Tryptophan Metabolite Concentrations Research Articles

Polysaccharides from Dendrobium devonianum ameliorate Salmonella typhimurium-induced ulcerative colitis by modulating ClostridiumXlVa, purine and tryptophan metabolism

Given the escalating severity of colitis caused by Salmonella infection and the growing challenge of drug resistance, there is an urgent demand for novel and effective treatment strategies with minimal side effects. Herein, we explored the potential therapeutic effects of polysaccharides on Ulcerative Colitis (UC). Our results showed that both purified polysaccharide from Dendrobium devonianum (DVP-1) and Crude polysaccharides from Dendrobium devonianum (CP) pre-treatment could prevent colon shortening and spleen enlargement, and alleviate colonic tissue damage. Western blot and RT-qPCR analyses revealed that DVP-1 and CP downregulated pro-inflammatory mediators while upregulating the expression of the anti-inflammatory mediator and tight junction proteins. Besides, 16S rRNA sequencing analysis showed that DVP-1 modulated gut dysbiosis by increasing the relative abundance of ClostridiumXlVa, and reducing the relative abundance of Alloprevotella. Additionally, DVP-1 and CP significantly increased the concentrations of tryptophan metabolites while decreasing purine metabolites. Taken together, these findings suggest that DVP-1 and CP yield potential benefits in alleviating UC primarily through restoring intestinal barrier function and regulating intestinal microbiota.

Alterations in tryptophan metabolism and de novo NAD+ biosynthesis within the microbiota-gut-brain axis in chronic intestinal inflammation.

Inflammatory bowel disease is an incurable and idiopathic disease characterized by recurrent gastrointestinal tract inflammation. Tryptophan metabolism in mammalian cells and some gut microbes comprise intricate chemical networks facilitated by catalytic enzymes that affect the downstream metabolic pathways of de novo nicotinamide adenine dinucleotide (NAD+) synthesis. It is hypothesized that a correlation exists between tryptophan de novo NAD+ synthesis and chronic intestinal inflammation. Transcriptome analysis was performed using high-throughput sequencing of mRNA extracted from the distal colon and brain tissue of Winnie mice with spontaneous chronic colitis and C57BL/6 littermates. Metabolites were assessed using ultra-fast liquid chromatography to determine differences in concentrations of tryptophan metabolites. To evaluate the relative abundance of gut microbial genera involved in tryptophan and nicotinamide metabolism, we performed 16S rRNA gene amplicon sequencing of fecal samples from C57BL/6 and Winnie mice. Tryptophan and nicotinamide metabolism-associated gene expression was altered in distal colons and brains of Winnie mice with chronic intestinal inflammation. Changes in these metabolic pathways were reflected by increases in colon tryptophan metabolites and decreases in brain tryptophan metabolites in Winnie mice. Furthermore, dysbiosis of gut microbiota involved in tryptophan and nicotinamide metabolism was evident in fecal samples from Winnie mice. Our findings shed light on the physiological alterations in tryptophan metabolism, specifically, its diversion from the serotonergic pathway toward the kynurenine pathway and consequential effects on de novo NAD+ synthesis in chronic intestinal inflammation. The results of this study reveal differential expression of tryptophan and nicotinamide metabolism-associated genes in the distal colon and brain in Winnie mice with chronic intestinal inflammation. These data provide evidence supporting the role of tryptophan metabolism and de novo NAD+ synthesis in IBD pathophysiology.

Effects of Different Protein Sources on Amino Acid Absorption and Plasma Appearance of Tryptophan, Large Neutral Amino Acids, and Tryptophan Metabolites in Pigs

