Tryptophan, kynurenine and the KTR

@article{pmid41263665,

title = {Systemic metabolite kinetics mirror skeletal muscle energy metabolism during acute aerobic exercise},

author = {David Walzik and Charlotte Wenzel and Jule Elisabeth Strotkötter and Leon Hoenen and Tiffany Y Wences Chirino and Sina Trebing and Adrian McCann and Per Magne Ueland and Philipp Zimmer and Niklas Joisten},

doi = {10.1152/ajpcell.00715.2025},

issn = {1522-1563},

year  = {2026},

date = {2026-01-01},

journal = {Am J Physiol Cell Physiol},

volume = {330},

number = {1},

pages = {C111--C118},

abstract = {Acute exercise increases energy demand in skeletal muscle and releases metabolic intermediates into circulation, yet the serum kinetics of exercise-mobilized metabolites remain poorly characterized. By applying high-frequency serial blood sampling and targeted metabolomics in a longitudinal exercise trial with 12 young, healthy adults (6 females, 6 males), we assessed temporal alterations in energy-related metabolites during acute aerobic exercise and after 1 h of recovery. We provide evidence for 42 exercise-responsive metabolites, including end products of glycolysis, tricarboxylic acid cycle intermediates, ketone bodies, and amino acids. Overall, the observed metabolic alterations closely resembled skeletal muscle energy metabolism, thereby refining fundamental principles of exercise biochemistry through detailed serum kinetics, including novel, so far uncharacterized responses in systemic energy homeostasis and interorgan crosstalk. In our study, we provide detailed serum kinetics of energy-related metabolites during acute aerobic exercise and after 1 h of recovery. Semantic interpretation of our results against the backdrop of fundamental principles of exercise biochemistry indicate that serum metabolites mirror skeletal muscle energy metabolism, thus providing new insights into systemic energy homeostasis and interorgan crosstalk.},

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@article{pmid41076267,

title = {Preoperative plasma short- and branched-chain fatty acids in relation to risk of complications after colorectal cancer surgery: a prospective cohort study},

author = {Niels Klaassen-Dekker and Erwin G Zoetendal and Edoardo Capuano and Renate M Winkels and Fränzel Jb van Duijnhoven and N Tjarda van Heek and Flip M Kruyt and Arve Ulvik and Adrian McCann and Per Magne Ueland and Johannes Hw de Wilt and Ellen Kampman and Dieuwertje E Kok},

doi = {10.1016/j.ajcnut.2025.10.001},

issn = {1938-3207},

year  = {2025},

date = {2025-12-01},

journal = {Am J Clin Nutr},

volume = {122},

number = {6},

pages = {1579--1590},

abstract = {BACKGROUND: Emerging evidence suggests that nutritional prehabilitation reduces risk of complications after colorectal cancer (CRC) surgery. The gut microbiota and its metabolic activity potentially link preoperative diet to postoperative outcomes.nnOBJECTIVE: To investigate associations between preoperative plasma levels of microbial-derived metabolites and postoperative complications in patients with CRC.nnMETHODS: We used data from a prospective cohort study among 1220 patients with nonmetastatic CRC. The short-chain fatty acids (SCFAs) acetate, propionate, butyrate, and valerate, as well as the branched-chain fatty acids (BCFAs) isovalerate, isobutyrate, and α-methylbutyrate, were measured in plasma collected at diagnosis. Prevalence ratios (PR) were calculated using regression models adjusted for age, sex, tumor location, smoking status, and physical health status.nnRESULTS: Acetate levels of 40.0 μmol/L were associated with a lower risk of any postoperative complications compared with the reference of 20.0 μmol/L [PR: 0.76; 95% confidence interval (CI): 0.62, 0.93]. Higher levels of propionate (per 1 μmol/L) were associated with a lower risk of any complications (PR: 0.84; 95% CI: 0.73, 0.96). Similar associations were found for acetate (per 20 μmol/L) and propionate (per 1 μmol/L) in relation to surgical complications (PR: 0.75; 95% CI: 0.60, 0.93; and PR: 0.83; 95% CI: 0.69, 1.00; respectively). No associations were found for BCFAs in relation to complications. Low (below median) total SCFA levels combined with high (above median) total BCFA levels were least favorable in terms of complication risk (PR: 1.35; 95% CI: 1.02, 1.80) when compared with a low SCFA/low BCFA profile.nnCONCLUSIONS: Our findings suggest that microbial fermentation processes, mainly those resulting in higher SCFA levels, may be linked to postoperative recovery. These findings provide leads for future studies investigating the role of preoperative diet, especially the balance between fiber and protein intake, and microbial metabolism in relation to postoperative recovery of patients with CRC. This study was registered at clinicaltrials.gov with registration number NCT03191110.},

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@article{pmid41141372,

title = {Factors associated with left ventricular mass during disease modifying antirheumatic drug therapy in patients with rheumatoid arthritis: the Joint Heart study},

author = {Anja Linde and Eva Gerdts and Bjørg T Fevang and Arve Ulvik and Per M Ueland and Klaus Meyer and Ester Kringeland and Helga Midtbø},

