Publications by authors named "Øivind Midttun"

147 Publications

Associations between plasma kynurenines and cognitive function in individuals with normal glucose metabolism, prediabetes and type 2 diabetes: the Maastricht Study.

Diabetologia 2021 Aug 19. Epub 2021 Aug 19.

MHeNs School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.

Aims/hypothesis: Studies investigating associations between kynurenines and cognitive function have generally been small, restricted to clinical samples or have found inconsistent results, and associations in the general adult population, and in individuals with type 2 diabetes in particular, are not clear. Therefore, the aim of the present study was to investigate cross-sectional associations between plasma kynurenines and cognitive function in a cohort of middle-aged participants with normal glucose metabolism, prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes.

Methods: Plasma kynurenines were quantified in 2358 participants aged 61 ± 8 years. Cross-sectional associations of kynurenines with cognitive impairment and cognitive domain scores were investigated using logistic, multiple linear and restricted cubic spline regression analyses adjusted for several confounders.

Results: Effect modification by glucose metabolism status was found for several associations with cognitive impairment, hence analyses were stratified. In individuals with prediabetes, 3-hydroxykynurenine (OR per SD 0.59 [95% CI 0.37, 0.94]) and 3-hydroxyanthranilic acid (0.67 [0.47, 0.96]) were associated with lower odds of cognitive impairment after full adjustment. In individuals with type 2 diabetes, kynurenine (0.80 [0.66, 0.98]), 3-hydroxykynurenine (0.82 [0.68, 0.99]), kynurenic acid (0.81 [0.68, 0.96]), xanthurenic acid (0.73 [0.61, 0.87]) and 3-hydroxyanthranilic acid (0.73 [0.60, 0.87]) were all associated with lower odds of cognitive impairment. Kynurenic acid (β per SD 0.07 [95% CI 0.02, 0.13]) and xanthurenic acid (0.06 [0.01, 0.11]) were also associated with better executive function/attention. No associations were observed in individuals with normal glucose metabolism.

Conclusions/interpretation: Several kynurenines were cross-sectionally associated with lower odds of cognitive impairment and better cognitive functioning in type 2 diabetes, while less widespread associations were seen in prediabetes. Low levels of kynurenines might be involved in the pathway of type 2 diabetes and cognitive decline but this needs further studies.
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http://dx.doi.org/10.1007/s00125-021-05521-4DOI Listing
August 2021

Inflammation-Related Marker Profiling of Dietary Patterns and All-cause Mortality in the Melbourne Collaborative Cohort Study.

J Nutr 2021 Jul 28. Epub 2021 Jul 28.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Background: Nutritional epidemiology research using self-reported dietary intake is prone to measurement error. Objective methods are being explored to overcome this limitation.

Objectives: We aimed to examine 1) the association between plasma markers related to inflammation and derive marker scores for dietary patterns [Mediterranean dietary score (MDS), energy-adjusted Dietary Inflammatory Index (E-DIITM), Alternative Healthy Eating Index 2010 (AHEI)] and 2) the associations of these marker scores with mortality.

Methods: Weighted marker scores were derived from the cross-sectional association between 30 plasma markers and each dietary score (assessed using food-frequency questionnaires) using linear regression for 770 participants in the Melbourne Collaborative Cohort Study (aged 50-82 y). Prospective associations between marker scores and mortality (n = 249 deaths) were assessed using Cox regression (median follow-up: 14.4 y).

Results: The MDS, E-DII, and AHEI were associated (P < 0.05) with 9, 14, and 11 plasma markers, respectively. Healthier diets (higher MDS and AHEI, and lower anti-inflammatory, E-DII) were associated with lower concentrations of kynurenines, neopterin, IFN-γ, cytokines, and C-reactive protein. Five of 6 markers common to the 3 dietary scores were components of the kynurenine pathway. The 3 dietary-based marker scores were highly correlated (Spearman ρ: -0.74, -0.82, and 0.93). Inverse associations (for 1-SD increment) were observed with all-cause mortality for the MDS marker score (HR: 0.84; 95% CI: 0.72-0.98) and the AHEI marker score (HR: 0.76; 95% CI: 0.66-0.89), whereas a positive association was observed with the E-DII marker score (HR: 1.18; 95% CI: 1.01-1.39). The same magnitude of effect was not observed for the respective dietary patterns.

Conclusions: Markers involved in inflammation-related processes are associated with dietary quality, including a substantial overlap between markers associated with the MDS, the E-DII, and the AHEI, especially kynurenines. Unfavorable marker scores, reflecting poorer-quality diets, were associated with increased mortality.
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http://dx.doi.org/10.1093/jn/nxab231DOI Listing
July 2021

Baked cod consumption delayed the development of kidney and liver dysfunction and affected plasma amino acid concentrations, but did not affect blood pressure, blood glucose or liver triacylglycerol concentrations in obese fa/fa Zucker rats.

Nutr Res 2021 08 12;92:72-83. Epub 2021 Jun 12.

Dietary Protein Research Group, Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway. Electronic address:

Obesity is associated with changes in amino acid metabolism, and studies show that ingestion of fish proteins influence amino acid composition in plasma and urine, in addition to affecting risk factors for metabolic syndrome. Since the majority of fish proteins consumed by humans are as fish fillet, it is of interest to investigate if cod fillet intake affects amino acid composition and metabolic disorders. We hypothesized that a modified AIN-93G diet containing cod fillet would affect amino acid compositions in plasma and urine in obese rats, and also affect risk factors for metabolic syndrome when compared to rats fed a regular AIN-93G diet with casein as the protein source. Obese Zucker fa/fa rats, a rat model of metabolic syndrome, received diets containing 25% protein from lyophilized baked cod fillet and 75% protein from casein (Baked cod diet), or a Control diet with casein for four weeks. The Baked cod diet affected the amino acid composition in plasma, with e.g., lower glycine, histidine, homoarginine, homocysteine, methionine, proline and tyrosine concentrations, but did not affect amino acid concentrations in urine. The concentrations of markers for kidney and liver dysfunction were lower in the Baked cod group, however blood pressure development, fasting and postprandial glucose, and hepatic triacylglycerol concentrations were similar to the Control group. To conclude, substituting 25% of dietary protein with baked cod fillet affected concentrations of some amino acids in plasma and delayed development of kidney and liver dysfunction, but did not affect blood pressure, glucose concentration or fatty liver.
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http://dx.doi.org/10.1016/j.nutres.2021.05.009DOI Listing
August 2021

Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults.

Sci Rep 2021 Jul 5;11(1):13805. Epub 2021 Jul 5.