BackgroundAbsorption of tryptophan (TRP) across the gut epithelium is potentially modulated by competing large neutral amino acids (LNAAs), which could affect the appearance of TRP and its metabolites in the bloodstream. ObjectivesThis study aimed to determine, in a growing pig model of an adult human, the absorption of TRP and other LNAAs from the gastrointestinal tract, and plasma appearance of TRP, LNAAs, and TRP metabolites, in response to dietary proteins varying in TRP content. MethodsPigs were adapted for 7 d to each of 4 diets that differed in their protein source and TRP content: 1) alpha-lactalbumin (AL; 9.95 mg TRP/g diet DM), 2) whey protein (6.59 mg TRP/g), 3) casein (3.73 mg TRP/g), or 4) zein (0.14 mg TRP/g). On day 8, pigs were euthanised after a 12-h fast (baseline), or 1, 2, 3, 4, or 6 h after they received a test meal consisting of 45 g protein, or a protein-free meal (n = 6 pigs at each time in each meal group). Tryptophan and LNAA absorption from the small intestine, and appearance of TRP, LNAAs, and TRP metabolites (melatonin, serotonin, kynurenine pathway metabolites), in the portal vein and systemic circulation, were determined. ResultsAL intake resulted in sustained elevated plasma TRP concentrations after an overnight fast. The amount of TRP absorbed was dose-dependently related to protein TRP content (P = 0.028), with fastest rates for pigs fed AL (371 mg/h). Portal and systemic plasma TRP, TRP/LNAA, and the TRP metabolites were highest (P ≤ 0.05) after AL intake, and remained above baseline levels for ∼4 h postprandially. Absorption rates of TRP correlated with postprandial plasma TRP and TRP metabolites (P ≤ 0.05). ConclusionsIn adult humans, postprandial plasma TRP and TRP metabolite concentrations can likely be modulated by the TRP content of the meal.

Exploring the Immunomodulatory Potential of Human Milk: Aryl Hydrocarbon Receptor Activation and Its Impact on Neonatal Gut Health.

Several metabolites of the essential amino acid tryptophan have emerged as key players in gut homeostasis through different cellular pathways, particularly through metabolites which can activate the aryl hydrocarbon receptor (AHR). This study aimed to map the metabolism of tryptophan in early life and investigate the effects of specific metabolites on epithelial cells and barrier integrity. Twenty-one tryptophan metabolites were measured in the feces of full-term and preterm neonates as well as in human milk and formula. The ability of specific AHR metabolites to regulate cytokine-induced IL8 expression and maintain barrier integrity was assessed in Caco2 cells and human fetal organoids (HFOs). Overall, higher concentrations of tryptophan metabolites were measured in the feces of full-term neonates compared to those of preterm ones. Within AHR metabolites, indole-3-lactic acid (ILA) was significantly higher in the feces of full-term neonates. Human milk contained different levels of several tryptophan metabolites compared to formula. Particularly, within the AHR metabolites, indole-3-sulfate (I3S) and indole-3-acetic acid (IAA) were significantly higher compared to formula. Fecal-derived ILA and milk-derived IAA were capable of reducing TNFα-induced IL8 expression in Caco2 cells and HFOs in an AHR-dependent manner. Furthermore, fecal-derived ILA and milk-derived IAA significantly reduced TNFα-induced barrier disruption in HFOs.

Chronic kidney disease alters tryptophan metabolite concentrations in male and female Sprague Dawley rats

Kynurenine is the first stable metabolite of tryptophan degradation. An increased ratio of kynurenine (KYN) to tryptophan (TRP) has been implicated in many disease states including chronic kidney disease (CKD) in humans. We hypothesized that we would see a similar increase in KYN/TRP in a CKD model in male and female rats. We induced CKD with a 0.25% adenine diet for 15 weeks and then measured a variety of renal parameters. Serum and kidneys were collected at sacrifice. We found that GFR was better preserved in CKD female rats compared to males (0.232 ± 0.056 vs. 0.081 ± 0.019 ml/min/100g BW) but was decreased significantly compared to controls (0.739 ± 0.048 female, 0.635 ± 0.099 male). Urine volume was elevated significantly in CKD rats compared to controls (80.0 ± 6.9 ml/day male CKD, 72.5 ± 4.7 female CKD vs. 13.3 ± 1.1 male CTL and 22.0 ± 1.8 female CTL). However, male CKD rats consumed significantly more water than female CKD (104.1 ± 7.3 ml/day male vs. 81.0 ± 5.1 female), although water consumption was similar in controls in both sexes (30.9 ± 2.6 male and 30.1 ± 2.5 female). Weekly food consumption and body weight were similar between same sex groups. Both male and female rats showed increased KYN/TRP in CKD compared to controls (0.102 ± 0.010 in male and 0.105 ± 0.011 in female CKD vs. 0.049 ± 0.005 and 0.033 ± 0.002 CTL). Similarly, kynurenic acid was elevated significantly in both sexes in CKD (305.7 ± 76.7 nmol/L male and 669.2 ± 140.7 female) compared to controls (92.3 ± 17.7 and 118.1 ± 14.7) respectively. These data show that the adenine feeding model of CKD reproduces many of the characteristics of human disease including alterations in TRP metabolites. This model will allow study of TRP metabolites in CKD progression. This work was supported by Career Development Award IK2 BX004997 from the United States Department of Veteran Affairs, Biomedical Laboratory Research and Development Service. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ginsenoside CK Alleviates DSS-Induced IBD in Mice by Regulating Tryptophan Metabolism and Activating Aryl Hydrocarbon Receptor via Gut Microbiota Modulation.

