The food metabolome: a window over dietary exposure

In the paper

“It is important to point out that the identities of many of the proposed biomarkers in Table 3 (marked with an asterisk) have not been fully validated with proper chemical standards because these standards are often not commercially available.”

In the paper

“The resulting misclassification of subjects, especially when sorting them according to dietary intake, can influence observed associations between dietary exposures and disease outcomes and underlies inconsistencies in published findings in the field of nutritional epidemiology (12).”

What the sources say

• Not checked yetcites [12] Marshall, 1999, Diet and health risk: risk patterns and disease-specific associations, Am J Clin Nutr source

In the paper

“The food metabolome is therefore highly complex and also highly variable.”

In the paper

“The various foods consumed by humans contain .25,000compounds, most of them being further metabolized in the human body (9).”

What the sources say

• Not checked yetcites [9] Wishart, 2013, HMDB 3.0—the Human Metabolome Database in 2013, Nucleic Acids Res

In the paper

“However, a number of random and systematic errors are inherent in such methods, including recall bias and difficulty in assessing portion sizes (11).”

What the sources say

• Not checked yetcites [11] Bingham, 2007, Epidemiologic assessment of sugars consumption using biomarkers: comparisons of obese and nonobese individuals in the European Prospective Investigation of Cancer Norfolk, Cancer Epidemiol Biomarkers Prev source

In the paper

“Some dietary compounds such as isothiocyanates and acrylamide also form adducts with blood albumin and hemoglobin (37,38), with half-lives varying between 3 and 8 wk, and may be used as longer-term biomarkers.”

What the sources say

• Not checked yetcites [37] Kumar, 2010, Determination of new biomarkers to monitor the dietary consumption of isothiocyanates, Biomarkers source
• Not checked yetcites [38] Outzen, 2011, Dietary determinants for Hb-acrylamide and Hb-glycidamide adducts in Danish non-smoking women, Br J Nutr source

In the paper

“Up to 200,000 different metabolites are estimated to occur in the plant kingdom, and combinations of several hundreds of secondary metabolites generally characterize each edible plant (6,64,65).”

What the sources say

• Not checked yetcites [6] Manach, 2009, The complex links between dietary phytochemicals and human health deciphered by metabolomics, Mol Nutr Food Res source
• Not checked yetcites [64] Fiehn, 2002, Metabolomics—the link between genotypes and phenotypes, Plant Mol Biol source
• Not checked yetcites [65] Iijima, 2008, Metabolite annotations based on the integration of mass spectral information, Plant J source

In the paper

“Proline betaine and lycopene are well-established biomarkers for citrus fruit and tomato products, respectively (44,45).”

What the sources say

• Not checked yetcites [44] Lloyd, 2011, Proline betaine and its biotransformation products in fasting urine samples are potential biomarkers of habitual citrus fruit consumption, Br J Nutr source
• Not checked yetcites [45] Al-Delaimy, 2005, Plasma carotenoids as biomarkers of intake of fruits and vegetables: individual-level correlations in the European Prospective Investigation into Cancer and Nutrition (EPIC), Eur J Clin Nutr source

In the paper

“The possible exceptions are the essential amino acids, essential fatty acids along with most vitamins, and minerals, which cannot be produced by humans and must originate from external dietary sources.”

In the paper

“Most of these compounds are common to all living organisms and identical to human endogenous metabolites.They cannot generally be used as dietary biomarkers because of their common identity and the impossibility to trace their dietary origin.”

In the paper

“The Folin assay, commonly used to estimate total polyphenols in foods (46), has also been applied to urine samples to compare polyphenol intake (47), but such use may be inappropriate because of the presence of interfering reducing metabolites in such complex biological matrices (46).”

What the sources say

• Not checked yetcites [46] Scalbert, 2005, Dietary polyphenols and the prevention of diseases, Crit Rev Food Sci Nutr source
• Not checked yetcites [47] Medina-Remón, 2011, Total polyphenol excretion and blood pressure in subjects at high cardiovascular risk, Nutr Metab Cardiovasc Dis source

In the paper

“In fact, there are .300different empirical rules that allow one to predict the fate of metabolites on the basis of their chemical structure (69).”

What the sources say

• Not checked yetcites [69] Langowski, 2002, Computer systems for the prediction of xenobiotic metabolism, Adv Drug Deliv Rev source

In the paper

“Lipophilic markers (carotenoids, lipids) (36) or biomarkers associated with erythrocytes (folate, fatty acids) (29) have longer half-lives (week to month) because of the equilibrium of biomarkers between blood and fatty tissues, or because of their integration into erythrocytes.”

What the sources say

• Not checked yetcites [36] Burri, 2001, Serum carotenoid depletion follows first-order kinetics in healthy adult women fed naturally low carotenoid diets, J Nutr source
• Not checked yetcites [29] Crews, 2001, A critical assessment of some biomarker approaches linked with dietary intake, Br J Nutr source

In the paper

“Dietary biomarkers not only include natural food constituents but also certain food additives such as iodine in milk (26) or food contaminants such as polychlorinated biphenyls in fatty fish (27).”

What the sources say

• Not checked yetcites [26] Brantsaeter, 2009, Evaluation of urinary iodine excretion as a biomarker for intake of milk and dairy products in pregnant women in the Norwegian Mother and Child Cohort Study (MoBa), Eur J Clin Nutr source
• Not checked yetcites [27] Turunen, 2010, Dioxins, polychlorinated biphenyls, methyl mercury and omega-3 polyunsaturated fatty acids as biomarkers of fish consumption, Eur J Clin Nutr source

In the paper

“These microbial metabolites include short-chain fatty acids, secondary bile acids, protein and amino acid metabolites, as well as plant polyphenol metabolites (67).”

What the sources say

• Not checked yetcites [67] Nicholson, 2012, Host-gut microbiota metabolic interactions, