Circulating Metabolic Markers Identify Patients at Risk for Tumor Recurrence: A Prospective Cohort Study in Colorectal Cancer Surgery.

OBJECTIVE: To investigate the spermidine pathway capability to predict patients at risk for tumor recurrence following colorectal cancer (CRC) surgery. SUMMARY BACKGROUND DATA: Recurrence rates after CRC surgery remain about 20%, despite an optimal technique and adjuvant therapy when necessary. Identification of risk biomarkers of recurrence is an unmet need. The spermidine pathway is indispensable for cell proliferation and differentiation, and is suggested to accelerate tumor spread. METHODS: Prospective cohort study of patients undergoing CRC surgery from 2015 to 2018. Plasma samples were collected before surgery and on postoperative day 4, and the spermidine pathway was assessed through mass spectrometry. Oncological outcomes were registered. RESULTS: 146 patients were included and 24 (16.4%) developed tumor recurrence. Higher levels of preoperative spermidine pathway components (spermidine, spermine, spermidine synthase enzyme, and spermine/arginine balance) were positively associated with recurrence. Surgery promoted a decrease in these pathway elements. The greater the decline was, the lower the risk of recurrence. Preoperative spermidine over the cut-off 0.198 µM displayed a 4.69-fold higher risk of recurrence. The spermine synthase enzyme behaved in the opposite direction. CONCLUSIONS: The spermidine pathway is associated with tumor recurrence following CRC surgery and, after confirmation in larger cohorts, could be translated as a risk biomarker of recurrence into clinical practice.

AlpsNMR: an R package for signal processing of fully untargeted NMR-based metabolomics.

SUMMARY: Nuclear magnetic resonance (NMR)-based metabolomics is widely used to obtain metabolic fingerprints of biological systems. While targeted workflows require previous knowledge of metabolites, prior to statistical analysis, untargeted approaches remain a challenge. Computational tools dealing with fully untargeted NMR-based metabolomics are still scarce or not user-friendly. Therefore, we developed AlpsNMR (Automated spectraL Processing System for NMR), an R package that provides automated and efficient signal processing for untargeted NMR metabolomics. AlpsNMR includes spectra loading, metadata handling, automated outlier detection, spectra alignment and peak-picking, integration and normalization. The resulting output can be used for further statistical analysis. AlpsNMR proved effective in detecting metabolite changes in a test case. The tool allows less experienced users to easily implement this workflow from spectra to a ready-to-use dataset in their routines. AVAILABILITY AND IMPLEMENTATION: The AlpsNMR R package and tutorial is freely available to download from http://github.com/sipss/AlpsNMR under the MIT license. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Full Workflows for the Analysis of Gas Chromatography-Ion Mobility Spectrometry in Foodomics: Application to the Analysis of Iberian Ham Aroma.

Gas chromatography-ion mobility spectrometry (GC-IMS) allows the fast, reliable, and inexpensive chemical composition analysis of volatile mixtures. This sensing technology has been successfully employed in food science to determine food origin, freshness and preventing alimentary fraud. However, GC-IMS data is highly dimensional, complex, and suffers from strong non-linearities, baseline problems, misalignments, peak overlaps, long peak tails, etc., all of which must be corrected to properly extract the relevant features from samples. In this work, a pipeline for signal pre-processing, followed by four different approaches for feature extraction in GC-IMS data, is presented. More precisely, these approaches consist of extracting data features from: (1) the total area of the reactant ion peak chromatogram (RIC); (2) the full RIC response; (3) the unfolded sample matrix; and (4) the ion peak volumes. The resulting pipelines for data processing were applied to a dataset consisting of two different quality class Iberian ham samples, based on their feeding regime. The ability to infer chemical information from samples was tested by comparing the classification results obtained from partial least-squares discriminant analysis (PLS-DA) and the samples' variable importance for projection (VIP) scores. The choice of a feature extraction strategy is a trade-off between the amount of chemical information that is preserved, and the computational effort required to generate the data models.

Impact in Plasma Metabolome as Effect of Lifestyle Intervention for Weight-Loss Reveals Metabolic Benefits in Metabolically Healthy Obese Women.

