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Tryptophan Availability for Kynurenine Pathway Metabolism across the Life span: Control Mechanisms and Focus on Aging, Exercise, Diet and Nutritional Supplements
Abstract
Tryptophan (Trp) availability for the kynurenine pathway (KP) across the life span is discussed. Free (non-albumin-bound) plasma Trp is the major determinant of the flux of Trp down the KP. Flux is the major determinant of kynurenine metabolite formation and is more effective than induction of hepatic Trp 2,3-dioxygenase (TDO) or extrahepatic indoleamine 2,3-dioxygenase (IDO). Flux is better expressed using the sum of plasma kynurenine and its metabolites, rather than kynurenine only. Under normal conditions, TDO controls Trp flux in liver and availability in plasma and can supply kynurenine for the extrahepatic pathway. Under certain pathological conditions associated with immune activation, IDO assumes the major role in control of Trp availability. Plasma Trp availability is increased during pregnancy, at birth, and by exercise, high protein and fat intake. Aging does not seem to exert a major effect on plasma Trp. Assessment of plasma Trp availability in health and disease requires measurement of concentrations of both free and total [Trp] in the first instance, followed, if necessary, by those of albumin and the physiological displacers of albumin-bound Trp, non-esterified fatty acids. Additional measures should include cortisol, cytokines, kynurenine and its metabolites.
This article is part of the Special Issue entitled ‘The Kynurenine Pathway in Health and Disease’.
... In blood, about 90 percent of Trp is bound to albumin, and the remaining unbound fraction, free Trp, is available for metabolization [88]. Displacement of Trp from albumin increases the free fraction of Trp in blood, potentially increasing Trp availability for serotonin synthesis in the brain [89]. Trp levels in the central nervous system, however, are dependent on transport across the blood brain barrier (BBB) by L-type amino acid transporter (LAT1) [88]. ...
... The first step of the kynurenine pathway is the conversion of Trp to formylkynurenine by one of two enzymes, tryptophan 2,3-dioxygenase (TDO) and indolamine 2,3-dioxygenase 1 (IDO1). TDO is activated by Trp itself and induced by glucocorticoids such as cortisol [89]. IDO1, on the other hand, is induced by pro-inflammatory cytokines, especially interferon gamma (IFN-) [90]. ...
... In general, higher age is associated with lower levels of Trp (reviewed in [89]). In the largest study to date, investigating two distinct community-based age groups (age 45-46 years (n = 3723) and age 70-72 years (n = 3329)), higher age was also associated with higher levels of Kyn, AA, KA, HK and neopterin, as well as higher KTR [38]. ...
The kynurenine pathway of tryptophan (Trp) metabolism generates multiple biologically active metabolites (kynurenines) that have been implicated in neuropsychiatric disorders. It has been suggested that modulation of kynurenine metabolism could be involved in the therapeutic effect of electroconvulsive therapy (ECT). We performed a systematic review with aims of summarizing changes in Trp and/or kynurenines after ECT and assessing methodological issues. The inclusion criterium was measures of Trp and/or kynurenines before and after ECT. Animal studies and studies using Trp administration or Trp depletion were excluded. Embase, MEDLINE, PsycInfo and PubMed were searched, most recently in July 2022. Outcomes were levels of Trp, kynurenines and ratios before and after ECT. Data on factors affecting Trp metabolism and ECT were collected for interpretation and discussion of the reported changes. We included 17 studies with repeated measures for a total of 386 patients and 27 controls. Synthesis using vote counting based on the direction of effect found no evidence of effect of ECT on any outcome variable. There were considerable variations in design, patient characteristics and reported items. We suggest that future studies should include larger samples, assess important covariates and determine between- and within-subject variability. PROSPERO (CRD42020187003).
... One of such processes that is taking importance is the tryptophan catabolism through the kynurenine pathway (KP). The KP is the main source of tryptophan degradation on mammals [23,24]. The KP activity is mainly limited by the enzymes tryptophan dioxygenase (TDO) and indoleamine dioxygenase (IDO); both enzymes produce N-formylkynurenine from the cleavage of tryptophan in hepatic and extrahepatic tissue, respectively [23,24]. ...
... The KP is the main source of tryptophan degradation on mammals [23,24]. The KP activity is mainly limited by the enzymes tryptophan dioxygenase (TDO) and indoleamine dioxygenase (IDO); both enzymes produce N-formylkynurenine from the cleavage of tryptophan in hepatic and extrahepatic tissue, respectively [23,24]. N-formylkynurenine is rapidly converted into kynurenine (KYN), which can be taken by kynurenine aminotransferase (KAT), kynureninase (KYNU), and kynurenine monooxygenase (KMO) to produce kynurenic acid (KYNA), anthranilic acid (ANA), and 3-hydroxykynurenine (3-HK), respectively [23,24]. ...
... The KP activity is mainly limited by the enzymes tryptophan dioxygenase (TDO) and indoleamine dioxygenase (IDO); both enzymes produce N-formylkynurenine from the cleavage of tryptophan in hepatic and extrahepatic tissue, respectively [23,24]. N-formylkynurenine is rapidly converted into kynurenine (KYN), which can be taken by kynurenine aminotransferase (KAT), kynureninase (KYNU), and kynurenine monooxygenase (KMO) to produce kynurenic acid (KYNA), anthranilic acid (ANA), and 3-hydroxykynurenine (3-HK), respectively [23,24]. Then, 3-hydroxyanthranilic acid (3-HANA) is produced and leads to a picolinic and quinolinic acid formation [23,24]. ...
Indoleamine dioxygenase (IDO), a rate limiting enzyme of the tryptophan catabolism through the kynurenine pathway (KP), has been related with a lower survival and a poor patient prognosis on several solid tumors, including gliomas. However, the use of IDO inhibitors as a therapeutic strategy for tumor treatment remains controversial in clinical trials and the role of other KP enzymes on tumor progression has remained poorly understood so far. Recently, different studies on different types of cancer have pointed out the importance of KP enzymes downstream IDO. Because of this, we conducted a bioinformatic analysis of the expression of different KP enzymes and their correlation with the gene expression of molecules related to the hallmarks of cancer in transcriptomic datasets from patients with different types of brain tumors including low grade gliomas, glioblastoma multiforme, neuroblastoma, and paraganglioma and pheochromocytoma. We found that KP enzymes that drive to NAD+ synthesis are overexpressed on different brain tumors compared to brain cortex data. Moreover, these enzymes presented positive correlations with the expression of genes related to immune response modulation, angiogenesis, Signal Transducer and Activator of Transcription (STAT) signaling, and Rho GTPase expression. These correlations suggest the relevance of the expression of the KP enzymes in brain tumor pathogenesis.
... Certainly, immune-mediated accelerated tryptophan metabolism is part of a larger crosstalk and consequences that are not isolated from other metabolic and redox changes that occur during inflammation. The cytokine interferon (IFN)-γ plays a major role, and some associated pathways are highly susceptible to modulation by lifestyle factors [3,4]. Human genetic data and various animal models suggest that balanced metabolism of tryptophan may support longer and/or disease-free survival. ...
... Hence, tryptophan and/or its degradation products seem to be suitable candidates for frailty biomarkers [7]. A decrease of serum/plasma total tryptophan and increases of both the kynurenine to tryptophan ratio (and neopterin) were observed also during healthy aging [3,8]; however sex-related differences and the nutritional status of study participant also play a role. The ratio of free to total tryptophan may be relevant for transport and further metabolic routes, too [3]. ...
... A decrease of serum/plasma total tryptophan and increases of both the kynurenine to tryptophan ratio (and neopterin) were observed also during healthy aging [3,8]; however sex-related differences and the nutritional status of study participant also play a role. The ratio of free to total tryptophan may be relevant for transport and further metabolic routes, too [3]. A larger systematic analysis of the parameters across lifespan would be needed to gain further information of agegrouped normal concentration ranges in the healthy population. ...
... The accumulation of ketone bodies following a ketogenic diet strongly impacts gut microbiota composition; in vivo and in vitro experiments demonstrated that ketone bodies selectively inhibit the growth of several Bifidobacterial spp., with downstream consequences for gut immune cells, especially Th17, and induce the decrease in the relative abundance of Actinobacteria (Ang et al., 2020). In an animal model of inflammatory colitis, it 3-β-hydroxybutyrate Increased Zhang et al., 2013;Dawiskiba et al., 2014;Kohashi et al., 2014;Keshteli et al., 2017 Increased Barberis et al., 2020;Bruzzone et al., 2020;San Juan et al., 2020;Páez-Franco et al., 2021;Meoni et al., 2021Acetone Increased Keshteli et al., 2017Increased Bruzzone et al., 2020San Juan et al., 2020Acetoacetate Increased Dawiskiba et al., 2014Keshteli et al., 2017Increased Bruzzone et al., 2020San Juan et al., 2020Glycerophospholipids Decreased Bjerrum et al., 2010, 2017Fan et al., 2015;Kolho et al., 2017;Scoville et al., 2018;Tefas et al., 2019Tefas et al., , 2020 Decreased Barberis et al., 2020;Wu et al., 2020;Song et al., 2020;Shen et al., 2020;Schwarz et al., 2021 Lysophospholipids Decreased Increased Barberis et al., 2020;Song et al., 2020;Schwarz et al., 2021Sphingolipids Decreased Fan et al., 2015Kolho et al., 2017 Decreased Barberis et al., 2020;Shen et al., 2020;Schwarz et al., 2021Increased Song et al., 2020 Decreased Esteve-Comas et al., 1992;Scoville et al., 2018;Lai et al., 2019;Manfredi et al., 2019 Increased Barberis et al., 2020;Schwarz et al., 2021;Thomas et al., 2020 Arachidonic acid (stools) Increased Jansson et al., 2009 Frontiers in Microbiology | www.frontiersin.org was observed that the ketogenic diet alters gut microbiota and serum metabolome, alleviating colitis (Kong et al., 2021). ...
... In COVID-19, the increase in picolinic acid reflects the activation of the enzymatic conversion of 2-amino-3-carboxymuconate-6-semialdehyde (ACMS) to 2-aminomuconic-6-semialdehyde. In turn, the latter undergoes either non-enzymatic cyclization to form picolinic acid or enzymatic transformation to 2-aminomuconic acid, yielding acetyl-CoA (Badawy, 2017). It is unclear why picolinic acid is increased in COVID-19, taking into account the alteration of brain functions during the disease (Chou et al., 2021;Marshall, 2021). ...
The integrity of the gastrointestinal tract structure and function is seriously compromised by two pathological conditions sharing, at least in part, several pathogenetic mechanisms: inflammatory bowel diseases (IBD) and coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. IBD and COVID-19 are marked by gut inflammation, intestinal barrier breakdown, resulting in mucosal hyperpermeability, gut bacterial overgrowth, and dysbiosis together with perturbations in microbial and human metabolic pathways originating changes in the blood and fecal metabolome. This review compared the most relevant metabolic and microbial alterations reported from the literature in patients with IBD with those in patients with COVID-19. In both diseases, gut dysbiosis is marked by the prevalence of pro-inflammatory bacterial species and the shortfall of anti-inflammatory species; most studies reported the decrease in Firmicutes, with a specific decrease in obligately anaerobic producers short-chain fatty acids (SCFAs), such as Faecalibacterium prausnitzii. In addition, Escherichia coli overgrowth has been observed in IBD and COVID-19, while Akkermansia muciniphila is depleted in IBD and overexpressed in COVID-19. In patients with COVID-19, gut dysbiosis continues after the clearance of the viral RNA from the upper respiratory tract and the resolution of clinical symptoms. Finally, we presented and discussed the impact of gut dysbiosis, inflammation, oxidative stress, and increased energy demand on metabolic pathways involving key metabolites, such as tryptophan, phenylalanine, histidine, glutamine, succinate, citrate, and lipids.
... A comprehensive mathematical model was established to provide a predictive tool that could facilitate identification of potential pathological changes in TRP metabolism. Existing reports suggest that hepatic and renal functions assumed the biological roles in the metabolic network of TRP, as our results indicated (20)(21)(22). Similarly, this study found that clinical hepatic and renal function indexes were tightly correlated with TRP metabolites. ...
... In addition to the reported KP metabolites, corresponding increases in IPA and 5-HIAA levels were also found in patients with EC with liver and kidney insufficiency. Under normal conditions, the TDO enzyme controls TRP flux in the liver and its availability in plasma, and may supply KYN to the extrahepatic pathway (21). Not to be stated, hepatic function exerted its prominent regulatory effect on the metabolic network of TRP. ...
Background
Perturbation of tryptophan (TRP) metabolism contributes to the immune escape of cancer; however, the explored TRP metabolites are limited, and their efficacy in clarifying the susceptibility and progression of esophageal cancer (EC) remains ambiguous. Our study sought to evaluate the effects of the TRP metabolic profile on the clinical outcomes of EC using a Chinese population cohort; and to develop a risk prediction model targeting TRP metabolism.
Method
A total of 456 healthy individuals as control subjects and 393 patients with EC who were followed up for one year as case subjects were enrolled. Quantification of the plasma concentrations of TRP and its metabolites was performed using HPLC-MS/MS. The logistic regression model was applied to evaluate the effects of the clinical characteristics and plasma metabolites of the subjects on susceptibility and tumor metastasis events, whereas Cox regression analysis was performed to assess the overall survival (OS) of the patients.
Results
Levels of creatinine and liver enzymes were substantially correlated with multiple metabolites/metabolite ratios in TRP metabolism, suggesting that hepatic and renal function would exert effects on TRP metabolism. Age- and sex-matched case–control subjects were selected using propensity score matching. Plasma exposure to 5-HT was found to be elevated 3.94-fold in case subjects (N = 166) compared to control subjects (N = 203), achieving an AUC of 0.811 for predicting susceptibility event. Subsequent correlation analysis indicated that a higher plasma exposure to 5-HIAA significantly increased the risk of lymph node metastasis (OR: 2.16, p = 0.0114). Furthermore, it was figured out that OS was significantly shorter for patients with elevated XA/KYN ratio (HR: 1.99, p = 0.0016), in which medium and high levels of XA/KYN versus low level had a significantly lower OS (HR: 0.48, p = 0.0080 and HR: 0.42, p = 0.0031, respectively).
