Positive Effects of Probiotic Therapy in Patients with Post-Infectious Fatigue.

Post-infectious fatigue is a common complication that can lead to decreased physical efficiency, depression, and impaired quality of life. Dysbiosis of the gut microbiota has been proposed as a contributing factor, as the gut-brain axis plays an important role in regulating physical and mental health. This pilot study aimed to investigate the severity of fatigue and depression, as well as the quality of life of 70 patients with post-infectious fatigue who received a multi-strain probiotic preparation or placebo in a double-blind, placebo-controlled trial. Patients completed questionnaires to assess their fatigue (fatigue severity scale (FSS)), mood (Beck Depression Inventory II (BDI-II)), and quality of life (short form-36 (SF-36)) at baseline and after 3 and 6 months of treatment. Routine laboratory parameters were also assessed, including immune-mediated changes in tryptophan and phenylalanine metabolism. The intervention was effective in improving fatigue, mood, and quality of life in both the probiotic and placebo groups, with greater improvements seen in the probiotic group. FSS and BDI-II scores declined significantly under treatment with both probiotics and placebo, but patients who received probiotics had significantly lower FSS (p < 0.001) and BDI-II (p < 0.001) scores after 6 months. Quality of life scores improved significantly in patients who received probiotics (p < 0.001), while patients taking a placebo only saw improvements in the "Physical limitation" and "Energy/Fatigue" subcategories. After 6 months neopterin was higher in patients receiving placebo, while no longitudinal changes in interferon-gamma mediated biochemical pathways were observed. These findings suggest that probiotics may be a promising intervention for improving the health of patients with post-infectious fatigue, potentially through modulating the gut-brain axis.

Interferon-gamma Mediated Metabolic Pathways in Hospitalized Patients During Acute and Reconvalescent COVID-19.

Background: Fatigue, sleep disturbance, and neurological symptoms during and after COVID-19 are common and might be associated with inflammation-induced changes in tryptophan (Trp) and phenylalanine (Phe) metabolism. Aim: This pilot study investigated interferon gamma inducible biochemical pathways (namely Trp catabolism, neopterin, tyrosine [Tyr], and nitrite formation) during acute COVID-19 and reconvalescence. Patients and methods: Thirty one patients with moderate to severe COVID-19 admitted to the University Hospital of Innsbruck in early 2020 (March-May) were followed up. Neurotransmitter precursors Trp, Phe, Tyr as well as kynurenine (Kyn), neopterin, nitrite, and routine laboratory parameters were analyzed during acute infection and at a follow-up (FU) 60 days thereafter. Clinical symptoms of patients (neurological symptoms, fatigue, sleep disturbance) were recorded and associations with concentrations of laboratory parameters investigated. Results and conclusion: Almost half of the patients suffered from neurological symptoms (48.4%), the majority of patients experienced sleep difficulties (56.7%) during acute COVID-19. Fatigue was present in nearly all patients. C-reactive protein (CRP), interleukin-6 (IL-6), neopterin, Kyn, Phe concentrations were significantly increased, and Trp levels depleted during acute COVID-19. Patients with sleep impairment and neurological symptoms during acute illness presented with increased CRP and IL-6 concentrations, Trp levels were lower in patients with sleep disturbance. In general, inflammatory markers declined during reconvalescence. A high percentage of patients suffered from persistent symptoms at FU (neurological symptoms: 17.2%, fatigue: 51.7%, sleeping disturbance: 34.5%) and had higher CRP concentrations. Nitrite and Phe levels were lower in patients with sleeping difficulties at FU and Kyn/Trp ratio, as indicator of IDO activity, was significantly lower in patients with neurological symptoms compared to patients without them at FU. In summary, inflammation induced alterations of amino acid metabolism might be related to acute and persisting symptoms of COVID-19.

High frequency repetitive transcranial magnetic stimulation improves cognitive performance parameters in patients with Alzheimer's disease - an exploratory pilot study.