Duke - NUS Medical School, Singapore, Singapore.

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.
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http://dx.doi.org/10.1038/s41598-021-93214-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257595PMC
July 2021

Association of markers of inflammation, the kynurenine pathway and B vitamins with age and mortality, and a signature of inflammaging.

J Gerontol A Biol Sci Med Sci 2021 Jun 12. Epub 2021 Jun 12.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.

Background: Inflammation is a key feature of aging. We aimed to i) investigate the association of 34 blood markers potentially involved in inflammatory processes with age and mortality, ii) develop a signature of 'inflammaging'.

Methods: Thirty-four blood markers relating to inflammation, B vitamin status and the kynurenine pathway were measured in 976 participants in the Melbourne Collaborative Cohort Study at baseline (median age=59 years) and follow-up (median age=70 years). Associations with age and mortality were assessed using linear and Cox regression, respectively. A parsimonious signature of inflammaging was developed and its association with mortality was compared with two marker scores calculated across all markers associated with age and mortality, respectively.

Results: The majority of markers (30/34) were associated with age, with stronger associations observed for neopterin, cystatin C, IL-6, TNF-α, several markers of the kynurenine pathway and derived indices KTR (kynurenine/tryptophan ratio), PAr index (ratio of 4-pyridoxic acid and the sum of pyridoxal 5´-phosphate and pyridoxal), and HK:XA (3-hydroxykynurenine/xanthurenic acid ratio). Many markers (17/34) showed an association with mortality, in particular IL-6, neopterin, CRP, quinolinic acid, PAr index, and KTR. The inflammaging signature included ten markers and was strongly associated of mortality (HR per SD=1.40, 95%CI:1.24-1.57, P=2x10 -8), similar to scores based on all age-associated (HR=1.38, 95%CI:1.23-1.55, P=4x10 -8) and mortality-associated markers (HR=1.43, 95%CI:1.28-1.60, P=1x10 -10), respectively. Strong evidence of replication of the inflammaging signature association with mortality was found in the Hordaland Health Study.

Conclusion: Our study highlights the key role of the kynurenine pathway and vitamin B6 catabolism in aging, along with other well-established inflammation-related markers. A signature of inflammaging based on ten markers was strongly associated with mortality.
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http://dx.doi.org/10.1093/gerona/glab163DOI Listing
June 2021

Quantifying Precision Loss in Targeted Metabolomics Based on Mass Spectrometry and Nonmatching Internal Standards.

Anal Chem 2021 06 20;93(21):7616-7624. Epub 2021 May 20.

Bevital, Laboratoriebygget, 9 etg., Jonas Lies veg 87, 5021 Bergen, Norway.

In mass spectrometry, reliable quantification requires correction for variations in ionization efficiency between samples. The preferred method is the addition of a stable isotope-labeled internal standard (SIL-IS). In targeted metabolomics, a dedicated SIL-IS for each metabolite of interest may not always be realized due to high cost or limited availability. We recently completed the analysis of more than 70 biomarkers, each with a matching SIL-IS, across four mass spectrometry-based platforms (one GC-MS/MS and three LC-MS/MS). Using data from calibrator and quality control samples added to 60 96-well trays (analytical runs), we calculated analytical precision (CV) retrospectively. The use of integrated peak areas for all metabolites and internal standards allowed us to calculate precision for all matching analyte (A)/SIL-IS (IS) pairs as well as for all nonmatching A/IS pairs within each platform (total = 1442). The median between-run precision for matching A/IS across the four platforms was 2.7-5.9%. The median CV for nonmatching A/IS (corresponding to pairing analytes with a non-SIL-IS) was 2.9-10.7 percentage points higher. Across all platforms, CVs for nonmatching A/IS increased with increasing difference in retention time (Spearman's rho of 0.17-0.93). The CV difference for nonmatching vs matching A/IS was often, but not always, smaller when analytes and internal standards were close structural analogs.
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http://dx.doi.org/10.1021/acs.analchem.1c00119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611570PMC
June 2021

Pre-diagnostic circulating concentrations of fat-soluble vitamins and risk of glioma in three cohort studies.

Sci Rep 2021 Apr 29;11(1):9318. Epub 2021 Apr 29.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Few prospective studies have evaluated the relation between fat-soluble vitamins and glioma risk. Using three cohorts-UK Biobank (UKB), Nurses' Health Study (NHS), and Health Professionals Follow-Up Study (HPFS), we investigated associations of pre-diagnostic concentrations of fat-soluble vitamins D, A, and E with incident glioma. In 346,785 participants (444 cases) in UKB, associations with vitamin D (25-hydroxyvitamin D [25(OH)D]) were evaluated by Cox proportional hazards regression. In NHS (52 cases, 104 controls) and HPFS (32 cases, 64 controls), associations with 25(OH)D, vitamin A (retinol), and vitamin E (α- and γ-tocopherol) were assessed using conditional logistic regression. Our results suggested plasma concentrations of 25(OH)D and retinol were not associated with glioma risk. Comparing the highest to lowest tertile, the multivariable hazard ratio (MVHR) for 25(OH)D was 0.87 (95% confidence interval [CI] 0.68-1.11) in UKB and the multivariable risk ratio (MVRR) was 0.97 (95% CI 0.51-1.85) in NHS and HPFS. In NHS and HPFS, the MVRR for the same comparison for retinol was 1.16 (95% CI 0.56-2.38). Nonsignificant associations were observed for α-tocopherol (MVRR = 0.61, 95% CI 0.29-1.32) and γ-tocopherol (MVRR  = 1.30, 95% CI 0.63-2.69) that became stronger in 4-year lagged analyses. Further investigation is warranted on a potential association between α- and γ-tocopherol and glioma risk.
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http://dx.doi.org/10.1038/s41598-021-88485-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084971PMC
April 2021

A comparison of complementary measures of vitamin B6 status, function, and metabolism in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

Am J Clin Nutr 2021 07;114(1):338-347

Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.

Background: Vitamin B6 insufficiency has been linked to increased risk of cancer and other chronic diseases. The circulating concentration of pyridoxal 5'-phosphate (PLP) is a commonly used measure of vitamin B6 status. Ratios of substrates indicating PLP coenzymatic function and metabolism may be useful complementary measures to further explore the role of vitamin B6 in health.

Objectives: We explored the sensitivity of 5 outcomes, namely PLP concentration, homocysteine:cysteine (Hcy:Cys), cystathionine:cysteine (Cysta:Cys), the 3´-hydroxykynurenine ratio (HKr), and the 4-pyridoxic acid ratio (PAr) to vitamin B6 intake as well as personal and lifestyle characteristics.