doi = {10.1016/j.ijcrp.2025.200521},

issn = {2772-4875},

year  = {2025},

date = {2025-12-01},

journal = {Int J Cardiol Cardiovasc Risk Prev},

volume = {27},

pages = {200521},

abstract = {BACKGROUND: We explored factors associated with left ventricular (LV) mass index during biological (b) or targeted synthetic (ts) disease modifying antirheumatic drug (DMARD) therapy in patients with rheumatoid arthritis (RA).nnMETHODS: Eighty-three outpatients with RA (age 55 ± 12 years, 71% women) with an indication for b/ts DMARD therapy were examined with echocardiography at baseline and after a mean follow-up of 22 months. LV mass was calculated according to guidelines and indexed for height.nnRESULTS: At baseline, 37% had hypertension, 6% diabetes, 21% obesity, and 100% were using b/ts DMARDs. During follow-up, 17% discontinued b/tsDMARD treatment. The LV mass index remained unchanged during follow-up (33.1 ± 8.1 g/m vs. 33.5 ± 7.3 g/m, p = 0.57, mean change 0.3 ± 4.9 g/m). Lower LV mass index at follow-up was observed in patients using bDMARDs at follow-up (31.7 ± 6.2 g/m vs. 36.6 ± 8.9 g/m, p = 0.001). In multivariable linear regression analyses, use of bDMARDs (β -0.22, p = 0.03) at follow-up were associated with lower LV mass index at follow-up, independent of C-reactive protein (CRP), age, sex, and obesity at baseline. Obesity at baseline (β 0.39, p < 0.001) was associated with a higher LV mass index both at baseline and follow-up. Higher CRP at baseline was associated with higher LV mass index at baseline (β 0.31, p = 0.001), but not at follow-up.nnCONCLUSION: In patients with RA on DMARD treatment, the mean LV mass index remained stable during 22 months of follow-up. Obesity was the strongest factor associated with higher LV mass index, while use of bDMARD throughout the study period was associated with lower LV mass index.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid41163346,

title = {Immunological Protein Signature During Acute Exercise},

author = {Charlotte Wenzel and David Walzik and Tiffany Wences and Sina Trebing and Klaus Meyer and Andreas Groll and Philipp Zimmer and Niklas Joisten},

doi = {10.1111/apha.70125},

issn = {1748-1716},

year  = {2025},

date = {2025-12-01},

journal = {Acta Physiol (Oxf)},

volume = {241},

number = {12},

pages = {e70125},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41461260,

title = {The effect of vitamin B12 supplementation during pregnancy on early motor performance. Secondary analyses from a double-blinded randomized controlled trial},

author = {Ingrid Kvestad and Manjeswori Ulak and Adrian McCann and Ram K Chandyo and Mari Hysing and Catherine Schwinger and Suman Ranjitkar and Per Magne Ueland and Sudha Basnet and Tor A Strand},

doi = {10.1016/j.tjnut.2025.101305},

issn = {1541-6100},

year  = {2025},

date = {2025-12-01},

journal = {J Nutr},

pages = {101305},

abstract = {BACKGROUND: In a recent double-blind randomized controlled trial (RCT) in Nepal, we found a negative effect of maternal vitamin B12 supplementation during pregnancy on motor performance in their young infants.nnOBJECTIVE: The objective of this study is to examine whether the negative effect of the vitamin B12 supplementation on motor performance in these infants aged 8-12 weeks differed by baseline maternal characteristics.nnMETHODS: These are secondary analyses of a RCT where 800 pregnant women were randomized to receive vitamin B12 or placebo from early pregnancy to 6 months post-partum. The outcome was motor development measured by the Test of Infant Motor Performance (TIMP) in 712 infants at age 8-12 weeks. We examined whether plasma markers of baseline maternal vitamin B12 status (cobalamin, total homocysteine (tHcy), methylmalonic acid (MMA) and cB12), folate and hemoglobin concentration, and socioeconomic status (SES) modified the effect of vitamin B12 on the TIMP scores. The subgrouping variables were categorized according to predefined cut- offs and included as interaction terms in generalized linear models, with treatment group as the exposure and TIMP scores (continuous and categorical) as the outcomes.nnRESULTS: Overall, the negative effect of the vitamin B12 supplementation was observed in most subgroups. Except for plasma folate concentration (p for interaction 0.015), the maternal baseline characteristics did not significantly modify the effect of vitamin B12 supplementation on the TIMP scores. There was a tendency for a stronger negative effect of vitamin B12 among infants of women with adequate baseline vitamin B12 status (i.e. concentrations of cobalamin >220, tHcy <10, MMA <0.26 and cB12 values>-0.5) and with folate concentration in the lower tertile.nnCONCLUSIONS: The negative effect of vitamin B12 supplementation on infant motor performance could not be explained by any subgroup specific effects. However, the effect appeared to be more pronounced in mothers with adequate B12 status.nnCLINICAL TRIAL: Registration ID and URL: NCT03071666,https://www.nnCLINICALTRIALS: gov/study/NCT03071666.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40966534,

title = {Persons With Multiple Sclerosis Reveal Distinct Kynurenine Pathway Metabolite Patterns: A Multinational Cross-Sectional Study},

author = {Marie Kupjetz and Martin Langeskov-Christensen and Morten Riemenschneider and Stefan Inerle and Uwe Ligges and Tobias Gaemelke and Nadine Patt and Jens Bansi and Roman Rudolf Gonzenbach and Marcel Reuter and Friederike Rosenberger and Tim Meyer and Adrian McCann and Per Magne Ueland and Simon Fristed Eskildsen and Mikkel Karl Emil Nygaard and Niklas Joisten and Lars Hvid and Ulrik Dalgas and Philipp Zimmer},