BACKGROUND: Currently available medication for Alzheimer's disease (AD) may slows cognitive decline only transitory, but has failed to bring about long term positive effects. For this slowly progressive neurodegenerative disease so far no disease modifying therapy exists. OBJECTIVE: To find out if non-pharmacologic non-ivasive neuromodulatory repetitive transcranial magnetic stimulation (rTMS) may offer a new alternative or an add on therapeutic strategy against loss of cognitive functions. METHODS: In this exploratory intervention study safety and symptom development before and after frontopolar cortex stimulation (FPC) using intermittent theta burst stimulation (iTBS) at 10 subsequent working days was monitored as add-on treatment in 28 consecutive patients with AD. Out of these, 10 randomly selected patients received sham stimulation as a control. In addition, ​serum concentrations of neurotransmitter precursor amino acids, of immune activation and inflammation markers, of brain derived neurotrophic factor (BDNF) as well as of nitrite were measured. RESULTS: Treatment was well tolerated, no serious adverse effects were observed. Improvement of cognition was detected by an increase of Mini Mental State Examination score (MMSE; p<0.01, paired rank test) and also by an increase in a modified repeat address phrase test, part of the 6-item cognitive ​impairment test (p < 0.01). A trend to an increase in the clock drawing test (CDT; p = 0.08) was also found in the verum treated group. Furtheron, in 10 of the AD patients with additional symptoms of depression treated with iTBS, a significant decrease in the HAMD-7 scale (p <0.01) and a trend to lower serum phenylalanine concentrations (p = 0.08) was seen. No changes of the parameters tested were found in the sham treated patients. CONCLUSION: Our preliminary results may indicate that iTBS is effective in the treatment of AD. Also a slight influence of iTBS on the metabolism of phenylalanine was found after 10 iTBS sessions. An impact of iTBS to influence the enzyme phenylalanine hydroxylase (PAH), as found in previous series of treatment resistant depression, could not be seen in this our first observational trial in 10 AD patients with comorbidity of depression. Longer treatment periods for several weeks in a higher number of AD patients with depression could cause more intense and disease modifying effects visible in different neurotransmitter concentrations important in the pathogenesis of AD.

Tryptophan-kynurenine metabolism during acute alcohol withdrawal in patients with alcohol use disorder: The role of immune activation.

BACKGROUND: Recent research has suggested that excessive alcohol consumption in patients with alcohol use disorder (AUD) is associated with chronic immune activation, which affects the metabolism of the neurotransmitter precursor amino acid tryptophan (TRP) and contributes to the complex pathophysiology of AUD. Our study investigated possible immune-associated alterations of TRP to kynurenine (KYN) metabolism in patients with AUD during acute alcohol withdrawal. METHODS: We measured serum concentrations of TRP, KYN, quinolinic (QUIN), kynurenic acid (KYNA), and the immune activation marker neopterin (NEO) at the first, fifth and 10th day of alcohol withdrawal in patients with AUD, who attended a standardized in-patient treatment program and underwent a detailed clinical assessment. RESULTS: Data from these individuals were compared to data from a reference control group (RCG). The primary outcome measures were the differences in serum concentrations of metabolites between AUD patients and RCG and correlations between NEO and metabolites of the tryptophan-kynurenine pathway. r = 0.695, p < 0.001) in the AUD group. Mixed models analysis showed that NEO concentrations were positively associated with QUIN but not with KYNA concentrations. Several behavioral symptoms correlated positively with QUIN concentrations and negatively with the KYNA/QUIN ratio. CONCLUSIONS: Our findings demonstrate that the changes in TRP catabolism in acute alcohol withdrawal resulting in increased KYN production could reflect the involvement of immune-associated activation of the enzyme indoleamine 2,3-dioxygenase, as NEO concentrations correlated with the KYN/TRP ratio. In addition, our data show that this low-grade immune activation may cause an imbalance in the production of neurotoxic and neuroprotective kynurenine metabolites in AUD.

High indoleamine-2,3-dioxygenase 1 (IDO) activity is linked to primary resistance to immunotherapy in non-small cell lung cancer (NSCLC).

