Plasma Tryptophan Concentrations Research Articles

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

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

Longitudinal associations of macronutrient and micronutrient intake with plasma kynurenines in colorectal cancer survivors up to 12 months posttreatment

BackgroundThe tryptophan-kynurenine pathway is increasingly recognized to play a role in health-related quality of life (HRQoL) after cancer. Because tryptophan is an essential amino acid, and vitamins and minerals act as enzymatic cofactors in the tryptophan-kynurenine pathway, a link between diet and kynurenines is plausible. ObjectivesThis study aimed to investigate the longitudinal associations of macronutrient and micronutrient intake with metabolites of the kynurenine pathway in colorectal cancer (CRC) survivors up to 12 mo posttreatment. MethodsIn a prospective cohort of stage I–III CRC survivors (n = 247), repeated measurements were performed at 6 wk, 6 mo, and 12 mo posttreatment. Macronutrient and micronutrient intake was measured by 7-d dietary records. Plasma concentrations of tryptophan and kynurenines were analyzed using liquid chromatography tandem mass spectrometry (LC/MS-MS). Longitudinal associations were analyzed using linear mixed models adjusted for sociodemographic, clinical, and lifestyle factors. ResultsAfter adjustment for multiple testing, higher total protein intake was positively associated with kynurenic acid (KA) (β as standard deviation [SD] change in KA concentration per 1 SD increase in total protein intake: 0.12; 95% CI: 0.04, 0.20), xanthurenic acid (XA) (standardized β: 0.22; 95% CI: 0.11, 0.33), 3-hydroxyanthranilic acid (HAA) (standardized β: 0.15; 95% CI: 0.04, 0.27) concentrations, and the kynurenic acid-to-quinolinic acid ratio (KA/QA) (standardized β: 0.12; 95% CI: 0.02,0.22). In contrast, higher total carbohydrate intake was associated with lower XA concentrations (standardized β: −0.18; 95% CI: −0.30, −0.07), a lower KA/QA (standardized β: −0.23; 95% CI: −0.34, −0.13), and a higher kynurenine-to-tryptophan ratio (KTR) (standardized β: 0.20; 95% CI: 0.10, 0.30). Higher fiber intake was associated with a higher KA/QA (standardized β: 0.11; 95% CI: 0.02, 0.21) and a lower KTR (standardized β: −0.12; 95% CI: −0.20, −0.03). Higher total fat intake was also associated with higher tryptophan (Trp) concentrations (standardized β: 0.18; 95% CI: 0.06, 0.30) and a lower KTR (standardized β: −0.13; 95% CI: −0.22, −0.03). For micronutrients, positive associations were observed for zinc with XA (standardized β: 0.13; 95% CI: 0.04, 0.21) and 3-hydroxykynurenine (HK) (standardized β: 0.12; 95% CI: 0.03, 0.20) concentrations and for magnesium with KA/QA (standardized β: 0.24; 95% CI: 0.13, 0.36). ConclusionsOur findings show that intake of several macronutrients and micronutrients is associated with some metabolites of the kynurenine pathway in CRC survivors up to 12 mo posttreatment. These results may be relevant for enhancing HRQoL after cancer through potential diet-induced changes in kynurenines. Further studies are necessary to confirm our findings.

Plasma Levels of Kynurenine, Soluble OX40 and Mir-138-5p Are Associated With Tumor-infiltrating Lymphocytes in Colorectal Cancer: An Exploratory Study.

Colorectal cancer (CRC) is one of leading cancers in terms of incidence and mortality. Interaction of tumor cells with the surrounding microenvironment plays a crucial role in the development and progression of CRC. Many pathways such as the kynurenine pathway, OX40/OX40L-mediated signaling and microRNAs targeting PD-L1 may be involved in CRC development by affecting T cell activation, thus creating an immune-deficient microenvironment. Herein, our goal was to assess the association between plasma levels of tryptophan (TRP), kynurenine (KYN), KYN/TRP ratio, soluble OX40 (sOX40) and PD-L1-targeting miR-138-5p and CRC risk. Plasma concentrations of TRP and KYN were determined by HPLC; sOX40 was measured by ELISA whereas circulating miR-138-5p was measured by quantitative PCR in pathologically confirmed CRC patients and colonoscopy-verified CRC-free controls without polyps (control group 1) and with polyps (control group 2). We found significantly lower plasma levels of TRP in CRC patients compared to control groups which resulted in significantly higher KYN/TRP ratio in CRC patients than in the controls (p=0.007). Plasma levels of sOX40 did not significantly differ between groups. The levels of circulating miR-138-5p were significantly lower in CRC patients (relative median value 0.02) than in the control groups (relative median values 0.2 and 4.29, respectively) (p=0.03). Plasma levels of KYN and sOX40 were considerably higher in patients with no tumor-infiltrating lymphocytes (TILs) than those with TILs whereas circulating miR-138-5p had opposite expression pattern in plasma. The kynurenine pathway and miR-138-5p are associated with CRC risk and plasma levels of KYN, sOX40 and miR-138-5p are related to TILs, making them possible target molecules in possible immunotherapeutic targets for CRC.