Medthods: Dietary intake and biomarker data were collected from participants from 3 nested case-control studies within the European Prospective Investigation into Cancer and Nutrition (EPIC). Bayesian regression models assessed the associations of the 5 biomarker outcomes with vitamin B6 intake and personal and lifestyle covariates. Analogous models examined the relations of Hcy:Cys, Cysta:Cys, and HKr with PLP.

Results: In total, 4608 participants were included in the analyses. Vitamin B6 intake was most strongly associated with PLP, moderately associated with Hcy:Cys, Cysta:Cys, and HKr, and not associated with PAr (fold change in marker given a doubling of vitamin B6 intake: PLP 1.60 [95% credible interval (CrI): 1.50, 1.71]; Hcy:Cys 0.87 [95% CrI: 0.84, 0.90]; Cysta:Cys 0.89 [95% CrI: 0.84, 0.94]; HKr 0.88 [95% CrI: 0.85, 0.91]; PAr 1.00 [95% CrI: 0.95, 1.05]). PAr was most sensitive to age, and HKr was least sensitive to BMI and alcohol intake. Sex and menopause status were strongly associated with all 5 markers.

Conclusions: We found that 5 different markers, capturing different aspects of vitamin B6-related biological processes, varied in their associations with vitamin B6 intake and personal and lifestyle predictors.
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http://dx.doi.org/10.1093/ajcn/nqab045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246608PMC
July 2021

Circulating B-vitamin biomarkers and B-vitamin supplement use in relation to quality of life in patients with colorectal cancer: results from the FOCUS consortium.

Am J Clin Nutr 2021 06;113(6):1468-1481

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

Background: B vitamins have been associated with the risk and progression of colorectal cancer (CRC), given their central roles in nucleotide synthesis and methylation, yet their association with quality of life in established CRC is unclear.

Objectives: To investigate whether quality of life 6 months postdiagnosis is associated with: 1) circulating concentrations of B vitamins and related biomarkers 6 months postdiagnosis; 2) changes in these concentrations between diagnosis and 6 months postdiagnosis; 3) B-vitamin supplement use 6 months postdiagnosis; and 4) changes in B-vitamin supplement use between diagnosis and 6 months postdiagnosis.

Methods: We included 1676 newly diagnosed stage I-III CRC patients from 3 prospective European cohorts. Circulating concentrations of 9 biomarkers related to the B vitamins folate, riboflavin, vitamin B6, and cobalamin were measured at diagnosis and 6 months postdiagnosis. Information on dietary supplement use was collected at both time points. Health-related quality of life (global quality of life, functioning scales, and fatigue) was assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 6 months postdiagnosis. Confounder-adjusted linear regression analyses were performed, adjusted for multiple testing.

Results: Higher pyridoxal 5'-phosphate (PLP) was cross-sectionally associated with better physical, role, and social functioning, as well as reduced fatigue, 6 months postdiagnosis. Associations were observed for a doubling in the hydroxykynurenine ratio [3-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3-hydroxyanthranilic acid + anthranilic acid); an inverse marker of vitamin B6] and both reduced global quality of life (β = -3.62; 95% CI: -5.88, -1.36) and worse physical functioning (β = -5.01; 95% CI: -7.09, -2.94). Dose-response relations were observed for PLP and quality of life. No associations were observed for changes in biomarker concentrations between diagnosis and 6 months. Participants who stopped using B-vitamin supplements after diagnosis reported higher fatigue than nonusers.

Conclusions: Higher vitamin B6 status was associated with better quality of life, yet limited associations were observed for the use of B-vitamin supplements. Vitamin B6 needs further study to clarify its role in relation to quality of life.
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http://dx.doi.org/10.1093/ajcn/nqaa422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168355PMC
June 2021

Alterations in the Kynurenine Pathway of Tryptophan Metabolism Are Associated With Depression in People Living With HIV.

J Acquir Immune Defic Syndr 2021 06;87(2):e177-e181

Department of Infectious Diseases, University of Copenhagen, Copenhagen, Denmark.

Background: People living with HIV have increased risk of depression compared with uninfected controls. The determinants of this association are unclear. Alterations in kynurenine (Kyn) metabolism have been associated with depression in uninfected individuals, but whether they are involved in the development of depression in the context of HIV infection is unknown.

Methods: A total of 909 people living with HIV were recruited from the Copenhagen Comorbidity in HIV infection study. Information regarding demographics and depression was obtained from questionnaires. HIV-related variables and use of antidepressant medication were collected from patient records. Logistic regression models before and after adjustment for confounders were used to test our hypotheses.

Results: The prevalence of depression was 11%. Among traditional risk factors, only being unmarried was associated with greater odds of depression. Higher levels of quinolinic-to-kynurenic acid ratio (P = 0.018) and higher concentrations of quinolinic acid (P = 0.048) were found in individuals with depression than in those without. After adjusting for confounders, high levels of quinolinic-to-kynurenic acid ratio and high concentrations of quinolinic acid remained associated with depression [adjusted odds ratio 1.61 (1.01; 2.59) and adjusted odds ratio 1.68 (1.02; 2.77), respectively].

Conclusions: The results from this study suggest that alterations in the kynurenine pathway of tryptophan metabolism are associated with the presence of depression in the context of HIV infection.
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http://dx.doi.org/10.1097/QAI.0000000000002664DOI Listing
June 2021

Associations of neopterin and kynurenine-tryptophan ratio with survival in primary sclerosing cholangitis.

Scand J Gastroenterol 2021 Apr 14;56(4):443-452. Epub 2021 Feb 14.

Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.

Background And Aims: Biomarkers of inflammation may be of clinical utility in primary sclerosing cholangitis (PSC). We aimed to investigate the interferon gamma-related biomarkers neopterin and kynurenine-tryptophanratio (KT-ratio) in PSC.

Methods: Circulating neopterin, tryptophan and kynurenine were measured with LC-MS/MS in multiple cross-sectional cohorts comprising in total of 524 PSC patients and 100 healthy controls from Norway, Germany and Sweden.

Results: Neopterin and KT-ratio were significantly increased in PSC patients compared with controls in both a discovery and a validation cohort from Norway. Furthermore, high neopterin and KT-ratio levels were associated with a shorter transplantation-free survival in the PSC patients in the Norwegian discovery cohort and the German validation cohort. However, in the validation PSC cohort from Sweden, no relationship between neopterin and KT-ratio and liver transplantation-free survival was observed. The correlations between neopterin and KT-ratio were moderate to strong and similar in all cohorts (rho 0.50-0.67). Neopterin and KT-ratio also correlated with C-reactive protein (rho 0.17-0.63) and revised Mayo risk score (rho 0.23-0.42) in all cohorts.

