BACKGROUND:Recent findings from the REPRIEVE study suggest statins provide greater cardiovascular protection in persons with HIV (PWH) than expected from low-density lipoprotein (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. METHODS: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. RESULTS:We included 1041 of whom 130 (12.5%) received statins. Statin-treated PWH were older (60 vs. 49 years), and more frequently men (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 [odds ratio (OR): 0.60; 95% confidence interval (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. CONCLUSION: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.

Background/Objectives: 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). Methods: 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. Results: 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. Conclusions: Within this large European study, we found weak to moderate associations between dietary intakes and concentrations of OCM-related nutrients.

Objective: Periodontitis is a condition characterised by inflammation. Neopterin and kynurenine-to-tryptophan ratio (KTR) are markers of immune system activation in response to inflammation whose elevated levels are linked to higher incidence and poorer prognosis of various systemic diseases. Their potential association with oral health remains underexplored. The aim of this study was to prospectively investigate the associations between these biomarkers and periodontal health status among community-dwelling adults in Hordaland County, Norway. Materials and methods: Neopterin and KTR were measured in 1,298 participants of the Hordaland Health Study, 1997–1999. Information on oral health indicators was obtained from the ‘Hordaland-Oral Health Survey’, 2020–2022. Ordinal logistic regression and negative binomial regression were used to explore the association between biomarkers and periodontitis, tooth loss, and current inflammation (extend of sites with pocket depth ≥4mm and bleeding on probing) and odds ratios (OR) and incidence rate ratios (IRR), along with respective 95% confidence intervals (CI) were reported. Results: No association was found between biomarker levels and periodontitis [neopterin: OR = 0.96, 95% CI: 0.69–1.33 for fourth (Q4) vs. first quartile (Q1); KTR: OR = 0.85, 95% CI: 0.61–1.18 for Q4 vs. Q1], tooth loss [neopterin: IRR = 1.00, 95% CI: 0.94–1.06 for Q4 vs. Q1; KTR: IRR = 0.97, 95% CI: 0.91–1.03 for Q4 vs. Q1) or extend of inflammation [neopterin: OR = 0.87, 95% CI: 0.70–1.09 for Q4 vs. Q1; KTR: OR = 0.98, 95% CI: 0.78–1.23 for Q4 vs. Q1]. Conclusion: Plasma levels of neopterin and KTR were not prospectively associated with periodontal health and number of missing teeth.

Recent studies demonstrate that Parkinson’s disease (PD) is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). Here, we used mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. We found increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B6 deficiency. Furthermore, increased QA tracked with CSF tau, CSF soluble TREM2 (sTREM2) and severity of both motor and non-motor PD clinical symptoms. Finally, PD patient subgroups with distinct KP profiles displayed distinct PD clinical features. These data validate the KP as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.

Parkinson's disease (PD) is a complex multisystem disorder clinically characterized by motor, non-motor, and premotor manifestations. Pathologically, PD involves neuronal loss in the substantia nigra, striatal dopamine deficiency, and accumulation of intracellular inclusions containing aggregates of α-synuclein. Recent studies demonstrate that PD is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). This multicenter study used highly sensitive liquid chromatography-tandem mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. Results indicate that increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B6 deficiency. Furthermore, increased QA tracked with CSF tau and severity of both motor and non-motor PD clinical dysfunction. Importantly, plasma and CSF kynurenine metabolites classified PD participants with a high degree of accuracy (AUC = 0.897). Finally, analysis of metabolite data revealed subgroups with distinct KP profiles, and these were subsequently found to display distinct PD clinical features. Together, these data further support the hypothesis that the KP serves as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.

Circulating concentrations of metabolites (collectively called kynurenines) in the kynurenine pathway of tryptophan metabolism increase during inflammation, particularly in response to interferon-gamma (IFN-γ). Neopterin and the kynurenine/tryptophan ratio (KTR) are IFN-γ induced inflammatory markers, and together with C-reactive protein (CRP) and kynurenines they are associated with various diseases, but comprehensive data on the strength of associations of inflammatory markers with circulating concentrations of kynurenines are lacking. We measured circulating concentrations of neopterin, CRP, tryptophan and seven kynurenines in 5314 controls from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). The associations of neopterin, KTR and CRP with kynurenines were investigated using regression models. In mixed models, one standard deviation (SD) higher KTR was associated with a 0.46 SD higher quinolinic acid (QA), and 0.31 SD higher 3-hydroxykynurenine (HK). One SD higher neopterin was associated with 0.48, 0.44, 0.36 and 0.28 SD higher KTR, QA, kynurenine and HK, respectively. KTR and neopterin respectively explained 24.1% and 16.7% of the variation in QA, and 11.4% and 7.5% of HK. CRP was only weakly associated with kynurenines in regression models. In summary, QA was the metabolite that was most strongly associated with the inflammatory markers. In general, the inflammatory markers were most strongly related to metabolites located along the tryptophan–NAD axis, which may support suggestions of increased production of NAD from tryptophan during inflammation.