Little is known regarding metabolic benefits of weight loss (WL) on the metabolically healthy obese (MHO) patients. We aimed to examine the impact of a lifestyle weight loss (LWL) treatment on the plasma metabolomic profile in MHO individuals. Plasma samples from 57 MHO women allocated to an intensive LWL treatment group (TG, hypocaloric Mediterranean diet and regular physical activity, n = 30) or to a control group (CG, general recommendations of a healthy diet and physical activity, n = 27) were analyzed using an untargeted 1H NMR metabolomics approach at baseline, after 3 months (intervention), and 12 months (follow-up). The impact of the LWL intervention on plasma metabolome was statistically significant at 3 months but not at follow-up and included higher levels of formate and phosphocreatine and lower levels of LDL/VLDL (signals) and trimethylamine in the TG. These metabolites were also correlated with WL. Higher myo-inositol, methylguanidine, and 3-hydroxybutyrate, and lower proline, were also found in the TG; higher levels of hippurate and asparagine, and lower levels of 2-hydroxybutyrate and creatine, were associated with WL. The current findings suggest that an intensive LWL treatment, and the consequent WL, leads to an improved plasma metabolic profile in MHO women through its impact on energy, amino acid, lipoprotein, and microbial metabolism.

Urinary 1H Nuclear Magnetic Resonance Metabolomic Fingerprinting Reveals Biomarkers of Pulse Consumption Related to Energy-Metabolism Modulation in a Subcohort from the PREDIMED study.

Little is known about the metabolome fingerprint of pulse consumption. The study of robust and accurate biomarkers for pulse dietary assessment has great value for nutritional epidemiology regarding health benefits and their mechanisms. To characterize the fingerprinting of dietary pulses (chickpeas, lentils, and beans), spot urine samples from a subcohort from the PREDIMED study were stratified using a validated food frequency questionnaire. Urine samples of nonpulse consumers (≤4 g/day of pulse intake) and habitual pulse consumers (≥25 g/day of pulse intake) were analyzed using a 1H nuclear magnetic resonance (NMR) metabolomics approach combined with multi- and univariate data analysis. Pulse consumption showed differences through 16 metabolites coming from (i) choline metabolism, (ii) protein-related compounds, and (iii) energy metabolism (including lower urinary glucose). Stepwise logistic regression analysis was applied to design a combined model of pulse exposure, which resulted in glutamine, dimethylamine, and 3-methylhistidine. This model was evaluated by a receiver operating characteristic curve (AUC > 90% in both training and validation sets). The application of NMR-based metabolomics to reported pulse exposure highlighted new candidates for biomarkers of pulse consumption and the impact on energy metabolism, generating new hypotheses on energy modulation. Further intervention studies will confirm these findings.

Circulating metabolic markers after surgery identify patients at risk for severe postoperative complications: a prospective cohort study in colorectal cancer.

BACKGROUND: Early detection of postoperative complications after colorectal cancer (CRC) surgery is associated with improved outcomes. The aim was to investigate early metabolomics signatures capable to detect patients at risk for severe postoperative complications after CRC surgery. MATERIALS AND METHODS: Prospective cohort study of patients undergoing CRC surgery from 2015 to 2018. Plasma samples were collected before and after surgery, and analyzed by mass spectrometry obtaining 188 metabolites and 21 ratios. Postoperative complications were registered with Clavien-Dindo Classification and Comprehensive Complication Index. RESULTS: One hundred forty-six patients were included. Surgery substantially modified metabolome and metabolic changes after surgery were quantitatively associated with the severity of postoperative complications. The strongest positive relationship with both Clavien-Dindo and Comprehensive Complication Index (ß=4.09 and 63.05, P <0.001) corresponded to kynurenine/tryptophan, against an inverse relationship with lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs). Patients with LPC18:2/PCa36:2 below the cut-off 0.084 µM/µM resulted in a sevenfold higher risk of major complications (OR=7.38, 95% CI: 2.82-21.25, P <0.001), while kynurenine/tryptophan above 0.067 µM/µM a ninefold (OR=9.35, 95% CI: 3.03-32.66, P <0.001). Hexadecanoylcarnitine below 0.093 µM displayed a 12-fold higher risk of anastomotic leakage-related complications (OR=11.99, 95% CI: 2.62-80.79, P =0.004). CONCLUSION: Surgery-induced phospholipids and amino acid dysregulation is associated with the severity of postoperative complications after CRC surgery, including anastomotic leakage-related outcomes. The authors provide quantitative insight on metabolic markers, measuring vulnerability to postoperative morbidity that might help guide early decision-making and improve surgical outcomes.

Quantitative plasma profiling by 1H NMR-based metabolomics: impact of sample treatment.

Introduction: There is evidence that sample treatment of blood-based biosamples may affect integral signals in nuclear magnetic resonance-based metabolomics. The presence of macromolecules in plasma/serum samples makes investigating low-molecular-weight metabolites challenging. It is particularly relevant in the targeted approach, in which absolute concentrations of selected metabolites are often quantified based on the area of integral signals. Since there are a few treatments of plasma/serum samples for quantitative analysis without a universally accepted method, this topic remains of interest for future research. Methods: In this work, targeted metabolomic profiling of 43 metabolites was performed on pooled plasma to compare four methodologies consisting of Carr-Purcell-Meiboom-Gill (CPMG) editing, ultrafiltration, protein precipitation with methanol, and glycerophospholipid solid-phase extraction (g-SPE) for phospholipid removal; prior to NMR metabolomics analysis. The effect of the sample treatments on the metabolite concentrations was evaluated using a permutation test of multiclass and pairwise Fisher scores. Results: Results showed that methanol precipitation and ultrafiltration had a higher number of metabolites with coefficient of variation (CV) values above 20%. G-SPE and CPMG editing demonstrated better precision for most of the metabolites analyzed. However, differential quantification performance between procedures were metabolite-dependent. For example, pairwise comparisons showed that methanol precipitation and CPMG editing were suitable for quantifying citrate, while g-SPE showed better results for 2-hydroxybutyrate and tryptophan. Discussion: There are alterations in the absolute concentration of various metabolites that are dependent on the procedure. Considering these alterations is essential before proceeding with the quantification of treatment-sensitive metabolites in biological samples for improving biomarker discovery and biological interpretations. The study demonstrated that g-SPE and CPMG editing are effective methods for removing proteins and phospholipids from plasma samples for quantitative NMR analysis of metabolites. However, careful consideration should be given to the specific metabolites of interest and their susceptibility to the sample treatment procedures. These findings contribute to the development of optimized sample preparation protocols for metabolomics studies using NMR spectroscopy.

Sperm physiology and in vitro fertilising ability rely on basal metabolic activity: insights from the pig model.

Whether basal metabolic activity in sperm has any influence on their fertilising capacity has not been explored. Using the pig as a model, the present study investigated the relationship of energetic metabolism with sperm quality and function (assessed through computer-assisted sperm analysis and flow cytometry), and fertility (in vitro fertilisation (IVF) outcomes). In semen samples from 16 boars, levels of metabolites related to glycolysis, ketogenesis and Krebs cycle were determined through a targeted metabolomics approach using liquid chromatography-tandem mass spectrometry. High-quality sperm are associated to greater levels of glycolysis-derived metabolites, and oocyte fertilisation and embryo development are conditioned by the sperm metabolic status. Interestingly, glycolysis appears to be the preferred catabolic pathway of the sperm giving rise to greater percentages of embryos at day 6. In conclusion, this study shows that the basal metabolic activity of sperm influences their function, even beyond fertilisation.

Present and future of metabolic and metabolomics studies focused on classical psychedelics in humans.