Dysbiosis of gut microbiota is believed to be associated with inflammatory bowel disease (IBD). Ginsenoside compound K (CK), the main metabolite of Panax ginseng ginsenoside, has proven effective as an anti-inflammatory agent in IBD. However, the mechanisms by which CK modulates gut microbiota to ameliorate IBD remain poorly understood. Herein, CK demonstrated the potential to suppress the release of proinflammatory cytokines by gut microbiota modulation. Notably, supplementation with CK promoted the restoration of a harmonious balance in gut microbiota, primarily by enhancing the populations of Lactobacillus and Akkermansia. Furthermore, CK considerably elevated the concentrations of tryptophan metabolites derived from Lactobacillus that could activate the aryl hydrocarbon receptor. Overall, the promising alleviative efficacy of CK primarily stemmed from the promotion of Lactobacillus growth and production of tryptophan metabolites, suggesting that CK should be regarded as a prospective prebiotic agent for IBD in the future.

MM165 - A Small Hybrid Molecule Modulates the Kynurenine Pathway and Attenuates Lipopolysaccharide-Induced Memory Deficits and Inflammation.

Cognitive dysfunctions are now recognized as core symptoms of various psychiatric disorders e.g., major depressive disorder. Sustained immune activation may leads to cognitive dysfunctions. Proinflammatory cytokines shunt the metabolism of tryptophan towards kynurenine and quinolinic acid may accumulate at toxic concentrations. This acid triggers an increase in neuronal nitric oxide synthase function and promotes oxidative stress. The searching for small molecules that can regulate tryptophan metabolites produced in the kynurenic pathway has become an important goal in developing treatments for various central nervous system diseases with an inflammatory component. Previously we have identified a small hybrid molecule - MM165 which significantly reduces depressive-like symptoms caused by inflammation induced by lipopolysaccharide administration. In the present study, we investigated whether this compound would mitigate cognitive deficits induced by lipopolysaccharide administration and whether treatment with it would affect the plasma or brain levels of quinolinic acid and kynurenic acid. Neuroinflammation was induced in rats by administering lipopolysaccharide at a dose of 0.5mg/kg body weight for 10 days. We conducted two tests: novel object recognition and object location, to assess the effect on memory impairment in animals previously treated with lipopolysaccharide. In plasma collected from rats, the concentrations of C-reactive protein and tumor necrosis factor alfa were determined. The concentrations of kynurenic acid and quinolinic acid were determined in plasma and homogenates obtained from the cerebral cortex of rats. Interleukin 6 in the cerebral cortex of rats was determined. Additionally, the body and spleen mass and spontaneous activity were measured in rats. Our study shows that MM165 may mitigate cognitive deficits induced by inflammation after administration of lipopolysaccharide and alter the concentrations of tryptophan metabolites in the brain. Compounds exhibiting a mechanism of action analogous to that of MM165 may serve as foundational structures for the development of a new class of antidepressants.