BACKGROUND: Metabolic profiling in non-small cell lung cancer (NSCLC) may identify key metabolic vulnerabilities and shows enormous discovery potential. Preclinical studies showed that metabolic rewiring in cancer plays an essential role in modulation of immunotherapy response. However, this situation is understudied in the clinical setting. Therefore, we aimed to evaluate the plasma metabolic profile of immune checkpoint inhibitor (CI) responding versus non-responding NSCLC patients. The aim of this project is to identify potential predictive biomarkers for CI response. METHODS: Plasma samples from CI treated NSCLC patients were analysed at baseline and at the first follow up scan by using a broad targeted metabolomics mass spectrometry panel, and were compared to healthy controls. For further validation of identified key alterations high-performance liquid chromatography (HPLC) for tryptophan (Trp) and kynurenine (Kyn) as indicator of IDO-activity was performed. RESULTS: Sixty-seven metabolites were significantly altered in NSCLC patients compared to healthy controls. The metabolic profile of patients with primary CI resistance showed an increase in indoleamine-2,3-dioxygenase (IDO) and a decrease in branched-chain amino acids (BCAA) compared to baseline concentrations. Deregulated IDO activity was validated by additional HPLC measurements, which revealed that baseline Trp levels were predictive for CI response. According to receiver operating characteristic (ROC)-analysis baseline Trp levels ≥49.3 µmol/L predicted disease control at the first follow up scan with a sensitivity of 89% and a specificity of 71%. CONCLUSIONS: We showed that NSCLC patients are characterized by a distinct metabolic profile compared to healthy controls. Moreover, metabolic changes during CI therapy were observed. Of those IDO metabolism seemed to play an important role in primary CI resistance. Trp as a surrogate parameter of IDO activity is a promising biomarker in patients undergoing treatment with CIs and might be a future marker in trials investigating IDO inhibitors.

The Immunopathogenesis of Alzheimer's Disease Is Related to the Composition of Gut Microbiota.

The microbiota-gut-brain axis plays an important role in the development of neurodegenerative diseases. Commensal and pathogenic enteric bacteria can influence brain and immune system function by the production of lipopolysaccharides and amyloid. Dysbiosis of the intestinal microbiome induces local and consecutively systemic immune-mediated inflammation. Proinflammatory cytokines then trigger neuroinflammation and finally neurodegeneration. Immune-mediated oxidative stress can lead to a deficiency of vitamins and essential micronutrients. Furthermore, the wrong composition of gut microbiota might impair the intake and metabolization of nutrients. In patients with Alzheimer's disease (AD) significant alterations of the gut microbiota have been demonstrated. Standard Western diet, infections, decreased physical activity and chronic stress impact the composition and diversity of gut microbiota. A higher abundancy of "pro-inflammatory" gut microbiota goes along with enhanced systemic inflammation and neuroinflammatory processes. Thus, AD beginning in the gut is closely related to the imbalance of gut microbiota. Modulation of gut microbiota by Mediterranean diet, probiotics and curcumin can slow down cognitive decline and alter the gut microbiome significantly. A multi-domain intervention approach addressing underlying causes of AD (inflammation, infections, metabolic alterations like insulin resistance and nutrient deficiency, stress) appears very promising to reduce or even reverse cognitive decline by exerting positive effects on the gut microbiota.

On the Possible Relevance of Bottom-up Pathways in the Pathogenesis of Alzheimer's Disease.

Dementia is an increasing health problem in older aged populations worldwide. Age-related changes in the brain can be observed decades before the first symptoms of cognitive decline appear. Cognitive impairment has chronic inflammatory components, which can be enhanced by systemic immune activation. There exist mutual interferences between inflammation and cognitive deficits. Signs of an activated immune system i.e. increases in the serum concentrations of soluble biomarkers such as neopterin or accelerated tryptophan breakdown along the kynurenine axis develop in a significant proportion of patients with dementia and correlate with the course of the disease, and they also have a predictive value. Changes in biomarker concentrations are reported to be associated with systemic infections by pathogens such as cytomegalovirus (CMV) and bacterial content in saliva. More recently, the possible influence of microbiome composition on Alzheimer's disease (AD) pathogenesis has been observed. These observations suggest that brain pathology is not the sole factor determining the pathogenesis of AD. Interestingly, patients with AD display drastic changes in markers of immune activation in the circulation and in the cerebrospinal fluid. Other data have suggested the involvement of factors extrinsic to the brain in the pathogenesis of AD. However, currently, neither the roles of these factors nor their importance has been clearly defined.