Conclusion
This study provides a pivotal basis for targeting endogenous TRP metabolism as a potential therapeutic intervention.
... IDO shows a much higher affinity with a Km of 3-50 µM in various sources. In contrast, TDO Abbreviations: IDO, Indoleamine 2,3-dioxygenase; HCC, hepatocellular carcinoma; KP, kynurenine pathway; Trp, tryptophan; DCs, dendritic cells; TNF-α, tumor necrosis factor-α; IL-6, Interleukin-6; TGF-α, transforming growth factor-α; α-GalCer, α-galactosylceramide; 1-L-MT, Levo-1-methyl tryptophan; 1-D-MT, Dextro-1-methyl tryptophan; CCl 4 , carbon tetrachloride; HFD, high-fat diet; Kyn, kynurenine; AHR, aryl hydrocarbon receptor; HCV, hepatitis C virus; HBV, hepatitis B virus; CTLs, cytotoxic T lymphocytes; mTOR, mammalian target of rapamycin; STAT3, signal transducer and activator of transcription 3. has very high Km values, whether in rat hepatocytes (100 µM), human liver (400 µM)or the purified human enzyme (190 µM) (10). The Trp metabolism contributes to immune regulation and has been well-covered in recent reviews (1,(11)(12)(13), whereas KP imbalance is related to numerous pathologies, including autoimmunity, viral infection, central nervous system (CNS) disorders, cardiovascular and cancer. ...
... Intriguingly, although IDO1 with a physiological state is not expressed in the liver, recent studies on liver dysfunction have found that the liver's pathological state is significantly increased (1,2,7,10,14). Iwamoto and co-workers reported that IDO mRNA and protein expression of liver and hepatocytes were not detected in the control group, while those were significantly enhanced in the acute hepatitis group, along with elevated IFNγ and Kyn levels (15). ...
Indoleamine 2,3-dioxygenase (IDO) is one of the initial rate-limiting enzymes of the kynurenine pathway (KP), which causes immune suppression and induction of T cell anergy. It is associated with the imbalance of immune homeostasis in numerous diseases including cancer, chronic viral infection, allergy, and autoimmune diseases. Recently, IDO has extended its role to liver field. In this review, we summarize the dysregulation and potentials of IDO in the emerging field of liver injuries, as well as current challenges for IDO targets. In particular, we discuss unexpected conclusions against previous work published. IDO is induced by pro-inflammatory cytokines in liver dysfunction and exerts an immunosuppressive effect, whereas the improvement of liver injury may require consideration of multiple factors besides IDO.
... In the context of using dietary interventions for mental health prevention and treatment, understanding tryptophan availability and metabolism may be important. For example, increased protein intake can lead to increased tryptophan availability, variations in carbohydrate intake can impact on free tryptophan levels, and nonesterified fatty acids can physiologically displace tryptophan from albumin [122,123]. Fluctuations in the availability of other amino acids that compete with tryptophan for transport across the blood brain barrier can also affect the central nervous system metabolic pool [122]. Direct tryptophan supplementation has been trialled as an intervention in people with depression as a way to improve serotonergic signalling [112]. ...
... For example, increased protein intake can lead to increased tryptophan availability, variations in carbohydrate intake can impact on free tryptophan levels, and nonesterified fatty acids can physiologically displace tryptophan from albumin [122,123]. Fluctuations in the availability of other amino acids that compete with tryptophan for transport across the blood brain barrier can also affect the central nervous system metabolic pool [122]. Direct tryptophan supplementation has been trialled as an intervention in people with depression as a way to improve serotonergic signalling [112]. ...
... Elevated levels of kynurenine have been associated with cognitive de cits and are implicated in the pathophysiology of several mental disorders. 3,4 While research has revealed metabolic connections between depression and both tryptophan and kynurenine, a de nitive causal relationship between kynurenine and depression has yet to be established. ...
Background: With advances in medical research, a growing association has been observed between kynurenine and depression. However, the causal relationship between kynurenine and depression remains unclear. Therefore, we utilized Mendelian randomization (MR) methods to investigate the causal link between kynurenine and depression.
Methods: We utilized extensive data from large-scale genome-wide association studies to identify single nucleotide polymorphisms that act as instrumental variables for kynurenineand depression in European ancestry populations, ensuring compliance with MR assumptions. We employed five MR algorithms, namely, weighted median, MR Egger, inverse variance weighted (IVW), simple mode, and weighted mode, with IVW as the primary analysis method. Sensitivity tests were conducted using Cochran's Q test, MR‒Egger intercept test, MR Pleiotropy Residual Sum and Outlier, and Leave-one-out analysis.
Results: The IVW analysis revealed that each standard deviation increase in kynurenine corresponded to a 1.4-fold increase in the risk of depression (OR=1.351, 95% CI=1.110~1.645, P=0.003). The direction of the effect size (positive or negative) was consistent with the findings from the other four algorithms. Sensitivity tests indicated no heterogeneity or horizontal pleiotropy among the instrumental variables.
Conclusion: Elevated levels of kynurenine have a causal relationship with an increased risk of developing depression.
... Additionally, any variations in the ratio have been associated with depression and anxiety [191,192]. The rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO), present in every tissue of the body including gut, and tryptophan-2,3-dioxygenase (TDO), which is localized in the liver, combine to create kynurenine from tryptophan [193]. When IDO is activated, tryptophan metabolism deviates from serotonin synthesis towards the formation of kynurenine and its downstream metabolites, kynurenic acid, anthranilic acid, and quinolinic acid [194]. ...
Emerging evidence have shown the importance of gut microbiota in regulating brain functions. The diverse molecular mechanisms involved in cross-talk between gut and brain provide insight into importance of this communication in maintenance of brain homeostasis. It has also been observed that disturbed gut microbiota contributes to neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and aging. Recently, gut microbiome-derived exosomes have also been reported to play an essential role in the development and progression of neurodegenerative diseases and could thereby act as a therapeutic target. Further, pharmacological interventions including antibiotics, prebiotics and probiotics can influence gut microbiome-mediated management of neurological diseases. However, extensive research is warranted to better comprehend this interconnection in maintenance of brain homeostasis and its implication in neurological diseases. Thus, the present review is aimed to provide a detailed understanding of gut-brain axis followed by possibilities to target the gut microbiome for improving neurological health.
... While several previous studies have comprehensively explored the impact of Trp metabolism and gut microbes on related diseases and the crosstalk between the two (16)(17)(18)(19)(20)(21)(22), there remains a notable gap in the literature regarding the relationship between microbial Trp metabolites and organismal immunity. To address this issue, we present a concise summary of recent discoveries regarding the gut microbiota's role in Trp metabolism. ...
Tryptophan (Trp) is an essential amino acid that can be metabolized via endogenous and exogenous pathways, including the Kynurenine Pathway, the 5-Hydroxyindole Pathway (also the Serotonin pathway), and the Microbial pathway. Of these, the Microbial Trp metabolic pathways in the gut have recently been extensively studied for their production of bioactive molecules. The gut microbiota plays an important role in host metabolism and immunity, and microbial Trp metabolites can influence the development and progression of various diseases, including inflammatory, cardiovascular diseases, neurological diseases, metabolic diseases, and cancer, by mediating the body’s immunity. This review briefly outlines the crosstalk between gut microorganisms and Trp metabolism in the body, starting from the three metabolic pathways of Trp. The mechanisms by which microbial Trp metabolites act on organism immunity are summarized, and the potential implications for disease prevention and treatment are highlighted.
... Aromatic amino acids (AAAs) refer to AAs that have an aromatic ring in the side chain, including Trp, tyrosine (Tyr), and Phe. Evidence suggests that less than 1% of dietary Trp is utilized for protein synthesis, and a considerable amount of dietary Trp is therefore metabolized by 3 pathways: (i) kynurenine pathway; (ii) serotonin pathway; (iii) decarboxylation (to tryptamine) and transamination (to indol-3-ylpyruvic acid) pathway, which is mediated by the gut microbiota (Badawy, 2017). At present, the metabolism of AAAs in gut microbes mainly focuses on Bacteroidetes and Firmicutes, among which, Clostridium sporogenes (from the phylum Firmicutes) has been extensively studied on the metabolism of AAAs. ...
Dietary nutrients and the gut microbiota are increasingly recognized to cross-regulate and entrain each other, and thus affect host health and immune-mediated diseases. Here, we systematically review the current understanding linking dietary nutrients to gut microbiota-host immune interactions, emphasizing how this axis might influence host immunity in health and diseases. Of relevance, we highlight that the implications of gut microbiota-targeted dietary intervention could be harnessed in orchestrating a spectrum of immune-associated diseases. amino acid, carbohydrate, lipid, trace element, vitamin, gut microbiota, immunity Citation:
... Alternatively, TRP can also be catabolized into kynurenine as a precursor to the Kynurenine Pathway and other downstream metabolites including kynurenic acid (KA). 23 KA also exhibits neuroactive properties and is a respiratory depressant. [24][25][26][27][28][29] However, there is a paucity of data regarding free circulating neurotransmitter levels specifically in preterm neonates and whether they are associated with respiratory insufficiency. ...
Background:
Hypoxemia is a physiological manifestation of immature respiratory control in preterm neonates, which is likely impacted by neurotransmitter imbalances. We investigated relationships between plasma levels of the neurotransmitter serotonin (5-HT), metabolites of tryptophan (TRP), and parameters of hypoxemia in preterm neonates.
Methods:
TRP, 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), and kynurenic acid (KA) were analyzed in platelet-poor plasma at ~1 week and ~1 month of life from a prospective cohort of 168 preterm neonates <31 weeks gestational age (GA). Frequency of intermittent hypoxemia (IH) events and percent time hypoxemic (<80%) were analyzed in a 6 h window after the blood draw.
Results:
At 1 week, infants with detectable plasma 5-HT had fewer IH events (OR (95% CI) = 0.52 (0.29, 0.31)) and less percent time <80% (OR (95% CI) = 0.54 (0.31, 0.95)) compared to infants with undetectable 5-HT. A similar relationship occurred at 1 month. At 1 week, infants with higher KA showed greater percent time <80% (OR (95% CI) = 1.90 (1.03, 3.50)). TRP, 5-HIAA or KA were not associated with IH frequency at either postnatal age. IH frequency and percent time <80% were positively associated with GA < 29 weeks.
Conclusions:
Circulating neuromodulators 5-HT and KA might represent biomarkers of immature respiratory control contributing to hypoxemia in preterm neonates.
Impact:
Hypoxemia events are frequent in preterm infants and are associated with poor outcomes. Mechanisms driving hypoxemia such as immature respiratory control may include central and peripheral imbalances in modulatory neurotransmitters. This study found associations between the plasma neuromodulators serotonin and kynurenic acid and parameters of hypoxemia in preterm neonates. Imbalances in plasma biomarkers affecting respiratory control may help identify neonates at risk of short- and long-term adverse outcomes.
... [5][6][7][8][9][10] Neuroactive 55 metabolites derived from the gut microbiota, including neurotransmitters and hormones (as well as their precursors), short chain fatty acids (SCFAs), and inflammatory factors have been suggested to mediate some of the associations between the gut environment and the brain, with potential impact on neurocognition. [11][12][13][14][15][16] Diet, through its strong influence on the gut microbiota, could thus play a key role in the modulation of these signaling molecules, ultimately affecting cognitive 60 function. [17][18][19][20][21][22][23][24][25] Importantly, very little is known about how positive dietary-microbiota interactions influence neurocognition, especially in humans. ...
Background:
Bariatric surgery leads to profound changes in gut microbiota and dietary patterns, both of which may interact to impact gut-brain communication. Though cognitive function improves postsurgery, there is a large variability in outcomes. How bariatric surgery-induced modifications in the gut microbiota and dietary patterns influence the variability in cognitive function is still unclear.
Objectives:
To elucidate the associations between bariatric surgery-induced changes in dietary and gut microbiota patterns with cognition and brain structure.
Setting:
University hospital.
Methods:
A total of 120 adult patients (≥30 years) scheduled to undergo a primary bariatric surgery along with 60 age-, sex-, and body mass index-matched patients on the surgery waitlist will undergo assessments 3-months presurgery and 6- and 12-month postsurgery (or an equivalent time for the waitlist group). Additionally, 60 age-and sex-matched nonbariatric surgery eligible individuals will complete the presurgical assessments only. Evaluations will include sociodemographic and health behavior questionnaires, physiological assessments (anthropometrics, blood-, urine-, and fecal-based measures), neuropsychological cognitive tests, and structural magnetic resonance imaging. Cluster analyses of the dietary and gut microbiota changes will define the various dietary patterns and microbiota profiles, then using repeated measures mixed models, their associations with global cognitive and structural brain alterations will be explored.
Results:
The coordinating study site (Centre intégré universitaire de santé et de services sociaux du Nord-de-l'Île-de-Montréal, QC, Canada), provided the primary ethical approval (Research Ethics Board#: MP-32-2022-2412).
Conclusions:
The insights generated from this study can be used to develop individually-targeted neurodegenerative disease prevention strategies, as well as providing critical mechanistic information.
... TDO is predominantly and constitutively expressed in the liver by the Tdo2 gene [45]. IDO is expressed predominantly in extrahepatic tissues including epididymis, intestines, spleen, lung, and brain by the Ido1 gene [46] and predominantly contributes to circulating kynurenine levels at the baseline and during inflammatory conditions [29,47], although TDO can also contribute to circulating kynurenine pools [48]. We therefore probed for Ido1 mRNA expression in the spleen, brain, and lung ( Figure 10A-C) and for Tdo2 expression in the liver ( Figure 10D). ...