Tryptophan metabolites and gut microbiota play an important role in pediatric migraine diagnosis

BackgroundThe pathogenesis of pediatric migraine remains unclear and presents challenges in diagnosis. Recently, growing evidence has indicated that the gut microbiota can exert modulatory functions at the gut-brain axis by directly or indirectly regulating tryptophan metabolism. Consequently, we aimed to elucidate the potential association among gut microbiota, tryptophan metabolism, and pediatric migraine while also identifying diagnostic biomarkers for pediatric migraine.MethodsThe gut microbiota composition of 33 migraine children and 42 healthy children, aged less than ten years, from the GMrepo database, was analyzed using the Shannon index, Simpson index, principal coordinates analysis, and Wilcoxon rank-sum test. Microbial diagnostic biomarkers were identified using linear discriminant analysis effect size, ridge regression, and random forest. Plasma concentrations of tryptophan metabolites investigated by enzyme-linked immunosorbent assay were compared between 51 migraine children and 120 healthy children, aged less than eighteen years, using t tests and analysis of variance. The receiver operating characteristic curve was performed to evaluate the diagnostic value of microbial and metabolite biomarkers in pediatric migraine.ResultsDifferences in the composition of gut microbiota, notably the genera that regulate tryptophan metabolism, were observed in pediatric migraine children. Further investigations revealed a significant decrease in plasma kynurenic acid levels (p < 0.001) among migraine children, along with a significant increase in serotonin (p < 0.05) and quinolinic acid (p < 0.001). Subsequently, we established the normal reference intervals for plasma concentrations of tryptophan metabolites in children. More importantly, the ratio of kynurenic acid to quinolinic acid (AUC: 0.871, sensitivity: 86.3%, specificity: 83.3%) exhibited excellent diagnostic efficacy for pediatric migraine.ConclusionOur study suggests that the gut microbiota may play an important role in the development of pediatric migraine by regulating tryptophan metabolism. We believe that microbial and metabolite biomarkers are sensitive diagnostic tests for pediatric migraine.Trial registrationThe study was registered at ClinicalTrials.gov (NCT05969990).

Interplay between diet, circulating indolepropionate concentrations and cardiometabolic health in US populations

ObjectivesTo identify indolepropionate (IPA)-predicting gut microbiota species, investigate potential diet–microbiota interactions, and examine the prospective associations of circulating IPA concentrations with type 2 diabetes (T2D) and coronary heart disease (CHD)...

Photoluminescence in mammal fur: 111 years of research.

Photoluminescence in the pelage of mammals, a topic that has gained considerable recent research interest, was first documented in the 1700s and reported sporadically in the literature over the last century. The first detailed species accounts were of rabbits and humans, published 111 years ago in 1911. Recent studies have largely overlooked this earlier research into photoluminescent mammalian taxa and their luminophores. Here we provide a comprehensive update on existing research on photoluminescence in mammal fur, with the intention of drawing attention to earlier pioneering research in this field. We provide an overview on appropriate terminology, explain the physics of photoluminescence, and explore pigmentation and the ubiquitous photoluminescence of animal tissues, before touching on the emerging debate regarding visual function. We then provide a chronological account of research into mammalian fur photoluminescence, from the earliest discoveries and identification of luminophores to the most recent studies. While all mammal fur is likely to have a general low-level photoluminescence due to the presence of the protein keratin, fur glows luminously under ultraviolet light if it contains significant concentrations of tryptophan metabolites or porphyrins. Finally, we briefly discuss issues associated with preserved museum specimens in studies of photoluminescence. The study of mammal fur photoluminescence has a substantial history, which provides a broad foundation on which future studies can be grounded.

Abstract MP66: The Interplay Between Diet, Circulating Indolepropionate Concentrations, and Cardiometabolic Health in US Populations