Pharmacological Targets of Kaempferol Within Inflammatory Pathways-A Hint Towards the Central Role of Tryptophan Metabolism.

The flavonoid kaempferol is almost ubiquitously contained in edible and medicinal plants and exerts a broad range of interesting pharmacological activities. Interactions with central inflammatory processes can be exploited to treat or attenuate symptoms of disorders associated with chronic immune activation during infections, malignancies, and neurodegenerative or cardiovascular disorders. Many drugs, phytochemicals, and nutritional components target the catabolism of the essential amino acid tryptophan by indoleamine 2,3-dioxygenase 1 (IDO-1) for immunomodulation. We studied the effects of kaempferol by in vitro models with human peripheral blood mononuclear cells (PBMC) and THP-1 derived human myelomonocytic cell lines. Kaempferol suppressed interferon-γ dependent immunometabolic pathways: Formation of the oxidative stress biomarker neopterin and catabolism of tryptophan were inhibited dose-dependently in stimulated cells. In-silico docking studies revealed a potential interaction of kaempferol with the catalytic domain of IDO-1. Kaempferol stimulated nuclear factor kappa B (NF-κB) signaling in lipopolysaccharide (LPS)-treated THP-1 cells, thereby increasing the mRNA expression of interleukin (IL) 1 beta, tumor necrosis factor, and nuclear factor kappa B subunit 1, while IL6 was downregulated. Data suggest that concerted effects of kaempferol on multiple immunologically relevant targets are responsible for its immunomodulatory activity. However, the immunosuppressive effects may be more relevant in a T-cell dominated context.

Tryptophan Metabolism and Related Pathways in Psychoneuroimmunology: The Impact of Nutrition and Lifestyle.

In the past, accelerated tryptophan breakdown was considered to be a feature of clinical conditions, such as infection, inflammation, and malignant disease. More recently, however, the focus has changed to include the additional modulation of tryptophan metabolism by changes in nutrition and microbiota composition. The regulation of tryptophan concentration is critical for the maintenance of systemic homeostasis because it integrates essential pathways involved in nutrient sensing, metabolic stress response, and immunity. In addition to tryptophan being important as a precursor for the synthesis of the neurotransmitter serotonin, several catabolites along the kynurenine axis are neuroactive. This emphasizes the importance of the immunometabolic fate of this amino acid for processes relevant to neuropsychiatric symptoms. In humans, besides hepatic catabolism, there is usually a strong relationship between immune activation-associated tryptophan breakdown and increased levels of biomarkers, such as neopterin, which has particular relevance for both acute and chronic diseases. A shift towards neopterin synthesis during oxidative stress may indicate a corresponding decrease in tetrahydrobiopterin, a cofactor of several mono-oxygenases, providing a further link between tryptophan metabolism and serotonergic and catecholaminergic neurotransmission. The psychoneuroimmunological consequences of tryptophan metabolism and the susceptibility of this pathway to modulation by a variety of nutritional and lifestyle-related factors have important implications for the development of both diagnostic and treatment options.

Neopterin levels and Kyn/Trp ratios were significantly increased in dengue virus patients and subsequently decreased after recovery.