Ozone (O3) is an air pollutant that primarily damages the lungs, but growing evidence supports the idea that O3 also harms the brain; acute exposure to O3 has been linked to central nervous system (CNS) symptoms such as depressed mood and sickness behaviors. However, the mechanisms by which O3 inhalation causes neurobehavioral changes are limited. One hypothesis is that factors in the circulation bridge communication between the lungs and brain following O3 exposure. In this study, our goals were to characterize neurobehavioral endpoints of O3 exposure as they relate to markers of systemic and pulmonary inflammation, with a particular focus on serum amyloid A (SAA) and kynurenine as candidate mediators of O3 behavioral effects. We evaluated O3-induced dose-, time- and sex-dependent changes in pulmonary inflammation, circulating SAA and kynurenine and its metabolic enzymes, and sickness and depressive-like behaviors in Balb/c and CD-1 mice. We found that 3 parts per million (ppm) O3, but not 2 or 1 ppm O3, increased circulating SAA and lung inflammation, which were resolved by 48 h and was worse in females. We also found that indoleamine 2,3-dioxygenase (Ido1) mRNA expression was increased in the brain and spleen 24 h after 3 ppm O3 and that kynurenine was increased in blood. Sickness and depressive-like behaviors were observed at all O3 doses (1–3 ppm), suggesting that behavioral responses to O3 can occur independently of increased SAA or neutrophils in the lungs. Using SAA knockout mice, we found that SAA did not contribute to O3-induced pulmonary damage or inflammation, systemic increases in kynurenine post-O3, or depressive-like behavior but did contribute to weight loss. Together, these findings indicate that acute O3 exposure induces transient symptoms of sickness and depressive-like behaviors that may occur in the presence or absence of overt pulmonary neutrophilia and systemic increases of SAA. SAA does not appear to contribute to pulmonary inflammation induced by O3, although it may contribute to other aspects of sickness behavior, as reflected by a modest effect on weight loss.
... This is further supported by our observed increase in KYN to Trp ratio, an index of TDO/IDO activity, in both 12-week plasma and kidney tissue from LPK rats. Since TDO and IDO are regulated by different mechanisms, 55 increased plasma and kidney levels of KP metabolites might result from activation of either enzyme. TDO expression levels are regulated mostly by systemic levels of Trp, glucagon and corticosteroids, 56 whereas the expression and activity of IDO are induced mainly by the pro-inflammatory cytokines. ...
Autosomal recessive polycystic kidney disease (ARPKD) is an early onset genetic disorder characterized by numerous renal cysts resulting in end stage renal disease. Our study aimed to determine if metabolic reprogramming and tryptophan (Trp) metabolism via the kynurenine pathway (KP) is a critical dysregulated pathway in PKD. Using the Lewis polycystic kidney (LPK) rat model of PKD and Lewis controls, we profiled temporal trends for KP metabolites in plasma, urine, and kidney tissues from 6- and 12-week-old mixed sex animals using liquid and gas chromatography, minimum n = 5 per cohort. A greater kynurenine (KYN) concentration was observed in LPK kidney and plasma of 12-week rats compared to age matched Lewis controls ( P ⩽ .05). LPK kidneys also showed an age effect ( P ⩽ .05) with KYN being greater in 12-week versus 6-week LPK. The metabolites xanthurenic acid (XA), 3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HAA) were significantly greater in the plasma of 12-week LPK rats compared to age matched Lewis controls ( P ⩽ .05). Plasma XA and 3-HK also showed an age effect ( P ⩽ .05) being greater in 12-week versus 6-week LPK. We further describe a decrease in Trp levels in LPK plasma and kidney (strain effect P ⩽ .05). There were no differences in KP metabolites in urine between cohorts. Using the ratio of product and substrates in the KP, a significant age-strain effect ( P ⩽ .05) was observed in the activity of the KYN/Trp ratio (tryptophan-2,3-dioxygenase [TDO] or indoleamine-2,3-dioxygenase [IDO] activity), kynurenine 3-monooxygenase (KMO), KAT A (kynurenine aminotransferase A), KAT B, total KAT, total KYNU (kynureninase), KYNU A, KYNU B, and total KYNU within LPK kidneys, supporting an activated KP. Confirmation of the activation of these enzymes will require verification through orthogonal techniques. In conclusion, we have demonstrated an up-regulation of the KP in alignment with progression of renal impairment in the LPK rat model, suggesting that KP activation may be a critical contributor to the pathobiology of PKD.
... The ENS is considered the 'second brain' of the gut and is made up of millions of neurons and is divided into two types of ganglia: spinal and submucosal plexus [52]. The gut microflora can control both the ENS and the CNS through neurotransmitters, neurotrophic factors, bacterial metabolites, intestinal barrier maintenance, and immune regulation [53]. The intestinal nervous system can detect over 30 neurotransmitters, most of which (ex. epinephrine, norepinephrine, acetylcholine, dopamine, and serotonin) are found in the CNS [54]. ...
Introduction and Objective. Every day, the human body is exposed to various stressors. Constant stress leads to a gradual weakening of the body, the disturbance of homeostasis and the emergence of somatic symptoms that require treatment. Due to chronic stress exposure, it seems important to support the body with natural supplementation, such as pre-pro-or synbiotics. The aim of the study was to review the latest reports from in vivo studies on the role of pre-pro-and synbiotics on the microbiota and the gut-brain axis (GBA) in stress exposure. Review methods. The article is an overview of literature reports from the past 5 years including in vivo studies examining the impact of pre-pro-and symbiotics on the gut microbiota and the GBA under stress conditions. Brief description of the state of knowledge. Data from the World Health Organization (WHO) indicate that continuous exposure to stress contributes to up to 60% of chronic diseases. An important role in responding to stress is played by a properly functioning microbiome. Numerous studies concerning the pathology of the digestive system and disturbed microbiome show their relationship with nervous system disorders, thus confirming the importance of a proper bidirectional communication between these 2 systems. Conclusions. Daily exposure to stress may disrupt the microbiota and proper functioning of the GBA. The cortisol released in response to stress is an essential physiological response that helps with coping in threatening situations. However, its release triggers a cascade of subsequent biochemical reactions dangerous to health, especially if they are triggered too often, i.e. under chronic stress. The latest scientific reports from in vivo studies clearly show that proper supplementation and diet (used with caution) can be a potential add-on therapy in the treatment of neuropsychiatric disorders. © 2022, Institute of Agricultural Medicine. All rights reserved.
... Furthermore, the expression of IDO, which metabolizes tryptophan, is known to be upregulated by glucocorticoids. 47 Higher levels of Kyn have also been linked to a decreased percentage of people taking corticosteroids, but not to the frequency of neurological symptoms in pSS patients. 35,36 In our study, although Trp levels were lower in prednisolone users and SS-A positive patients, no statistically significant difference was observed. ...
Objective
We aimed to investigate the plasma levels of tryptophan (Trp) and its metabolites in patients with primary Sjögren’s syndrome (pSS).
Methods
The study included 34 pSS patients and 42 healthy individuals, and serum Trp and kynurenine (Kyn) concentrations were measured by liquid chromatography with tandem mass spectrometry. Trp degradation was predicted using the ratio of Kyn and Trp concentrations (Kyn/Trp).
Results
In our study, the mean serum Trp concentration was found to be considerably lower in the pSS group than in the control group (P = .001). The levels of Kyn (P = .019) and the Kyn/Trp ratio (P < .001) were significantly higher in the pSS group than in the control group. The Kyn/Trp ratio was negatively correlated with C-reactive protein (r = −0.369, P = .032).
Conclusion
We found that Kyn pathway metabolism was altered in patients with pSS. This suggests that Trp metabolism may be closely linked to the disease pathogenesis of pSS.
... The Kynurenine-axis is another metabolic pathway that relies significantly on the enzymes indoleamine IDO-1 and TDO [83]. Despite acceptable stability in the activity of TDO, the activity of IDO-1 is greatly enforced in monocyte-derived cells via pro-inflammatory cytokines such as IFN-γ, IL-2, and -6 or TNF-α [84]. ...
In recent decades, neuropsychiatric disorders such as major depressive disorder, schizophrenia, bipolar, etc., have become a global health concern, causing various detrimental influences on patients. Tryptophan is an important amino acid that plays an indisputable role in several physiological processes, including neuronal function and immunity. Tryptophan’s metabolism process in the human body occurs using different pathways, including the kynurenine and serotonin pathways. Furthermore, other biologically active components, such as serotonin, melatonin, and niacin, are by-products of Tryptophan pathways. Current evidence suggests that a functional imbalance in the synthesis of Tryptophan metabolites causes the appearance of pathophysiologic mechanisms that leads to various neuropsychiatric diseases. This review summarizes the pharmacological influences of tryptophan and its metabolites on the development of neuropsychiatric disorders. In addition, tryptophan and its metabolites quantification following the neurotransmitters precursor are highlighted. Eventually, the efficiency of various biomarkers such as inflammatory, protein, electrophysiological, genetic, and proteomic biomarkers in the diagnosis/treatment of neuropsychiatric disorders was discussed to understand the biomarker application in the detection/treatment of various diseases.
... Additionally, alterations in the microbiome appear to play a role in mental disorders, so the peripheral measured TRYCATs might also hint at reduced microbiome functions in SMI (Ortega et al., 2022). Furthermore, TRYCATs themselves seem to be regulated brain-speci cally (Badawy, 2017) and vary in their ability to pass the brain-blood barrier (Fukui et al., 1991, Marx, Lane, et al., 2021. Recently, in a secondary analysis of the SCZ dataset of the Psychiatric Genomic Consortium (PGC), an interaction (rs13265509, p = 1.1×10 − 7 ) in a locus containing the IDO2 (Indoleamine 2,3-dioxygenase 2) gene, which also plays a role in the kynurenine pathway, was reported to be associated with gene-sex interaction in SCZ (Blokland et al., 2022). ...
Background
Previous studies have linked disturbances in the kynurenine pathway, responsible for the main catabolism of tryptophan and a key regulator of the immune system, to mental disorders such as major depressive disorder (MDD), bipolar disorder (BD) or schizophrenia (SCZ). However, the relationship between tryptophan catabolism and the presentation of psychiatric disorders seems to be rather complex, as up to now results have mostly been inconsistent or even contradictory. In this study, we measured plasma levels of tryptophan catabolites (TRYCATs: tryptophan, kynurenine, kynurenic acid and quinolinic acid) in a sample of in total 175 participants consisting of individuals suffering from an acute disease episode seeking inpatient treatment as well as healthy controls (HC) to investigate whether individual metabolites could serve as a biomarker for differential diagnosis.
Results
Significantly decreased levels of tryptophan, kynurenine, kynurenic acid and quinolinic acid were found in the patient group as a whole. This was mainly driven by the difference between BD patients and HC. Specifically, the manic symptom domain in manic and mixed phase BD patients displayed significantly lower kynurenine and kynurenic acid levels. We could not find significant differences between the psychiatric disorders disqualifying TRYCATs as biomarkers for differential diagnosis. None of the assessed potential demographic or pharmaceutical confounding factors revealed a significant correlation to TRYCAT concentrations. Upon reaching (partial) remission, the changes in TRYCAT levels partially normalized in the patient group.
Conclusions
Our data suggests an involvement of the kynurenine pathway in mental disorders, especially BD. Although we cannot prove a causal relationship, underlying mechanisms might include pro-inflammatory states in the central nervous system and/or increased neurotoxicity contributing to the immune assault. Also considering the manifold, but inconsistent previous analyses regarding TRYCAT concentrations in psychiatric disease, larger, cross-sectional and longitudinal studies will be needed for detangling the mystery about the role the tryptophan catabolism plays in the pathophysiology of mental disorders and for answering the burning question if it might constitute a possible therapeutic target in the future.
... The main kynurenine pathway enzymes are shown in red. IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase; KATs, kynurenine aminotransferases; KYNU, kynureninase; KMO, kynurenine 3-monooxigenase; 3HAO, 3hydroxyanthranilic acid dioxygenase; QPRT, quinolinic acid phosphoribosyltransferase; ACMSD, aminocarboxymuconate-semialdehyde decarboxylase; NAD, nicotinamide adenine dinucleotide; CoA, coenzyme A. is converted to N′-formylkynurenine by the action of either TDO mainly in liver or IDO extrahepatically (Bender, 1983;Badawy, 2017). Most previous studies on KP regulation have focused on the first and most rate-limiting enzyme, hepatic TDO. ...
Inflammatory disorders are associated with the activation of tryptophan (TRYP) catabolism via the kynurenine pathway (KP). Several reports have demonstrated the role of KP in the immunopathophysiology of both leprosy and coronavirus disease 19 (COVID-19). The nervous system can be affected in infections caused by both Mycobacterium leprae and SARS-CoV-2, but the mechanisms involved in the peripheral neural damage induced by these infectious agents are not fully understood. In recent years KP has received greater attention due the importance of kynurenine metabolites in infectious diseases, immune dysfunction and nervous system disorders. In this review, we discuss how modulation of the KP may aid in controlling the damage to peripheral nerves and the effects of KP activation on neural damage during leprosy or COVID-19 individually and we speculate its role during co-infection.
... In addition, although we excluded the subjects who consumed L-tryptophan containing supplements, we didn't consider the effect of consuming protein and tryptophan-rich diet on KYN levels. 31 Even though, our results are consistent with other research with regard to the significant correlation between KYN and eGFR reported in similar populations. 10,11,20,22 In conclusion, the study findings have demonstrated that the increase in CKD stages and the regression in kidney functions are associated with the significant increase in KYN level in CKD patients. ...
Background
Chronic kidney disease (CKD) is a worldwide issue due to the high prevalence and the serious complications, including death. Kidney functions are routinely evaluated by measuring creatinine levels, which are influenced by many factors (age, sex, diet, race, and body mass). Kynurenine is the first stable metabolite in the kynurenine pathway, which is activated in the course of CKD. Kynurenine levels in plasma can be correlated to kidney functions in CKD patients. We investigated the relationship between kynurenine levels and kidney functions indicators, and the influence of some variables (sex, age, and preexisting hypertension or diabetes) on its levels in CKD patients.
Material And Methods
The study included 66 CKD patients in stages 3 to 5 seen at Tishreen University Hospital, and 22 subjects served as control. Kynurenine levels were measured by using a kynurenine ELISA kit (IDK ® immundiagnostik).