doi = {10.1212/NXI.0000000000200461},

issn = {2332-7812},

year  = {2025},

date = {2025-11-01},

journal = {Neurol Neuroimmunol Neuroinflamm},

volume = {12},

number = {6},

pages = {e200461},

abstract = {BACKGROUND AND OBJECTIVES: Kynurenine pathway (KP) metabolites modulate inflammatory activity and neuronal viability. The consequences of KP imbalance partly resemble the molecular mechanisms of multiple sclerosis (MS). An improved understanding of KP imbalance and its relevance in MS requires holistic approaches beyond single-metabolite investigations. Thus, we aimed to explore the presence of KP metabolite patterns in MS and to evaluate their relevance in relation to participant characteristics and clinical measures.nnMETHODS: In this multinational cross-sectional analysis, we determined serum concentrations of KP metabolites in persons with MS and healthy individuals using targeted metabolomics (LC-MS/MS). Analyses were conducted between March 24, 2022, and August 9, 2024. The source studies were conducted in Denmark, Germany, and Switzerland. All participants were aged 18 years or older and free of acute or chronic diseases besides MS. Persons with MS had mild to moderate disease severity (Expanded Disability Status Scale [EDSS] score ≤6.5). Following the investigation of individual metabolites, we explored KP metabolite patterns using exploratory factor analysis. Associations between KP metabolite patterns and participant characteristics, MS symptoms, and MRI metrics were investigated using correlation analyses, proportional odds regression, and multiple linear regression.nnRESULTS: The MS cohort included 353 participants (67.1% female) with a mean (SD) age of 46.1 (12.4) years. The mean (SD) EDSS score was 3.1 (1.8). The healthy control (HC) cohort included 111 participants (53.2% female) with a mean (SD) age of 45.7 (16.6) years. Persons with MS showed 2 distinct KP metabolite patterns: an inflammation-driven neurotoxic pattern () and a neuroprotective pattern (). Greater  was associated with a higher EDSS score, older age, and higher body fat percentage. Greater  was associated with a lower EDSS score and higher cardiorespiratory fitness.nnDISCUSSION: Using a data-driven approach, we demonstrate the presence of 2 KP metabolite patterns,  and , in MS. Greater  and lower  were both associated with greater disease severity. Future studies need to investigate the KP metabolite patterns across the MS disability spectrum and may use comparable approaches to investigate whether KP imbalance follows similar or disease-specific patterns in diseases other than MS.nnTRIAL REGISTRATION INFORMATION: NCT03322761, NCT02661555, NCT04762342, NCT04356248, DRKS00017091, DRKS00031445, DRKS00028792, DRKS00029105.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid41315409,

title = {Associations between systemic inflammation and cognitive trajectories post-stroke},

author = {Heidi Vihovde Sandvig and Ingvild Saltvedt and Trine Holt Edwin and Stina Aam and Katinka Nordheim Alme and Rannveig Sakshaug Eldholm and Stian Lydersen and Tom Eirik Mollnes and Ragnhild Munthe-Kaas and Per Magne Ueland and Arve Ulvik and Torgeir Wethal and Anne-Brita Knapskog},

doi = {10.1038/s41598-025-27119-1},

issn = {2045-2322},

year  = {2025},

date = {2025-11-01},

journal = {Sci Rep},

volume = {15},

number = {1},

pages = {42791},

abstract = {Our objective was to explore whether plasma inflammatory biomarkers and related metabolites in acute phase and 3 months after stroke were associated with different cognitive trajectories and with changes in cognition post-stroke. The Norwegian Cognitive Impairment After Stroke (Nor-COAST) study was a prospective, multicentre cohort study of patients with acute stroke, followed up at 3, 18, and 36 months post-stroke. First, we modelled cognitive trajectory groups based on Montreal Cognitive Assessment (MoCA) scores and used multinominal logistic regression to study the associations between systemic inflammatory biomarkers/metabolites and group membership. Second, using mixed linear regression, we investigated whether the same biomarkers/metabolites were associated with changes in MoCA scores over time, stratified by pre-stroke cognitive status. The 466 participants had mean (SD) age 72 (12) years, 59% were males, and mean (SD) NIHSS score at admittance was 4 (4.8). Higher acute-phase values of the terminal complement complex, interleukin 6, macrophage inflammatory protein 1α, neopterin, quinolinic acid, and PA ratio = 4-pyridoxic acid / (pyridoxal + pyridoxal 5'-phosphate) and higher 3-month values of neopterin were associated with increased risk of being in the group characterized by low and declining MoCA score compared to the group of best MoCA score (p < 0.01). Higher acute-phase values of tumour necrosis factor and interleukin 8, were associated with progressive decline in the MoCA score (p < 0.01). Premorbid factors, and in particular pre-stroke frailty, had more impact on the models than stroke-related factors, and partly confounded several of these associations. Higher degrees of systemic inflammation in the acute phase were associated with worse cognitive trajectories and may reflect the response to the acute stroke, stroke-related complications and/or premorbid conditions.Trial registration: ClinicalTrials.gov: NCT02650531. Retrospectively registered January 8, 2016. First participant included May 18, 2015.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41055969,

title = {Inhibition of Th1-type immune responses in persons with HIV with current statin exposure},

author = {Andreas Dehlbæk Knudsen and Marco Gelpi and Moises A Suarez-Zdunek and Josefine A Loft and Per Magne Ueland and Sisse Rye Ostrowski and Øivind Midttun and Esteban Martinez and Susanne D Nielsen},

doi = {10.1097/QAD.0000000000004366},

issn = {1473-5571},

year  = {2025},

date = {2025-10-01},

journal = {AIDS},

abstract = {BACKGROUND: Recent findings from the REPRIEVE study suggest statins provide greater cardiovascular protection in persons with HIV (PWH) than expected from LDL cholesterol reduction alone. Statins may modulate Th1-type immune responses, including interferon-gamma (IFN-γ), neopterin, and kynurenine metabolism. We investigated if statin use in PWH was associated with suppression of Th1-type immune responses.nnMETHODS: This cross-sectional study included PWH from the Copenhagen Comorbidity in HIV infection (COCOMO) study. Demographic and clinical variables were collected through questionnaires and physical examinations. Plasma IFN-γ, neopterin, kynurenine-to-tryptophan ratio (marker of indoleamine 2,3-dioxygenase [IDO]-1 activity), interleukin (IL)-6, IL-1β, soluble CD14, and clinical data were measured in plasma. Multivariable logistic regression models were adjusted for age, sex, waist-to-hip ratio, metabolic syndrome, physical activity, high-sensitivity C-reactive protein, and LDL cholesterol.nnRESULTS: We included 1041 of whom 130 (12.5%) received statins. Statin-treated PWH were older (60 vs. 49 years), and more frequently male (92% vs. 84%). In unadjusted analyses, odds of elevated markers of Th1 immune responses did not differ significantly between groups. After multivariable adjustment, statin exposure was associated with lower odds of high kynurenine-to-tryptophan ratio (OR: 0.60; 95%CI 0.37-0.98), IFN-γ (OR 0.58; 95%CI 0.36-0.92), and neopterin (OR 0.58; 95%CI 0.36-0.92). No significant associations were observed for IL-6, IL-1β, or soluble CD14.nnCONCLUSIONS: In PWH, statin therapy was independently associated with suppression of Th1-type immune responses. These findings support a lipid-independent, immunomodulatory mechanism by which statins may confer cardiovascular protection in HIV infection and warrant confirmation in prospective studies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41150634,