OBJECTIVES: During dengue fever, a pronounced gamma-interferon immune response produces neopterin and promotes tryptophan degradation by the enzyme indoleamine-2,3-dioxygenase 1 (IDO-1). Activated IDO-1 is indicated by an increased kynurenine to tryptophan ratio (Kyn/Trp) in patients. METHODS: Plasma levels of neopterin, kynurenine, and tryptophan were measured in 72 hospitalized dengue virus (DENV) patients and 100 healthy individuals. Plasma levels of neopterin, kynurenine, and tryptophan were also measured prospectively in a second cohort of 13 DENV patients; on the day of hospitalization, on day 2-3 at discharge, and 7-10 days after discharge. DENV RNA positivity was determined by qualitative and quantitative methodologies. RESULTS: DENV RNA-positive patients presented significantly higher levels of neopterin (mean 36.5nmol/l) and Kyn/Trp ratios (mean 102µmol/mmol) compared to DENV RNA-negative individuals. A significant correlation between neopterin levels and Kyn/Trp ratios was observed in both DENV RNA-positive (Spearman's rho=0.37, p< 0.01) and DENV RNA-negative (Spearman's rho=0.89, p<0.001) patients. Kyn/Trp ratios were negatively correlated with platelet counts (Spearman's rho=-0.43, p<0.01) and positively correlated with liver enzymes: AST (Spearman's rho=0.68, p<0.01) and ALT (Spearman's rho=0.51, p<0.05). In addition, the follow-up data presented a significant decrease in neopterin levels and Kyn/Trp ratios within 10 days after hospital entry. CONCLUSIONS: Neopterin levels and Kyn/Trp ratios were significantly increased in DENV patients and subsequently decreased after recovery.

Tolerability of inhaled N-chlorotaurine in humans: a double-blind randomized phase I clinical study.

BACKGROUND: N-chlorotaurine (NCT), a long-lived oxidant produced by human leukocytes, can be synthesized chemically and used topically as a well-tolerated antiseptic to different body regions including sensitive ones. The aim of this study was to test the tolerability of inhaled 1% NCT in aqueous solution upon repeated application. METHODS: The study was performed double-blind and randomized with a parallel test group (1% NCT) and control group (0.9% NaCl as placebo). There were two Austrian centres involved, the hospitals, Natters and Vöcklabruck. Healthy, full age volunteers were included, 12 in each centre. A total of 12 patients were treated with NCT, and 12 with placebo, exactly half of each group from each centre. The single dose was 1.2 ml inhaled over a period of 10 min using an AKITA JET nebulizer. One inhalation was done every day for five consecutive days. The primary criterion of evaluation was the forced expiratory volume in 1 second (FEV1). Secondary criteria were subjective sensations, further lung function parameters such as airway resistance, physical examination, and blood analyses (gases, electrolytes, organ function values, pharmacokinetic parameters taurine and methionine, immune parameters). RESULTS: All included 15 females and 9 males completed the treatment and the control examinations according to the study protocol. FEV1 (100.83% ± 8.04% for NCT and 92.92% ± 11.35% for controls) remained unchanged and constant during the treatment and in control examinations 1 week and 3 months after the treatment (98.75% ± 7.37% for NCT and 91.17% ± 9.46% for controls, p > 0.082 between time points within each group). The same was true for all other objective parameters. Subjective mild sensations with a higher frequency in the test group were chlorine taste ( p < 0.01) and occasional tickle in the throat ( p = 0.057). Taurine and methionine plasma concentrations did not change within 60 min after inhalation or later on. CONCLUSIONS: Inhaled NCT is well tolerated as in other applications of different body regions. Side effects are mild, topical and transitory. The study was registered prospectively in the European Clinical Trials Database of the European Medicines Agency. The EudraCT number is 2012-003700-12.

Immunometabolism in the Pathogenesis of Depressive Disorders - Therapeutic Considerations.

There exists a critical link between immunological processes and metabolic changes. Furthermore, it becomes more and more evident that changes in immunometabolic pathways are highly interconnected with psychological processes and the nervous system. Depressive disorders are a major contributor to the overall burden of disease worldwide. Despite extensive research, therapeutic interventions are often not satisfying. This may be due to the yet only partially elucidated pathobiochemistry underlying the development of depression which may be influenced by multiple factors including genetics, environment, lifestyle, and importantly by the immunological status. In this review article, the roles and consequences of the interferon gamma-dependent pathways of tryptophan breakdown and neopterin formation are discussed, as well as phenylalanine metabolism, trying to provide a rational link between immunology, metabolism and mental status. Besides underlining the complexity of the mechanism involved in the development of depression, the knowledge on relevant biomarkers may be useful in orchestrating personalized therapy regimes.