Conclusions: Neopterin and KT-ratio were elevated in PSC and associated with liver transplantation-free survival in two independent PSC cohorts, highlighting a possible role of interferon gamma-driven inflammation in the pathogenesis. However, the lack of association with survival in one of the cohorts reduces the potential clinical value of neopterin and KT-ratioas biomarkers and highlights the need to validate new biomarkers in PSC in multiple cohorts.
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http://dx.doi.org/10.1080/00365521.2021.1880627DOI Listing
April 2021

Effect of high intake of cod or salmon on serum total neopterin concentration: a randomised clinical trial.

Eur J Nutr 2021 Sep 12;60(6):3237-3248. Epub 2021 Feb 12.

Department of Clinical Medicine, University of Bergen, Haukeland University Hospital, 5021, Bergen, Norway.

Purpose: Primarily, to investigate the effect of high intake of cod (lean fish) or salmon (fatty fish) on serum concentration of total neopterin, a marker of cellular immune activation that is associated with cardiovascular disease. Second, to investigate effects of high cod/salmon intake on antioxidant vitamins and elements essential for activity of antioxidant enzymes.

Methods: In this randomised clinical trial, 63 participants with overweight/obesity consumed 750 g/week of either Atlantic cod (N = 22) or Atlantic salmon (N = 22) or were instructed to continue their normal eating habits but avoid fish intake (Control group, N = 19) for 8 weeks. Food intake was recorded, and fasting serum were collected at baseline and endpoint.

Results: Serum total neopterin concentration was reduced in the Cod group (median change - 2.65 (25th, 75th percentiles - 3.68, - 0.45) nmol/l, P = 0.018) but not in the Salmon group (median change 0.00 (25th, 75th percentiles - 4.15, 3.05) nmol/l, P = 0.59) when compared with the Control group after 8 weeks. The estimated daily intake of selenium, iron, magnesium and zinc were similar between all groups. Increased serum concentration of selenium was observed only after cod intake when compared to the Control group (P = 0.017). Changes in serum concentrations of copper, iron, magnesium, all-trans retinol, α-tocopherol and γ-tocopherol were similar between the groups.

Conclusion: A high intake of cod, but not of salmon, lowered serum total neopterin concentration when compared to the Control group.

Clinical Trial Registration: This trial was registered at clinicaltrials.gov as NCT02350595.
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http://dx.doi.org/10.1007/s00394-021-02497-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354862PMC
September 2021

Kynurenic Acid Protects Against Reactive Glial-associated Reductions in the Complexity of Primary Cortical Neurons.

J Neuroimmune Pharmacol 2021 Sep 3;16(3):679-692. Epub 2021 Jan 3.

Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.

Brain glia produce neuroactive metabolites via tryptophan-kynurenine catabolism. A role for kynurenine pathway (KP) metabolites is proposed in reactive glial associated neurodegeneration. The aim of this investigation was to assess the role of KP induction and KP metabolites in driving reactive glial associated neuronal atrophy. Rat primary mixed glia, and enriched microglial and astroglial cultures were stimulated with IFNγ (10 ng/ml) for 24 hours. KP induction in mixed glial cells was confirmed by raised expression of the rate limiting KP enzyme indoleamine 2,3 dioxygenase (IDO) and raised concentrations of KP metabolites kynurenic acid (KYNA) and quinolinic acid (QUIN) in the conditioned media. Conditioned media was transferred onto immature (3 days) and mature (21 days) primary cortical neurons in vitro for 24 hours. IFNγ-stimulated mixed glial conditioned media reduced neurite outgrowth and complexity of both immature and mature neurons and co-localised expression of synaptic markers determined by immunocytochemistry. Pre-treatment of mixed glial cells with the IDO inhibitor, 1-methyltryptophan (1-MT) (L) prevented these effects of IFNγ-stimulated mixed glial conditioned media. KYNA increased complexity and synapse formation in mature cortical neurons and protected against reduced neuronal complexity and co-localised expression of synaptic markers induced by conditioned media from IFNγ-stimulated mixed glia and by treatment of neuronal cells with QUIN (1 µM). Overall, this study supports a role for the KP in driving neuronal atrophy associated with reactive glia and indicates that inhibition of the KP in glia, or raising the concentration of the astrocytic metabolite KYNA, protects against reactive microglial and QUIN-associated neuronal atrophy.
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http://dx.doi.org/10.1007/s11481-020-09976-xDOI Listing
September 2021

Effects of high intake of cod or salmon on gut microbiota profile, faecal output and serum concentrations of lipids and bile acids in overweight adults: a randomised clinical trial.

Eur J Nutr 2021 Jun 27;60(4):2231-2248. Epub 2020 Oct 27.

Dietary Protein Research Group, Department of Clinical Medicine, Haukeland University Hospital, University of Bergen, 5021, Bergen, Norway.

Purpose: To explore whether high intake of cod or salmon would affect gut microbiota profile, faecal output and serum concentrations of lipids and bile acids.

Methods: Seventy-six adults with overweight/obesity with no reported gastrointestinal disease were randomly assigned to consume 750 g/week of either cod or salmon, or to avoid fish intake (Control group) for 8 weeks. Fifteen participants from each group were randomly selected for 72 h faeces collection at baseline and end point for gut microbiota profile analyses using 54 bacterial DNA probes. Food intake was registered, and fasting serum and morning urine were collected at baseline and end point.

Results: Sixty-five participants were included in serum and urine analyses, and gut microbiota profile was analysed for 33 participants. Principal component analysis of gut microbiota showed an almost complete separation of the Salmon group from the Control group, with lower counts for bacteria in the Bacteroidetes phylum and the Clostridiales order of the Firmicutes phyla, and higher counts for bacteria in the Selenomonadales order of the Firmicutes phylum. The Cod group showed greater similarity to the Salmon group than to the Control group. Intake of fibres, proteins, fats and carbohydrates, faecal daily mass and output of fat, cholesterol and total bile acids, and serum concentrations of cholesterol, triacylglycerols, non-esterified fatty acids and total bile acids were not altered in the experimental groups.

Conclusion: A high intake of cod or salmon fillet modulated gut microbiota but did not affect faecal output or serum concentrations of lipids and total bile acids.

Clinical Trial Registration: This trial was registered at clinicaltrials.gov as NCT02350595.
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http://dx.doi.org/10.1007/s00394-020-02417-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137623PMC
June 2021

Elevated plasma cotinine is associated with an increased risk of developing IBD, especially among users of combusted tobacco.