title = {A Very-Low Energy Fast Involves Increased Adipose Inflammatory Gene Expression: A 6-Day Feeding Trial (FASTOMICS-6)},

author = {Marianne Bråtveit and Pouda P Strømland and Johnny Laupsa-Borge and Lillian Skumsnes and Vigdis H Dagsland and Silje Kvistad and Elinor C Vogt and Adrian McCann and Håvard L Thorsen and Andreas P Diamantopoulos and Bjørn Gunnar Nedrebø and Gunnar Mellgren and Simon N Dankel},

doi = {10.1210/clinem/dgaf570},

issn = {1945-7197},

year  = {2025},

date = {2025-10-01},

journal = {J Clin Endocrinol Metab},

abstract = {BACKGROUND: Fasting and ketogenic diets may have health benefits, but we lack a deeper understanding of tissue mechanisms and associated metabolome changes, particularly in humans.nnOBJECTIVE: Determine changes in subcutaneous adipose tissue (SAT) gene expression, plasma metabolomics and circulating serum markers after a 6-day very-low-energy fast.nnMETHODS: 13 patients with obesity (mean BMI = 41.6) underwent a week-long in-hospital feeding study (600 kcal/day). Body composition was assessed by bioimpedance. Blood and SAT were collected on day 1 and 7 for metabolomics (GC-MS/MS) and transcriptomics (RNA-sequencing). Biological pathways were inferred from affected gene sets (GSEA) and gene networks that correlated with plasma metabolites (WGCNA).nnRESULTS: Relative mean change (95% CI) in fat mass and fat-free mass was -2.07% (-2.93, -1.20) and -4.42% (-5.53, -3.28), respectively. Marked significant changes (relative mean change (95% CI)) were observed in total ketone bodies (acetoacetate + β-hydroxybutyrate) (+615% (366, 999)), fasting insulin (-41.2% (-53.1, -26.4)) and HOMA2-IR (-31.8% (-41.4, -20.6)), as well as α-hydroxybutyrate (+103% (69.9, 142)) and the advanced glycation end-products (AGEs) Carboxyethyl-Lysine (-46.0% (-53.6, -37.2)) and Carboxymethyl-Lysine (-50.9% (-59.8, -40.1)). GSEA indicated upregulated inflammatory responses, and downregulated oxidative phosphorylation, adipogenesis, fatty acid metabolism and mTORC1 signaling (p<0.01) in SAT.nnCONCLUSION: After a 6-day very-low energy fast, adipose inflammatory gene expression increased concomitant with decreased plasma AGEs and improved insulin sensitivity. These data suggest a role for inflammatory and autophagy-associated pathways in the metabolic adaptation to a ketogenic very-low energy fast.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41176280,

title = {Serum Vitamin A Is Associated with Variations in the Relationship between Plasma B6 Vitamers and Cardiovascular Disease Risk},

author = {Indu Dhar and Gard Ft Svingen and Arve Ulvik and Espen Ø Bjørnestad and Jørn V Sagen and Ottar K Nygård},

doi = {10.1016/j.tjnut.2025.10.036},

issn = {1541-6100},

year  = {2025},

date = {2025-10-01},

journal = {J Nutr},

abstract = {BACKGROUND: Low concentrations of biologically active B6 vitamer, pyridoxal 5'-phosphate (PLP) are associated with an increased risk of cardiovascular disease (CVD). Vitamin A (Vit-A) promotes lipid homeostasis and the transport cholesterol. Vit-A may also stimulate the intracellular transport of PLP.nnOBJECTIVES: This study aimed to investigate whether Vit-A is associated with variations in the relationship of systemic B6-vitamers with incident acute myocardial infarctions (AMIs).nnMETHODS: A total of 4091 patients undergoing elective coronary angiography for suspected stable angina pectoris were studied. Associations of different plasma B6 vitamers, including PLP, pyridoxal (PL), 4-pyridoxic acid (PA), and PA/PL ratio with the risk of AMI according to median concentrations of Vit-A, were explored in Cox regression models.nnRESULTS: Serum Vit-A demonstrated positive associations with PLP and PA/PL ratio at baseline (P < 0.001 for both). During a median follow-up of 7.5 y, 521 (12.7%) patients suffered an AMI. In age and sex-adjusted analyses, plasma PLP, PA, and PA/PL ratio showed an overall association with incident AMI {hazard ratio (HR) [95% confidence interval (CI)] per SD: 0.90 [0.82, 0.99; P = 0.02], 1.14 [1.05, 1.23; P < 0.001], and 1.28 [1.18, 1.39; P < 0.001], respectively}. However, low plasma PLP and high PA/PL ratio were associated with an increased risk of AMI primarily among patients with high compared with low Vit-A concentrations [HR (95% CI) per SD: 0.77 (0.68, 0.88; P < 0.001, P-interaction = 0.002) and 1.36 (1.23, 1.49; P < 0.001, P-interaction = 0.05), respectively]. The interactions persisted after multivariable adjustment (both P-interactions ≤ 0.04).nnCONCLUSIONS: The relationship between vitamin B6 indexes and AMI risk varied according to serum Vit-A concentrations. Additional research is needed to clarify the importance of Vit-A and B6 bioavailability in atherosclerotic CVD. This trial was registered at clinicaltrials.gov as NCT00354081.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40378971,

title = {Tryptophan-kynurenine metabolites associate with inflammation and immunologic phenotypes in common variable immunodeficiency},