PDF file - 113K, Odds ratios with 95% Confidence Intervals (CI) of lung cancer for circulating levels of Tryptophan, Kynurenine and Kynurenine/Tryptophan ratio by smoking status. P for trend were assessed by the base 2 logarithm of the circulating levels.

PDF - 2930K, Timeline describing the collection of smoking information and methylation measurements for the study participants.

Abstract Background Epidemiological studies often investigate amino acids and their metabolites as biomarkers, but do not always consistently use fasting or non-fasting blood samples, or may lack information on the prandial status of the study participants. Since little information is available on the effects of the prandial status on many biomarkers, and since blood is typically sampled early in the day with participants in a fasting state or after having consumed a light meal in many trials, the main purpose of this study was to investigate the short-term effects of a light breakfast on serum concentrations of amino acids and related metabolites. Methods Blood was collected from sixty-three healthy adults (36 women) in the fasting state and at set times for 120 min after intake of a light breakfast with low protein content (14 g protein, 2218 kJ). Relative changes in serum biomarker concentrations from fasting to postprandial serum concentrations were tested using T test. Results The serum concentrations of 13 of the 20 measured amino acids were significantly changed 60 min following breakfast intake, with the most marked effects seen as increases in alanine (34%) and proline (45%) concentrations. The response did not reflect the amino acid composition of the breakfast. The concentrations of seven kynurenine metabolites were significantly decreased after breakfast. Conclusion Consumption of a light breakfast affected serum concentrations of several amino acids and related metabolites, underlining the importance of having information regarding the participants’ prandial state at the time of blood sampling in studies including these biomarkers. Trial registration This trial was registered at clinicaltrials.gov as NCT02350595 (registered January 2015).

Objectives Vitamin B2 (riboflavin) has a prime role in metabolic reactions imperative to cell cycle and proliferation. We investigated the associations between serum concentrations of riboflavin flavin mononucleotide with the risk of pancreatic cancer in a nested case-control study involving 58 cases and 104 matched controls. Methods The Singapore Chinese Health Study, an ongoing prospective cohort study of 63,257 Chinese Singaporeans. Conditional logistic regression method was used to evaluate these associations with adjustment for potential confounders including the level of education, body mass index, smoking status, alcohol consumption, history of diabetes, serum cotinine and pyridoxal 5′-phosphate, estimated glomerular filtration rate, and total methyl donors (ie, the sum of serum choline, betaine, and methionine). Results The risk of pancreatic cancer increased with increasing level of serum riboflavin in a dose-dependent manner, especially in men ( P trend = 0.003). The odds ratio (95% confidence intervals) of pancreatic cancer for the second and third tertiles of serum riboflavin, compared with the lowest tertile, were 9.92 (1.65–59.77) and 25.59 (3.09–212.00), respectively. This positive association was stronger in individuals with a longer follow-up period (≥7 years). Conclusions The findings suggest a potential role of riboflavin in the development of pancreatic cancer, especially in men.

Supplementary Figure 1. Hazard ratios (HR) and 95% confidence intervals (CI) for a doubling in season-adjusted 25(OH)D3 concentration by potential effect modifiers.

PDF - 225K, Evaluation of the additional effect of grandmother smoking on DNA methylation at the 26 CpGs of interest, given the mother smoked in her pregnancy. Each point represents the association for each CpG in each category. *Significance threshold p<0.0019 (below the line is not statistically significant).

PDF file - 71K, Spearman partial correlation coefficients between biomarkers among controls of a nested case-control study in the EPIC cohort.

PDF file - 100K, Odds Ratios with 95% Confidence Intervals (CI) of Lung Cancer for circulating levels of Tryptophan, Kynurenine and Kynurenine/Tryptophan ratio by histological type. P for trend were assessed by the base 2 logarithm of the circulating levels.

PDF - 16K, Association between the combined mother and grandmother smoking categories and DNA methylation at 26 CpGs of interest. Each point represents the association for each CpG in each smoking category. *Significance threshold p<0.0019 (below the line is not statistically significant).

PDF - 80K, Association between the timing of mother smoking (before and during pregnancy) and DNA methylation at 26 CpGs of interest. Each point represents the association for each CpG in each smoking category. *Significance threshold p<0.0019 (below the line is not statistically significant).

Supplementary Tables 1 and 2 from Biomarkers Related to One-Carbon Metabolism as Potential Risk Factors for Distal Colorectal Adenomas

PDF file - 98K, Odds ratios with 95% Confidence Intervals (CI) of lung cancer for circulating levels of Kynurenic acid, 3-Hydroxykynurenine, Anthralinic acid, Xanthurenic acid, 3-Hydroxyantranilic acid and Neopterine. P for trend were assessed by the base 2 logarithm of the circulating levels.

PDF file - 90K, Linear regression for circulating Tryptophan, Kynurenine and Kynurenine/tryptophan ratio in relation to food groups, lifestyle factors and other circulating biomarkers of a nested case-control study in the EPIC cohort. Ratios of circulating concentrations with 95% Confidence Intervals (CI) were calculated as 2 raised to the power of the beta estimates from linear regression models with log2-circulating concentrations as response.