PLoS One 2020 2;15(7):e0235536. Epub 2020 Jul 2.

Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden.

Objective: Smoking has previously been associated with inflammatory bowel disease (IBD), but no study has reported on cotinine, an objective, biochemical measure of tobacco use. We aimed at testing the hypothesis that cotinine levels among healthy subjects are associated with an increased risk of developing IBD in later life.

Design: We analysed plasma cotinine and evaluated corresponding lifestyle questionnaires that included tobacco habits in subjects (n = 96) who later developed late-onset IBD (70 ulcerative colitis (UC) and 26 Crohn's disease (CD)) and in sex and age-matched controls (n = 191).

Results: Patients who later developed IBD had significantly higher plasma cotinine levels compared to controls. In multivariable analysis, higher log-cotinine was associated with a higher risk of developing IBD (OR 1.34 (95% CI 1.01-1.63)). After stratifying for time to diagnosis, the association was only significant in subjects with shorter time (< 5.1 years) to diagnosis (OR 1.45 (1.09-1.92)). The findings were similar for UC- and CD-cases, but did not reach statistical significance in CD-cases. Although plasma cotinine concentrations were higher in snuff users compared to combusted tobacco users, no increase in the risk of IBD and lower risk of developing IBD among subjects with shorter time (< 5.1 years) to diagnosis was seen among snuff users.

Conclusions: Cotinine, a biomarker of tobacco use, is associated with increased risk of developing late-onset IBD in general, and UC in particular. No increased risk among snuff users indicates that other components in combusted tobacco than nicotine may be involved in the pathogenesis of IBD among smokers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235536PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332008PMC
September 2020

Effect of Cod Residual Protein Supplementation on Markers of Glucose Regulation in Lean Adults: A Randomized Double-Blind Study.

Nutrients 2020 May 16;12(5). Epub 2020 May 16.

Dietary Protein Research Group, Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway.

Large quantities of protein-rich cod residuals, which are currently discarded, could be utilized for human consumption. Although fish fillet intake is related to beneficial health effects, little is known about the potential health effects of consuming cod residual protein powder. Fifty lean adults were randomized to consume capsules with 8.1 g/day of cod residual protein (Cod-RP) or placebo capsules (Control group) for eight weeks, in this randomized, double-blind study. The intervention was completed by 40 participants. Fasting glucose and insulin concentrations were unaffected by Cod-RP supplementation, whereas plasma concentrations of α-hydroxybutyrate, β-hydroxybutyrate and acetoacetate all were decreased compared with the Control group. Trimethylamine N-oxide concentration in plasma and urine were increased in the Cod-RP group compared with the Control group. To conclude, the reduction in these potential early markers of impaired glucose metabolism following Cod-RP supplementation may indicate beneficial glucoregulatory effects of cod residual proteins. Trimethylamine N-oxide appears to be an appropriate biomarker of cod residual protein intake in lean adults.
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http://dx.doi.org/10.3390/nu12051445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285039PMC
May 2020

Lipid parameters and vitamin A modify cardiovascular risk prediction by plasma neopterin.

Heart 2020 07 12;106(14):1073-1079. Epub 2020 May 12.

Centre for Nutrition, Department of Clinical Science, University of Bergen, Bergen, Norway.

Objectives: Oxidised cholesterol metabolites are linked to increased production of the active vitamin A (Vit-A) form and monocyte/macrophage activation, which may be reflected by neopterin, a marker of both interferon-γ-mediated immune activation and coronary artery disease risk. We examined the influence of serum lipid parameters and Vit-A on the risk association between neopterin and incident acute myocardial infarction (AMI).

Methods: We included 4130 patients with suspected stable angina pectoris (SAP), of whom 80% received lipid-lowering treatment with statins. Risk associations between plasma neopterin and AMI are given as HRs per SD increase in log-transformed neopterin.

Results: During a median follow-up of 7.5 years, 530 (12.8%) patients experienced an AMI. In age-adjusted and sex-adjusted analysis, plasma neopterin was positively associated with incident AMI (HR (95% CI) per SD: 1.26 (1.17 to 1.35)). However, the estimates were most pronounced in patients with serum low-density lipoprotein cholesterol (LDL-C) or apolipoprotein (apo) B100 below-median (HR (95% CI) per SD: 1.35 (1.24 to 1.48) and 1.42 (1.27 to 1.58), respectively; both p ≤0.03). We also observed a particularly strong risk association in those with above-median Vit-A (HR (95% CI) per SD: 1.32 (1.21 to 1.44); p=0.03). The estimates were slightly modified after multivariable adjustment.

Conclusions: In patients with suspected SAP, the majority of whom receiving statin therapy, high plasma neopterin was associated with increased risk of AMI particularly among those with low LDL-C and apoB100 or high Vit-A levels. The particularly strong relationship of plasma neopterin with residual cardiovascular risk in patients with low lipid levels should be further investigated.
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http://dx.doi.org/10.1136/heartjnl-2019-316165DOI Listing
July 2020

A prospective evaluation of serum methionine-related metabolites in relation to pancreatic cancer risk in two prospective cohort studies.

Int J Cancer 2020 10 7;147(7):1917-1927. Epub 2020 Apr 7.

Division of Cancer Control and Population Science, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Deficiencies in methyl donor status may render DNA methylation changes and DNA damage, leading to carcinogenesis. Epidemiological studies reported that higher dietary intake of choline is associated with lower risk of pancreatic cancer, but no study has examined the association of serum choline and its metabolites with risk of pancreatic cancer. Two parallel case-control studies, one nested within the Shanghai Cohort Study (129 cases and 258 controls) and the other within the Singapore Chinese Health Study (58 cases and 104 controls), were conducted to evaluate the associations of baseline serum concentrations of choline, betaine, methionine, total methyl donors (i.e., sum of choline, betaine and methionine), dimethylglycine and trimethylamine N-oxide (TMAO) with pancreatic cancer risk. In the Shanghai cohort, odds ratios and 95% confidence intervals of pancreatic cancer for the highest quartile of choline, betaine, methionine, total methyl donors and TMAO were 0.27 (0.11-0.69), 0.57 (0.31-1.05), 0.50 (0.26-0.96), 0.37 (0.19-0.73) and 2.81 (1.37-5.76), respectively, compared to the lowest quartile. The corresponding figures in the Singapore cohort were 0.85 (0.23-3.17), 0.50 (0.17-1.45), 0.17 (0.04-0.68), 0.33 (0.10-1.16) and 1.42 (0.50-4.04). The inverse associations of methionine and total methyl donors including choline, betaine and methionine with pancreatic cancer risk in both cohorts support that DNA repair and methylation play an important role against the development of pancreatic cancer. In the Shanghai cohort, TMAO, a gut microbiota-derived metabolite of dietary phosphatidylcholine, may contribute to higher risk of pancreatic cancer, suggesting a modifying role of gut microbiota in the dietary choline-pancreatic cancer risk association.
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http://dx.doi.org/10.1002/ijc.32994DOI Listing
October 2020

Metabolic analysis of amino acids and vitamin B6 pathways in lymphoma survivors with cancer related chronic fatigue.

