Plasma Tryptophan Concentrations Research Articles

Plasma indoleamine 2,3-dioxygenase, a highly sensitive blood-based screening tool for active tuberculosis disease in HIV-infected pregnant women

Background: The World Health Organization has identified the need for a non-sputum-based test capable of detecting active tuberculosis (TB) as a key TB control intervention. Indoleamine 2,3-dioxygenase (IDO) is an enzyme, which converts tryptophan to kynurenines. Recently, IDO activity has been proposed as a blood-based TB biomarker. We investigated whether plasma IDO activity, as measured by kynurenine-to-tryptophan ratio, could be used to screen HIV-infected pregnant women for active TB disease. Methods and materials: Using a commercial enzyme-linked immunosorbent assay (ELISA), we measured plasma tryptophan and kynurenine concentration to determine IDO activity in 78 HIV-infected pregnant women with active TB disease. We compared HIV-infected active TB cases to 120 control subjects from the same cohort with no TB, matched by age, and gestational age. Results: Plasma IDO activity was significantly elevated during pregnancy than in non-pregnant state, and increased transiently during labour (P < 0.0001). There was, however, a marked elevation of IDO activity in TB patients at the time of TB diagnosis (enrolment time-point) compared to pregnant women with no-TB (P < 0.0001). Using a previously determined cut-off of 0.080 in non-pregnant subjects, IDO activity showed a sensitivity of 97% (CI 91–99), specificity of 81% (CI 77–84), PPV 66% and NPV of 99% at the time of TB diagnosis. A receiver operating characteristic curve (ROC) gave area under curve of 0.96 (CI 95–98, P value < 0.0001). The optimal cut-off in pregnant women, however, was calculated as 0.10 with sensitivity of 96% (CI 89–99), specificity of 90% (CI 87–92), PPV 73% and NPV 99%. Conclusion: Plasma IDO activity is a sensitive blood-based screening test for TB in pregnant women living HIV. IDO activity can be measured using ELISA. IDO activity should be used to screen pregnant women at risk active TB disease.

Gut microbiota profile and selected plasma metabolites in type 1 diabetes without and with stratification by albuminuria.

Abnormal gut microbiota and blood metabolome profiles have been reported both in children and adults with uncomplicated type 1 diabetes as well as in adults with type 1 diabetes and advanced stages of diabetic nephropathy. In this study we aimed to investigate the gut microbiota and a panel of targeted plasma metabolites in individuals with type 1 diabetes of long duration without and with different levels of albuminuria. In a cross-sectional study we included 161 individuals with type 1 diabetes and 50 healthy control individuals. Individuals with type 1 diabetes were categorised into three groups according to historically measured albuminuria: (1) normoalbuminuria (<3.39mg/mmol); (2) microalbuminuria (3.39-33.79mg/mmol); and (3) macroalbuminuria (≥33.90mg/mmol). From faecal samples, the gut microbiota composition at genus level was characterised by 16S rRNA gene amplicon sequencing and in plasma a targeted profile of 31 metabolites was analysed with ultra HPLC coupled to MS/MS. Study participants were aged 60 ± 11years (mean ± SD) and 42% were women. The individuals with type 1 diabetes had had diabetes for a mean of 42 ± 15years and had an eGFR of 75 ± 25mlmin-1 (1.73m)-2. Measures of the gut microbial beta diversity differed significantly between healthy controls and individuals with type 1 diabetes, either with micro- or macroalbuminuria. Taxonomic analyses showed that 79 of 324 genera differed in relative abundance between individuals with type 1 diabetes and healthy controls and ten genera differed significantly among the three albuminuria groups with type 1 diabetes. For the measured plasma metabolites, 11 of 31 metabolites differed significantly between individuals with type 1 diabetes and healthy controls. When individuals with type 1 diabetes were stratified by the level of albuminuria, individuals with macroalbuminuria had higher plasma concentrations of indoxyl sulphate and L-citrulline than those with normo- or microalbuminuria and higher plasma levels of homocitrulline and L-kynurenine compared with individuals with normoalbuminuria. Whereas plasma concentrations of tryptophan were lower in individuals with macroalbuminuria compared with those with normoalbuminuria. We demonstrate that individuals with type 1 diabetes of long duration are characterised by aberrant profiles of gut microbiota and plasma metabolites. Moreover, individuals with type 1 diabetes with initial stages of diabetic nephropathy show different gut microbiota and plasma metabolite profiles depending on the level of albuminuria. Graphical abstract.