author = {Silje F Jørgensen and Peder R Braadland and Thor Ueland and Mai S A Fraz and Annika E Michelsen and Kristian Holm and Liv T Osnes and Marius Trøseid and Per Magne Ueland and Børre Fevang and Pål Aukrust and Johannes R Hov},

doi = {10.1016/j.jaci.2025.04.031},

issn = {1097-6825},

year  = {2025},

date = {2025-09-01},

journal = {J Allergy Clin Immunol},

volume = {156},

number = {3},

pages = {814--824.e11},

abstract = {BACKGROUND: A large proportion of patients with common variable immunodeficiency (CVID) have autoimmune and inflammatory manifestations characterized by chronic T-cell- and monocyte/macrophage activation of unknown etiology. The tryptophan-kynurenine pathway has previously been linked to immune activation involving T cells and monocytes/macrophages, as well as with gut microbial dysbiosis in some inflammatory diseases.nnOBJECTIVE: We aimed to characterize the tryptophan-kynurenine pathway in CVID and its potential association with clinical/immunologic phenotype and gut microbial dysbiosis.nnMETHODS: Serum concentrations of a set of tryptophan-kynurenine pathway metabolites and neopterin were measured using liquid chromatography-tandem mass spectrometry in a discovery cohort (n = 40), a validation cohort (n = 53), and healthy controls (n = 60). B-cell phenotype was analyzed in both cohorts, whereas inflammatory markers (enzyme immunoassay), lipopolysaccharide, gut microbial composition, and food frequency questionnaire were measured in the discovery cohort.nnRESULTS: Compared to healthy controls, CVID patients had increased metabolism of the tryptophan-kynurenine pathway as assessed by increased kynurenine/tryptophan ratio, quinolinic acid, and 3-hydroxykynurenine in both the discovery and validation cohorts. The findings were most pronounced in the subgroup with autoimmune/inflammatory complications but was to some degree also observed in CVID patients with infection only. In CVID, the metabolites in the tryptophan-kynurenine pathway associated with soluble (s) markers of monocyte (sCD14, sCD163, neopterin) and T-cell (sCD25) activation as well as B-cell phenotype (eg, naïve B cells). Individual gut microbial taxa may influence tryptophan-kynurenine pathway metabolites, but not lipopolysaccharide or diet.nnCONCLUSION: We found altered levels of several metabolites in the tryptophan-kynurenine pathway in two different CVID cohorts associated with systemic inflammation and B-cell phenotype.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40592074,

title = {Prevalence of depressive symptoms in the general population with a fully structured interview with skips vs. unconditional sequential assessment: implications for clinical and psychiatric epidemiology studies},

author = {Ana Vilar and Ivet Bayes-Marin and Samantha Álvarez-Salazar and Jorge Piqueras-Marques and Santiago Batlle Vila and Carlos G Forero},

doi = {10.1016/j.jpsychires.2025.06.010},

issn = {1879-1379},

year  = {2025},

date = {2025-09-01},

journal = {J Psychiatr Res},

volume = {189},

pages = {424--434},

abstract = {Diagnostic methods in psychiatry often rely on categorical approaches, such as the skip-out procedure, which conditionally assesses symptoms based on prior responses. This study evaluates how assessment methods influence the prevalence of depressive symptoms and Major Depressive Episode (MDE), comparing the skip-out approach with a sequential assessment that evaluates all symptoms independently. It also examines how assessment method affects symptom associations and explores the relationship between self-perceived mental health and symptom count. We conducted a cross-sectional analysis of 2005 Spanish adults using a self-administered online version of the WHO Composite International Diagnostic Interview (CIDI) 3.0. MDE prevalence, symptom frequencies, and associations were compared between skip-out and sequential assessments. Odds ratios with 95 % confidence intervals analyzed symptom associations with MDE, while intercorrelations and self-perceived mental health ratings were evaluated by symptom count. The skip-out method identified only 25 % of the cases detected by the sequential assessment (102 vs. 407), indicating a 75 % reduction in the detected MDE cases. Core symptoms like sadness and anhedonia were more strongly associated with MDE under skip-out, whereas non-core symptoms were better captured by sequential assessment. Sadness and concentration difficulties showed the strongest links to impairment. Over half of individuals reporting five or more symptoms rated their mental health as good or excellent. These results suggest that clinical and epidemiological assessments should consider the use of skip-out logic, as it may substantially underestimate depression prevalence and diversity. Improving assessment strategies may enhance early detection, reduce underdiagnosis, and support more tailored public health interventions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40609749,

title = {Infant vitamin B12 status and its predictors - cross-sectional baseline results from an ongoing randomized controlled trial},

author = {Sol Maja G Bjørkevoll and Maria O'Keeffe and Carolien Konijnenberg and Beate S Solvik and Alida F Sødal and Siri Kaldenbach and Adrian McCann and Per M Ueland and Ingrid Kvestad and Elisabeth Ersvær and Mads N Holten-Andersen and Kjersti S Bakken and Tor A Strand},