Background: Indolepropionate (IPA), a tryptophan metabolite of human gut microbiota origin, is associated with lower risk of type 2 diabetes (T2D) in humans. The complex interplay among tryptophan intake, the gut microbiome, prebiotics, circulating IPA concentrations, and T2D risk has not been investigated. Objectives: We aimed to identify IPA-producing gut microbiota species and investigate potential diet-microbiota interaction on circulating IPA concentrations. Methods: We included 287 men from the Men’s Lifestyle Validation Study, a sub-study of the Health Professionals Follow-Up Study (HPFS), who provided up to two pairs of fecal samples and two blood samples approximately six months apart. Dietary intake was assessed using 7-day diet records. We identified microbial taxonomic features associated with plasma IPA concentrations using generalized linear regression and calculated a rank-based species score to reflect IPA-producing potential. Associations between plasma concentrations of tryptophan metabolites and T2D risk were examined in 13,032 participants from Nurses’ Health Study (NHS), NHSII, and HPFS. Results: Plasma IPA concentrations were associated with overall gut microbial profiles (permutational analysis of variance test, p=0.001). We identified 17 microbial species, such as Eubacterium eligens, Butyrivibrio crossotus , and Faecalibacterium prausnitzii , whose abundance was significantly associated with increased plasma IPA concentrations (false discovery rate &lt; 0.05). A significant association between higher tryptophan intake and higher IPA concentrations was only observed among men who had higher fiber intake and a higher microbial species score consisting of the 17 species (p-interaction &lt; 0.01). Similar modulation was also observed for major tryptophan food contributors including vegetables (p-interaction &lt; 0.01), red/processed meat (p-interaction = 0.02), egg (p-interaction 0.01), dairy (p-interaction = 0.01), and whole grain (p-interaction &lt; 0.01). Moreover, interactions persisted for all fiber subtypes (soluble/insoluble fiber and pectin). We documented 1,744 incident T2D cases during 218,603 person-years of follow-up. Plasma concentrations of tryptophan and three kynurenine-pathway metabolites (kynurenine, xanthurenate, and quinolinate) were positively associated with T2D risk while an inverse association was found for IPA. Conclusions: Specific microbial species and dietary fiber jointly modulate the associations between tryptophan intake and circulating IPA concentrations. In a subsequent analysis, IPA levels were predictive of lower T2D risk. Our findings suggest that the health effects of dietary tryptophan may depend on both gut microbiome composition and prebiotic consumption.

The study of tryptophan metabolite concentrations in blood serum and fecal extracts from obese children

We found that changes in the concentrations of tryptophan metabolites in the blood serum and in the intestinal contents are one of the mechanisms for the formation of metabolic coupling in the system "macroorganism-intestinal microbiota", which undergoes significant changes in the development of obesity. Although blood kynurenine remained basically unchanged in obese children we found an increase in some of its serum metabolites: anthranilic, kynurenic and xanthurenic acids. It is noteworthy that in the analysis of fecal matter in obese children, revealed a 2-fold increase in the level of kynurenine while the concentration of kynurenine pathway metabolites corresponded to the level of the group of healthy children. This may indicate the metabolic activation of the microbiota associated with the intestinal mucosa. This is also supported by the absence of statistically significant differences in the concentration of indole in healthy children and in obese children in fecal analyses, and a significant increase in the concentration of indole-3-lactate and indole-3-acetate in the blood serum of obese children.

Hypoxia Inducible Factor 1α Inhibits the Expression of Immunosuppressive Tryptophan-2,3-Dioxygenase in Glioblastoma.

Abnormal circulation in solid tumors results in hypoxia, which modulates both tumor intrinsic malignant properties as well as anti-tumor immune responses. Given the importance of hypoxia in glioblastoma (GBM) biology and particularly in shaping anti-tumor immunity, we analyzed which immunomodulatory genes are differentially regulated in response to hypoxia in GBM cells. Gene expression analyses identified the immunosuppressive enzyme tryptophan-2,3-dioxygenase (TDO2) as the second most downregulated gene in GBM cells cultured under hypoxic conditions. TDO2 catalyses the oxidation of tryptophan to N-formyl kynurenine, which is the first and rate-limiting step of Trp degradation along the kynurenine pathway (KP). In multiple GBM cell lines hypoxia reduced TDO2 expression both at mRNA and protein levels. The downregulation of TDO2 through hypoxia was reversible as re-oxygenation rescued TDO2 expression. Computational modeling of tryptophan metabolism predicted reduced flux through the KP and lower intracellular concentrations of kynurenine and its downstream metabolite 3-hydroxyanthranilic acid under hypoxia. Metabolic measurements confirmed the predicted changes, thus demonstrating the ability of the mathematical model to infer intracellular tryptophan metabolite concentrations. Moreover, we identified hypoxia inducible factor 1α (HIF1α) to regulate TDO2 expression under hypoxic conditions, as the HIF1α-stabilizing agents dimethyloxalylglycine (DMOG) and cobalt chloride reduced TDO2 expression. Knockdown of HIF1α restored the expression of TDO2 upon cobalt chloride treatment, confirming that HIF1α controls TDO2 expression. To investigate the immunoregulatory effects of this novel mechanism of TDO2 regulation, we co-cultured isolated T cells with TDO2-expressing GBM cells under normoxic and hypoxic conditions. Under normoxia TDO2-expressing GBM cells suppressed T cell proliferation, while hypoxia restored the proliferation of the T cells, likely due to the reduction in kynurenine levels produced by the GBM cells. Taken together, our data suggest that the regulation of TDO2 expression by HIF1α may be involved in modulating anti-tumor immunity in GBM.