PLoS One 2020 10;15(1):e0227384. Epub 2020 Jan 10.

Department of Oncology, National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital, Oslo, Norway.

Chronic cancer-related fatigue (CF) is a common and distressing condition in a subset of cancer survivors and common also after successful treatment of malignant lymphoma. The etiology and pathogenesis of CF is unknown, and lack of biomarkers hampers development of diagnostic tests and successful therapy. Recent studies on the changes of amino acid levels and other metabolites in patients with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) have pointed to possible central defects in energy metabolism. Here we report a comprehensive analysis of serum concentrations of amino acids, including metabolites of tryptophan, the kynurenine pathway and vitamin B6 in a well characterized national Norwegian cohort of lymphoma survivors after high-dose therapy and autologous stem cell transplantation. Among the 20 standard amino acids in humans, only tryptophan levels were significantly lower in both males and females with CF compared to non-fatigued survivors, a strikingly different pattern than seen in CFS/ME. Markers of tryptophan degradation by the kynurenine pathway (kynurenine/tryptophan ratio) and activation of vitamin B6 catabolism (pyridoxic acid/(pyridoxal + pyridoxal 5'-phosphate), PAr index) differed in survivors with or without CF and correlated with known markers of immune activation and inflammation, such as neopterin, C-reactive protein and Interleukin-6. Among personal traits and clinical findings assessed simultaneously in participating survivors, higher neuroticism score, obesity and higher PAr index were significantly associated with increased risk of CF. Collectively, these data point to low grade immune activation and inflammation as a basis for CF in lymphoma survivors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227384PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953873PMC
April 2020

Plasma kynurenines and prognosis in patients with heart failure.

PLoS One 2020 10;15(1):e0227365. Epub 2020 Jan 10.

Department of Clinical Science, University of Bergen, Bergen, Norway.

Background: Metabolites of the kynurenine pathway (mKP) relate to important aspects of heart failure pathophysiology, such as inflammation, energy-homeostasis, apoptosis, and oxidative stress. We aimed to investigate whether mKP predict mortality in patients with heart failure.

Methods: The study included 202 patients with heart failure (73.8% with coronary artery disease (CAD)), propensity score matched to 384 controls without heart disease, and 807 controls with CAD (71%). All underwent coronary angiography and ventriculography at baseline. Plasma mKP, pyridoxal 5'phosphate (PLP) and CRP were measured at baseline. Case-control differences were assessed by logistic regression and survival by Cox regression, adjusted for age, gender, smoking, diabetes, ejection fraction, PLP, eGFR and CRP. Effect measures are reported per standard deviation increments.

Results: Higher plasma levels of kynurenine, 3- hydroxykynurenine (HK), quinolinic acid (QA), the kynurenine-tryptophan-ratio (KTR) and the ratio of HK to xanthurenic acid (HK/XA) were detected in heart failure compared to both control groups. The mortality rate per 1000 person-years was 55.5 in patients with heart failure, 14.6 in controls without heart disease and 22.2 in CAD controls. QA [HR 1.80, p = 0.013], HK [HR 1.77, p = 0.005], HK/XA [HR 1.67, p < 0.001] and KTR [HR 1.55, p = 0.009] were associated with increased mortality in patients with heart failure, while XA [HR 0.68-0.80, p = 0.013-0.037] were associated with lower mortality in all groups. HK and HK/XA had weak associations with increased mortality in CAD-controls.

Conclusion: Elevated plasma levels of mKP and metabolite ratios are associated with increased mortality, independent of CAD, in patients with heart failure.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227365PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953806PMC
April 2020

Short-term treatment with a peroxisome proliferator-activated receptor α agonist influences plasma one-carbon metabolites and B-vitamin status in rats.

PLoS One 2019 5;14(12):e0226069. Epub 2019 Dec 5.

Department of Clinical Science, University of Bergen, Bergen, Norway.

Introduction: Peroxisome proliferator-activated receptors (PPARs) have been suggested to be involved in the regulation of one-carbon metabolism. Previously we have reported effects on plasma concentrations of metabolites along these pathways as well as markers of B-vitamin status in rats following treatment with a pan-PPAR agonist. Here we aimed to investigate the effect on these metabolites after specific activation of the PPARα and PPARγ subtypes.

Methods: For a period of 12 days, Male Wistar rats (n = 20) were randomly allocated to receive treatment with the PPARα agonist WY-14.643 (n = 6), the PPARγ agonist rosiglitazone (n = 6) or placebo (n = 8). The animals were sacrificed under fasting conditions, and plasma concentration of metabolites were determined. Group differences were assessed by one-way ANOVA, and planned comparisons were performed for both active treatment groups towards the control group.

Results: Treatment with a PPARα agonist was associated with increased plasma concentrations of most biomarkers, with the most pronounced differences observed for betaine, dimethylglycine, glycine, nicotinamide, methylnicotinamide, pyridoxal and methylmalonic acid. Lower levels were observed for flavin mononucleotide. Fewer associations were observed after treatment with a PPARγ agonist, and the most notable was increased plasma serine.

Conclusion: Treatment with a PPARα agonist influenced plasma concentration of one-carbon metabolites and markers of B-vitamin status. This confirms previous findings, suggesting specific involvement of PPARα in the regulation of these metabolic pathways as well as the status of closely related B-vitamins.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226069PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894826PMC
March 2020

The Associations Between Cognitive Prognosis and Kynurenines Are Modified by the Apolipoprotein ε4 Allele Variant in Patients With Dementia.

Int J Tryptophan Res 2019 15;12:1178646919885637. Epub 2019 Nov 15.

Department of Clinical Science, University of Bergen, Bergen, Norway.

Background: The apolipoprotein E ε4 gene variant (APOEε4) confers considerable risk for dementia and affects neuroinflammation, brain metabolism, and synaptic function. The kynurenine pathway (KP) gives rise to neuroactive metabolites, which have inflammatory, redox, and excitotoxic effects in the brain.

Aim: To assess whether the presence of at least one APOEε4 allele modifies the association between kynurenines and the cognitive prognosis.