What tomorrow will bring: Expectations for the next day predicting the cortisol awakening response in young adults

Perinatal depression (PND) affects 15% of mothers. Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line of treatment for PND but are not always efficacious. Previously, we found significant reductions in plasma tryptophan concentrations and higher hippocampal proinflammatory cytokine, IL-1β levels, due to maternal SSRI treatment. Both inflammation and tryptophan-kynurenine metabolic pathway (TKP) are associated with SSRI efficacy in individuals with major depressive disorder (MDD). TKP is divided into neuroprotective and neurotoxic pathways. Higher metabolite concentrations of the neurotoxic pathway are associated with depression onset and implicated in SSRI efficacy. Metabolites in TKP were investigated in a rodent model of de novo postpartum depression (PPD) given treatment with the SSRI, fluoxetine (FLX). Dams were administered corticosterone (CORT) (40 mg/kg, s.c.), and treated with the SSRI, fluoxetine (FLX) (10 mg/kg, s.c.), during the postpartum for 22 days after parturition. Plasma TKP metabolite concentrations were quantified on the last day of treatment. Maternal postpartum CORT increased neurotoxic metabolites and co-enzyme/cofactors in dams (3-hydroxykynurenine, 3-hydroxyanthranilic acid, vitamin B2, flavin adenine dinucleotide). The combination of both CORT and FLX shifted the neuroprotective-to-neurotoxic ratio towards neurotoxicity. Postpartum FLX decreased plasma xanthurenic acid concentrations. Together, our data indicate higher neurotoxic TKP expression due to maternal postpartum CORT treatment, similar to clinical presentation of MDD. Moreover, maternal FLX treatment showed limited efficacy to influence TKP metabolites, which may correspond to its limited efficacy to treat depressive-like endophenotypes in the postpartum. Overall suggesting changes in TKP may be used as a biomarker of de novo PPD and antidepressant efficacy and targeting this pathway may serve as a potential therapeutic target.

Postpartum fluoxetine increased maternal inflammatory signalling and decreased tryptophan metabolism: Clues for efficacy

Perinatal depression (PND) affects approximately 15% of women, and de novo postpartum depression affects approximately 40% of PND cases. Selective serotonin reuptake inhibitors (SSRIs) are a common class of antidepressants prescribed to treat PND. However, the safety and efficacy of SSRIs have been questioned in both clinical and preclinical research. Here, using a preclinical rodent model of de novo postpartum depression, we aim to better understand neuroinflammatory cytokines and tryptophan mechanisms that may be related to SSRI efficacy. Rat dams were treated with high corticosterone (CORT; 40 mg/kg, s.c.) for 22 days in the postpartum period to simulate a depressive-like endophenotype. Concurrently, a subset of dams was treated with the SSRI, fluoxetine (FLX; 10 mg/kg, s.c.), in the postpartum period. We showed, consistent with previous studies, that although maternal FLX treatment prevented CORT-induced disturbances in maternal care behavior during the early postpartum, it failed to prevent the expression of CORT-induced passive coping behavior in the late postpartum. Furthermore, FLX treatment, regardless of CORT treatment, increased maternal hippocampal IL-1β, plasma CXCL1, and decreased maternal plasma tryptophan, 4′-pyridoxic acid, and pyridoxal concentrations. Maternal CORT treatment reduced maternal hippocampal IFN-γ, and both hippocampal and plasma TNF-α. Our work suggests that the limited efficacy of FLX in the late postpartum may be associated with elevated levels of the proinflammatory cytokine IL-1β in the maternal hippocampus, elevated plasma CXCL1, decreased plasma tryptophan concentration, and changes in vitamin B6 dependent tryptophan-kynurenine pathway. These findings suggest novel pathways for improving SSRI efficacy in alleviating perinatal depression.

Lactalbumin, Not Collagen, Augments Muscle Protein Synthesis with Aerobic Exercise.

Protein ingestion and the ensuing hyperaminoacidemia stimulates skeletal muscle protein synthesis in the postexercise period. This response facilitates muscle remodeling, which is important during intensified training. The aim of this study was to determine whether supplementation with α-lactalbumin (LA), with high leucine and tryptophan contents, would improve responses to short periods of intensified aerobic training compared with supplementation with an isonitrogenous quantity of collagen peptides (CP). Endurance-trained participants (5 male, 6 female, 24 ± 4 yr, V˙O2 = 53.2 ± 9.1 mL·kg·min, peak power output = 320 ± 48 W; means ± SD) consumed a controlled diet (1.0 g·kg·d protein) and refrained from habitual training for 11 d while taking part in this double-blind randomized, crossover trial. The two intervention phases, which consisted of brief intensified training (4 × 4-min cycling intervals at 70% of peak power output on 3 consecutive days) combined with the ingestion of LA or CP supplements after exercise (20 g) and before sleep (40 g), were separated by 4 d of washout without protein supplementation (i.e., the control phase). In response to each phase, myofibrillar (MyoPS), sarcoplasmic protein synthesis (SarcPS) rates (via H2O ingestion) and parameters of sleep quality were measured. LA ingestion increased plasma leucine (P < 0.001) and tryptophan concentrations (P < 0.001) relative to CP. Intensified training increased MyoPS and SarcPS above the washout phase in LA- and CP-supplemented phases (P < 0.01), with increases being 13% ± 5% and 5% ± 7% greater with LA than CP for MyoPS (P < 0.01) and SarcPS, respectively (P < 0.01). Despite an isonitrogenous diet, protein synthesis was enhanced to a greater extent when trained participants consumed LA compared with CP during intensified aerobic training, suggesting that protein quality is an important consideration for endurance-trained athletes aiming to augment adaption to exercise training.