Results
Kynurenine levels were significantly increased with the increase in CKD stage ( P < .001), and were correlated with eGFR ( r = −.631, P < .001), creatinine levels ( r = −.464, P < .001), and urea levels ( r = .528, P < .001). Kynurenine plasma levels were not influenced by age, sex, diabetes, and hypertension in CKD patients.
Conclusion
Kynurenine is a promising marker for estimating kidney functions, and its relation with kidney functions is not affected by age, sex, and presence of hypertension or diabetes in CKD patients.
... There is a wide range of foods in which tryptophan is abundant, such as: red meat, fish, eggs, chess, soybeans, bread, oat bran, and cruciferous vegetables (1,2). After consumption of food containing L-Trp, host cells can carry out their metabolism via two major metabolic pathways known as the kynurenine pathway and the serotonin pathway (3). Of the total dietary tryptophan, about 95% is metabolized via the kynurenine pathway by two ratelimiting enzymes found in various tissues of the body, namely: the liver (tryptophan 2,3-dioxygenase (TDO)) and extrahepatic tissues (indoleamine 2,3) -dioxygenase (IDO)) (4-6) (Fig. 1). ...
Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine synthesized in vertebrates mainly in the pineal gland, and is known to be involved mainly in thermoregulation and control of the circadian rhythm. That indoleamine can affect the auto-, para- and endocrine pathways, regulating body functions and affecting the metabolism of animals and humans. In addition to the pineal gland, melatonin can be synthesized in many extra-pineal tissues, mainly in the gastrointestinal tract. Previous studies have shown that melatonin plays an important role in the defense system of the gastrointestinal mucosa, demonstrating a protective effect on the gastrointestinal tract and the acceleration of healing of chronic ulcers through the scavenging of reactive oxygen metabolites (ROS) and the activation of protective nitric oxide (NO) and vasodilator neuropeptides released from the sensory afferent neurons. The process of converting the melatonin precursor L-tryptophan into melatonin is already known, but not all aspects of this process for the synthesis of other metabolites of this pathway have been fully elucidated and this issue remains poorly understood. In this study, the conversion of L-tryptophan to melatonin and other metabolites was determined in gastric mucosa collected from rats with or without intragastric (i.g.) melatonin or L-tryptophan administration, both administered at a single dose of 50 mg/kg. For the determination of five metabolites of L-tryptophan: kynurenine, 5-hydroxytryptamine, 5-hydroxytryptophan, anthranilic acid, indole-3-acetic acid together with melatonin, we have modified the previously developed high-performance liquid chromatography (HPLC) method using a native fluorescence detection system and UV-VIS. The obtained results show that: 1) L-tryptophan is converted into melatonin in the gastric mucosa during the day, e.g. after eating a meal containing L-tryptophan, as it was imitated and confirmed by our study, in which this amino acid was administered directly to the stomach, 2) the gastric mucosa is capable of producing melatonin in much greater amounts than those recorded in the blood serum of rats given a single dose of L-tryptophan, and 3) apart from melatonin, the only serum levels of these five metabolites of the L-tryptophan metabolic pathway are detectable, while their level in the gastric mucosa is low and barely detectable under physiological conditions. Our present observations support the notion that the gastric mucosa is one of the main sources of melatonin production from L-tryptophan outside the pineal gland.
... Vitamin B group and iron content are known to mediate activity of enzymes engaged in tryptophan metabolism. Vitamin B6 was found to be vital for functioning of tryptophan hydroxylase (serotonin pathway enzyme), kynureninase (produce 3-hydroxyanthranillic acid from 3-hydroxykynurenic acid) and kynurenine aminotransferase (KATs) (produce KYNA from kynurenine) (Majewski et al., 2016) and the activity of kynurenine mono-oxygenase (KMO) is dependent on Vitamin B2 (Badawy, 2017b). The rate limiting step of KP is the activation of IDO/TDO enzyme which is dependent on heme iron. ...
The present study is conducted to understand the association of mood profile with the kynurenine pathway (KP) metabolites, and cerebral hemodynamics in freshly recruited central armed forces personnel. Profile of Mood States questionnaire was utilized to assess mood profile, and Total Mood Disturbance (TMD) score was calculated. Transcranial Doppler was used to record blood flow velocity bilaterally of the middle cerebral artery. Chromatographic profile of the kynurenine metabolites was obtained in serum. Further, personnel were stratified according to sociodemographic variables (gender, age and diet) to observe the changes in their KP metabolic status. An activation of the kynurenic acid branch of the KP and the reduction in the mean blood flow velocity, and an increase in Gosling pulsatility index (PI) were observed in females having high TMD score. On gender comparative analysis, kynurenine metabolites of quinolinic acid branch and serotonin were significantly high in males. In males, with increase in age, a significant increase in the quinolinic acid branch of the KP was observed. Furthermore, a significant difference in level metabolites of the KP among the vegetarian and non-vegetarian groups was also observed. In conclusion we observed that increased TMD score was associated with cerebral hypoperfusion and higher vascular resistance along with activation of the KP. Our findings highlighted the importance of multi-facet brain function to showcase the close interaction of various dimensionalities and true picture of the assessee.
... Abbreviations: AD, Alzheimer's disease; ASD, autism spectrum disorder; MS, multiple sclerosis; PD, Parkinson's disease; HDP, host defense proteins; EC, enterochromaffin cells; 5-HT, 5-hydroxytryptamine (serotonin); SCFAs, short-chain fatty acids; GABA, g-aminobutyric acid; LPS, lipopolysaccharide; TPH, tryptophan hydroxylase. and immunity (42,60,61). How these microbial products influence brain function still needs to be elucidated, since blood-brain barrier (BBB) and several feedback loops inhibit direct access to the brain. ...
The human body is full of an extensive number of commensal microbes, consisting of bacteria, viruses, and fungi, collectively termed the human microbiome. The initial acquisition of microbiota occurs from both the external and maternal environments, and the vast majority of them colonize the gastrointestinal tract (GIT). These microbial communities play a central role in the maturation and development of the immune system, the central nervous system, and the GIT system and are also responsible for essential metabolic pathways. Various factors, including host genetic predisposition, environmental factors, lifestyle, diet, antibiotic or nonantibiotic drug use, etc., affect the composition of the gut microbiota. Recent publications have highlighted that an imbalance in the gut microflora, known as dysbiosis, is associated with the onset and progression of neurological disorders. Moreover, characterization of the microbiome-host cross talk pathways provides insight into novel therapeutic strategies. Novel preclinical and clinical research on interventions related to the gut microbiome for treating neurological conditions, including autism spectrum disorders, Parkinson's disease, schizophrenia, multiple sclerosis, Alzheimer's disease, epilepsy, and stroke, hold significant promise. This review aims to present a comprehensive overview of the potential involvement of the human gut microbiome in the pathogenesis of neurological disorders, with a particular emphasis on the potential of microbe-based therapies and/or diagnostic microbial biomarkers. This review also discusses the potential health benefits of the administration of probiotics, prebiotics, postbiotics, and synbiotics and fecal microbiota transplantation in neurological disorders.
... Approximately 95% of the ingested Trp is degraded into kynurenine, kynurenic acid, xanthurenic acid, quinolinic acid, and picolinic acid through the kynurenine pathway. Additionally, approximately 1-2% of the ingested Trp is degraded into 5-HT and melatonin through the 5-HT pathway [28]. There are two major synthetic routes of 5-HT in the brain stem and peripheral neurons. ...
Citation: Liu, N.; Sun, S.; Wang, P.; Sun, Y.; Hu, Q.; Wang, X. The Mechanism of Secretion and Metabolism of Gut-Derived 5-Hydroxytryptamine. Int. J. Mol. Sci.
... The activity of TDO, which is predominantly expressed in the liver, is substrate-regulated and thus relatively stable (at least in the absence of glucocorticoids). In contrast, the activity of IDO-1 is strongly induced in monocyte-derived cells by pro-inflammatory cytokines, mainly IFN-, but also IL-2 and -6 or TNF-↵ play a role, and is inhibited by anti-inflammatory cytokines such as IL-4 [17][18][19]. The serum/plasma kynurenine to tryptophan ratio has been established as a proxy for IDO-1 activity when paralleled by elevated levels of pro-inflammatory mediators such as neopterin [20]. ...
Immune-mediated inflammatory processes and oxidative stress are involved in the aetiopathogenesis of bipolar disorder (BD) and weight-associated comorbidities. Tryptophan breakdown via indoleamine 2,3-dioxygenase-1 (IDO-1) along the kynurenine axis concomitant with a pro-inflammatory state was found to be more active in BD, and associated with overweight/obesity. This study aimed to investigate tryptophan metabolism in BD compared to controls (C), stratified by weight classes, in a longitudinal setting, dependent on the incidence of BD episodes. Peripheral tryptophan, kynurenine, and neopterin were assessed in the serum of 226 BD individuals and 142 C. Three samples in a longitudinal assessment were used for 75 BD individuals. Results showed a higher kynurenine/tryptophan in both BD compared to C and overweight compared to normal weight persons. Levels remained stable over time. In the longitudinal course, no differences were found between individuals who were constantly euthymic or not, or who had an illness episode or had none. Findings indicate that tryptophan, kynurenine, and IDO-1 activity may play a role in pathophysiology in BD but are not necessarily associated with clinical manifestations. Accelerated tryptophan breakdown along the kynurenine axis may be facilitated by being overweight. This may increase the risk of accumulation of neurotoxic metabolites, impacting BD symptomatology, cognition, and somatic comorbidities.
... In regards to neuronal pathways, the vagus nerve (VN) acts as a link between the gut and the brain by providing a physical connection from the enteric nervous system (ENS) to the CNS [57]. Although the precise mechanisms by which the brain and microbiota are functionally linked remain to be elucidated, we know that the brain can regulate gastrointestinal functions by triggering the release of signalling molecules from intestinal cells into the gut lumen [58]. In turn, microbe-derived metabolites such as neurotransmitters, hormones, choline metabolites, vitamins and SCFAs can both directly and indirectly influence the CNS physiology. ...
Metabolism and nutrition have a significant role in epigenetic modifications such as DNA methylation, which can influence gene expression. Recently, it has been suggested that bioactive nutrients and gut microbiota can alter DNA methylation in the central nervous system (CNS) through the gut–brain axis, playing a crucial role in modulating CNS functions and, finally, behavior. Here, we will focus on the effect of metabolic signals in shaping brain DNA methylation during adulthood. We will provide an overview of potential interactions among diet, gastrointestinal microbiome and epigenetic alterations on brain methylation and behavior. In addition, the impact of different diet challenges on cytosine methylation dynamics in the adult brain will be discussed. Finally, we will explore new ways to modulate DNA hydroxymethylation, which is particularly abundant in neural tissue, through diet.
... By the aging process, the activity of TDO and IDO decreased, and mild inflammation associated with the aging process may be explained by the activation of IDO [15]. It was indicated that changes in the level of various anti-inflammatory and pro-inflammatory cytokines contribute to increasing serum levels of KYN, NEOP, decreased serum levels of TRP, and consequently greater levels of KYN/TRP ratio in elder adults [16,17]. All these alterations are accompanied by chronic inflammation that induces various illnesses such as cardiovascular diseases, cancers, and type 2 diabetes in elder individuals [18]. ...
Background
Regular physical activity may create a positive effect on aging-related immune activation.AimsThe present study aimed to evaluate the effects of 12 weeks of resistance training (RT) on serum levels of interferon-gamma (IFN-γ), neopterin (NEOP), tryptophan (TRP), kynurenine (KYN), and KYN/TRP ratio in elderly men.Methods30 elderly men (age 66.23 ± 0.57 years) were randomly divided into two groups: resistance training group (RET, n = 15) and control group (CTR, n = 15). Participants in RET carried out 12 weeks of resistance training protocols with an intensity of 60% one-repetition maximum (3 x/week, 4 sets of the six exercise circuits). Anthropometric measurements and blood samples were assessed before (pre-test) and after (post-test) of a 12-week intervention.ResultsThe results showed that there was a significant increase in the levels of TRP in RET (P < 0.05). Also, a significant decrease was observed in the levels of IFN-γ, NEOP, KYN, and KYN/TRP ratio in RET (P < 0.05). Also, results indicated a significant difference between the RET and CTR in the levels of IFN-γ, TRP, KYN, and KYN/TRP ratio (P < 0.05). However, there were no significant differences between RET and CTR in the levels of NEOP (P > 0.05).Conclusion
Our results show the positive effect of resistance training on enhancing TRP and decreasing KYN, NEOP, and KYN/TRP ratio in elderly men. It seems that regular resistance training may have beneficial effects on aging-related immune activation.
... Tryptophan (Trp), an essential amino acid, has four known downriver metabolism pathways: the kynurenine, decarboxylation and transamination and serotonin pathways [13]. An overwhelming percentage of tryptophan is catabolized along the kynurenine pathway and generates a variety of metabolites with recognized biological roles in regulating immune responses [14,15]. ...
Plenty of research has revealed virus induced alternations in metabolic pathways, which is known as metabolic reprogramming. Studies focusing on COVID-19 have uncovered significant changes in metabolism, resulting in the perspective that COVID-19 is a metabolic disease. Reprogramming of amino acid, glucose, cholesterol and fatty acid is distinctive characteristic of COVID-19 infection. These metabolic changes in COVID-19 have a critical role not only in producing energy and virus constituent elements, but also in regulating immune response, offering new insights into COVID-19 pathophysiology. Remarkably, metabolic reprogramming provides great opportunities for developing novel biomarkers and therapeutic agents for COVID-19 infection. Such novel agents are expected to be effective adjuvant therapies. In this review, we integrate present studies about major metabolic reprogramming in COVID-19, as well as the possibility of targeting reprogrammed metabolism to combat virus infection.
... Microbiota have a key role in regulating the metabolism of tryptophan, an essential amino acid that comes from the food we eat. Tryptophan is the precursor for serotonin, but the majority of tryptophan in the body is metabolized through the kynurenine pathway (metabolites include quinolinic acid and kynurenic acid, which have neurotoxic and neuroprotective properties, respectively), whereas only a small percentage of tryptophan is metabolized to serotonin (80)(81)(82)(83)(84). Tryptophan is metabolized to a wide variety of metabolites after initial catabolism by indoleamine-2.3deoxygenase ...