Psychedelics are classical hallucinogen drugs that induce a marked altered state of consciousness. In recent years, there has been renewed attention to the possible use of classical psychedelics for the treatment of certain mental health disorders. However, further investigation to better understand their biological effects in humans, their mechanism of action, and their metabolism in humans is needed when considering the development of future novel therapeutic approaches. Both metabolic and metabolomics studies may help for these purposes. On one hand, metabolic studies aim to determine the main metabolites of the drug. On the other hand, the application of metabolomics in human psychedelics studies can help to further understand the biological processes underlying the psychedelic state and the mechanisms of action underlying their therapeutic potential. This review presents the state of the art of metabolic and metabolomic studies after lysergic acid diethylamide (LSD), mescaline, N,N-dimethyltryptamine (DMT) and ß-carboline alkaloids (ayahuasca brew), 5-methoxy-DMT and psilocybin administrations in humans. We first describe the characteristics of the published research. Afterward, we reviewed the main results obtained by both metabolic and metabolomics (if available) studies in classical psychedelics and we found out that metabolic and metabolomics studies in psychedelics progress at two different speeds. Thus, whereas the main metabolites for classical psychedelics have been robustly established, the main metabolic alterations induced by psychedelics need to be explored. The integration of metabolomics and pharmacokinetics for investigating the molecular interaction between psychedelics and multiple targets may open new avenues in understanding the therapeutic role of psychedelics.

Grape polyphenols decrease circulating branched chain amino acids in overfed adults.

Introduction and aims: Dietary polyphenols have long been associated with health benefits, including the prevention of obesity and related chronic diseases. Overfeeding was shown to rapidly induce weight gain and fat mass, associated with mild insulin resistance in humans, and thus represents a suitable model of the metabolic complications resulting from obesity. We studied the effects of a polyphenol-rich grape extract supplementation on the plasma metabolome during an overfeeding intervention in adults, in two randomized parallel controlled clinical trials. Methods: Blood plasma samples from 40 normal weight to overweight male adults, submitted to a 31-day overfeeding (additional 50% of energy requirement by a high calorie-high fructose diet), given either 2 g/day grape polyphenol extract or a placebo at 0, 15, 21, and 31 days were analyzed (Lyon study). Samples from a similarly designed trial on females (20 subjects) were collected in parallel (Lausanne study). Nuclear magnetic resonance (NMR)-based metabolomics was conducted to characterize metabolome changes induced by overfeeding and associated effects from polyphenol supplementation. The clinical trials are registered under the numbers NCT02145780 and NCT02225457 at ClinicalTrials.gov. Results: Changes in plasma levels of many metabolic markers, including branched chain amino acids (BCAA), ketone bodies and glucose in both placebo as well as upon polyphenol intervention were identified in the Lyon study. Polyphenol supplementation counterbalanced levels of BCAA found to be induced by overfeeding. These results were further corroborated in the Lausanne female study. Conclusion: Administration of grape polyphenol-rich extract over 1 month period was associated with a protective metabolic effect against overfeeding in adults.

Circulating linoleic acid at the time of myocardial infarction and risk of primary ventricular fibrillation.

Primary ventricular fibrillation (PVF) is a major driver of cardiac arrest in the acute phase of ST-segment elevation myocardial infarction (STEMI). Enrichment of cardiomyocyte plasma membranes with dietary polyunsaturated fatty acids (PUFA) reduces vulnerability to PVF experimentally, but clinical data are scarce. PUFA status in serum phospholipids is a valid surrogate biomarker of PUFA status in cardiomyocytes within a wide range of dietary PUFA. In this nested case-control study (n = 58 cases of STEMI-driven PVF, n = 116 control non-PVF STEMI patients matched for age, sex, smoking status, dyslipidemia, diabetes mellitus and hypertension) we determined fatty acids in serum phospholipids by gas-chromatography, and assessed differences between cases and controls, applying the Benjamini-Hochberg procedure on nominal P-values to control the false discovery rate (FDR). Significant differences between cases and controls were restricted to linoleic acid (LA), with PVF patients showing a lower level (nominal P = 0.002; FDR-corrected P = 0.027). In a conditional logistic regression model, each one standard deviation increase in the proportion of LA was related to a 42% lower prevalence of PVF (odds ratio = 0.58; 95% confidence interval, 0.37, 0.90; P = 0.02). The association lasted after the inclusion of confounders. Thus, regular consumption of LA-rich foods (nuts, oils from seeds) may protect against ischemia-driven malignant arrhythmias.