Elevated fecal calprotectin in patients with Alzheimer's dementia indicates leaky gut.

Fecal concentrations of calprotectin were examined in 22 patients with Alzheimer's disease (AD) and compared with serum concentrations of aromatic amino acids. Calprotectin concentrations were mean ± SEM 140 ± 31.9 mg/kg, 16 patients (73%) presented with concentrations outside normal (>50 mg/kg). Concentrations correlated inversely with serum levels of tryptophan, tyrosine and phenylalanine (all p < 0.05). Increased concentrations of fecal calprotectin indicate a disturbed intestinal barrier function in AD patients which could be of relevance for the lowering of essential aromatic amino acids concentrations in the blood.

Lavender oil suppresses indoleamine 2,3-dioxygenase activity in human PBMC.

BACKGROUND: Lavender remedies have been used in traditional medicine because of antimicrobial, anti-inflammatory and mood alleviating effects, but underlying molecular mechanisms are not yet fully elucidated. Recently, studies investigating the effects of lavender oil in the context of psychiatric disorders have indicated potent pharmacological properties. Metabolism of tryptophan by indoleamine 2,3-dioxygenase (IDO) was found to provide a biochemical link between immunology and neuroendocrinology and to be a frequent target of natural products. METHODS: In this in vitro study, interferences of lavender oil and constituents (-)-linalool, (+)-α-pinene and (+)-limonene with tryptophan catabolism by IDO and formation of neopterin via guanosine triphosphate (GTP)-cyclohydrolase-I and of interferon-γ have been investigated using unstimulated and phytohemagglutinin (PHA)-stimulated human peripheral blood mononuclear cells (PBMC). RESULTS: Treatment with lavender oil dose-dependently suppressed PHA-induced tryptophan breakdown and kynurenine formation. Similar effects were observed for the three constituents. In parallel, formation of neopterin and interferon-γ was diminished upon lavender oil treatment. In unstimulated PBMC, effect of lavender oil treatment was similar, but less pronounced. CONCLUSION: Data from this in vitro study suggest that lavender oil treatment might contribute to the modulation of the immune and neuroendocrine system by interfering with activation-induced tryptophan breakdown and IDO activity.

Activated immune system and inflammation in healthy ageing: relevance for tryptophan and neopterin metabolism.

Immune activation not only accompanies inflammation in various disorders including infections, autoimmune syndromes and cancer, but it also represents a characteristic feature of ageing. Immune deviations which are most widely expressed in the elderly include increased neopterin production and tryptophan breakdown. These biochemical events result from the activation of the immune system and are preferentially triggered by pro-inflammatory stimuli, such as the Th1-type cytokine interferon-γ. They seem to play a role in the development of several age-related disorders and might be involved in the pathogenesis of common symptoms, including neurobehavioral disorders (e.g., cognitive and mood disturbances), anemia, cachexia, weight-loss but also immunodeficiency. Concentrations of the biomarkers neopterin and Kyn/Trp were found to be predictive of overall disease specific mortality in coronary artery disease, infections and various types of cancer. Immune activation and inflammation are also accompanied by high output of reactive oxygen species and thereby may lead to the development of oxidative stress and contribute to the vitamin deficiency which is often observed in the elderly. Accordingly, increases in neopterin were found to correlate with a substantial decline in key vitamins, including folate and vitamin-B6, - B12, -C, -D and -E.

Tryptophan metabolism in post-withdrawal alcohol-dependent patients.