Methods: A total of 152 patients with sera for metabolite measurements and APOE genotype were included from the Dementia of Western Norway. The participants had mild Alzheimer disease and Lewy body dementia. Apolipoprotein E ε4 gene variant allele status was classified as one or more ε4 versus any other. Mini-Mental State Examination (MMSE) was measured at baseline and for 5 consecutive years. Mann-Whitney tests and linear mixed-effects models were used for statistical analysis.

Results: There were no significant differences in serum concentrations of tryptophan and kynurenine according to the presence or absence of APOEε4. High serum concentrations of kynurenic acid, quinolinic acid, and picolinic acid, and a higher kynurenine-to-tryptophan ratio, were all associated with more cognitive decline in patients without APOEε4 compared to those with the APOEε4 allele (-value of the interactions < .05).

Conclusions: Kynurenic acid, quinolinic acid, picolinic acid, and the kynurenine-to-tryptophan ratio were associated with a significant increase in cognitive decline when the APOEε4 variant was absent, whereas there was a relatively less decline when the APOEε4 variant was present.
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http://dx.doi.org/10.1177/1178646919885637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859685PMC
November 2019

Five salmon dinners per week were not sufficient to prevent the reduction in serum vitamin D in autumn at 60° north latitude: a randomised trial.

Br J Nutr 2020 02 25;123(4):419-427. Epub 2019 Nov 25.

Dietary Protein Research Group, Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway.

Low serum concentrations of several vitamins have been linked to increased risk of diseases including insulin resistance and type 2 diabetes (T2D). Fish is a good source of several vitamins, and the prevalence of T2D is low in populations with high fish intake. The aim of the present study was to investigate the effects of high fish intake on vitamins in serum from adults in autumn in South-Western Norway at 60° north latitude. In this randomised clinical trial, sixty-three healthy participants with overweight/obesity consumed 750 g/week of either cod (n 22) or salmon (n 22) as five weekly dinners or were instructed to continue their normal eating habits but avoid fish intake (Control group, n 19) for 8 weeks. The estimated vitamin D intake was significantly increased in the Salmon group when compared with the Cod group (P = 6·3 × 10-4) and with the Control group (P = 3·5 × 10-6), with no differences between groups for estimated intake of vitamins A, B1, B2, B3, B6, B9, C and E. Serum 25-hydroxyvitamin D3 concentration was decreased in all groups after 8 weeks; however, the reduction in the Salmon group was significantly smaller compared with the Cod group (P = 0·013) and the Control group (P = 0·0060). Cod and salmon intake did not affect serum concentrations of the other measured vitamins. The findings suggest that 750 g/week of salmon was not sufficient to prevent a decrease in serum 25-hydroxyvitamin D3 in autumn in South-Western Norway in adults with overweight/obesity.
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http://dx.doi.org/10.1017/S0007114519002964DOI Listing
February 2020

Plasma Cotinine Cutoff for Distinguishing Smokers From Nonsmokers Among Persons Living With HIV.

J Acquir Immune Defic Syndr 2019 12;82(5):e54-e56

Viro-immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen.

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http://dx.doi.org/10.1097/QAI.0000000000002189DOI Listing
December 2019

Urinary Cotinine Is as Good a Biomarker as Serum Cotinine for Cigarette Smoking Exposure and Lung Cancer Risk Prediction.

Cancer Epidemiol Biomarkers Prev 2020 01 4;29(1):127-132. Epub 2019 Nov 4.

Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Cotinine is a metabolite of nicotine. Serum and urinary cotinine are validated biomarkers for cigarette exposure. Their performance for lung cancer risk prediction has not been simultaneously examined in epidemiologic studies.

Methods: A nested case-control study, including 452 incident lung cancer cases and 452 smoking-matched controls in the Shanghai cohort study, was conducted. Mass spectrometry-based methods were used to quantify cotinine in serum and urine samples collected from current smokers at baseline, on average 10 years before cancer diagnosis of cases. Logistic regression was used to estimate ORs, 95% confidence intervals (CI), and AUC ROC for lung cancer associated with higher levels of cotinine.

Results: Serum and urinary cotinine levels were significantly higher in lung cancer cases than controls. Compared with the lowest quartile serum cotinine (≤0.40 nmol/mL), the OR of lung cancer for smokers in the highest quartiles (>1.39 nmol/mL) was 5.46 (95% CI, 3.38-8.81). Similarly, the OR was 5.49 (95% CI, 3.39-8.87) for highest (>16.38 nmol/mg creatinine) relative to the lowest quartile of urinary total cotinine (≤4.11 nmol/mg creatinine). A risk prediction model yielded an AUC of 0.72 (95% CI, 0.69-0.75) for serum cotinine and 0.72 (95% CI, 0.69-0.75) for urinary total cotinine combined with smoking history.

Conclusions: Urinary and serum cotinine have the same performance in prediction of lung cancer risk for current smokers.

Impact: Urinary cotinine is a noninvasive biomarker that can replace serum cotinine in risk prediction of future lung cancer risk for current smokers.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695222PMC
January 2020

Kynurenines, Neuropsychiatric Symptoms, and Cognitive Prognosis in Patients with Mild Dementia.

Int J Tryptophan Res 2019 29;12:1178646919877883. Epub 2019 Sep 29.

Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway.

Introduction: Circulating tryptophan (Trp) and its downstream metabolites, the kynurenines, are potentially neuroactive. Consequently, they could be associated with neuropsychiatric symptoms and cognitive prognosis in patients with dementia.

Objective: The objective of this study was to assess associations between circulating kynurenines, cognitive prognosis, and neuropsychiatric symptoms.

Methods: We measured baseline serum Trp, neopterin, pyridoxal 5'-phosphate (PLP), and 9 kynurenines in 155 patients with mild dementia (90 with Alzheimer's disease, 65 with Lewy body dementia). The ratios between kynurenine and Trp and kynurenic acid (KA) to kynurenine (KKR) were calculated. The Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI) were administered at baseline and annually over 5 years. Associations between baseline metabolite concentrations with MMSE and the NPI total score were assessed using a generalized structural equation model (mixed-effects multiprocess model), adjusted for age, sex, current smoking, glomerular filtration rate, and PLP. Post hoc associations between KKRs and individual NPI items were assessed using logistic mixed-effects models. False discovery rate (0.05)-adjusted values ( values) are reported.

Results: Kynurenine had a nonlinear quadratic relationship with the intercept of the MMSE scores over 5 years ( < 0.05), but not with the slope of MMSE decline. Kynurenine was associated with a higher NPI total score over time ( < 0.001). Post hoc, both KKR and KA were associated with more hallucinations ( < 0.05).