Major depressive disorder (MDD) is a prominent cause of disability worldwide. Current antidepressant drugs produce full remission in only about one-third of MDD patients and there are no biomarkers to guide physicians in selecting the best treatment for individuals. There is an urgency to learn more about the etiology of MDD and to identify new targets that will lead to improved therapy and hopefully aid in predicting and preventing MDD. There has been extensive interest in the roles of the immune system and the gut microbiome in MDD and in how these systems interact. Gut microbes can contribute to the nature of immune responses, and a chronic inflammatory state may lead to increased responsiveness to stress and to development of MDD. The gut microbiome-immune system-brain axis is bidirectional, is sensitive to stress and is important in development of stress-related disorders such as MDD. Communication between the gut and brain involves the enteric nervous system (ENS), the autonomic nervous system (ANS), neuroendocrine signaling systems and the immune system, and all of these can interact with the gut microbiota. Preclinical studies and preliminary clinical investigations have reported improved mood with administration of probiotics and prebiotics, but large, carefully controlled clinical trials are now necessary to evaluate their effectiveness in treating MDD. The roles that several gut microbe-derived molecules such as neurotransmitters, short chain fatty acids and tryptophan play in MDD are reviewed briefly. Challenges and potential future directions associated with studying this important axis as it relates to MDD are discussed.
... In the last two decades, a theory has emerged that metabolism of TRP via KP is involved in the control of immune responses, to keep autoimmunity in check [28][29][30]. TRP is an essential amino acid critical for protein synthesis and the generation of several bioactive compounds with important physiological functions, including serotonin, tryptamine, indoles, kynurenines, and nicotinamide adenine dinucleotide (NAD+) [31]. Humans lack the biochemical pathways to synthesize TRP, which must be gathered from the diet. ...
The kynurenine pathway (KP) is highly regulated in the immune system, where it promotes immunosuppression in response to infection or inflammation. Indoleamine 2,3-dioxygenase 1 (IDO1), the main enzyme of KP, has a broad spectrum of activity on immune cells regulation, controlling the balance between stimulation and suppression of the immune system at sites of local inflammation, relevant to a wide range of autoimmune and inflammatory diseases. Various autoimmune diseases, among them endocrinopathies, have been identified to date, but despite significant progress in their diagnosis and treatment, they are still associated with significant complications, morbidity, and mortality. The precise cellular and molecular mechanisms leading to the onset and development of autoimmune disease remain poorly clarified so far. In breaking of tolerance, the cells of the innate immunity provide a decisive microenvironment that regulates immune cells’ differentiation, leading to activation of adaptive immunity. The current review provided a comprehensive presentation of the known role of IDO1 and KP activation in the regulation of the innate and adaptive arms of the immune system. Significant attention has been paid to the immunoregulatory role of IDO1 in the most prevalent, organ-specific autoimmune endocrinopathies—type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis.
Background:
Accumulating evidence have shown that diet and nutrition play significant roles in mental illness, such as depression, anxiety and bipolar disorder. However, comprehensive evaluation of the relationship between nutrition and schizophrenia is lacking.
Objective:
The present review aims to synthetic elaborate the associations between nutrition and schizophrenia. Relevant studies on dietary patterns, macronutrients, micronutrients were performed through a literature search to synthesize the extracted data.
Summary:
Dietary interventions may help prevent the occurrence of schizophrenia, or delay symptoms: Healthy diets like nutritious plant-based foods and high-quality protein, have been linked to reducing the risk or symptoms of schizophrenia. Moreover, diet high in saturated fat and sugar is linked to more serious outcomes of schizophrenia. Additionally, when N-acetylcysteine acts as an adjuvant therapy, the overall symptoms of schizophrenia are significantly reduced. Also nascent evidence showed mental disorders may be related to intestinal microbiota dysfunction. Our study offered important insights into the dietary habits of patients with schizophrenia and the potential impact of nutritional factors on the disease. We also emphasized the need for further research, particularly in the form of large randomized double-blind controlled trials, to better understand the effects of nutrients on schizophrenia symptoms in different populations and disease types.
The radiotracer 1-(2-[18 F]fluoroethyl)-L-tryptophan (L-[18 F]FETrp or [18 F]FETrp) is a substrate of indoleamine 2,3-dioxygenase (IDO), the initial and key enzyme of the kynurenine pathway associated with tumoral immune resistance. In preclinical PET studies, [18 F]FETrp is highly accumulated in a wide range of primary and metastatic cancers, such as lung cancer, prostate cancer, and gliomas. However, the clinical translation of this radiotracer into the first-in-human trial has not been reported, partially due to its racemization during radiofluorination which renders the purification of the final product challenging. However, efficient purification is essential for human studies in order to assure radiochemical and enantiomeric purity. In this work, we report a fully automated radiosynthesis of [18 F]FETrp on a Synthra RNPlus research module, including a one-pot two steps radiosynthesis, dual independent chiral and reverse-phase semi-preparative HPLC purifications, and solid-phase extraction (SPE) assisted formulation. The presented approach has led to its Investigational New Drug (IND) application and approval that allows the testing of this tracer in humans.
Background: Depression is reportedly associated with alterations in kynurenine pathway metabolites (kynurenines). Several kynurenines are involved in glutamate signaling, and some have potentially neurotoxic effects while others are considered neuroprotective. The pathway is upregulated under inflammatory conditions, which is associated with depression. Modulation of kynurenine metabolism has been investigated as a potential mechanism in electroconvulsive therapy (ECT), an effective treatment for major depressive disorder, particularly in late-life depression. However, results have been inconclusive. Here we aimed to investigate changes in tryptophan and kynurenines in older patients treated with ECT. Methods: We analyzed levels of tryptophan, eight kynurenine pathway metabolites and the inflammation marker neopterin in serum samples collected at baseline and after a full ECT series for 48 patients with late-life depression from the Dutch MODECT study. Results: There were no significant changes in the concentration of single metabolites after ECT, but a significant reduction in the ratio of kynurenic acid to 3-hydroxykynurenine (KA/HK). Analyses of change in kynurenines after ECT in remitters and non-remitters revealed no clear patterns or link to the therapeutic effect of ECT. There was considerable covariation between neopterin and several kynurenines. Limitations: Variations in diet and serum collection timing may have impacted the results. Conclusions: This study did not show consistent changes in the kynurenine pathway activation or balance between neuroactive metabolites after ECT. Still, changes in kynurenines were strongly related to changes in neopterin concentrations. This demonstrates the importance of considering inflammation when investigating the effect of ECT on the kynurenine pathway.
Background:
Inflammatory cytokine interleukin-6 (IL-6) plays a pivotal role in skeletal muscle degradation after intra-abdominal sepsis (IAS), with mechanism remained to be elucidated. Indoleamine 2,3-dioxygenase 1 (IDO-1), a key enzyme in converting tryptophan into kynurenine, could be activated by IL-6, and kynurenine has been shown to be involved in muscle degradation. We hypothesized that IL-6 could promote muscle degradation via tryptophan-IDO-1-kynurenine pathway in IAS patients.
Methods:
Serum and rectus abdominis (RA) were obtained from IAS or non-IAS patients. Mouse model of IAS-induced muscle wasting was generated by caecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection. IL-6 signalling was blocked by anti-mouse IL-6 antibody (IL-6-AB), and the IDO-1 pathway was blocked by navoximod. To elucidate the role of kynurenine in muscle mass and physiology, kynurenine was administered to IAS mice treated with IL-6-AB.
Results:
Compared to non-IAS patients, kynurenine levels in serum (+2.30-fold vs. non-IAS, P < 0.001) and RA (+3.11-fold vs. non-IAS, P < 0.001) were elevated, whereas tryptophan levels in serum (-53.65% vs. non-IAS, P < 0.01) and RA (-61.39% vs. non-IAS, P < 0.01) were decreased. Serum IL-6 level of the IAS group was significantly higher compared to non-IAS patients (+5.82-fold vs. non-IAS, P = 0.01), and muscle cross-sectional area (MCSA) was markedly reduced compared to non-IAS patients (-27.73% vs. non-IAS, P < 0.01). In animal experiments, IDO-1 expression was up-regulated in the small intestine, colon and blood for CLP or LPS-treated mice, and there was correlation (R2 = 0.66, P < 0.01) between serum and muscle kynurenine concentrations. Navoximod significantly mitigated IAS-induced skeletal muscle loss according to MCSA analysis (+22.94% vs. CLP, P < 0.05; +23.71% vs. LPS, P < 0.01) and increased the phosphorylated AKT (+2.15-fold vs. CLP, P < 0.01; +3.44-fold vs. LPS, P < 0.01) and myosin heavy chain (+3.64-fold vs. CLP, P < 0.01; +2.13-fold vs. LPS, P < 0.01) protein expression in myocytes. In the presence of anti-IL-6 antibody, a significantly decreased IDO-1 expression was observed in the small intestine, colon and blood in CLP or LPS mice (all P < 0.01), whereas the decrease of MCSA was alleviated (+37.43% vs. CLP + IgG, P < 0.001; +30.72% vs. LPS + IgG, P < 0.001). In contrast, additional supplementation of kynurenine decreased the MCSA in septic mice treated with IL-6-AB (both P < 0.01).
Conclusions:
This study provided novel insights into the tryptophan-IDO-1-kynurenine-dependent mechanisms that underlie inflammatory cytokine-induced skeletal muscle catabolism during intra-abdominal sepsis.
Objectives
Kynurenine, kynurenic and quinolinic acid are important metabolites in tryptophan metabolism. Due to an involvement in glutamatergic neurotransmission and immune response, previous studies have investigated this pathway in mental disorders such as major depressive disorder (MDD), bipolar disorder (BD) or schizophrenia (SCZ). Tryptophan and kynurenine have been shown to be decreased across disorders, hinting at the missing link how inflammation causes neurotoxicity and psychiatric symptoms. The main aim of our study was to investigate if individual catabolites could serve as diagnostic biomarkers for MDD, BD and SCZ.
Methods
We measured plasma levels of tryptophan, kynurenine, kynurenic acid, quinolinic acid and ratio of quinolinic acid/kynurenic acid using mass spectrometry in n= 175 participants with acute episodes and after remission, compared with controls.
Results
Decreased levels of all tryptophan catabolites were found in the whole patient group, driven by the difference between BD and HC. Manic and mixed phase BD individuals displayed significantly lower kynurenine and kynurenic acid levels. We could not find significant differences between disorders. Upon reaching remission, changes in catabolite levels partially normalized.
Conclusions
Our data suggests an involvement of the kynurenine pathway in mental disorders, especially BD but disqualifying those metabolites as biomarkers for differential diagnosis.
Vascular cognitive impairment (VCI) and depression frequently coexist in geriatric populations and reciprocally increase disease risks. We assert that a shared pre-disease state of the psycho-immune-neuroendocrine (PINE) network model mechanistically explains bidirectional associations between VCI and depression. Five pathophysiological sub-networks are identified that are shared by VCI and depression: neuroinflammation, kynurenine pathway imbalance, hypothalamic-pituitary-adrenal (HPA) axis overactivity, impaired neurotrophic support and cerebrovascular dysfunction. These do not act independently, and their complex interactions necessitate a systems biology approach to better define disease pathogenesis. The PINE network is already established in the context of non-communicable diseases (NCDs) such as depression, hypertension, atherosclerosis, coronary heart disease and type 2 diabetes mellitus. We build on previous literature to specifically explore mechanistic links between MDD and VCI in the context of PINE pathways and discuss key mechanistic commonalities linking these comorbid conditions and identify a common pre-disease state which precedes transition to VCI and MDD. We expand the model to incorporate bidirectional interactions with biological ageing. Diathesis factors for both VCI and depression feed into this network and the culmination of shared mechanisms (on an ageing substrate) lead to a critical network transition to one or both disease states. A common pre-disease state underlying VCI and depression can provide clinicians a unique opportunity for early risk assessment and intervention in disease development. Establishing the mechanistic elements and systems biology of this network can reveal early warning or predictive biomarkers together with novel therapeutic targets. Integrative studies are recommended to elucidate the dynamic networked biology of VCI and depression over time.
Alcohol (ethanol-EtOH) is among the most popularly consumed beverage globally. EtOH was earlier demonstrated to elicit cognitive impairment and depressive-like effects in both human and animal studies. Rutin (R) is known for its antioxidant, anti-inflammatory, immunomodulatory and anti-depressive properties among others. Herein, we investigate the impact of rutin on EtOH-induced cognitive impairment and depressive-like effects in rats and the involvement of the indoleaminergic pathway. Three groups of eight rats each were orally exposed to drinking water (group 1), EtOH (5 g/kg bwt)-group 2 (via oral gavage), and EtOH + R (5 g/kg bwt + 50 mg/kg bwt)-group 3 (via oral gavage) for 35 days. Results showed that exposure to EtOH significantly (p < 0.0001) reduced spontaneous alternation in Y-maze and increased immobility time in tail suspension test (TST) which indicates cognitive impairment and depressive-like behavior in rats. We observed increased IDO activity/expression, and inflammatory responses, with attendant disruption in antioxidant systems and concomitant elevation in malondialdehyde (MDA) levels in the cerebral cortex and hippocampus. Following rutin co-exposure, an EtOH-mediated increase in IDO activity/expression and decrease in antioxidant enzymes in addition to an increase in markers of inflammatory response and MDA production was significantly (p < 0.0001) prevented compared with control. Additionally, altered behavioral indices were prevented by rutin co-exposure. Taken together these findings reveals the involvement of the indoleaminergic pathway in rutin preventive influence against EtOH-induced cognitive impairment and depressive-like behavior in rats.