Lipopolysaccharide-induced changes in the kynurenine pathway and symptoms of sickness behavior in humans

Metabolites of the kynurenine pathway are hypothesized to be implicated in inflammation-associated depression, but there is a lack of experimental studies in humans assessing the kinetics of kynurenine metabolites in relation to experimentally-induced sickness. The aim of the present study was to assess changes in the kynurenine pathway and to explore its relation to symptoms of sickness behavior during an acute experimental immune challenge.This double-blind placebo-controlled randomized cross-over study included 22 healthy human participants (n = 21 both sessions, Mage = 23.4, SD = 3.6, nine women) who received an intravenous injection of 2.0 ng/kg lipopolysaccharide (LPS) and saline (placebo) on two different occasions in a randomized order. Blood samples (0 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 7 h post-injection) were analyzed for kynurenine metabolites and inflammatory cytokines. The intensity of symptoms of sickness behavior was assessed using the 10-item Sickness Questionnaire at 0 h, 1.5 h, 3 h, 5 h, and 7 h post-injection.LPS induced significantly lower concentrations of plasma tryptophan (at 2 h, 4 h, 5 h, and 7 h post-injection), kynurenine (at 2 h, 3 h, 4 h, and 5 h post-injection), nicotinamide (at 4 h, 5 h, and 7 h post-injection), and higher levels for quinolinic acid at 5 h post-injection as compared to placebo. LPS did not affect kynurenic acid, 3-hydroxykynurenine, and picolinic acid. The development of the sickness symptoms was largely similar across items, with the highest levels around 1.5–3 h post-injection. Changes in plasma levels of kynurenine metabolites seem to coincide rather than precede or follow changes in subjective sickness. Exploratory analyses indicate that higher Sickness Questionnaire total scores at 1.5–5 h post-injection were correlated with lower kynurenic acid and nicotinamide levels.These results lend further support for LPS-induced changes in the kynurenine pathway, but may not, as interpreted from blood levels, causally link to LPS-induced acute symptoms of sickness behavior. Future research may consider a larger sample to further scrutinize the role of the kynurenine pathway in the sickness response.

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

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

Normative Data on Serum and Plasma Tryptophan and Kynurenine Concentrations from 8089 Individuals Across 120 Studies: A Systematic Review and Meta-Analysis.

In this systematic review and meta-analysis, a normative dataset is generated from the published literature on the kynurenine pathway in control participants extracted from case-control and methodological validation studies. Study characteristics were mapped, and studies were evaluated in terms of analytical rigour and methodological validation. Meta-analyses of variance between types of instruments, sample matrices and metabolites were conducted. Regression analyses were applied to determine the relationship between metabolite, sample matrix, biological sex, participant age and study age. The grand mean concentrations of tryptophan in the serum and plasma were 60.52 ± 15.38 μM and 51.45 ± 10.47 μM, respectively. The grand mean concentrations of kynurenine in the serum and plasma were 1.96 ± 0.51 μM and 1.82 ± 0.54 μM, respectively. Regional differences in metabolite concentrations were observed across America, Asia, Australia, Europe and the Middle East. Of the total variance within the data, mode of detection (MOD) accounted for up to 2.96%, sample matrix up to 3.23%, and their interaction explained up to 1.53%; the latter of which was determined to be negligible. This review was intended to inform future empirical research and method development studies and successfully synthesised pilot data. The pilot data reported in this study will inform future precision medicine initiatives aimed at targeting the kynurenine pathway by improving the availability and quality of normative data.