Metabolomics and integrated network analysis reveal roles of endocannabinoids and large neutral amino acid balance in the ayahuasca experience.

There has been a renewed interest in the potential use of psychedelics for the treatment of psychiatric conditions. Nevertheless, little is known about the mechanism of action and molecular pathways influenced by ayahuasca use in humans. Therefore, for the first time, our study aims to investigate the human metabolomics signature after consumption of a psychedelic, ayahuasca, and its connection with both the psychedelic-induced subjective effects and the plasma concentrations of ayahuasca alkaloids. Plasma samples of 23 individuals were collected both before and after ayahuasca consumption. Samples were analysed through targeted metabolomics and further integrated with subjective ratings of the ayahuasca experience (i.e., using the 5-Dimension Altered States of Consciousness Rating Scale [ASC]), and plasma ayahuasca-alkaloids using integrated network analysis. Metabolic pathways enrichment analysis using diffusion algorithms for specific KEGG modules was performed on the metabolic output. Compared to baseline, the consumption of ayahuasca increased N-acyl-ethanolamine endocannabinoids, decreased 2-acyl-glycerol endocannabinoids, and altered several large-neutral amino acids (LNAAs). Integrated network results indicated that most of the LNAAs were inversely associated with 9 out of the 11 subscales of the ASC, except for tryptophan which was positively associated. Several endocannabinoids and hexosylceramides were directly associated with the ayahuasca alkaloids. Enrichment analysis confirmed dysregulation in several pathways involved in neurotransmission such as serotonin and dopamine synthesis. In conclusion, a crosstalk between the circulating LNAAs and the subjective effects is suggested, which is independent of the alkaloid concentrations and provides insights into the specific metabolic fingerprint and mechanism of action underlying ayahuasca experiences.

Leptin Supplementation During Lactation Restores Key Liver Metabolite Levels Malprogrammed by Gestational Calorie Restriction.

INTRODUCTION: Perinatal nutritional factors can program offspring metabolic phenotype and risk to obesity. This study investigates the potential role of leptin supplementation (during lactation) in ameliorating the malprogrammed effects caused by mild maternal calorie restriction during gestation, on young rat offspring liver metabolic response. METHODS AND RESULTS: Untargeted and targeted metabolomics studies on liver samples are performed by NMR and GC-MS, respectively. Global DNA methylation and the expression by RT-PCR of key genes involved in different pathways are also determined. By NMR, 15 liver metabolites are observed to be altered in the offspring of gestational calorie-restricted dams (CR group), at days 25-27 of life. Physiological leptin supplementation during lactation partially reverted the effect of CR condition for most of these metabolites. Moreover, targeted fatty acid analysis by GC-MS shows a significant decrease in the hepatic concentration of certain very long-chain fatty acids (VLCFA) in CR offspring, partially or totally reverted by leptin supplementation. No remarkable changes are found in global DNA methylation or mRNA expression. CONCLUSION: Physiological leptin supplementation during lactation contributes to the reversion of changes caused by maternal mild calorie restriction on the liver metabolome. This agrees with a putative role of leptin supplementation preventing or reversing metabolic disturbances caused by gestational metabolic malprogramming.

Metabolic Signature of a Functional High-Catechin Tea after Acute and Sustained Consumption in Healthy Volunteers through 1H NMR Based Metabolomics Analysis of Urine.

Functional tea beverages have emerged as a novel approach to achieving health benefits associated with tea. The use of metabolomics may improve the evaluation of their consumption and their effects. The current study aimed at exploring the urinary signature of exposure to a functional high-catechin tea (HCT) using untargeted NMR-based metabolomics. Ten volunteers participated in a crossover intervention study. Individuals consumed an HCT or a control beverage over a period of 28 days. Multilevel partial least-squares discriminant analysis (ML-PLS-DA) was used for paired comparisons. A further crossover model was performed to assess the significant changes. The consumption of the HCT resulted in the excretion of theanine, epicatechin, pyrogallol sulfate, and higher levels of 3-methyl-2-oxovalerate and succinate, as well as unknown compounds. In conclusion, the present work established novel urinary signatures of a functional drink. Such signatures may be potential biomarkers and/or reflect certain benefits of functional tea beverages.