Impact of Daily Preventive Zinc or Therapeutic Zinc Supplementation for Diarrhea on Plasma Biomarkers of Environmental Enteric Dysfunction among Rural Laotian Children: A Randomized Controlled Trial.

.Environmental enteric dysfunction (EED) may be ameliorated by zinc supplementation. The objective of this study was to investigate the impact of different forms of zinc supplementation on biomarkers of EED (i.e., plasma citrulline, kynurenine, and tryptophan concentrations and the kynurenine:tryptophan [KT] ratio) among young Laotian children. In a double-blind randomized controlled trial, 3,407 children aged 6–23 months were randomized into one of four groups: daily preventive zinc dispersible tablets (PZ; 7 mg zinc), daily multiple micronutrient powders (MNP; 10 mg zinc, 6 mg iron, and 13 other micronutrients), therapeutic zinc supplements for diarrhea treatment (TZ; 20 mg/day for 10 days), or daily placebo powder, and followed up for ∼36 weeks. Plasma samples at baseline and endline for 359 children were analyzed for citrulline, kynurenine, and tryptophan concentrations. At baseline, the prevalence of stunting and zinc deficiency was 37% and 76.5%, respectively. The mean plasma citrulline, kynurenine, and tryptophan concentrations were 24.6 ± 5.4 µmol/L, 3.27 ± 0.83 µmol/L, and 72.3 ± 12.9 µmol/L, respectively; the mean KT ratio (×1,000) was 45.9 ± 12.0. At endline, neither plasma citrulline, kynurenine, or tryptophan concentrations, nor the KT ratio differed among intervention groups (P > 0.05). In this population, PZ, MNP, and TZ had no overall effect on plasma concentrations of citrulline, kynurenine, and tryptophan, or the KT ratio. The need remains to better understand the etiology of EED, and the development of biomarkers to diagnose EED and evaluate the impact of interventions.

PSIX-24 Effects of rice feeding on growth performance and protein (amino acids) metabolism in weaning piglets

Abstract This experiment was conducted to clarify the effects of feeding rice on growth performance and protein (amino acids) metabolism in weaning piglets. Sixteen weaning piglets with an average initial weight of 7.5 kg were divided into two groups. One group was fed a corn-soybean meal based diet, and the other was fed a rice-soybean meal diet. Each diet contained about 46% of corn or rice. A 2-week growth trial was conducted and growth performance, dry matter and crude protein digestibility, liver lysine-ketoglutarate reductase activity, plasma urea nitrogen, glucose, insulin, and free amino acids concentrations were measured. The average daily gain (g/d) and feed efficiency (gain/feed) in rice-fed piglets were significantly higher than those in corn-fed piglets. Average feed intake, however, was not significantly different between corn- and rice-fed piglets. Dry matter and and crude protein digestibility were not significantly different between two groups. Liver lysine-ketoglutarate reductase activity tended to be lower (P = 0.073) in rice-fed piglets than that in corn-fed piglets. Plasma urea nitrogen concentration in rice-fed piglets was significantly lower than that in corn-fed piglets. Plasma glucose and insulin concentrations were significantly higher in rice-fed piglets than those in corn-fed piglets. Plasma free valine, isoleucine, tryptophan, and glysine concentrations were significantly higher in rice-fed piglets than those in corn-fed piglets. On the other hand, plasma histidine concentration in rice-fed piglets was significantly lower than that in corn-fed piglets. In conclusion, these results clearly show that rice feeding affects the protein and amino acids metabolism and improves the growth performance in weaning piglets. Rice could be considered to be a good feedstuff for weaning piglets.

Tryptophan Intake and Tryptophan Losses in Hemodialysis Patients: A Balance Study.

Tryptophan depletion is common in hemodialysis patients. The cause of this depletion remains largely unknown, but reduced nutritional tryptophan intake, losses during dialysis or an increased catabolism due to an inflammatory state are likely contributors. Currently, little is known about tryptophan homeostasis in hemodialysis patients. We assessed dietary tryptophan intake, measured plasma tryptophan during dialysis, and measured the combined urinary and dialysate excretion of tryptophan in 40 hemodialysis patients (66 ± 15 years and 68% male). Patients had low tryptophan concentrations (27 ± 9 µmol/L) before dialysis. Mean dietary tryptophan intake was 4454 ± 1149 µmol/24 h. Mean urinary tryptophan excretion was 15.0 ± 12.3 μmol/24 h, dialysate excretion was 209 ± 67 μmol/24 h and combined excretion was 219 ± 66 µmol/24 h, indicating only 5% of dietary tryptophan intake was excreted. No associations were found between plasma tryptophan concentration and tryptophan intake, plasma kynurenine/tryptophan ratio or inflammatory markers. During dialysis, mean plasma tryptophan concentration increased 16% to 31 ± 8 µmol/L. Intradialytic increase in plasma tryptophan was associated with a lower risk of mortality, independent of age, sex and dialysis vintage (HR: 0.87 [0.76–0.99]; P = 0.04). Tryptophan intake was well above the dietary recommendations and, although tryptophan was removed during dialysis, mean plasma tryptophan increased during dialysis. The cause of this phenomenon is unknown, but it appears to be protective.