Dietary supplementation with tryptophan increases the plasma concentrations of tryptophan, kynurenine, and melatonin in Yili mares

Context Tryptophan (Trp) is the precursor of melatonin (MT) and the latter plays vital physiological roles in mares. Aims The purpose of this experiment was to investigate the effects of dietary Trp supplementation on the plasma Trp, kynurenine (Kyn), 5-hydroxytryptophan (5-HT), and melatonin (MT) concentrations in female Yili horses. Methods Twenty Yili mares aged 2 years with mean bodyweight (BW) of 263.5 ± 14.77 kg and of similar stature were selected and randomly allocated to the control (CON; basal diet), basal diet plus Trp at 20 mg/kg BW (TRP1), basal diet plus Trp at 40 mg/kg BW (TRP2), or basal diet plus Trp at 60 mg/kg BW (TRP3) group. Key results The plasma total Trp, Kyn, and MT concentrations in all Trp groups steadily increased, reached their peak values, and gradually decreased after Trp supplementation between 0 h and 12 h. However, the plasma 5-HT concentration displayed the opposite trend. Peak plasma total Trp and 5-HT concentrations were attained between 1 h and 3 h, while those of KYN and MT appeared between 4 h and 6 h after Trp supplementation. The plasma total Trp and Kyn concentrations were significantly higher in TRP2 and TRP3 than in CON between 1 h and 12 h (P < 0.05) after Trp supplementation. The plasma 5-HT concentration was significantly (P < 0.05) lower in TRP1 than in CON at 3 h, 4 h, 6 h, 9 h, and 12 h after Trp supplementation. The plasma MT concentrations in TRP1 and TRP2 were significantly (P < 0.05) higher than in CON at 3 h, 4 h, and 12 h, and at 0 h, 1 h, and 12 h after Trp supplementation (P < 0.05). Conclusions Dietary Trp supplementation can increase the plasma total Trp, Kyn, and MT concentrations in Yili mares and the optimal Trp dosage was 20 mg/kg BW. Implication The addition of Trp to a basal diet or feed may increase the plasma total Trp, Kyn, and MT concentrations in female horses.

Alteration of the kynurenine pathway is inversely associated with the humoral immune response in patients with SARS-CoV-2

BackgroundThe scale and the course of antibody production in patients with SARS-CoV-2 is highly variable. Factors involved in the immune regulation during the infection may play a major role in the antibody response. We investigated the relationship between the inflammatory markers of the kynurenine pathway and the concentration of antibodies against SARS-CoV-2 in infected patients 8 – 11 days after admission. MethodsThe study included 72 SARS-CoV-2 - positive inpatients hospitalized between August 2020 and April 2021. The plasma concentrations of tryptophan, kynurenine, anti-SARS-CoV-2 antibodies and the leucocyte count were measured 8 – 11 days after admission. The kynurenine/tryptophan ratio (KYN/TRP ratio) was calculated. Tertiles based on the values for tryptophan, kynurenine, KYN/TRP ratio and the leucocytes were generated. ResultsStatistically significant correlations were observed between anti-SARS-CoV-2 antibodies and tryptophan, kynurenine, KYN/TRP ratio and the leucocytes (p-values < 0.001–0.007). The high kynurenine and KYN/TRP ratio tertiles showed significantly lower antibody titers compared to the low tertiles (p-values 0.017 and < 0.001). The low tryptophan and leucocytes tertiles showed significantly lower antibody titers compared to the high tertiles (p-values 0.001 and 0.008). ConclusionPatients with higher activation levels of the kynurenine pathway tended to develop lower anti-SARS-CoV-2 antibody titers.

PSXI-20 Evaluation of the Effects of Hempseed Cake on Immune Parameters in Response to an Endotoxin Challenge in Finishing Steers