Integrated Lipidomics and Proteomics Point to Early Blood-Based Changes in Childhood Preceding Later Development of Psychotic Experiences: Evidence From the Avon Longitudinal Study of Parents and Children.

BACKGROUND: The identification of early biomarkers of psychotic experiences (PEs) is of interest because early diagnosis and treatment of those at risk of future disorder is associated with improved outcomes. The current study investigated early lipidomic and coagulation pathway protein signatures of later PEs in subjects from the Avon Longitudinal Study of Parents and Children cohort. METHODS: Plasma of 115 children (12 years of age) who were first identified as experiencing PEs at 18 years of age (48 cases and 67 controls) were assessed through integrated and targeted lipidomics and semitargeted proteomics approaches. We assessed the lipids, lysophosphatidylcholines (n = 11) and phosphatidylcholines (n = 61), and the protein members of the coagulation pathway (n = 22) and integrated these data with complement pathway protein data already available on these subjects. RESULTS: Twelve phosphatidylcholines, four lysophosphatidylcholines, and the coagulation protein plasminogen were altered between the control and PEs groups after correction for multiple comparisons. Lipidomic and proteomic datasets were integrated into a multivariate network displaying a strong relationship between most lipids that were significantly associated with PEs and plasminogen. Finally, an unsupervised clustering approach identified four different clusters, with one of the clusters presenting the highest case-control ratio (p < .01) and associated with a higher concentration of smaller low-density lipoprotein cholesterol particles. CONCLUSIONS: Our findings indicate that the lipidome and proteome of subjects who report PEs at 18 years of age are already altered at 12 years of age, indicating that metabolic dysregulation may contribute to an early vulnerability to PEs and suggesting crosstalk between these lysophosphatidylcholines, phosphatidylcholines, and coagulation and complement proteins.

Impact of Sample Storage on the NMR Fecal Water Metabolome.

The study of the fecal metabolome is an important area of research to better understand the human gut microbiome and its impact on human health and diseases. However, there is a lack of work in examining the impact of storage and processing conditions on the metabolite levels of fecal water. Furthermore, there is no universal protocol used for the storage of fecal samples and preparation of fecal water. The objective of the current study was to examine the impact of different storage conditions on fecal samples prior to metabolite extraction. Fecal samples obtained from nine healthy individuals were processed under different conditions: (1) fresh samples prepared immediately after collection, (2) fecal samples stored at 4 °C for 24 h prior to processing, and (3) fecal samples stored at -80 °C for 24 h prior to processing. All samples were analyzed using NMR spectroscopy, multivariate statistical analysis, and repeated measures ANOVA. Samples which were frozen at -80 °C prior to extraction of the metabolites exhibited an increase in the number of metabolites including branched-chain amino acids, aromatic amino acids, and tricarboxylic acid cycle intermediates. Storage of fecal samples at 4 °C ensured higher fidelity to freshly processed samples leading to the recommendation that fecal samples should not be frozen prior to extraction of fecal water. Furthermore, the work highlights the need to standardize sample storage of fecal samples to allow for the accurate study of the fecal metabolome.

Untargeted 1H NMR-Based Metabolomics Analysis of Urine and Serum Profiles after Consumption of Lentils, Chickpeas, and Beans: An Extended Meal Study To Discover Dietary Biomarkers of Pulses.