Neurological and psychiatric disorders are a category of chronic diseases that are widespread and pose serious mental and physical health problems for patients. The substrates, products, and enzymes of Tryptophan metabolism all contribute to the development of neurological and psychiatric disorders. This paper deals with three metabolic pathways of tryptophan that produce a series of metabolites called tryptophan Catabolics (TRYCATs). These metabolites are involved in pathological processes such as excitotoxicity, neuroinflammation, oxidative stress, and mitochondrial damage and are closely associated with neurological and psychiatric disorders such as Alzheimer’s disease and depression. Here, we review the elements that affect how tryptophan metabolism is regulated, including inflammation and stress, exercise, vitamins, minerals, diet and gut microbes, glucocorticoids, and aging, as well as the downstream regulatory effects of tryptophan metabolism, including the regulation of glutamate (Glu), immunity, G-protein coupled receptor 35 (Gpr35), nicotinic acetylcholine receptor (nAChR), aryl hydrocarbon receptor (AhR), and dopamine (DA). In order to advance the general understanding of tryptophan metabolism in neurological and psychiatric disorders, this paper also summarizes the current situation and effective drugs of tryptophan metabolism in the treatment of neurological and psychiatric disorders and considers its future research prospects.
The gut microbiota is an essential part of the gastrointestinal tract and recent research including clinical and preclinical studies, shed light on the interaction between the gut and the brain. A rising amount of evidence strongly proves the involvement of gut microbes in brain function and their contribution in altering behavior, mood, and ultimately in the pathogenesis of certain neurological conditions. The gut microbiota produces and modulates neurotransmitters such as GABA, serotonin, dopamine, glutamate, etc. Furthermore, there is a presence of a biological link between the microbiota, immune signaling, and CNS suggesting that microbial metabolites could regulate both neurological and immunological activities in the brain. Thus, this review focuses on the bidirectional communication between the gut and brain; its impact and role in the modulation of various neurological disorders such as schizophrenia, depression, anxiety, etc. and attempts to explore the underlying mechanism for the same. The article also discusses studies involving germ-free mice, studies on the effects of faeces transfer of microbiota and research involving the composition of gut microbiota in animal models. The effects of probiotics, and prebiotics on neurological disorders are also discussed, along with the clinical studies for each of them. In nutshell, extensive studies are required to explore this bidirectional communication between the gut and brain, which might help researchers to develop new therapeutic targets in treating neurological disorders and increase our understanding of the gut-brain axis.
Obesity and aging predispose to numerous, yet overlapping chronic diseases. For example, metabolic abnormalities, including insulin resistance (IR) and type 2 diabetes (T2D) are important causes of morbidity and mortality. Low‐grade chronic inflammation of tissues, such as the liver, visceral adipose tissue and neurological tissues, is considered a significant contributor to these chronic diseases. Thus, it is becoming increasingly important to understand what drives this inflammation in affected tissues. Recent evidence, especially in the context of obesity, suggests that the intestine plays an important role as the gatekeeper of inflammatory stimuli that ultimately fuel low‐grade chronic tissue inflammation. In addition to metabolic diseases, abnormalities in the intestinal mucosal barrier have been linked to a range of other chronic inflammatory conditions, such as neurodegeneration and aging. The flow of inflammatory stimuli from the gut is in part controlled by local immunological inputs impacting the intestinal barrier. Here, we will review the impact of obesity and aging on the intestinal immune system and its downstream consequences on gut barrier function, which is strongly implicated in the pathogenesis of obesity and age‐related diseases. In particular, we will discuss the effects of age‐related intestinal dysfunction on neurodegenerative diseases.
After the world faced the epidemic of COVID-19 caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), novel clinical evidence and genetics related to this virus are emerging. This virus presents a broad range of clinical manifestations that mainly include various asymptomatic infections and severe pneumonia that are followed by multiple organ failures which could lead to death. The immune system has a critical role in the protection of the body against viruses and diseases and the production of antibodies against pathogens. The present study aimed to investigate the effect of COVID-19 on immune responses of the body. A comprehensive collection of related clinical trials and reviews on the issue of COVID-19 were searched. The main focus of the reviewed studies was on immune response in COVID-19. In this regard, various databases of PubMed, EMBASE, Scopus, CINAHL Plus, Cochrane Library, and Google Scholar were reviewed and all related articles from 2010 to 2021 were investigated. All records were searched in the English language and finally records with the highest thematic relevance were included in the main criteria of the study. It is well-known that the immune system's response to the SARS-CoV-2 virus involves all the components of the immune system that are responsible for viral elimination and recovery of the body. However, these immune system responses are involved in the progression of COVID-19 to a severe and lethal process. When the period of COVID-19 in the body increases, the regulation between protective and altered responses will be lost because of exacerbation of the inflammatory components. Therefore, all the responsible factors which affect immunity should be investigated just like that performed in this study.
Background
Immune activation or high levels of stress may lead to increased metabolism of tryptophan during pregnancy. Porphyromonas gingivalis (Pg), the “keystone” periodontal pathogen, induces immune and indoleamine 2,3-dioxygenase (IDO) activation. Thus, we hypothesized that larger gestational decreases in tryptophan and elevations in neopterin and kynurenine would occur in pregnant women with elevated Ig G antibodies to Pg capsular (K) serotypes.
Methods
Venous blood of 52 Hispanic pregnant women with a mean age (SD) of 31.8 (5.9) years was sampled once per trimester of pregnancy (V1, V2, V3), and plasma was obtained and stored. ELISAs were used to measure Pg capsular (K) serotype IgG serointensity (V1 only) and neopterin levels (V1-V3). Tryptophan and kynurenine (V1-V3) were measured with high-performance liquid chromatography. The participants having IgG serointensity for any of the seven Pg K serotypes in the highest quartile were defined as the “High PgK_IgG” group and those having Ig G serointensity for all K serotypes in the lowest three quartiles were defined as the “Low PgK_IgG” group . Statistics included multivariable linear and nonparametric methods.
Results
Significant decreases in plasma tryptophan levels and increases in neopterin during gestation were found in “High PgK_IgG” women but not in “Low PgK_IgG”. Kynurenine changes were not significantly different between the two groups.
Conclusions
If replicated in larger studies and further characterized clinically, radiologically, and microbiologically, our results may potentially lead to novel interventional targets as well as developing more complete prognostic and predictive interactive biomarkers for adverse obstetrical outcomes and peripartum depression, and their prevention.
The intestinal mucosal barrier is critical for the absorption of nutrients and the health of both humans and animals. Recent publications from clinical and experimental studies have shown the importanceof the nutrients‐bacteria‐host interaction for the intestinal homeostasis. Dysfunction of these interactions has been reported to be associated with metabolic disorders and development of intestinal diseases, such as the irritable bowel syndrome and inflammatory bowel diseases. Tryptophan and its metabolites, including kynurenine, kynurenic acid, and 5‐hydroxytrptamine, can influence the proliferation of enterocytes, intestinal integrity and immune response, as well as intestinal microbiota, therefore regulating and contributing to the intestinal health. In this review, we highlight recent findings on the effect of tryptophan and its metabolites on the mucosal barrier and intestinal homeostasis and its regulation of innate immune response. Moreover, we present the signaling pathways related to Trp metabolism, such as mammalian target of rapamycin, aryl hydrocarbon receptor, and pregnane X receptor, that contribute to the intestinal homeostasis and discuss future perspectives on spontaneous interference in host tryptophan metabolism as potential clinical strategies of intestinal diseases. This article is protected by copyright. All rights reserved
Background
CKD, characterized by retained uremic solutes, is a strong and independent risk factor for thrombosis after vascular procedures . Urem ic solutes such as indoxyl sulfate (IS) and kynurenine (Kyn) mediate prothrombotic effect through tissue factor (TF). IS and Kyn biogenesis depends on multiple enzymes, with therapeutic implications unexplored. We examined the role of indoleamine 2,3-dioxygenase-1 (IDO-1), a rate-limiting enzyme of kynurenine biogenesis, in CKD-associated thrombosis after vascular injury.
Methods
IDO-1 expression in mice and human vessels was examined. IDO-1 −/− mice, IDO-1 inhibitors, an adenine-induced CKD, and carotid artery injury models were used.
Results
Both global IDO-1 −/− CKD mice and IDO-1 inhibitor in wild-type CKD mice showed reduced blood Kyn levels, TF expression in their arteries, and thrombogenicity compared with respective controls. Several advanced IDO-1 inhibitors downregulated TF expression in primary human aortic vascular smooth muscle cells specifically in response to uremic serum. Further mechanistic probing of arteries from an IS-specific mouse model, and CKD mice, showed upregulation of IDO-1 protein, which was due to inhibition of its polyubiquitination and degradation by IS in vascular smooth muscle cells. In two cohorts of patients with advanced CKD, blood IDO-1 activity was significantly higher in sera of study participants who subsequently developed thrombosis after endovascular interventions or vascular surgery.
Conclusion
Leveraging genetic and pharmacologic manipulation in experimental models and data from human studies implicate IS as an inducer of IDO-1 and a perpetuator of the thrombotic milieu and supports IDO-1 as an antithrombotic target in CKD.
Tryptophan (Trp) is an aromatic amino acid which is synthesized through the shikimate/chorismate pathway. Behind that this amino acid is part of proteins; the relevance of Trp resides as a precursor of secondary metabolism which includes relevant molecules such as auxin (indole-3-acetic acid, IAA), serotonin and melatonin which have a wide range of functions in higher plants including physiological processes such as seed germination, root growth and development, senescence, flowering or fruit ripening as well as in the mechanism of response against biotic and abiotic stresses. The main goal of this chapter is to provide a comprehensive overview of these pleiotropic signalling molecules and its implication in physiological processes as well as stress environmental conditions in higher plants.
Immune escape is an early phenomenon in cancer development/progression. Indoleamine 2,3-dioxygenase 1 (IDO1) is a normal endogenous mechanism of acquired peripheral immune tolerance and may therefore be tumor-promoting. This study investigated the clinical relevance of IDO1 expression by immune cells in the lymph nodes and blood and of the serum kynurenine/tryptophan (Kyn/Trp) ratio in 65 systemic treatment naïve stage I-III melanoma patients. Blood samples were collected within the first year of diagnosis. Patients had a median follow-up of 61 months. High basal IDO1 expression in peripheral monocytes and low IFNγ-induced IDO1 upregulation correlated with worse outcome independent from disease stage. Interestingly studied factors were not interrelated. During follow-up, the risk of relapse was 9% (2/22) in the subgroup with high IFNγ-induced IDO1 upregulation in monocytes. In contrast, if IDO1 upregulation was low, relapse occurred in 30% (3/10) of patients with low basal IDO1 expression in monocytes and in 61.5% (8/13) in the subgroup with high basal IDO1 expression in monocytes (Log-Rank test, p=0.008). This study reveals some immune features in the blood of early stage melanoma that may be of relevance for disease outcome. These may offer a target for sub-stratification and early intervention.
Suicide is a multifaceted phenomenon, related to an everlasting interconnection between biological, psychosocial, sociological, philosophical, and cultural aspects of human life. Immune system, which is constantly responding to changing environments and changing in response to them, seems to play a major role in this interaction. Multiple studies have reported increased risk of suicidal behaviours after or during inflammatory conditions. Individuals that engage in suicidal behaviours also have increased concentrations of inflammatory markers, such as interleukins 1β and 6, tumour necrosis factor α, and C-reactive protein, both in blood and the central nervous system (CNS). Stress, which is frequently mentioned among the major risk factors for suicidal behaviours, is also associated with a wide immune system dysregulation, entailing glucocorticoid system disruption and a low-grade inflammation. Mechanisms connecting systemic inflammation and CNS changes include damage to blood-brain barrier and interoceptive alterations, both resulting in changes in the communication between the periphery and the brain. Meanwhile, in CNS, pro-inflammatory cytokines may activate microglia causing a shift in tryptophan metabolism, preferentially generating cellular energy and toxic by-products of kynurenine pathway rather than serotonin. These changes in brain homeostasis lead to anatomical and functional brain alterations, most notably prefrontal cortex and insula, engendering maladaptive behavioural phenotypes, such as anhedonia and impulsivity that may mediate the association between inflammation and suicide. This chapter will provide a condensed overview of this complex association between inflammation and suicidal behaviours, presenting major findings in this area and explaining key pathways linking them.
The purpose of the study was to investigate whether prolonged exercises influence the activity of liver tryptophan oxygenase. Hepatic tryptophan oxygenase activity was assessed in male Wistar rats after swimming for 4, 8, 12 or 16 h. Simultaneously blood corticosterone concentration was determined in blood plasma. After swimming for 4 or 8 h the enzyme activity was increased. More prolonged swimming sets caused enzyme activities below the control level. Enzyme activity alterations were concordant with changes in blood level of corticosterone (r=0.537, p<0.01).
In 1953 Medawar pointed out that survival of the genetically disparate (allogeneic) mammalian conceptus contradicts the laws of tissue transplantation. Rapid T cell-induced rejection of all allogeneic concepti occurred when pregnant mice were treated with a pharmacologic inhibitor of indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme expressed by trophoblasts and macrophages. Thus, by catabolizing tryptophan, the mammalian conceptus suppresses T cell activity and defends itself against rejection.
Tryptophan (Trp) requirements in pregnancy are several-fold: (1) the need for increased protein synthesis by mother and for fetal growth and development; (2) serotonin for signaling pathways; (3) kynurenic acid for neuronal protection; (4) quinolinic acid for NAD+ synthesis (5) other kynurenines for suppressing fetal rejection. These goals could not be achieved if maternal plasma [Trp] is depleted. Although plasma total (free + albumin-bound) Trp is decreased in pregnancy, free Trp is elevated. The above requirements are best expressed in terms of a Trp utilisation concept. Briefly, Trp is utilised as follows: (1) In early and mid- pregnancy, emphasis is on increased maternal Trp availability to meet the demand for protein synthesis and fetal development, most likely mediated by maternal liver Trp 2,3-dioxygenase inhibition by progesterone and oestrogens. (2) In mid- and late pregnancy, Trp availability is maintained and enhanced by the release of albumin-bound Trp by albumin depletion and non- esterified fatty acid (NEFA) elevation, leading to increased flux of Trp down the kynurenine pathway to elevate immunosuppressive kynurenines. An excessive release of free Trp could undermine pregnancy by abolishing T-cell suppression by kynurenines. Detailed assessment of parameters of Trp metabolism and disposition and related measures (free and total Trp, albumin, NEFA, kynurenine and its metabolites and pro- and anti-inflammatory cytokines in maternal blood and, where appropriate, placental and fetal material) in normal and abnormal pregnancies may establish missing gaps in our knowledge of the Trp status in pregnancy and help identify appropriate intervention strategies.