Abstract Hempseed cake, a byproduct of industrial hemp and subsequent hempseed oil extraction processes, contains cannabinoids and fatty acids that could be potentially therapeutic for livestock, but little is known about the extent to which hempseed cake can influence immune response variables of cattle. An endotoxin challenge experiment using crossbred steers (n = 5; initial BW = 542 kg, SD = 40 kg) was conducted to evaluate the effects of hempseed cake treatment (HEMP) and dried corn distillers grains plus solubles treatment (DDGS; each included at 20% of diet DM in respective treatments) in comparison with a dry-rolled corn-based negative control treatment (CON) on plasma glucose, non-esterified fatty acids (NEFA), urea nitrogen (PUN), rectal temperature, twelve cytokine (IFNγ, IL-1α, IL-6, IL-8, IL-10, IL-36RA, IP10, MCP-1, MIP-1α, MIP-1β, TNFα, and VEGF-A), and amino acid concentrations at five timepoints after administration of endotoxin (lipopolysaccharide; LPS). Steers were administered LPS at 0.25 μg/kg BW, and blood was collected via jugular venipuncture before and 1, 2, 4 and 6-hours post-bolus injection. Data were analyzed as repeated measures using the MIXED procedure of SAS, and pre-bolus values was used as a covariate. A treatment by hour interaction (P = 0.04) was observed for PUN, and pre-bolus PUN was greatest (P &amp;lt; 0.01) in steers fed the HEMP. Plasma IL-1α, IL-36RA, and TNF-α were least (P ≤ 0.02), while IL-10 and MIP-1α tended (P ≤ 0.10) to be less in steers fed the HEMP diet. Plasma isoleucine, leucine, tryptophan, and tyrosine concentrations were greatest (P ≤ 0.04) in steers fed the DDGS diet, plasma aspartic acid and glycine concentrations were greatest (P ≤ 0.02) for steers fed the DDGS and CON diets. Overall, these data suggest that hempseed cake has potential to reduce inflammation by influencing cytokine production, but more research is needed to further understand animal growth performance and health implications.

Two-day fasting affects kynurenine pathway with additional modulation of short-term whole-body cooling: a quasi-randomised crossover trial.

Metabolites of the kynurenine (KYN) pathway of tryptophan (TRP) degradation have attracted interest as potential pathophysiological mediators and future diagnostic biomarkers. A greater knowledge of the pathological implications of the metabolites is associated with a need for a better understanding of how the normal behaviour and physiological activities impact their concentrations. This study aimed to investigate whether fasting (FAST) and whole-body cold-water immersion (CWI) affect KYN pathway metabolites. Thirteen young women were randomly assigned to receive the 2-d FAST with two 10-min CWI on separate days (FAST-CWI), 2-d FAST without CWI (FAST-CON), 2-d two CWI on separate days without FAST (CON-CWI) or the 2-d usual diet without CWI (CON-CON) in a randomised crossover fashion. Changes in plasma concentrations of TRP, kynurenic acid (KYNA), 3-hydroxy-kynurenine (3-HK), picolinic acid (PIC), quinolinic acid (QUIN) and nicotinamide (NAA) were determined with ultra-performance liquid chromatography-tandem mass spectrometer. FAST-CWI and FAST-CON lowered TRP concentration (P < 0·05, ηp2 = 0·24), and increased concentrations of KYNA, 3-HK and PIC (P < 0·05, ηp2 = 0·21-0·71) with no additional effects of CWI. The ratio of PIC/QUIN increased after FAST-CWI and FAST-CON trials (P < 0·05) but with a blunted effect in the FAST-CWI trial (P < 0·05) compared with the FAST-CON trials (ηp2 = 0·67). Concentrations of QUIN and NAA were unaltered. This study demonstrated that fasting for 2 d considerably impacts the concentration of several metabolites in the KYN pathway. This should be considered when discussing the potential of KYN pathway metabolites as biomarkers.

Effect of Varying Levels of Dietary Tryptophan on Aggression and Abnormal Behavior in Growing Pigs.

Body lesions, resulting from tail-biting and ear-biting, can result in decreased health and welfare in pigs. Tryptophan, an indispensable amino acid, is needed to support protein deposition, and the synthesis of the neurotransmitter serotonin, which is important to mood, sleep-wake and eating patterns and might play a role in aggression and abnormal behavior. Two randomized block design studies were conducted to assess the influence of varying dietary tryptophan levels on aggression and abnormal behavior in 8-week-old pigs. Six diets were formulated which met or exceeded all nutrient requirements yet differed according to the dietary tryptophan content. The first study included control (100% standardized ileal digestible tryptophan), supplemented (175% standardized ileal digestible tryptophan), and supplement-plus (250% standardized ileal digestible tryptophan) experimental diets, while the second study included deficient (80% standardized ileal digestible tryptophan), adequate control (105% standardized ileal digestible tryptophan), and extra-tryptophan (130% standardized ileal digestible tryptophan) experimental diets. Concentrations of plasma tryptophan and large neutral amino acids (tyrosine, isoleucine, leucine, valine, and phenylalanine) were analyzed using ultra-performance liquid chromatography and the tryptophan to large neutral amino acid ratio was calculated. Analysis for time active, lying, and engaging in aggressive interactions was carried out using 10-min scan samples to determine behavioral time budgets of the pigs on different experimental diets. Pigs fed diets with supplemented tryptophan had higher concentrations of both plasma tryptophan and tryptophan to large neutral amino acid ratio compared to the pigs fed the control diet (P < 0.05) in the first study, while no significant differences were detected for plasma tryptophan or the tryptophan to large neutral amino acid ratio in the second study. Diet did not have an effect (P > 0.05) on weight, feed intake or behavior throughout the studies. The results suggest that an increase in dietary tryptophan relative to large neutral amino acids, fed for 29 days, impacts circulating plasma tryptophan and therefore, serotonin concentrations in the pig. Despite an increase in circulating plasma tryptophan in response to an increase in dietary tryptophan in the first study, we failed to see an impact of the dietary treatment on body, tail and ear-biting behavior under the conditions studied.