Effects of dietary lysine on productivity, reproductive performance, protein and lipid metabolism-related gene expression in laying duck breeders

This study investigated whether dietary lysine (Lys) affects productive performance and expression of genes related to protein and lipid metabolism in laying duck breeders. Longyan duck breeders (n = 540, 19 wk of age) were randomly assigned to 6 groups with 6 replicates of 15 birds each. Breeders were fed diets with 6 total Lys levels (6.4, 7.2, 8.0, 8.8, 9.6, and 10.4g/kg) for 26 wk duration. Egg production, egg weight, egg mass, feed conversion ratio, hatchability, hatchling weight, albumen weight, eggshell weight, yolk weight, and yolk proportion increased with dietary Lys levels (P < 0.05). Dietary Lys level had a linear (P < 0.05) and quadratic (P < 0.05) effects on maternal hepatic expression of mechanistic target of rapamycin, eukaryotic translation initiation factor 4E binding protein 1, ubiquitin conjugating enzyme E2K (UBE2K), cathepsin B (CTSB), and quadratically (P < 0.05) increased the concentrations of plasma Lys, leucine, threonine, and tryptophan in duck breeders. In contrast, maternal dietary Lys suppressed expression of proteasome 26S subunit, UBE2K, and CTSB in the liver of hatchlings. Moreover, relative expression of peroxisome proliferator-activated receptors alpha, carnitine palmitoyltransferase 1A, and very low density apolipoprotein-II increased linearly (P < 0.05) and quadratically (P < 0.05), and that of VLDL receptor (VLDLR) decreased quadratically (P < 0.05) in the liver of duck breeders with increasing dietary Lys levels; hepatic triglyceride and cholesterol contents were reduced. Maternal dietary Lys suppressed hepatic expression of VLDLR in the hatchlings. A diet containing 8.6g Lys/kg promoted protein turnover and lipid metabolism in laying duck breeders, which positively reflected in the productivity and reproductive performance.

Use of selective serotonin reuptake inhibitors is associated with very low plasma-free serotonin concentrations in humans.

Background Selective serotonin reuptake inhibitors (SSRIs) block the serotonin transporter on neurons, but also on platelets, thus decreasing platelet serotonin concentrations in users of SSRIs. Data on plasma-free serotonin concentrations in SSRI users are lacking, while plasma-free serotonin is available for receptor binding and plays a role in several pathophysiological processes. We therefore measured the plasma-free and platelet serotonin concentrations in users of SSRIs and age-matched healthy controls, and we analysed plasma concentrations of the serotonin precursor tryptophan and serotonin metabolite 5-hydroxyindoleamineacetic acid (5-HIAA). Methods For this cross-sectional single-centre case control study, participants were recruited at the departments of Psychiatry and General Medicine. High-performance liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) was used to measure plasma-free and platelet serotonin, plasma tryptophan and 5-HIAA concentrations. Preanalytical conditions were optimized by careful blood collection, rapid sample handling, high-speed centrifugation, drug and diet restrictions and age-matched controls. Results In 64 SSRI users, median concentrations of plasma-free and platelet serotonin were 10-fold and 14-fold lower, respectively, than in 64 matched controls. Patients using higher dose SSRIs or those with higher affinity for the serotonin transporter had lower plasma-free and platelet serotonin concentrations. Compared with controls, SSRI users had similar median plasma tryptophan concentrations but slightly higher plasma 5-HIAA concentrations. Conclusion SSRI users have low platelet serotonin and low plasma-free serotonin. This could not be explained by lower concentrations of its precursor tryptophan, and only partially by increased breakdown to 5-HIAA.

Impact of Preventive and Therapeutic Zinc Supplements on Citrulline Concentration and the kynurenine: tryptophan Ratio Among Lao Children: A Randomized Controlled Trial (OR07-02-19)

