several recognized beneficial effects on the host. Extensive research has indicated positive effects of 2'-FL on cognitive development in the brain, yet its molecular mechanisms have remained elusive. This study aimed to assess the impact of 2'-FL on the gut-brain axis microbiota and cognitive function in growing mice, along with its potential mechanisms of action. RESULTS: Following long-term supplementation for 4 weeks, 2'-FL was found to enhance cognitive memory function in growing mice (3 weeks old) as assessed through Y-maze, novel object recognition, and water maze tests. Analysis via 16S rRNA sequencing revealed significant alterations in gut microbiota diversity and composition induced by 2'-FL, notably increasing the relative abundance of Bacteroides and Lactobacillus genera. Additionally, 2'-FL significantly elevated levels of 5-hydroxytryptamine (5-HT) and 5-hydroxytryptophan (5-HTP) in the hippocampal tissue. However, antibiotic intervention abolished the cognitive advantage conferred by 2'-FL, highlighting the critical role of gut microbiota in mediating its effects. Similarly, short-term supplementation with 2'-FL for 7 days indicated rapid changes in gut microbiota composition preceding cognitive improvements, further suggesting a potential causal relationship between gut microbiota characteristics and cognition. Further, in vitro experiments with mouse feces suggested that 2'-FL may influence tryptophan hydroxylase levels in the gut microbiota and inhibit the activity of 5-hydroxytryptophan decarboxylase, potentially leading to increased accumulation of 5-HTP. Additionally, 2'-FL may indirectly impact tryptophan hydroxylase levels in enterochromaffin cells by promoting short-chain fatty acid production, which could support 5-HTP synthesis. Elevated 5-HTP produced by the gut system enters the bloodstream, crosses the blood-brain barrier, and may potentially enhance brain 5-HT levels. CONCLUSION: This study offers preliminary evidence that the cognitive-promoting effects of 2'-FL in mice may be closely associated with gut microbiota and 5-HT.

This study investigated the effects of dietary 5-hydroxytryptophan (5-HTP) supplementation on growth performance, apparent total tract digestibility (ATTD), blood profile, intestinal morphology, transcriptomics, and microbial composition in weaned piglets. A total of twenty-four 28-day-old weaned piglets (Landrace × Large Yorkshire, 8.28 ± 1.09 kg) were randomly divided into 3 dietary treatments with 8 replicates. The dietary treatments include basal diet (CON), CON diet containing 250 or 500 mg/kg 5-HTP. The results revealed that supplementation with 250 mg/kg 5-HTP significantly increased (P < 0.05) the average daily gain (ADG) and resulted in a lower (P < 0.05) feed conversion ratio (FCR), while also decreased (P < 0.05) the diarrhea rate compared to the CON group. The ATTD of crude protein (CP) was lower in the 500 mg/kg group (P < 0.05) compared with the 250 mg/kg group. Furthermore, supplementation with 5-HTP led to significantly increased (P < 0.05) plasma albumin (ALB) and total protein (TP). In addition, supplementation with 5-HTP, particularly in the 250 mg/kg group, significantly increased (P < 0.05) serum serotonin (5-HT), growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels, and improved the ratio of villus height to crypt depth in the jejunum and ileum. The transcriptomic analysis revealed that the majority of differentially expressed genes (DEGs) induced by 5-HTP were related to digestion and immunity in the ileum, and 5-HTP enhanced (P < 0.05) intestinal glucose transporter 2 (GLUT2), solute carrier family 1 member 1 (SLC1A1) and solute carrier family 7 member 7 (SLC7A7) mRNA expression in weaned piglets. Furthermore, supplementation with 250 mg/kg 5-HTP increased (P < 0.05) abundance of Firmicutes, Actinobacteriota, Lachnospiracea, Ruminococcaceae and Megasphaera and decreased (P < 0.05) abundance of Spirochaetes and Treponema. Collectively, the study demonstrated that 5-HTP supplementation, particularly at 250 mg/kg, positively impacted growth performance, gut health, and microbiome composition in weaned piglets. These findings suggest the potential of using 5-HTP as a dietary supplement to enhance the health and productivity of