Association of plasma tryptophan concentration with periaqueductal gray matter functional connectivity in migraine patients

Altered periaqueductal gray matter (PAG) functional connectivity contributes to brain hyperexcitability in migraine. Although tryptophan modulates neurotransmission in PAG projections through its metabolic pathways, the effect of plasma tryptophan on PAG functional connectivity (PAG-FC) in migraine has not been investigated yet. In this study, using a matched case-control design PAG-FC was measured during a resting-state functional magnetic resonance imaging session in migraine without aura patients (n = 27) and healthy controls (n = 27), and its relationship with plasma tryptophan concentration (TRP) was assessed. In addition, correlations of PAG-FC with age at migraine onset, migraine frequency, trait-anxiety and depressive symptoms were tested and the effect of TRP on these correlations was explored. Our results demonstrated that migraineurs had higher TRP compared to controls. In addition, altered PAG-FC in regions responsible for fear-cascade and pain modulation correlated with TRP only in migraineurs. There was no significant correlation in controls. It suggests increased sensitivity to TRP in migraine patients compared to controls. Trait-anxiety and depressive symptoms correlated with PAG-FC in migraine patients, and these correlations were modulated by TRP in regions responsible for emotional aspects of pain processing, but TRP did not interfere with processes that contribute to migraine attack generation or attack frequency.

Assessment of tryptophan and kynurenine as prognostic markers in patients with SARS-CoV-2

BackgroundImmune dysregulation and inflammation in patients with SARS-CoV-2 is associated with a poor clinical outcome. We investigated the value of the inflammatory markers tryptophan and kynurenine in predicting the survival outcome of patients with SARS-CoV-2. MethodsThe study included 252 inpatients with a SARS-CoV-2 infection hospitalized between August 2020 and April 2021. Two groups were generated based on disease survival (survival group: n = 199; deceased group: n = 53). Plasma concentrations of tryptophan, kynurenine and interleukin-6 (IL-6) were measured on admission. In a subset of patients (n = 105; 81 survivors and 24 deceased) concentrations of tryptophan and kynurenine were checked 7 days after admission. The kynurenine/tryptophan ratio (TRP/KYN ratio) was calculated. ResultsOn admission, the deceased group showed significantly higher concentrations of kynurenine and a significantly higher KYN/TRP ratio compared to the survival group (p-values < 0.001). Kynurenine and the KYN/TRP ratio significantly correlated with IL-6 (ρ = 0.441 and 0.448, p-values < 0.001). In the survival group, kynurenine and the KYN/TRPratio were significantly lower after seven days (p-values < 0.001). In the deceased group, no significant differences were found between the measurements. ConclusionKynurenine and the KYN/TRP ratio are potentially useful parameters in predicting the survival outcome in SARS-CoV-2 positive patients.