Conclusions: Kynurenine has a complex relationship with cognition, where both low and high levels were associated with poor cognitive performance. A higher KKR indicated risk for neuropsychiatric symptoms, especially hallucinations.
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http://dx.doi.org/10.1177/1178646919877883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769202PMC
September 2019

Tryptophan catabolites as metabolic markers of vitamin B-6 status evaluated in cohorts of healthy adults and cardiovascular patients.

Am J Clin Nutr 2020 01;111(1):178-186

Department of Clinical Science, University of Bergen, Bergen, Norway.

Background: Vitamin B-6 status is routinely measured as pyridoxal 5'-phosphate (PLP) in plasma. Low concentrations of PLP are associated with rheumatic, cardiovascular, and neoplastic diseases. We have previously shown that vitamin B-6 status affects the kynurenine (Kyn) pathway of tryptophan (Trp) catabolism.

Objective: This study aimed to comprehensively evaluate the use of Kyns as potential markers of functional vitamin B-6 status across 2 large cohorts.

Methods: We measured circulating concentrations of the first 6 metabolites in the Trp catabolic pathway by LC-MS-MS in the community-based Hordaland Health Study (HUSK; n = 7017) and cardiovascular patient-based Western Norway Coronary Angiography Cohort (WECAC; n = 4161). Cross-sectional and longitudinal associations of plasma PLP with Kyns were estimated using linear and nonlinear regression-based methods.

Results: 3'-Hydroxykynurenine (HK), a substrate, and all 4 products formed directly by the PLP-dependent enzymes kynurenine transaminase and kynureninase contributed to the explanation of circulating PLP in multivariable-adjusted regression models. The construct HK:(kynurenic acid + xanthurenic acid + 3'-hydroxyanthranilic acid + anthranilic acid), termed HK ratio (HKr), was related to plasma PLP with standardized regression coefficients (95% CIs) of -0.47 (-0.49, -0.45) and -0.46 (-0.49, -0.43) in HUSK and WECAC, respectively. Across strata of cohort and sex, HKr was 1.3- to 2.7-fold more sensitive, but also 1.7- to 2.9-fold more specific to changes in PLP than a previously proposed marker, HK:xanthurenic acid. Notably, the association was strongest at PLP concentrations < ∼20 nmol/L, a recognized threshold for vitamin B-6 deficiency. Finally, PLP and HKr demonstrated highly sex-specific and corroborating associations with age.

Conclusions: The results demonstrate that by combining 5 metabolites in the Kyn pathway into a simple index, HKr, a sensitive and specific indicator of intracellular vitamin B-6 status is obtained. The data also underscore the merit of evaluating alterations in Kyn metabolism when investigating vitamin B-6 and health.
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http://dx.doi.org/10.1093/ajcn/nqz228DOI Listing
January 2020

Abdominal Adipose Tissue Is Associated With Alterations in Tryptophan-Kynurenine Metabolism and Markers of Systemic Inflammation in People With Human Immunodeficiency Virus.

J Infect Dis 2020 01;221(3):419-427

Viro-immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: While both adipose tissue accumulation and tryptophan metabolism alterations are features of human immunodeficiency virus (HIV) infection, their interplay is unclear. We investigated associations between abdominal adipose tissue, alterations in kynurenine pathway of tryptophan metabolism, and systemic inflammation in people with HIV (PWH).

Methods: Eight hundred sixty-four PWH and 75 uninfected controls were included. Plasma samples were collected and analyzed for kynurenine metabolites, neopterin, high-sensitivity C-reactive protein (hs-CRP), and lipids. Regression models were used to test associations in PWH.

Results: PWH had higher kynurenine-to-tryptophan ratio than uninfected individuals (P < .001). In PWH, increase in waist-to-hip ratio was associated with higher kynurenine-to-tryptophan ratio (P = .009) and quinolinic-to-kynurenic acid ratio (P = .006) and lower kynurenic acid concentration (P = .019). Quinolinic-to-kynurenic acid ratio was associated with higher hs-CRP (P < .001) and neopterin concentrations (P < .001), while kynurenic acid was associated with lower hs-CRP (P = .025) and neopterin concentrations (P = .034).

Conclusions: In PWH, increase in abdominal adipose tissue was associated with increased quinolinic-to-kynurenic acid ratio, suggesting activation of proinflammatory pathway of kynurenine metabolism, with reduction of anti-inflammatory molecules and increase in systemic inflammation. Our results suggest dysregulation of kynurenine metabolism associated with abdominal fat accumulation to be a potential source of inflammation in HIV infection.
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http://dx.doi.org/10.1093/infdis/jiz465DOI Listing
January 2020

Creatinine, total cysteine and uric acid are associated with serum retinol in patients with cardiovascular disease.

Eur J Nutr 2020 Sep 9;59(6):2383-2393. Epub 2019 Sep 9.

Centre for Nutrition, Department of Clinical Science, University of Bergen, Haukelandsbakken, 5009, Bergen, Norway.

Purpose: We hypothesized that biomarkers and dietary factors related to cardiovascular disease risk were associated with serum retinol and evaluated these potential associations in patients with suspected coronary artery disease (CAD).

Methods: We used cross-sectional data from 4116 patients hospitalised for suspected CAD. Dietary data were obtained from a subgroup of 1962 patients using a food frequency questionnaire. Potential biomarkers and dietary factors were explored using linear regression modelling adjusted for age and sex. Regression coefficients and corresponding confidence intervals (CI) are given as  % change in serum retinol per unit change in the predictors. Analyses were performed in the total population and in strata of serum retinol tertiles.

Results: In age- and sex-adjusted models, serum creatinine (standardized β: 0.38, 95% CI [0.35, 0.42]), plasma total cysteine (0.26, [0.23, 0.29]), serum uric acid (0.30, [0.26, 0.33]) and plasma neopterin (0.22, [0.18, 0.25]) were positively associated, whereas plasma serine (- 0.15, [- 0.18, - 0.12]) and serum C-reactive protein (- 0.15, [- 0.18, - 0.12]) were inversely associated with serum retinol. When we included the significant biomarkers in a multivariate model, the model explained 33% of the variability (R = 0.33) in serum retinol. The results were similar in the lower and upper tertiles of serum retinol. Weak or no associations were observed for dietary factors.

Conclusions: In patients with suspected CAD, concentrations of creatinine, cysteine and uric acid were positively associated with serum retinol. Future studies should assess whether retinol concentrations are influenced by metabolic alterations in patients at risk of cardiovascular disease.
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http://dx.doi.org/10.1007/s00394-019-02086-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413901PMC
September 2020
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