doi = {10.1016/j.ajcnut.2025.06.029},

issn = {1938-3207},

year  = {2025},

date = {2025-09-01},

journal = {Am J Clin Nutr},

volume = {122},

number = {3},

pages = {803--810},

abstract = {BACKGROUND: Vitamin B12 is a crucial micronutrient for infant growth and development.nnOBJECTIVE: The objective of this study was to describe vitamin B12 status in Norwegian infants aged 6-15 wk using multiple biomarkers and cut-off approaches, and to identify its predictors.nnMETHODS: From November 2021 through August 2024, infants aged 6-15 wk and their mothers were recruited from public health clinics in Innlandet County, Norway, as part of an ongoing randomized controlled trial. Plasma cobalamin and methylmalonic acid (MMA) concentrations were analyzed among all infants in the cohort (n = 644), and total homocysteine (tHcy) concentrations were analyzed in a subgroup (n = 358). The combined indicator for vitamin B12 status (cB12) was calculated by Fedosov's equation. Low status was defined using multiple cut-off approaches. Potential predictors of infant vitamin B12 status were evaluated using regression models.nnRESULTS: Mean (standard deviation [SD]) infant age was 9.1 (1.8) wk. The median (interquartile range) concentrations were: cobalamin 242 (192, 322) pmol/L, tHcy 7.4 (6.2, 9.4) μmol/L, and MMA 0.34 (0.21, 0.77) μmol/L. The mean (SD) cB12 was -0.5 (0.7). Eight percent had cobalamin <148 pmol/L, and 40% <221 pmol/L. Sixty-seven percent had tHcy >6.5 μmol/L, 19% >10 μmol/L, and 4% >13 μmol/L. Sixty-four percent had MMA>0.26 μmol/L. Exclusively breastfed infants had 40% lower cobalamin and 30% higher tHcy compared with nonbreastfed infants. Partially breastfed infants had 21% lower cobalamin and 12% higher tHcy compared with nonbreastfed infants.nnCONCLUSION: A substantial proportion of Norwegian infants have biochemical signs of low vitamin B12 status, given that the cut-offs were established in adults. Lower status was observed in partially and exclusively breastfed infants, compared with nonbreastfed infants. However, it is unclear whether these biomarker patterns have clinical significance. Further research is needed to determine consequences of low vitamin B12 biomarker concentrations in early infancy. This trial was registered as NCT05005897.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40158742,

title = {Modeling how iso-caloric macronutrient substitutions are longitudinally associated with plasma kynurenines in colorectal cancer survivors up to 12 months post-treatment},

author = {Daniëlle D B Holthuijsen and Eline H van Roekel and Martijn J L Bours and Per M Ueland and Stéphanie O Breukink and Maryska L G Janssen-Heijnen and Joop L Konsten and Eric T P Keulen and Adrian McCann and Stefanie Brezina and Biljana Gigic and Dieuwertje E Kok and Cornelia M Ulrich and Matty P Weijenberg and Simone J P M Eussen},

doi = {10.1016/j.jnutbio.2025.109910},

issn = {1873-4847},

year  = {2025},

date = {2025-07-01},

journal = {J Nutr Biochem},

volume = {141},

pages = {109910},

abstract = {Dietary intake of several macronutrients is associated with plasma kynurenines after colorectal cancer (CRC), and kynurenines have been linked to health-related outcomes. It is unknown how macronutrient substitution affects plasma kynurenines, which may be relevant for developing guidelines to improve post-CRC quality of life through dietary changes. Using iso-caloric substitution models, we investigated how substituting one macronutrient with another is longitudinally associated with plasma tryptophan, kynurenines, and kynurenine ratios in CRC survivors. Measurements were performed at 6-weeks, 6-months, and 12-months post-treatment in 247 stage I-III CRC survivors. Macronutrient intake was measured by 7-d dietary records and plasma kynurenines by LC/MS-MS. For analysis, we applied linear mixed models with false discovery rate (FDR) to adjust for multiple testing. After FDR adjustment, substituting 100 kcal/d of total carbohydrates with 100 kcal/d of total protein was associated with higher plasma concentrations of kynurenic acid (KA), xanthurenic acid (XA), and a higher kynurenic acid-to-quinolinic acid (KA/QA) ratio. Substituting 100 kcal/d of total carbohydrates with 100 kcal/d of total fat was associated with higher tryptophan concentrations, higher KA/QA ratio, and a lower kynurenine-to-tryptophan ratio (KTR) and hydroxykynurenine ratio (HKr). Substituting 100 kcal/d of total fat with 100 kcal/d of total protein was associated with higher XA concentrations. Altogether, iso-caloric macronutrient substitutions, particularly substituting carbohydrates with protein or fat, were longitudinally associated with higher concentrations of potentially favourable kynurenines and ratios (i.e., KA, XA, and KA/QA ratio) and lower ratios with pro-inflammatory or neurotoxic properties (i.e., KTR and HKr) in CRC survivors up to 12-months post-treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40279290,

title = {Kynurenines and neopterin are interferon-gamma-inducible biomarkers for Sjögren's disease},

author = {Valéria Valim and Fabíola R Oliveira and Samira T Miyamoto and Érica V Serrano and Gabriela M Balarini and Leandro A Tanure and Gilda A Ferreira and Eliana Zandonade and Johan G Brun and Malin Jonsson and Elisabeth Maeland and Arve Ulvik and Per Magne Ueland and Roland Jonsson and Piotr M Mydel},

doi = {10.1093/rheumatology/keaf158},

issn = {1462-0332},

year  = {2025},

date = {2025-07-01},

journal = {Rheumatology (Oxford)},

volume = {64},

number = {7},

pages = {4404--4413},

abstract = {OBJECTIVES: The aim was to investigate whether kynurenine pathway metabolites and neopterin increase probability for Sjögren's disease (SjD) and their associations with clinical parameters and inflammatory biomarkers.nnMETHODS: In this case-control study, 97 SjD patients and 63 age- and sex-matched healthy volunteers were enrolled. Clinical and immunological characteristics, EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) and the EULAR Sjögren's Syndrome Patient-Report Index (ESSPRI) were evaluated. High-sensitivity C-reactive protein (hs-CRP), cysteine, leptin, resistin, adiponectin, interleukins, chemokines and TNF receptors I and II were analyzed using a multiplex system. The concentrations of cystatin-C, neopterin, tryptophan, vitamin B6 and kynurenine metabolites were assessed using liquid chromatography-tandem mass spectrometry.nnRESULTS: Tryptophan levels were lower in SjD (P = 0.012), and kynurinine (P = 0.005), kynurenine/tryptophan ratio (KTR) (P = 0.001) and neopterin (P = 0.02) were higher. Kynurenine (OR 2.51, 95%CI 1.44-5.64), KTR (OR 3.45, 95% CI 1.76-6.74), neopterin (OR 4.28, 95% CI 1.95-9.42) and vitamin B6 metabolite (PAr) (OR 3.34, 95% CI 1.19-9.39) increased the chances for SjD. They were associated with disease activity, longer disease duration, depression, impaired salivary flow, hypergammaglobulinemia, neutropenia, hypocomplementemia and positive anti-Ro/SSA and anti-La/SSB. Neopterin correlated with kynurenines, and both were also associated with PAr and pro-inflammatory cytokines, mainly TNF-α, IL-1β and TNF receptors I and II.nnCONCLUSION: Kynurenines and neopterin are interferon-gamma-inducible biomarkers associated with more chances for SjD and with disease activity, glandular dysfunction, autoantibodies and immunological and inflammatory biomarkers.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40367835,