High legume intake has been shown to have beneficial effects on the health of humans. The use of nutritional biomarkers, as a complement to self-reported questionnaires, could assist in evaluating dietary intake and downstream effects on human health. The aim of this study was to investigate potential biomarkers of the consumption of pulses (i.e., white beans, chickpeas, and lentils) by using untargeted NMR-based metabolomics. Meals rich in pulses were consumed by a total of 11 participants in a randomized crossover study and multilevel partial least-squares regression was employed for paired comparisons. Metabolomics analysis indicated that trigonelline, 3-methylhistidine, dimethylglycine, trimethylamine, and lysine were potential, though not highly specific, biomarkers of pulse intake. Furthermore, monitoring of these metabolites for a period of 48 h after intake revealed a range of different excretion patterns among pulses. Following the consumption of pulses, a metabolomic profiling revealed that the concentration ratios of trigonelline, choline, lysine, and histidine were similar to those found in urine. In conclusion, this study identified potential urinary biomarkers of exposure to dietary pulses and provided valuable information about the time-response effect of these putative biomarkers.

Biomarkers of legume intake in human intervention and observational studies: a systematic review.

There is a growing interest in assessing dietary intake more accurately across different population groups, and biomarkers have emerged as a complementary tool to replace traditional dietary assessment methods. The purpose of this study was to conduct a systematic review of the literature available and evaluate the applicability and validity of biomarkers of legume intake reported across various observational and intervention studies. A systematic search in PubMed, Scopus, and ISI Web of Knowledge identified 44 studies which met the inclusion criteria for the review. Results from observational studies focused on soy or soy-based foods and demonstrated positive correlations between soy intake and urinary, plasma or serum isoflavonoid levels in different population groups. Similarly, intervention studies demonstrated increased genistein and daidzein levels in urine and plasma following soy intake. Both genistein and daidzein exhibited dose-response relationships. Other isoflavonoid levels such as O-desmethylangolensin (O-DMA) and equol were also reported to increase following soy consumption. Using a developed scoring system, genistein and daidzein can be considered as promising candidate markers for soy consumption. Furthermore, genistein and daidzein also served as good estimates of soy intake as evidenced from long-term exposure studies marking their status as validated biomarkers. On the contrary, only few studies indicated proposed biomarkers for pulses intake, with pipecolic acid and S-methylcysteine reported as markers reflecting dry bean consumption, unsaturated aliphatic, hydroxyl-dicarboxylic acid related to green beans intake and trigonelline reported as marker of peas consumption. However, data regarding criteria such as specificity, dose-response and time-response relationship, reliability, and feasibility to evaluate the validity of these markers is lacking. In conclusion, despite many studies suggesting proposed biomarkers for soy, there is a lack of information on markers of other different subtypes of legumes. Further discovery and validation studies are needed in order to identify reliable biomarkers of legume intake.

Correction to: Biomarkers of legume intake in human intervention and observational studies: a systematic review.

[This corrects the article DOI: 10.1186/s12263-018-0614-6.].

Biomarkers of intake for coffee, tea, and sweetened beverages.

Non-alcoholic beverages are important sources of nutrients and bioactive compounds that may influence human health and increase or decrease the risk of chronic diseases. A wide variety of beverage constituents are absorbed in the gut, found in the systemic circulation and excreted in urine. They may be used as compliance markers in intervention studies or as biomarkers of intake to improve measurements of beverage consumption in cohort studies and reveal new associations with disease outcomes that may have been overlooked when using dietary questionnaires. Here, biomarkers of intake of some major non-alcoholic beverages-coffee, tea, sugar-sweetened beverages, and low-calorie-sweetened beverages-are reviewed. Results from dietary intervention studies and observational studies are reviewed and analyzed, and respective strengths and weaknesses of the various identified biomarkers discussed. A variety of compounds derived from phenolic acids, alkaloids, and terpenes were shown to be associated with coffee intake and trigonelline and cyclo(isoleucylprolyl) showed a particularly high specificity for coffee intake. Epigallocatechin and 4'-O-methylepigallocatechin appear to be the most sensitive and specific biomarkers for green or black tea, while 4-O-methylgallic acid may be used to assess black tea consumption. Intake of sugar-sweetened beverages has been assessed through the measurement of carbon-13 enrichment of whole blood or of blood alanine in North America where sugar from sugarcane or corn is used as a main ingredient. The most useful biomarkers for low-calorie-sweetened beverages are the low-calorie sweeteners themselves. Further studies are needed to validate these biomarkers in larger and independent populations and to further evaluate their specificity, reproducibility over time, and fields of application.