Serotonin is the main tryptophan metabolite associated with psychiatric comorbidity in abstinent cocaine-addicted patients

The lack of effective treatments and a high rate of relapse in cocaine addiction constitute a major health problem. The present study was conducted to examine the expression of tryptophan-derived metabolites in the context of cocaine addiction and psychiatric comorbidity, which is common in addicted subjects. Abstinent patients with cocaine use disorder (CUD) and control subjects were recruited for a cross-sectional study. Participants were assessed with a semi-structured diagnostic interview (PRISM) based on DSM-IV-TR for substance and mental disorders. Plasma concentrations of tryptophan metabolites and their association with relevant CUD-related variables and psychiatric comorbidity were explored. We observed decreased plasma kynurenic acid concentrations in the cocaine group, however no associations between CUD-related variables and tryptophan-derived metabolites were found. In contrast, 5-HT concentrations were increased in CUD-patients and the diagnosis of different psychiatric disorders in the cocaine group was related to higher plasma 5-HT concentrations compared with non-comorbid patients. Therefore, while changes in plasma kynurenic acid concentrations appear to be directly associated with lifetime CUD, changes in 5-HT concentrations are associated with psychiatric comorbidity. These results emphasize the need to find potential biomarkers for a better stratification of cocaine-addicted patients in order to develop therapeutic approaches to prevent cocaine relapse.

Tryptophan metabolite concentrations in depressed patients before and after electroconvulsive therapy

Tryptophan and kynurenine pathway (KP) metabolites are implicated in the pathophysiology of depression. We aimed to investigate their plasma concentrations in medicated patients with depression (n = 94) compared to age- and sex-matched healthy controls (n = 57), and in patients with depression after electroconvulsive therapy (ECT) in a real-world clinical setting, taking account of co-variables including ECT modality and heterogenous psychopathology. Depression severity was assessed using the Hamilton Depression Rating Scale (HAM-D24). Tryptophan (TRP) and kynurenine (KYN) metabolite concentrations [anthranilic acid (AA), 3-hydroxyanthranilic acid (3HAA), picolinic acid (PA), kynurenic acid (KYNA), and xanthurenic acid (XA)] and KYNA/KYN and KYNA/quinolinic acid (QUIN) ratios were lower in patients compared to controls. For the total group there was no significant change in KP metabolites post-ECT or correlations with mood ratings. However, improvements in mood score were correlated with increased KYN, 3-hydroxykynurenine (3HK), 3HAA, QUIN, and KYN/TRP in a subgroup of unipolar depressed patients. Additionally, in remitters baseline KYN, 3HK, and QUIN were associated with baseline HAM-D24 scores, and changes in 3HK and 3HAA concentrations post-ECT correlated with improvement in mood. KYN, KYNA, AA, 3HK, XA, PA, and QUIN were increased in a smaller 3-month follow-up group (n = 19) compared to pre-ECT concentrations. Overall, the results indicate that ECT mobilizes the KP, where a moderate association between selected metabolites and treatment response in unipolar depressed patients is evident.

Abstract # 4258 Plasma tryptophan metabolite concentrations in depression and the response to electroconvulsive therapy

Abstract # 4258 Plasma tryptophan metabolite concentrations in depression and the response to electroconvulsive therapy

Increased levels of 3-hydroxykynurenine parallel disease severity in human acute pancreatitis.