Cytokines are important mediators of various aspects of health and disease, including appetite, glucose and lipid metabolism, insulin sensitivity, skeletal muscle hypertrophy and atrophy. Over the past decade or so, considerable attention has focused on the potential for regular exercise to counteract a range of disease states by modulating cytokine production. Exercise stimulates moderate to large increases in the circulating concentrations of interleukin (IL)-6, IL-8, IL- 10, IL-1 receptor antagonist, granulocyte-colony stimulating factor, and smaller increases in tumor necrosis factor-α, monocyte chemotactic protein-1, IL-1β, brain-derived neurotrophic factor, IL-12p35/p40 and IL-15. Although many of these cytokines are also expressed in skeletal muscle, not all are released from skeletal muscle into the circulation during exercise. Conversely, some cytokines that are present in the circulation are not expressed in skeletal muscle after exercise. The reasons for these discrepant cytokine responses to exercise are unclear. In this review, we address these uncertainties by summarizing the capacity of skeletal muscle cells to produce cytokines, analyzing other potential cellular sources of circulating cytokines during exercise, and discussing the soluble factors and intracellular signaling pathways that regulate cytokine synthesis (e.g., RNA-binding proteins, microRNAs, suppressor of cytokine signaling proteins, soluble receptors). Copyright © 2015 International Society of Exercise and Immunology. All rights reserved.
Functional loss of blood-brain barrier (BBB) is suggested to be pivotal to pathogenesis and pathology of vascular-based neurodegenerative disorders such as Alzheimer's disease. We recently reported in wild-type mice maintained on standard diets, progressive deterioration of capillary function with aging concomitant with heightened neuroinflammation. However, the mice used in this study were relatively young (12 months of age) and potential mechanisms for loss of capillary integrity were not investigated per se. The current study therefore extended the previous finding to investigate the effect of aging on BBB integrity in aged mice at 24 months and its potential underlying molecular mechanisms.
Immunomicroscopy analyses confirmed significantly increased capillary permeability with heightened neuroinflammation in naturally aged 24-month old mice compared to young control at 3 months of age. Aged mice showed significant attenuation in the expression of BBB tight junction proteins, occludin-1 and to lesser extent ZO-1 compared to young mice. In addition, TNF-α in cerebral endothelial cells of aged mice was significantly elevated compared to controls and this was associated with heightened peripheral inflammation. The expression of ICAM-1 and VCAM-1 remained unelevated, and no sign of leukocyte recruitment was observed in aged mice.
The BBB breakdown that occurs during ordinary aging is associated with inflammation and disruption of tight junction complex assembly but not through leukocyte trafficking.
Preeclampsia is a cardiovascular disorder of late pregnancy that is, commonly characterized by hypertension, renal structural damage and dysfunction, and fetal growth restriction. Prevailing etiologic models of this disorder include T-cell dysfunction as an initiating cause of preeclampsia. Indoleamine 2,3-dioxygenase (IDO), an enzyme that mediates the conversion of tryptophan to kynurenine, has been linked to preeclampsia in humans, and is known to regulate T-cell activity and an endothelial-derived relaxing factor. To test the hypothesis that IDO is causally involved in the pathogenesis of preeclampsia, mice deficient for IDO (IDO-KO) were generated on a C57BL/6 background. IDO-KO and wild-type C57BL/6 mice were bred, and preeclampsia phenotypes were evaluated during pregnancy. Pregnant IDO-KO mice exhibited pathognomonic renal glomerular endotheliosis, proteinuria, pregnancy-specific endothelial dysfunction, intrauterine growth restriction, and mildly elevated blood pressure compared to wild-type mice. Together these findings highlight an important role for IDO in the generation of phenotypes typical of preeclampsia. Loss of IDO function may represent a risk factor for the development of preeclampsia. By extension, increased IDO activity, reductions in IDO reactants, or increases in IDO products may represent novel therapeutic approaches for this disorder.
The pellagragenic effect of leucine (Leu) has been proposed to involve modulation of L-tryptophan (Trp) metabolism along the hepatic kynurenine pathway. Here, we discuss some of the mechanisms suggested and report the effects in healthy volunteers of single doses of Leu (4.05-6.75 g) administered in a 16-amino acid mixture on concentrations of plasma Trp and its kynurenine metabolites. Flux of Trp through Trp 2,3-dioxygenase (TDO) is dose-dependently enhanced most probably by Leu and can be attributed to TDO activation. Trp oxidation is better expressed using plasma total kynure-nines, rather than kynurenine, and free, rather than total, Trp. Increased hepatic Trp oxidation may be an additional mechanism of action of branched-chain amino acids in the acute Trp depletion test. Inhibition of intestinal absorption or hepatic uptake of Trp by Leu can be excluded. Potential mechanisms of the aggravation of pellagra symptoms by Leu are discussed.
Vitamins B2 and B6 are cofactors in the kynurenine pathway. Many of the kynurenines are neuroactive compounds with immunomodulatory effects. In the present study, we aimed to investigate plasma concentrations of vitamins B2 and B6 as determinants of kynurenines and two markers of interferon-γ-mediated immune activation (kynurenine:tryptophan ratio (KTR) and neopterin). We measured the concentrations of vitamins B2 and B6 vitamers, neopterin, tryptophan and six kynurenines (i.e. kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid) in plasma from 7051 individuals. Dietary intake of vitamins B2 and B6 was assessed using a validated FFQ. Associations were investigated using partial Spearman's correlations, generalised additive models, and segmented or multiple linear regression. The B2 vitamer, riboflavin, was positively associated with 3-hydroxyanthranilic acid and xanthurenic acid, with correlation coefficients, as obtained by segmented regression, of 0·20 (95 % CI 0·16, 0·23) and 0·24 (95 % CI 0·19, 0·28), at riboflavin concentrations below the median value (13·0 nmol/l). The vitamin B6 vitamer, pyridoxal 5'-phosphate (PLP), was positively associated with most kynurenines at PLP concentrations < 39·3-47·0 nmol/l, and inversely associated with 3-hydroxykynurenine with the association being more prominent at PLP concentrations < 18·9 nmol/l. Riboflavin and PLP were associated with xanthurenic acid only at relatively low, but normal concentrations of both vitamers. Lastly, PLP was negatively correlated with neopterin and KTR. These results demonstrate the significant and complex determination of kynurenine metabolism by vitamin status. Future studies on B-vitamins and kynurenines in relation to chronic diseases should therefore integrate data on relevant biomarkers related to B-vitamins status and tryptophan metabolism.
The decrease in maternal plasma total (free + albumin-bound) tryptophan (Trp) during the third pregnancy trimester is attributed to induction of indoleamine 2,3-dioxygenase (IDO). When measured, free [Trp] is increased because of albumin depletion and non-esterified fatty acid elevation. The Trp depletion concept in pregnancy is therefore not supported because of incorrect interpretation of changes in Trp disposition and also for not addressing mouse strain differences in Trp-related responses and potential inhibition of Trp transport by the IDO inhibitor 1-methyl tryptophan. Application of the Trp utilization concept in pregnancy offers several physiological advantages favoring fetal development and successful outcome, namely provision of Trp for fetal protein synthesis and growth, serotonin for signaling pathways, kynurenic acid for neuroprotection, quinolinic acid for NAD(+) synthesis, and other kynurenines for suppression of T cell responses. An excessive increase in Trp availability could compromise pregnancy by undermining T cell suppression, e.g., in pre-eclampsia.
IDO2 is implicated in tryptophan catabolism and immunity but its physiological functions are not well established. Here we report the characterization of mice genetically deficient in IDO2, which develop normally but exhibit defects in IDO-mediated T cell regulation and inflammatory responses. Construction of this strain was prompted in part by our discovery that IDO2 function is attenuated in macrophages from Ido1-/- mice due to altered message splicing, generating a functional mosaic with implications for interpreting findings in Ido1-/- mice. No apparent defects were observed in Ido2-/- mice in embryonic development or hematopoietic differentiation, with wild-type profiles documented for kynurenine in blood serum and for immune cells in spleen, lymph nodes, peritoneum, thymus and bone marrow of naïve mice. In contrast, upon immune stimulation we determined that IDO1-dependent T regulatory cell generation was defective in Ido2-/- mice, supporting Ido1-Ido2 genetic interaction and establishing a functional role for Ido2 in immune modulation. Pathophysiologically, both Ido1-/- and Ido2-/- mice displayed reduced skin contact hypersensitivity responses, but mechanistic distinctions were apparent, with only Ido2 deficiency associated with a suppression of immune regulatory cytokines that included GM-CSF, G-CSF, IFN-γ, TNFα, IL-6 and MCP-1/CCL2. Different contributions to inflammation were likewise indicated by the finding that Ido2-/- mice did not phenocopy Ido1-/- mice in the reduced susceptibility of the latter to inflammatory skin cancer. Taken together, our results offer an initial glimpse into immune modulation by IDO2, revealing its genetic interaction with IDO1 and distinguishing its non-redundant contributions to inflammation.
Novel methods for cytokine analysis allow for the simultaneous measurement of 25 cytokines in 50 muL serum or plasma. Data on values of most of these cytokines in non-infected newborn infants are lacking. We analyzed levels of 25 cytokines in the first week of life in non-infected preterm and term infants and related them to gestational age.
During the first week after birth, no trend over time was found in any of the cytokines, except for IL-1Ra and IL-6 where higher values were found in the first four hours. Between 24 and 72 hrs levels of IL-1Ra,IL-2,IL-8,IL-12,IL-13,IL-15,IL-17,IFNgamma,MIP-1a,MCP-1,TNFa were lower in infants born after 30-32wks compared to infants >=36wks; levels of IL-6,IL-10,IP-10 were lower in preterm infants of both 30-32 and 33-36 weeks. No difference between groups for any of the levels was found for IL-1b,IL-2r,IL-4,IL-5,IL-7,IFNa,MIP-1b,GM-CSF,Eotaxin and RANTES.
Levels of 25 interleukines are stable in the first week of life in non-infected infants. Infants born after 30-32wks showed lower levels of fourteen cytokines compared to infants born after more then 36wks. This indicates a lower stimulation or activation of Th-1 cells, monocytes and dendritic cells in these infants.
Circulating neopterin and kynurenine/tryptophan ratio (KTR) increase during inflammation and serve as markers of cellular immune activation, but data on other determinants of these markers and metabolites of the kynurenine pathway are sparse. We measured neopterin, tryptophan, kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and xanthurenic acid in plasma in two age groups, i.e 45-46 years (n=3723) and 70-72 years (n=3329). Differences across categories of the potential determinants, including: age, gender, renal function, body mass index (BMI), smoking, and physical activity were tested by Mann-Whitney U test and multiple linear regression including age group, gender, renal function, and lifestyle factors. In this multivariate model, neopterin, KTR and most kynurenines were 20-30% higher in the older group, whereas tryptophan was 7% lower. Men had 6-19% higher concentrations of tryptophan and most kynurenines than women of the same age. Compared to the 4th age-specific eGFR quartile, the 1st quartile was associated with higher concentrations of neopterin (25%) and KTR (24%), and 18-36% higher concentrations of kynurenines, except 3-hydroxyanthranilic acid. Additionally, KTR, tryptophan and all kynurenines, except anthranilic acid, were 2-8% higher in overweight and 3-17% higher in obese, than in normal weight individuals. Heavy smokers had 4-14% lower levels of tryptophan and most kynurenines than non-smokers. Age and renal function were the strongest determinants of plasma neopterin, KTR, and most kynurenines. These findings are relevant for the design and interpretation of studies investigating the role of plasma neopterin, KTR and kynurenines in chronic diseases.
Compounds that activate tryptophan pyrrolase in other animals like methylene blue, hematin, EDTA, and calciumion did not affect fish enzyme activity. Neutralized ascorbic acid showed an inhibitory effect. Time-activity and enzyme concentration-activity curves were determined in three methods of assay. Km was estimated via the Lineweaver-Burk plot to be 80mM. The enzyme was partially purified by a four-step process: solubilization, DEAE Sephadex A-50 chromatography (batch method), and by two consecutive DEAE Sepharose CL-6B chromatographs. The partially purified enzyme was highly unstable so that no characterization was at all possible. Tryptophan pyrrolase (L-tryptophan-oxygen 2, 3-oxidoreductase (decyclizing), EC 1.13.11.11) oxidizes tryptophan to formylkynurenine by opening its heterocyclic ring. In rats, this step is rate-limiting under normal conditions. The enzyme has a short life of 2.5h1) and is subject to regulation by four mechanisms: (i) substrate availability, (ii) hormonal induction, (iii)
We investigated how changes in tryptophan pyrrolase activity and tryptophan loads affect the breakdown of tryptophan was estimated by injecting rats with [ring-2-14-C]tryptophan and measuring respiratory 14-CO2. We concluded, contrary to previous reports, that induction of tryptophan pyrrolase definitely will increase the rate of tryptophan breakdown. Tryptophan loads also increase tryptophan breakdown even in circumstances where there is no increase in tryptophan pyrrolase activity, presumably by increasing the saturation of the enzyme. After a tryptophan load (50 mg per kg) the increase in liver tryptophan concentration lasts only 30 min. The rapid return of liver tryptophan to normal may be due partly to the high turnover rate of liver tryptophan. We estimate that tryptophan pyrrolase degrades tryptophan in vivo at a rate that is equivalent to the whole liver tryptophan concentration in 7.5 min or less.
There are indications that serotonergic neurotransmission is disturbed in several psychiatric disorders. One explanation may be disturbed transport of tryptophan (precursor for serotonin synthesis) across cell membranes. Human fibroblast cells offer an advantageous model to study the transport of amino acids across cell membranes, since they are easy to propagate and the environmental factors can be controlled. The aim of this study was to functionally characterize tryptophan transport and to identify the main transporters of tryptophan in fibroblast cell lines from healthy controls.