L. rhamnosus improves the immune response and tryptophan catabolism in laying hen pullets

In mammals, early-life probiotic supplementation is a promising tool for preventing unfavourable, gut microbiome-related behavioural, immunological, and aromatic amino acid alterations later in life. In laying hens, feather-pecking behaviour is proposed to be a consequence of gut-brain axis dysregulation. Lactobacillus rhamnosus decreases stress-induced severe feather pecking in adult hens, but whether its effect in pullets is more robust is unknown. Consequently, we investigated whether early-life, oral supplementation with a single Lactobacillus rhamnosus strain can prevent stress-induced feather-pecking behaviour in chickens. To this end, we monitored both the short- and long-term effects of the probiotic supplement on behaviour and related physiological parameters. We hypothesized that L. rhamnosus would reduce pecking behaviour by modulating the biological pathways associated with this detrimental behaviour, namely aromatic amino acid turnover linked to neurotransmitter production and stress-related immune responses. We report that stress decreased the proportion of cytotoxic T cells in the tonsils (P = 0.047). Counteracting this T cell depression, birds receiving the L. rhamnosus supplementation significantly increased all T lymphocyte subset proportions (P < 0.05). Both phenotypic and genotypic feather peckers had lower plasma tryptophan concentrations compared to their non-pecking counterparts. The probiotic supplement caused a short-term increase in plasma tryptophan (P < 0.001) and the TRP:(PHE + TYR) ratio (P < 0.001). The administration of stressors did not significantly increase feather pecking in pullets, an observation consistent with the age-dependent onset of pecking behaviour. Despite minimal changes to behaviour, our data demonstrate the impact of L. rhamnosus supplementation on the immune system and the turnover of the serotonin precursor tryptophan. Our findings indicate that L. rhamnosus exerts a transient, beneficial effect on the immune response and tryptophan catabolism in pullets.

Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial

BackgroundAdministration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects.MethodsThe present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18–40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models.ResultsSystemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP.ConclusionsOur findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway.Trial registrationThis study is based on a study registered at ClinicalTrials.gov, NCT03392701. Registered 21 December 2017.

Postpartum corticosterone and fluoxetine shift the tryptophan-kynurenine pathway in dams

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

Effect of a Synbiotic Supplement on Fear Response and Memory Assessment of Broiler Chickens Subjected to Heat Stress.

Simple SummaryHeat stress is a serious environmental problem, challenging poultry health and welfare globally, especially during summer season. The breeding program of faster-growing broiler chickens affects their biological homeostasis, causing structural and functional damage to the brain, leading to mental disorders. Improvement in the gut microbiota with synbiotic dietary supplements has become a useful biotherapeutic method for treating various diseases, including neuroinflammation-induced mental illness and memory damage. Therefore, this study aimed to assess the effect of a dietary synbiotic supplement on fear response and memory assessment in heat-stressed broiler chickens. We used 360 1-day-old broiler chicks and assigned them to one of three dietary treatments: a regular diet mixed with a synbiotic containing a probiotic (Enterococcus faecium, Pediococcus acidilactici, Bifidobacterium animalis, and Lactobacillus reuteri) and a prebiotic (fructooligosaccharides) at 0, 0.5, and 1.0 g/kg. Object memory, touch, novel object, isolation, and tonic immobility tests were conducted at relative days of age. At 42 day, blood was collected for detecting corticosterone and tryptophan concentrations and examining heterophile/lymphocyte ratios. The data suggest that the synbiotic-reduced heat-stress responses and related emotional disorder may be mainly caused by increasing the activation of the serotonergic system via the microbiota–gut–brain axis. The aim of this study was to evaluate the effect of a synbiotic containing a probiotic (Enterococcus faecium, Pediococcus acidilactici, Bifidobacterium animalis, and Lactobacillus reuteri) and a prebiotic (fructooligosaccharides) on fear response, memory assessment, and selected stress indicators in broilers subjected to heat stress. A total of 360 1-day-old Ross 708 chicks were evenly divided among three treatments: a basal diet mixed with a synbiotic at 0 (G-C), 0.5 (G-0.5X), and 1.0 (G-1.0X) g/kg. After 15 d, the broilers were exposed to 32 °C for 9 h daily until 42 d. The object memory test was conducted at 15 day; touch, novel object, and isolation tests were conducted at 35 day; tonic immobility (TI) took place at 41 day. At 42 day, plasma corticosterone and tryptophan concentrations and heterophile/lymphocyte (H/L) ratios were measured. Compared to controls, synbiotic-fed broilers, regardless of concentration, had a shorter latency to make the first vocalization, with higher vocalization rates during the isolation test (p = 0.001). the G-1.0 group had the lowest H/L ratio (p = 0.001), but higher plasma tryptophan concentrations and a greater number of birds could reach the observer during the touch test (p = 0.001 and 0.043, respectively). The current results indicate that the synbiotic can be used as a growth promoter to reduce the fear response and stress state of heat-stressed broilers.

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

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

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

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

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

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