Inhibition of kynurenine 3-monooxygenase (KMO) protects against multiple organ dysfunction (MODS) in experimental acute pancreatitis (AP). We aimed to precisely define the kynurenine pathway activation in relation to AP and AP-MODS in humans, by carrying out a prospective observational study of all persons presenting with a potential diagnosis of AP for 90 days. We sampled peripheral venous blood at 0, 3, 6, 12, 24, 48, 72 and 168 hours post-recruitment. We measured tryptophan metabolite concentrations and analysed these in the context of clinical data and disease severity indices, cytokine profiles and C-reactive protein (CRP) concentrations. 79 individuals were recruited (median age: 59.6 years; 47 males, 59.5%). 57 met the revised Atlanta definition of AP: 25 had mild, 23 moderate, and 9 severe AP. Plasma 3-hydroxykynurenine concentrations correlated with contemporaneous APACHE II scores (R2 = 0.273; Spearman rho = 0.581; P < 0.001) and CRP (R2 = 0.132; Spearman rho = 0.455, P < 0.001). Temporal profiling showed early tryptophan depletion and contemporaneous 3-hydroxykynurenine elevation. Furthermore, plasma concentrations of 3-hydroxykynurenine paralleled systemic inflammation and AP severity. These findings support the rationale for investigating early intervention with a KMO inhibitor, with the aim of reducing the incidence and severity of AP-associated organ dysfunction.

Evaluation of indoleamine 2,3-dioxygenase expression and kynurenine pathway metabolites levels in serum samples of diabetic retinopathy patients

Context: Diabetic retinopathy (DR) is the leading cause of acquired blindness. The involvement of indoleamine 2, 3-dioxygenase (IDO) and kynurenines, the products of tryptophan degradation in various pathological conditions was well documented.Objective: The aim of the present study was to determine the expression of IDO and levels of tryptophan metabolites in serum samples of DR patients.Materials and methods: Tryptophan and its metabolites, i.e. kynurenine, kynurenic acid and 3-hydroxy kynurenine were measured by HPLC in serum of normal subjects as well as non-proliferative (NPDR) and proliferative DR (PDR) patients. The expression of IDO was measured using semi-quantitative reverse transcriptase polymerase chain reaction.Results: Elevated expression of IDO and levels of kynurenine, kynurenic acid and 3-hydroxykynurenine were observed in NPDR and a higher expression was observed in PDR. No significant change was noticed in levels of tryptophan.Conclusion: An elevation in the concentrations of tryptophan metabolites and IDO expression was evident in diabetic retinopathy patients. The results indicate probable association of IDO and tryptophan metabolites with DR.

Concentrations of serotonin and its related substances in the cerebrospinal fluid in patients with Alzheimer type dementia

We studied concentrations of free and total serotonin (5-hydroxytryptamine, 5-HT) and its related substances in the cerebrospinal fluid from patients with Alzheimer type dementia (ATD) compared with controls. In ATD patients, concentrations of total 5-HT, tryptophan, 5-hydroxytryptophan (5-HTP), melatonin, kynurenine, and 3-hydroxykynurenine decreased significantly. The rate of concentration of tryptophan metabolites to that of tryptophan was significantly reduced for total 5-HT and 3-hydroxykynurenine only. The 5-hydroxyindoleacetic acid (5-HIAA)5-HT ratio was significantly larger in ATD patients than in controls. The greater reduction in the 3-hydroxykynurenine concentration (81% vs. controls) than in the total 5-HT concentration (51% vs. controls) suggests that the metabolism of tryptophan to 5-HT and 3-hydroxykynurenine is in favor of 5-HT.

Difference in the concentration of tryptophan metabolites between maternal and umbilical foetal blood

Maternal and umbilical foetal blood at delivery were analysed for tryptophan metabolites by using fully automated high-performance liquid chromatography. The metabolites detected in 100 μl of maternal plasma were kynurenine, serotonin, 5-hydroxyindoleacetic acid, indolelactic acid, indoleacetic acid and indolepropionic acid. These metabolites were present in various amounts in the protein-bound form. Except for indolepropionic acid, the concentrations of tryptophan metabolites were significantly higher in umbilical foetal plasma than in maternal plasma. In addition,3-hydroxyanthranilic acid was present in umbilical foetal blood, but not in maternal blood. Furthermore, kynurenic acid was also detected in amniotic fluids.