Tryptophan kinetic parameters (Vmax and Km) at low and high concentrations were measured in fibroblasts using the cluster tray method. Uptake of 3H (5)-L-tryptophan at different concentrations in the presence and absence of excess concentrations of inhibitors or combinations of inhibitors of amino acid transporters were also measured. Tryptophan transport at high concentration (0.5 mM) had low affinity and high Vmax and the LAT1 isoform of system-L was responsible for approximately 40% of the total uptake of tryptophan. In comparison, tryptophan transport at low concentration (50 nM) had higher affinity, lower Vmax and approximately 80% of tryptophan uptake was transported by system-L with LAT1 as the major isoform. The uptake of tryptophan at the low concentration was mainly sodium (Na+) dependent, while uptake at high substrate concentration was mainly Na+ independent. A series of different transporter inhibitors had varying inhibitory effects on tryptophan uptake.
This study indicates that tryptophan is transported by multiple transporters that are active at different substrate concentrations in human fibroblast cells. The tryptophan transport trough system-L was mainly facilitated by the LAT1 isoform, at both low and high substrate concentrations of tryptophan.
A simple, rapid isocratic liquid chromatographic procedure with ultraviolet and fluorimetric detection is described for the separation and quantification of L-tryptophan (Trp) and six of its kynurenine metabolites (kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic, kynurenic, xanthurenic and anthranilic acids). Using the Perkin Elmer LC 200 system, a reverse phase Synergi 4 μ fusion-RP80 A column (250 × 4.6 mm) (Phenomenex), and a mobile phase of 10 mM sodium dihydrogen phosphate: methanol (73:27, by vol) at pH 2.8 and a flow rate of 1.0-1.2 ml/min at 37 °C, a run took ∼13 min. The run took <7 min at 40 °C and a 1.4 ml/min flow rate. Limits of detection of all 7 analytes were 5-72 nM and their recoveries from human plasma and rat serum and liver varied between 62% and 111%. This simple method is suitable for high throughput work and can be further developed to include quinolinic acid and other Trp metabolites.
Many aspects of serotonergic activity, both central and peripheral in origin, undergo significant changes with human aging. These alterations might predispose elderly people to develop mood disorders. Because previous work showed that increasing the peripheral availability of tryptophan (TRP) to the brain holds antidepressant properties, this study evaluated whether TRP availability to the brain is increased during prolonged exercise in older men.
Nineteen males age 64 ± 3 yr completed a treadmill exercise bout at an HR eliciting ∼68% V˙O(2peak) for 60 min. Fasting blood was collected at rest, after 30 and 60 min of exercise, and at 90 min (after exercise). Branched-chain amino acids (BCAA), total and free TRP, prolactin, ammonia, nonesterified fatty acids, glucose, and lactate were measured.
Changes in free TRP/BCAA ratio and prolactin were used as peripheral proxies of central serotonin synthesis rate and activity. The free TRP/BCAA ratio observed at baseline was increased by 102% after 1 h of exercise (P < 0.0001) and remained elevated after exercise (78% above baseline, P < 0.001). The free TRP portion in serum increased from 2.8 ± 0.7 to 5.7 ± 1.8 μmol·L⁻¹ after 1 h of exercise (P < 0.001) and was strongly correlated with plasma nonesterified fatty acid contents (r₁₇ = 0.887, P < 0.0001, all time points). Serum prolactin was significantly elevated after 1 h of exercise (8.6 ± 2.4 μg·L⁻¹, P < 0.001) and was positively correlated with free TRP/BCAA ratio (r₁₆ = 0.48, P < 0.05, all time points).
These results concur with previous observations in younger men and unveil that significant elevations in TRP availability to the brain are encountered during sustained exercise in older men. These results provide support to the hypothesis that increases in serotonin synthesis and activity might be involved in the antidepressant effect of exercise in the elderly.
The kynurenine pathway of tryptophan catabolism plays an important role in several biological systems affected by aging. We quantified tryptophan and its metabolites kynurenine (KYN), kynurenine acid (KYNA), picolinic acid (PIC) and quinolinic acid (QUIN), and activity of the kynurenine pathway enzymes indoleamine 2,3-dioxygenase (IDO), tryptophan 2,3-dioxygenase (TDO) and quinolinic acid phosphoribosyltransferase (QPRTase), in the brain, liver and kidney of young, middle-aged and old female Wistar rats. Tryptophan levels and TDO activity decreased in all tissues with age. In contrast, brain IDO activity increased with age, while liver and kidney IDO activity decreased with age. The levels of KYN, KYNA, QUIN and PIC in brain all increased with age, while the levels of KYN in the liver and kidney showed a tendency to decrease. The levels of KYNA in the liver did not change, but the levels of KYNA in the kidney increased. The levels of PIC and QUIN increased significantly in the liver but showed a tendency to decrease in the kidney. QPRTase activity in both brain and liver decreased with age but was elevated in the kidney in middle-aged (12-month-old) rats. These age-associated changes in tryptophan metabolism have the potential to impact upon major biological processes, including lymphocyte function, pyridine (NAD(P)(H)) synthesis and N-methyl-d-aspartate (NMDA)-mediated synaptic transmission, and may therefore contribute to several degenerative changes of the elderly.
The aims were to provide proofs of mechanism and principle by establishing the ability of kynurenine metabolites to inhibit the liver mitochondrial low K(m) aldehyde dehydrogenase (ALDH) activity after administration and in vivo, and to induce aversion to alcohol.
Kynurenic acid (KA), 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HAA) were administered to normal male Wistar rats and ALDH activity was determined both in vitro in liver homogenates and in vivo (by measuring blood acetaldehyde following ethanol administration). Alcohol consumption was studied in an aversion model in rats and in alcohol-preferring C57 mice.
ALDH activity was significantly inhibited by all three metabolites by doses as small as 1 mg/kg body wt. Blood acetaldehyde accumulation after ethanol administration was strongly elevated by KA and 3-HK and to a lesser extent by 3-HAA. All three metabolites induced aversion to alcohol in rats and decreased alcohol preference in mice.
The above kynurenine metabolites of tryptophan induce aversion to alcohol by inhibiting ALDH activity. An intellectual property covering the use of 3-HK and 3-HAA and derivatives thereof in the treatment of alcoholism by aversion awaits further development.
1-methyl-D-tryptophan (1-D-MT) is currently being used in clinical trials in patients with relapsed or refractory solid tumors with the aim of inhibiting indoleamine-2,3-dioxygenase (IDO)-mediated tumor immune escape. IDO is expressed in tumors and tumor-draining lymph nodes and degrades tryptophan (trp) to create an immunsuppressive micromilieu both by depleting trp and by accumulating immunosuppressive metabolites of the kynurenine (kyn) pathway. Here we show that proliferation of alloreactive T-cells cocultured with IDO1-positive human cancer cells paradoxically was inhibited by 1-D-MT. Surprisingly incubation with 1-D-MT increased kyn production of human cancer cells. Cell-free assays revealed that 1-D-MT did not alter IDO1 enzymatic activity. Instead, 1-D-MT induced IDO1 mRNA and protein expression through pathways involving p38 MAPK and JNK signalling. Treatment of cancer patients with 1-D-MT has transcriptional effects that may promote rather than suppress anti-tumor immune escape by increasing IDO1 in the cancer cells. These off-target effects should be carefully analyzed in the ongoing clinical trials with 1-D-MT.
It is increasingly recognized that psychological stress influences inflammatory responses and mood. Here, we investigated whether psychological stress (combined acoustic and restraint stress) activates the tryptophan (Trp) catabolizing enzyme indoleamine 2,3-dioxygenase 1(IDO1) and thereby alters the immune homeostasis and behavior in mice. We measured IDO1 mRNA expression and plasma levels of Trp catabolites after a single 2-h stress session and in repeatedly stressed (4.5-days stress, 2-h twice a day) naïve BALB/c mice. A role of cytokines in acute stress-induced IDO1 activation was studied after IFNgamma and TNFalpha blockade and in IDO1(-/-) mice. RU486 and 1-Methyl-L-tryptophan (1-MT) were used to study role of glucocorticoids and IDO1 on Trp depletion in altering the immune and behavioral response in repeatedly stressed animals. Clinical relevance was addressed by analyzing IDO1 activity in patients expecting abdominal surgery. Acute stress increased the IDO1 mRNA expression in brain, lung, spleen and Peyer's patches (max. 14.1+/-4.9-fold in brain 6-h after stress) and resulted in a transient depletion of Trp (-25.2+/-6.6%) and serotonin (-27.3+/-4.6%) from the plasma measured 6-h after stress while kynurenine levels increased 6-h later (11.2+/-9.3%). IDO1 mRNA up-regulation was blocked by anti-TNFalpha and anti-IFNgamma treatment. Continuous IDO1 blockade by 1-MT but not RU486 treatment normalized the anti-bacterial defense and attenuated increased IL-10 inducibility in splenocytes after repeated stress as it reduced the loss of body weight and behavioral alterations. Moreover, kynurenic acid which remained increased in 1-MT treated repeatedly stressed mice was identified to reduce the TNFalpha inducibility of splenocytes in vitro and in vivo. Thus, psychological stress stimulates cytokine-driven IDO1 activation and Trp depletion which seems to have a central role for developing stress-induced immunosuppression and behavioral alteration. Since patients showed Trp catabolism already prior to surgery, IDO is also a possible target enzyme for humans modulating immune homeostasis and mood.
Chronic low-grade inflammation is a characteristic of ageing that may lead to alterations in health status and quality of life. In addition to intrinsic biological factors, recent data suggest that poor nutritional habits may largely contribute to this condition. The present study aimed at assessing mental and physical components of quality of life and at determining their relationship to vitamin E status, inflammation and tryptophan (TRP) metabolism in the elderly. Sixty-nine elderly subjects recruited from the Three-City cohort study participated in the study. Quality of life was assessed using the medical outcomes study thirty-six-item short-form health survey (SF-36). Biological assays included the measurement of plasma vitamin E (alpha-tocopherol), inflammatory markers, including IL-6 and C-reactive protein, and TRP metabolism. Results showed that participants with poor physical health status, as assessed by the SF-36, exhibited lower circulating concentrations of alpha-tocopherol together with increased concentrations of inflammatory markers. Similarly, poor mental health scores on the SF-36 were associated with lower concentrations of alpha-tocopherol, but also with decreased concentrations of TRP. These findings indicate that nutritional status, notably as it relates to vitamin E, is associated with immune function and quality of life in the elderly.
Although nutrients, including amino acids and their metabolites such as serotonin (5-HT), are strong modulators of anxiety-related behavior, the metabolic pathway(s) responsible for this physiological modulation is not fully understood. Regarding tryptophan (Trp), the initial rate-limiting enzymes for the kynurenine pathway of tryptophan metabolism are tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). Here, we generated mice deficient for tdo (Tdo(-/-)). Compared with wild-type littermates, Tdo(-/-) mice showed increased plasma levels of Trp and its metabolites 5-hydroxyindoleacetic acid (5-HIAA) and kynurenine, as well as increased levels of Trp, 5-HT and 5-HIAA in the hippocampus and midbrain. These mice also showed anxiolytic modulation in the elevated plus maze and open field tests, and increased adult neurogenesis, as evidenced by double staining of BrdU and neural progenitor/neuronal markers. These findings demonstrate a direct molecular link between Trp metabolism and neurogenesis and anxiety-related behavior under physiological conditions.
Regulation of human immune cell cytokine production in vivo is not well understood due in part to limitations on imposing experimental conditions. We proposed that life-imposed conditions (pregnancy, birth, age, gender), combined with large sample size, repeat sampling, and family-based recruitment would serve to reveal peripheral blood cell-derived cytokine patterns reflective of in vivo regulation regarding Th1/Th2 balance and familial correlation. Mononuclear cells were obtained from 483 trios in the Tucson Infant Immune Study: from mothers pre- and postpartum, infants at birth and at 3 mo, and fathers. Con A/PMA-stimulated supernatants were assayed by ELISA for IFN-gamma, IL-4, IL-13, IL-5, and IL-10 and allergen-stimulated supernatants for IFN-gamma, IL-4, and IL-13. Mitogen-stimulated prepartum samples were not globally Th2 biased, differing from postpartum only by a modestly reduced IFN-gamma:IL-5 ratio. Prepartum samples actually produced less IL-10 and IL-13 although more IL-5 than paternal samples. Newborns were also not globally Th2 biased, with mitogen stimulation producing approximately 10-fold less IL-4, IL-5, and IFN-gamma than adults but only 2- to 3-fold less IL-13 and IL-10. Despite these group differences, all cytokines showed marked positive intraindividual correlations (all p < 0.001). Allergen stimulation gave results consistent with a lack of global Th2 bias. Mitogen stimulation revealed parent-child and parent-parent correlations. Thus, rather than a global Th2 bias, cytokine production in pregnant mothers and newborns appears regulated so as to maintain a relative balance among the cytokines, with the nature of the balance differing in mothers and infants and with production influenced by familial factors that include shared environment.
Oxidation of tryptophan and urinary excretion of N¹-methylnicotinamide were studied in weanling rats fed ad libitum for 10 days 12% casein diets containing from 0 to 500 mg of nicotinamide per kilogram of diet. N¹-methylnicotinamide was measured in urine collected during the last 3 days of the experiment. After the feeding period, rats fed the niacin-free and 500 mg nicotinamide diets were placed in metabolic cages, and each rat was given 4 g (dry weight) of diet containing a tracer dose of dl-[7a-¹⁴C]tryptophan. Expired CO2 was collected hourly for 10 hours. From rats consuming levels of nicotinamide ranging between 20 and 150 mg/kg of diet, N¹-methylnicotinamide excretion increased linearly with increasing nicotinamide intake. From these results and others from this laboratory (4), it was calculated that an additional 10–11 mg of dietary tryptophan above the approximately 20 mg/day essential for growth are needed by the growing rat for the formation of 1 mg of nicotinamide. The addition of 500 mg of nicotinamide per kilogram of diet to a niacin-free diet had no effect on the oxidation of dl-[7a-¹⁴C] tryptophan.
We have previously hypothesized that mental fatigue is caused by neuronal brain