ObjectivesTo investigate the impact of different forms of zinc supplementation on plasma citrulline (CIT), kynurenine (KYN) and tryptophan (TRP) concentrations and the kynurenine: tryptophan ratio (KTR), considered as markers of intestinal function and systemic inflammatory response, among young Lao children. MethodsIn a randomized controlled double-blind trial, 3407 children aged 6–23 mo were randomized into one of four groups and followed for ∼36 weeks: daily preventive zinc dispersible tablet (7 mg zinc; PZ), daily multiple micronutrient powder (10 mg zinc, 6 mg iron and 13 other micronutrients; MNP), therapeutic zinc supplements for the treatment of diarrhea (20 mg/d for 10 days with each diarrhea episode; TZ), or daily placebo powder (Control). Plasma samples at baseline and endline for 359 children participating in the parent trial were analyzed at the NIH West Coast Metabolomics Center (UC Davis); plasma CIT, KYN and TRP concentrations were determined by hydrophilic interaction chromatography (HILIC) quadrupole time of flight mass spectrometer (QTOF) tandem mass spectrometry (MS/MS). Linear regression models were used to assess the treatment effect, controlling for baseline value, child age and district. ResultsThe parent trial found no overall group-wise effects on linear growth or diarrhea outcomes. In the subgroup included in the present analyses, mean age at enrollment was 16.0 ± 4.9 mo, 37% were stunted and 83% were zinc deficient. At baseline, mean plasma CIT, KYN and TRP concentrations were 24.6 ± 5.4 μM, 3.27 ± 0.83 μM and 72.3 ± 12.9 μM, respectively; the mean KT ratio was 0.046 ± 0.013. 5% of children had low CIT (< 17 μM) and no children had low TRP (< 35 μM). At endline, there were no differences among intervention groups in mean plasma CIT (25.0–26.6 μM, P = 0.287), KYN (2.96–3.11 μM, P = 0.115), TRP (66.1–70.0 μM, P = 0.151) or the KTR (0.046–0.047, P = 0.981). ConclusionsIn this population, PZ, MNP and TZ had no overall effect on plasma concentrations of CIT, KYN, TRP and the KTR. We plan to further explore if these markers of intestinal function were predictive of subsequent linear growth, or modified the growth response to supplementation. Funding SourcesThe Bill & Melinda Gates Foundation, Nutrition International and the Mathile Institute for the Advancement of Human Nutrition.

Tryptophan metabolism and its relationship with central nervous system toxicity in people living with HIV switching from efavirenz to dolutegravir

The mechanisms underlying central nervous system (CNS) toxicities in antiretroviral-treated persons living with HIV (PLWH) remain elusive. We investigated the associations between markers of tryptophan metabolism and measurements of CNS toxicity in PLWH. In a prospective study, virologically suppressed PLWH receiving efavirenz-containing antiretroviral regimens with ongoing CNS toxicity were switched to dolutegravir-containing regimens and followed up for 12 weeks. Plasma tryptophan and kynurenine concentrations and the kynurenine/tryptophan ratio were calculated. Ten CNS toxicities were graded according to the ACTG adverse events scale. Scores ranged from 0 (none) to 3 (severe) and were summed, giving a total from 0 to 30. Paired-samples t tests and linear mixed model analyses were conducted to assess changes in, and relationships between, laboratory and clinical parameters. Mean kynurenine plasma concentration increased from baseline to week 12 (2.15 to 2.50 μmol/L, p = 0.041). No significant changes were observed for tryptophan (54.74 to 56.42 μmol/L, p = 1.000) or kynurenine/tryptophan ratio (40.37 to 41.08 μmol/L, p = 0.276). Mean CNS toxicity score decreased from 10.00 to 4.63 (p < 0.001). Plasma kynurenine concentration correlated with CNS toxicity score: for every 1 μmol/L increase in kynurenine concentration observed, a 1.7 point decrease was observed in CNS toxicity score (p < 0.038). A similar trend was observed for the kynurenine/tryptophan ratio: for every 1 μmol/mmol increase observed in kynurenine/tryptophan ratio, a 0.1 point decrease was observed in CNS toxicity score (p = 0.054). Switching from efavirenz to dolutegravir was associated with increases in plasma kynurenine concentration and improvements in CNS toxicity scores. Underlying mechanisms explaining the rise in kynurenine concentrations need to be established.