AIMS: The aim of the study was to investigate the parameters of tryptophan and phenylalanine metabolism and their associations to immune system activation and to behavioural symptoms during medium-term withdrawal (4-12 weeks of abstinence) in alcohol-dependent patients. METHODS: Biochemical assays and clinical assessments at the beginning of treatment (fourth week of alcohol abstinence in average) and prior to the discharge after 8 weeks of treatment. RESULTS: Kynurenine to tryptophan ratio (Kyn/Trp) slightly correlated with neopterin levels in early post-withdrawal period (Week 4 of abstinence) but this association disappeared after 12 weeks of abstinence. Phenylalanine and tyrosine concentrations as well as phenylalanine to tyrosine ratio (Phe/Tyr) decreased between Weeks 4 and 12 of abstinence. Kynurenine and Kyn/Trp increased significantly at 12th week of abstinence when compared with the beginning of the study (Week 4 of abstinence). At Week 12, Kyn/Trp significantly correlated with such behavioural symptoms as fatigue, irritability and sleep disturbances. CONCLUSIONS: Tryptophan breakdown in early stages may be influenced by the increased activity of indoleamine 2,3-dioxygenase but the increase of Kyn/Trp between Weeks 4 and 12 of abstinence seems to be independent of immune changes and correlates with behavioural symptoms in later stages of the post-withdrawal course. A possible role of kynurenine metabolites in mediation of the increased stress sensibility in post-withdrawal alcohol-dependent patients is discussed.

Immunological alterations in individuals exposed to metal(loid)s in the Panasqueira mining area, Central Portugal.

Environmental studies performed in Panasqueira mine area (central Portugal) identified high concentrations of several metal(loid)s in environmental media, and individuals environmentally and occupationally exposed showed higher levels of As, Cr, Mg, Mn, Mo, Pb and Zn in blood, urine, hair and nails when compared to unexposed controls. To evaluate the presence of immunological alterations attributable to environmental contamination, we quantified neopterin, kynurenine, tryptophan, and nitrite concentrations in plasma, and analysed the percentage of several lymphocytes subsets, namely CD3(+), CD4(+) and CD8(+) T-cells, CD19(+) B-cells, and CD16(+)56(+) natural killer (NK) cells in a group of individuals previously tested for metal(loid) levels in different biological matrices. The environmentally exposed group had significantly lower levels of %CD8(+) and higher CD4(+)/CD8(+) ratios, whereas the occupationally exposed individuals showed significant decreases in %CD3(+) and %CD4(+), and significant increases in %CD16(+)56(+), when compared to controls. Analysed biomarkers were found to be influenced by age, particularly neopterin, kynurenine and kynurenine to tryptophan ratio (Kyn/Trp) with significantly higher levels in older individuals, and %CD3(+), %CD8(+) and %CD19(+) with significantly lower values in older individuals. Males environmentally exposed showed significantly lower values of %CD19(+) when compared to control females. The concentration of Pb in toenails was associated to the level of neopterin, kynurenine and Kyn/Trp ratio (all direct), and the concentration of Mn in blood to the level of %CD8(+), %CD19(+) (both inverse) and CD4(+)/CD8(+) ratio (direct). Overall our results show that the metal(loid) contamination in Panasqueira mine area induced immunotoxic effects in exposed populations, possibly increasing susceptibility to diseases.

TiO(2) nanoparticles and bulk material stimulate human peripheral blood mononuclear cells.

Nanomaterials are increasingly produced and used throughout recent years. Consequently the probability of exposure to nanoparticles has risen. Because of their small 1-100nm size, the physicochemical properties of nanomaterials may differ from standard bulk materials and may pose a threat to human health. Only little is known about the effects of nanoparticles on the human immune system. In this study, we investigated the effects of TiO2 nanoparticles and bulk material in the in vitro model of human peripheral blood mononuclear cells (PBMC) and cytokine-induced neopterin formation and tryptophan breakdown was monitored. Both biochemical processes are closely related to the course of diseases like infections, atherogenesis and neurodegeneration. OCTi60 (25nm diameter) TiO2 nanoparticles and bulk material increased neopterin production in unstimulated PBMC and stimulated cells significantly, the effects were stronger for OCTi60 compared to bulk material, while P25 TiO2 (25nm diameter) nanoparticles had only little influence. No effect of TiO2 nanoparticles on tryptophan breakdown was detected in unstimulated cells, whereas in stimulated cells, IDO activity and IFN-γ production were suppressed but only at the highest concentrations tested. Because neopterin was stimulated and tryptophan breakdown was suppressed in parallel, data suggests that the total effect of particles would be strongly pro-inflammatory.