title = {The kynurenine pathway and markers of neurodegeneration and cerebral small vessel disease: The Maastricht Study},

author = {Lieke Bakker and Inez H G B Ramakers and Marleen M J van Greevenbroek and Walter H Backes and Jacobus F A Jansen and Miranda T Schram and Carla J H van der Kallen and Casper G Schalkwijk and Anke Wesselius and Arve Ulvik and Per M Ueland and Frans R J Verhey and Simone J P M Eussen and Sebastian Köhler},

doi = {10.1016/j.jns.2025.123522},

issn = {1878-5883},

year  = {2025},

date = {2025-07-01},

journal = {J Neurol Sci},

volume = {474},

pages = {123522},

abstract = {BACKGROUND: The kynurenine pathway, the main metabolic pathway of tryptophan degradation, has been mostly studied in neurodegenerative disorders, while its role in cerebrovascular pathology is less clear. We investigated whether kynurenines are associated with markers of neurodegeneration and cerebrovascular pathology in the general population.nnMETHODS: Cross-sectional data was used from 1589 individuals (60.0 ± 8.0 years, 54.3 % men) who participated in The Maastricht Study, an observational population-based cohort study. Plasma concentrations of tryptophan, kynurenines, and neopterin were quantified. Neurodegeneration was measured by volumes of intracranial cerebrospinal fluid (CSF), while cerebrovascular pathology was measured by white matter hyperintensity (WMH) volume and presence of cerebral small vessel disease (cSVD), defined as the presence of lacunar infarcts, cerebral microbleeds or a Fazekas score ≥ 2, all derived from 3 T MRI. Associations of kynurenines with these markers were investigated using linear, logistic, and restricted cubic spline regression models adjusted for confounders.nnRESULTS: Fully adjusted analyses indicated that higher levels of 3-hydroxyanthranilic acid, kynurenine, kynurenic acid, quinolinic acid, and neopterin were associated with lower CSF volume. For the latter four, associations were non-linear and restricted to participants with already below average concentrations. Higher levels of tryptophan and anthranilic acid were associated with higher CSF volumes in participants with above-average levels. Higher levels of the kynurenine-tryptophan ratio were associated with a lower WMH volume. No evidence was found for associations between individual kynurenines and WMH volume or cSVD presence.nnCONCLUSIONS: These findings suggest that several kynurenines are associated with neurodegeneration in community-dwelling older adults, but not with cerebrovascular damage.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40717068,

title = {Associations of one-carbon metabolism, related B-vitamins and ApoE genotype with cognitive function in older adults: identification of a novel gene-nutrient interaction},

author = {Shane Gordon and Leane Hoey and Helene McNulty and Jordan Keenan and Faith Pangilinan and Lawrence C Brody and Mary Ward and J J Strain and Liadhan McAnena and Adrian McCann and Anne M Molloy and Conal Cunningham and Kevin McCarroll and Catherine F Hughes},

doi = {10.1186/s12916-025-04276-8},

issn = {1741-7015},

year  = {2025},

date = {2025-07-01},

journal = {BMC Med},

volume = {23},

number = {1},

pages = {440},

abstract = {BACKGROUND: The role of one-carbon metabolism and related B-vitamins in cognitive function in ageing is well-documented, particularly for folate and vitamin B12, with vitamin B6 and riboflavin receiving much less attention. ApoE is a well-established genetic risk factor for Alzheimer's disease, but the role of B-vitamins in modifying this risk remains largely unexplored. We examined associations between folate, B12, B6, riboflavin, and cognitive function in older adults, including interactions with the ApoE ε4 genotype.nnMETHODS: Community-dwelling older adults (≥ 60 years) from the Trinity-Ulster-Department of Agriculture (TUDA) study were stratified as ApoE ε4 carriers (ε3/ε4 and ε4/ε4 genotypes; n = 1205) or non-ε4 carriers (n = 3348). Cognitive function was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), the Frontal Assessment Battery, and the Mini-Mental State Examination. Logistic regression models were used to evaluate the association between cognitive dysfunction (defined as RBANS score < 80) and a range of variables, including biomarkers of folate, vitamins B12, B6, and riboflavin status, plasma homocysteine levels, and ApoE ε4 genotype.nnRESULTS: Lower status of vitamin B12 (holotranscobalamin; adjusted odds ratio (OR 1.30; 95% CI: 1.08-1.58, p = 0.007), vitamin B6 (OR 1.37; 95% CI: 1.12-1.67, p = 0.002), riboflavin (OR 1.73; 95% CI: 1.44-2.09, p < 0.001), and higher plasma homocysteine (OR 1.50; 95% CI: 1.22-1.83, p < 0.001) were each associated with higher risk of cognitive dysfunction. The ApoE ε4 genotype interacted adversely with low B12 status (p = 0.030) and elevated homocysteine (p = 0.008) in relation to cognitive outcomes.nnCONCLUSIONS: Low status of vitamin B12, B6, riboflavin, and/or elevated homocysteine were each associated with a greater risk of cognitive dysfunction. A novel interaction between ApoE ε4 and low B12 or higher homocysteine was associated with an increased risk of cognitive dysfunction. Improving B-vitamin status may have important public health benefits for dementia prevention. Further investigation, ideally in the form of randomised trials, is however required to demonstrate a causative relationship and confirm whether intervention with B-vitamins can confer a beneficial effect in maintaining better cognitive health in at-risk older people.nnTRIAL REGISTRATION: TUDA study: ClinicalTrials.gov no. NCT02664584 (27/01/2016).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40252731,