Invited commentary

The human gastrointestinal tract is colonized with around 1014 microorganisms that are collectively termed the microbiota. Disruptions in the microbiota have been shown to correlate not only with gut disease but also with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. Short-chain fatty acid byproducts such as butyrate, propionate, and acetate act as a major energy source for intestinal epithelial cells and therefore strengthen the mucosal barrier. There is much interest in the ability to modify the gut microbiota. It has been shown that an acute change in diet, for instance, to one that is strictly animal based or plant based, can alter the microbial composition within just 24 hours of initiation. Animal studies have also shown that diets high in fat or high in sugar can cause circadian rhythm disruption. The authors of this manuscript perform a pilot study showing that baseline plasma concentrations of multiple gut microbiome-modulated indole- and phenyl-derived metabolites are associated with advanced atherosclerosis and predict risk of postoperative cardiovascular events and mortality. They specifically note that patients with advanced atherosclerosis have significantly lower baseline plasma concentrations of tryptophan and of indole and indole derivatives indole-3-aldehyde and indole-3-propionic acid and higher plasma concentrations of kynurenine/tryptophan ratio compared with age-matched controls. Tryptophan deletion has been associated with activation of inflammatory pathways. Given the fact that cardiovascular disease is a chronic inflammatory disease, it is not surprising that tryptophan metabolism has been correlated with cardiovascular disease. They further showed a significant relationship between these metabolites and ankle-brachial indexes in the entire cohort. This is the first reported association of these metabolites with peripheral arterial disease or with major postoperative adverse cardiac events. Although this is a pilot study, these are promising biomarkers to help stratify our patients and to educate are patients with more details for outcomes and progression of disease. The “cure” for atherosclerotic disease is the holy grail of cardiovascular research. Atherosclerotic disease is a complex disease, and characterization of the underlying mechanisms is therefore difficult. However, there is increasing evidence that “you may be what you eat” in that the microbiota may have a more prominent role in cardiovascular disease. How the microbiota influences atherosclerosis is still in question, but it could be through promoting plaque development by activation of the immune system, alterations in cholesterol metabolism, or production of bacterial metabolites that could be biomarkers for severity of disease. Whether cardiovascular disease can be successfully treated by targeting the microbiota is still unclear. Having patients adhere to strict diets can be troublesome; however, better education of our patients for improvement in their dietary choices may have an impact on progression of their disease. So, in fact, what your parents taught you, “you are what you eat,” may very well be true. The opinions or views expressed in this commentary are those of the authors and do not necessarily reflect the opinions or recommendations of the Journal of Vascular Surgery or the Society for Vascular Surgery Plasma microbiome-modulated indole- and phenyl-derived metabolites associate with advanced atherosclerosis and postoperative outcomesJournal of Vascular SurgeryVol. 68Issue 5PreviewMultiple studies have shown that gut microbes contribute to atherosclerosis, and there is mounting evidence that microbial metabolism of dietary nutrients influences pathophysiology. We hypothesized that indole- and phenyl-derived metabolites that originate solely or in part from bacterial sources would differ between patients with advanced atherosclerosis and age- and sex-matched controls without clinically apparent atherosclerosis. Full-Text PDF Open Archive

Altered tryptophan catabolite concentrations in major depressive disorder and associated changes in hippocampal subfield volumes

BackgroundTryptophan depletion is a well-replicated biological finding in Major Depressive Disorder (MDD). The kynurenine pathway (KP) and its rate-limiting tryptophan degrading enzyme, indolamine 2,3 dioxygenase (IDO), have been implicated in the pathogenesis of depression. IDO expression is driven by inflammatory cytokines, providing a putative link between inflammation and neuropathology. This study examined circulating concentrations of C-reactive protein (CRP), plasma tryptophan, kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN) and whole blood mRNA expression of IDO in patients with major depressive disorder (MDD) compared with healthy controls (HC). MethodsA diagnosis of major depression was made according to DSM-IV. Depression severity was assessed using the Hamilton depression (HAM-D) rating scale. 74 MDD patients, 39 with a first presentation of MDD (fpMDD) and 35 with chronic or recurrent episodes (rMDD), and 37 HC were recruited to the study. Whole blood and plasma samples were collected. Expression of markers in whole blood were measured by PCR, circulating CRP by ELISA and KP metabolites by LC–MS/MS. Hippocampal cornu ammonis (CA) and subiculum volumes were determined by MRI and calculated using FreeSurfer. ResultsTryptophan concentrations were significantly reduced in MDD compared to HC. There was a positive correlation between QUIN and both CRP concentrations and whole blood IDO1 in MDD. KYNA concentrations were reduced in MDD patients presenting with a first episode (fpMDD) compared to those presenting with recurrent depression (rMDD) and HC. By contrast QUIN concentrations were elevated in rMDD compared to fpMDD and HC. KYNA/QUIN was reduced in MDD and rMDD but not fpMDD compared to HC. Hippocampal subfield volumes were smaller in MDD patients than HC for CA1 (left only), CA2/3 (left and right) and CA4 (right only). CRP and CA1 volumes were negatively correlated bilaterally in MDD patients. KYNA and subiculum volume were positively correlated bilaterally. DiscussionThis study found evidence of KP metabolism imbalance in MDD patients in addition to tryptophan reduction and mild immune activation. Relationships between CRP and KYNA with some hippocampal subfield volumes in MDD patients suggest that this inflammatory signature may be associated with reduced hippocampal subfield volumes in depression.

Plasma concentration of tryptophan and pregnancy-induced hypertension

Introduction. Pregnancy-induced hypertension (PIH) is one of the main clinical problems of unexplained etiopathogenesis. New factors involved in the pathogenesis of this disease are still being searched. The available literature lacks data regarding the differences in tryptophan concentrations in physiological and PIH-complicated pregnancy. Previous studies have shown that L-tryptophan treatment reduces blood pressure in hypertensive rats. The direct vascular effects of tryptophan have not been fully explored. In this study, the stimulating effect of tryptophan on the development of PIH was revealed. The aim of the present study was to assess the differences in plasma tryptophan concentrations in physiological pregnancies and pregnancies complicated with hypertension in the third trimester. Material and methods. The study was carried on 105 complicated by PIH and 105 pregnant women with blood pressure within normal limits between 25 and 41 weeks of gestation. Tryptophan concentration was determined by the automated ion-exchange chromatography using an Amino Acid Analyser (AAA 400) by Ingos, Czech Republic. Tryptophan concentration was expressed in μmol/cm 3 plasma. Results. The mean concentration of tryptophan in the third trimester of physiological pregnancy was found to be 0.035 ± 0.009 μmol/cm 3 , whereas in PIH — 0.099 ± 0.007 μmol/cm 3 . Conclusions. The development of PIH in pregnant women is likely to be caused by increased concentrations of tryptophan, which is a substrate for production of serotonin and tryptamine. Further studies are needed to analyse the kinetics of tryptophan metabolism.

Revisiting the tryptophan-serotonin deficiency and the inflammatory hypotheses of major depression in a biopsychosocial approach.

BackgroundThe aim of this cross-sectional study was to identify important biopsychosocial correlates of major depression. Biological mechanisms, including the inflammatory and the tryptophan-serotonin deficiency hypotheses of major depression, were investigated alongside health-related quality of life, life satisfaction, and social support.MethodsThe concentrations of plasma tryptophan, plasma kynurenine, plasma kynurenic acid, serum quinolinic acid, and the tryptophan breakdown to kynurenine were determined alongside health-related quality of life (Medical Outcome Study Form, SF-36), life satisfaction (Life Satisfaction Questionnaire, FLZ), and social support (Social Support Survey, SSS) in 71 depressive patients at the time of their in-patient admittance and 48 healthy controls.ResultsCorresponding with the inflammatory hypothesis of major depression, our study results suggest a tryptophan breakdown to kynurenine in patients with major depression, and depressive patients had a lower concentration of neuroprotective kynurenic acid in comparison to the healthy controls (Mann–Whitney-U: 1315.0; p = 0.046). Contradicting the inflammatory theory, the concentrations of kynurenine (t: −0.945; df = 116; p = 0.347) and quinolinic acid (Mann-Whitney-U: 1376.5; p = 0.076) in depressive patients were not significantly different between depressed and healthy controls. Our findings tend to support the tryptophan-serotonin deficiency hypothesis of major depression, as the deficiency of the serotonin precursor tryptophan in depressive patients (t: −3.931; df = 116; p < 0.001) suggests dysfunction of serotonin neurotransmission. A two-step hierarchical linear regression model showed that low tryptophan concentrations, low social support (SSS), occupational requirements (FLZ), personality traits (FLZ), impaired physical role (SF-36), and impaired vitality (SF-36) predict higher Beck Depression Inventory (BDI-II) scores.DiscussionOur study results argue for the validity of a biopsychosocial model of major depression with multiple pathophysiological mechanisms involved.

Tryptophan metabolism along the kynurenine and serotonin pathways reveals substantial differences in colon and rectal cancer

Induction of tryptophan (TRP) catabolism is an adaptation mechanism to restrict excessive acute immune response in tissues. In the tumour microenvironment, TRP catabolism’s dysregulation plays an important role in local antitumour immune response suppression. We investigated changes in the plasma concentrations of TRP and its metabolites in a cohort of colorectal cancer (CRC) patients at different tumour stages and in subjects at risk of developing CRC. TRP metabolites were assessed along kynurenine and serotonin pathways, and the activity of involved enzymes and their tissue expression were monitored. Plasmatic levels of tryptophan metabolites were quantified in 80 patients’ plasma samples by means of High-Pressure Liquid Chromatography coupled to UltraViolet/Fluorescence Detectors (HPLC-UV/FD), after a simple dilution step. Tissue IDO1 gene expression during to the adenoma-carcinoma sequence and samples were obtained from formalin-fixed and paraffin-embedded (FFPE) normal colon and tumour tissues from a subset of patients (n = 21). Altered TRP concentrations were detected in plasma samples concomitant to pre-cancerous lesion and persisted during the adenoma-carcinoma transition. Moreover, the anatomical site of cancer lesions (colon or rectum) strongly influences the TRP metabolic profiles. Colon cancer patients exhibited increased TRP catabolism with respect to those affected by rectal cancer, suggesting that TRP’s metabolism alterations play an important role in the onset and progression of colon cancer, but not in those of rectal cancer.