Tryptophan breakdown is increased in euthymic overweight individuals with bipolar disorder: a preliminary report.

OBJECTIVES: Individuals with bipolar disorder (BD) are disproportionately affected by symptoms of being overweight and metabolic syndrome when compared to the general population. The pertinence of this observation is underscored by observations that excess weight is associated with a more complex illness presentation, course, and outcome in BD. We present the first preliminary report of our BIPFAT study, which explored shared hypothesized pathophysiological pathways between being overweight and having BD. METHODS: We investigated the tryptophan-kynurenine metabolism pathway as a proxy of dysregulated inflammatory homeostasis in euthymic, overweight individuals with BD (n = 78) compared to healthy controls (n = 156). RESULTS: Both blood kynurenine concentrations and the kynurenine to tryptophan ratio [(Kyn:Trp); an estimate of tryptophan breakdown] were significantly higher in the total sample of euthymic patients with BD, with greater increases noted in both parameters in the subsample of overweight patients with BD. When compared to controls, peripheral neopterin concentrations were significantly lower. Within the BD group, there were also significant between-group differences in neopterin concentrations, with higher levels in those who were overweight and in subjects with BD in the later stages of illness compared to earlier stages. CONCLUSIONS: Increased tryptophan breakdown, as well as neopterin levels in BD, may be an indirect mediator of immune-mediated inflammation. In BD, this may account for the high prevalence of medical comorbidities and increased mortality. The observation of increased kynurenine levels and Kyn:Trp, and altered circulating neopterin levels provides indirect evidence of increased activity of tryptophan-degrading indoleamine 2,3-dioxygenase in euthymic individuals with BD, underscoring the role of inflammatory mediators as a causative and/or consequent factor. More robust abnormalities in the overweight subsample underscore the additional inflammatory burden of medical comorbidity and suggest a shared pathophysiology as well as a mechanism mediating BD and cardiovascular disease.

Immunomodulatory properties of cacao extracts - potential consequences for medical applications.

Anti-inflammatory properties of cacao, fruits of Theobroma cacao L. (Sterculiaceae), are well documented, and therapeutic applications are described for gastrointestinal, nervous, and cardiovascular abnormalities. Most, if not all of these disease conditions involve inflammation or immune activation processes. The pro-inflammatory cytokine interferon-γ (IFN-γ) and related biochemical pathways like tryptophan breakdown by indoleamine 2,3-dioxygenase (IDO) and neopterin formation are deeply involved in their pathogenesis. Neopterin concentrations and the kynurenine to tryptophan ratio (Kyn/Trp, an estimate of IDO activity) are elevated in a significant proportion of patients with virus infections, cancer, autoimmune syndrome, neurodegeneration, and coronary artery disease. Moreover, higher neopterin and Kyn/Trp concentrations are indicative for poor prognosis. When investigating the effect of aqueous or ethanolic extracts of cacao on IFN-γ, neopterin and Kyn/Trp concentrations in mitogen-stimulated human peripheral blood mononuclear cells, breakdown of tryptophan by IDO, and formation of neopterin and IFN-γ were dose-dependently suppressed. The effects observed in the cell-based assays are associated with the antioxidant activity of the cacao extracts as determined by the cell-free oxygen radical absorption capacity assay. The influence of cacao extracts on IDO activity could be of particular relevance for some of the beneficial health effects ascribed to cacao: tryptophan breakdown by IDO is strongly involved in immunoregulation, and the diminished availability of tryptophan limits the biosynthesis of neurotransmitter serotonin. The inhibition of tryptophan breakdown by cacao constituents could thus be relevant not only for immune system restoration in patients, but also contribute to mood elevation and thereby improve quality of life. However, the available data thus far are merely in vitro only and future studies need to investigate the influence of cacao on tryptophan metabolism in vivo.