title = {Vitamin B status is related to disease severity and modulated by endurance exercise in individuals with multiple sclerosis: a secondary analysis of a randomized controlled trial},

author = {Sergen Belen and Nadine Patt and Marie Kupjetz and Per M Ueland and Adrian McCann and Roman Gonzenbach and Jens Bansi and Philipp Zimmer},

doi = {10.1016/j.ajcnut.2025.04.014},

issn = {1938-3207},

year  = {2025},

date = {2025-06-01},

journal = {Am J Clin Nutr},

volume = {121},

number = {6},

pages = {1403--1414},

abstract = {BACKGROUND: Low circulating concentrations of B vitamins are linked to various chronic and neurodegenerative diseases. Notably, pyridoxal 5'-phosphate (vitamin B) deficiency is linked to altered inflammatory responses and cellular immune function, both critical in multiple sclerosis (MS). Nevertheless, most MS research has focused on folate (vitamin B) and vitamin B, leaving other B vitamins understudied.nnOBJECTIVES: This secondary analysis investigated B-vitamin serum concentrations and related metabolites across MS phenotypes (primary progressive MS, relapsing-remitting MS, and secondary progressive MS) and disease severity levels. Additionally, the impact of endurance exercise on B-vitamin concentrations was investigated.nnMETHODS: In total, 106 individuals with MS participated in a randomized controlled trial, including different endurance exercise conditions. Serum B-vitamin concentrations were analyzed in 99 participants before and after 3 wk of intervention. Before analysis, participants were dichotomized to 1 of the 2 disability groups based on their expanded disability status scale (EDSS) score: EDSS (n = 47, EDSS: 5.86 ± 0.56) and EDSS (n = 52, EDSS: 3.59 ± 0.83).nnRESULTS: Higher EDSS scores were associated with lower pyridoxal 5'-phosphate (vitamin B-6) concentrations (r: -0.32; 95% CI: -0.49, -0.12; P = 0.011), with the EDSS group also showing lower baseline pyridoxal 5'-phosphate (vitamin B) concentrations (β: -0.18; 95% CI: -0.30, -0.07; P = 0.007) than the EDSS group. Significant time × EDSS group interactions were evident for pyridoxal 5'-phosphate (vitamin B; β: 0.05; 95% CI: 0.02, 0.08; P = 0.011), pyridoxal (vitamin B; β: 0.05; 95% CI: 0.02, 0.09; P = 0.005), and riboflavin (vitamin B; β: 0.06; 95% CI: 0.02, 0.09; P = 0.008), showing increases in these vitamers in the EDSS group postexercise. N1-Methylnicotinamide (vitamin B; β: -0.11; 95% CI: -0.15, -0.06; P < 0.001) decreased in both groups over time.nnCONCLUSIONS: Disease severity is associated with distinct B-vitamin profiles in individuals with MS, although endurance exercise appears to modify specific B-vitamin concentrations. This trial was registered at clinicaltrials.gov as NCT04356248.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40573081,

title = {Association Between Dietary Intake and Blood Concentrations of One-Carbon-Metabolism-Related Nutrients in European Prospective Investigation into Cancer and Nutrition},

author = {Jin Young Park and Heleen Van Puyvelde and Lea Regazzetti and Joanna L Clasen and Alicia K Heath and Simone Eussen and Per Magne Ueland and Mattias Johansson and Carine Biessy and Raul Zamora-Ros and José María Huerta and Maria-Jose Sánchez and Marga Ocke and Matthias B Schulze and Catarina Schiborn and Tonje Bjørndal Braaten and Guri Skeie and Carlotta Sacerdote and Jesús Castilla and Therese Karlsson and Ingegerd Johansson and Cecilie Kyrø and Anne Tjønneland and Tammy Y N Tong and Verena Katzke and Rashmita Bajracharya and Cristina Lasheras and Øivind Midttun and Stein Emil Vollset and Paolo Vineis and Giovanna Masala and Pilar Amiano and Rosario Tumino and Ivan Baldassari and Elisabete Weiderpass and Elio Riboli and Marc J Gunter and Heinz Freisling and Sabina Rinaldi and David C Muller and Inge Huybrechts and Pietro Ferrari},

doi = {10.3390/nu17121970},

issn = {2072-6643},

year  = {2025},

date = {2025-06-01},

journal = {Nutrients},

volume = {17},

number = {12},

abstract = { We examined the association between dietary intake and blood concentrations of one-carbon metabolism (OCM)-related nutrients in the European Prospective Investigation into Cancer and Nutrition (EPIC).  Blood concentrations and dietary intake of the vitamins riboflavin (B2), Pyridoxal 5'-phosphate (PLP and B6), folate (B9), B12, and methionine, concentrations of homocysteine, and dietary intake of betaine, choline, and cysteine were pooled from 16,267 participants in nine EPIC nested case-control studies. Correlation analyses between dietary intakes and blood concentrations were carried out. Principal component (PC) analysis identified latent factors in the two sets of measurements.  Pearson correlations between dietary intakes and blood concentrations ranged from 0.08 for methionine to 0.12 for vitamin B2, 0.15 for vitamin B12, 0.17 for vitamin B6, and 0.19 for folate. Individual dietary intakes showed higher correlations (ranging from -0.14 to 0.82) compared to individual blood concentrations (from -0.31 to 0.29). Correlations did not vary by smoking status, case-control status, or vitamin supplement use. The first PC of dietary intakes was mostly associated with methionine, vitamin B12, cysteine, and choline, while the first PC of blood concentrations was associated with folate and vitamin B6.  Within this large European study, we found weak to moderate associations between dietary intakes and concentrations of OCM-related nutrients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}