Relation of plasma tryptophan concentrations during pregnancy to maternal sleep and mental well-being: The GUSTO cohort

BackgroundEvidence suggests a relation between plasma tryptophan concentrations and sleep and mental well-being. As no studies have been performed in pregnant women, we studied the relation of plasma tryptophan concentrations during pregnancy with sleep quality, and mood during and after pregnancy. MethodsPregnant women (n = 572) from the Growing Up in Singapore Towards healthy Outcomes study completed the Pittsburgh Sleep Quality Index (PSQI), the Edinburgh Postnatal Depression Scale (EPDS) and the State-Trait Anxiety Inventory (STAI) at 26–28 weeks gestation and three months post-delivery. Plasma tryptophan concentrations were measured at 26–28 weeks gestation. Poisson regressions estimated prevalence ratios (PR) for the association between tryptophan and poor sleep quality (PSQI global score > 5), probable antenatal depression (EPDS ≥ 15) and probable anxiety (STAI-state ≥ 41) were calculated adjusting for covariates. ResultsMean plasma tryptophan concentrations was 48.0µmol/L (SD: 8.09). Higher plasma tryptophan concentrations were associated with a lower prevalence of antenatal poor sleep quality adjusting for covariates [PR: 0.88 (95% CI 0.80, 0.97) per 10µmol/L], especially in those participants who also suffered from anxiety symptoms [PR: 0.80 (95% CI 0.67, 0.95)]. No associations were observed between tryptophan concentrations during pregnancy and postnatal sleep quality or mental well-being. LimitationSubjective measures were used to assess sleep and mental well-being. ConclusionsWe observed that higher plasma tryptophan concentrations were associated with a 12% lower prevalence of poor sleep quality during pregnancy, in particular among those with anxiety symptoms. These findings suggest the importance of having adequate tryptophan concentrations during pregnancy.

Tryptophan metabolism in patients with primary immune thrombocytopenia with high dose of dexamethasone

目的研究原发免疫性血小板减少症（ITP）患者大剂量地塞米松治疗前后色氨酸代谢状态。方法2014年1月1日至2015年5月31日期间25例新诊断ITP患者纳入研究，男11例、女14例，中位年龄57（27~87）岁，初诊时中位PLT为16（0~32）×109/L。治疗方案：地塞米松40 mg/d×4 d，口服。治疗前后，采用实时定量PCR检测外周血单个核细胞（PBMC）内吲哚胺-2,3-双加氧酶（IDO）、色氨酰t-RNA合成酶（TTS）基因mRNA表达，ELISA法检测血清IDO、TTS浓度，高效液相色谱分析法（HPLC）检测血清色氨酸、犬尿氨酸浓度。以25名健康志愿者为正常对照组。结果①在中位随访时间11（6~18）个月内，17例患者获得持续缓解（完全反应16例、有效1例），2例无效，6例复发。将患者按疗效分为持续缓解组（17例）和无效/复发组（8例）。②持续缓解组（17例）患者治疗后PBMC中IDO、TTS基因mRNA相对表达量均低于治疗前（2.54±0.86对19.85±5.36，t=3.188，P=0.003；0.68±0.19对45.39±15.83，t=2.842，P=0.008），与正常对照组比较差异无统计学意义（t=2.313，P=0.027；t=1.127，P=0.268）。治疗前血清IDO[（21.91±0.37）U/ml]高于正常对照组（t=4.468，P<0.001），治疗后[（19.34±0.42）U/ml]与正常对照组比较差异无统计学意义（t=2.170，P=0.370）；治疗前血清TTS浓度[（9.14±0.22）µg/L]与正常对照组比较差异无统计学意义（t=1.220，P=0.229），治疗后[（13.37±0.54）µg/L]高于治疗前（t=7.302，P<0.001）。血清色氨酸浓度治疗后低于治疗前[（19.85±5.36）µmol/L对（54.72±6.50）µmol/L，t=19.551，P<0.001]，与正常对照组比较差异无统计学意义（t=1.027，P=0.311）；治疗后犬尿氨酸浓度高于治疗前[（0.56±0.26）µmol/L对（0.22±0.13）µmol/L，t=17.013，P<0.001]，与正常对照组比较差异无统计学意义（t=2.075，P=0.448）。③无效/复发组患者治疗前后IDO、TTS基因mRNA表达水平及血清IDO、TTS色氨酸、犬尿氨酸浓度差异均无统计学意义（P>0.01）。结论ITP患者体内存在色氨酸代谢异常；大剂量地塞米松治疗后获得持续缓解患者体内色氨酸代谢异常得到纠正。

Randomised clinical trial on the effect of a single oral administration of l-tryptophan, at three dose rates, on reaction speed, plasma concentration and haemolysis in horses

Tryptophan (TRP) is marketed as a calmative for horses despite reservations about its efficacy. The aim of this study was to measure the effect of oral TRP administration on the reaction speed of horses. Sixty mature horses were used in a two stage randomised, blind, cross-over study, receiving a placebo and an oral dose of TRP (30, 60 or 120 mg/kg body weight), before undergoing a reaction speed test. Blood samples were taken up to 96 h after TRP administration, to identify signs of acute haemolytic anaemia. Plasma TRP concentrations were increased (P < 0.001) by the administration of TRP paste. However, TRP had no effect on the reaction speed of horses when startled. There was no evidence of alterations in clinical pathology parameters in 432 blood samples. While the safety of these doses of TRP can be confirmed, there was no evidence to suggest that a single dose of TRP is an effective calmative for horses.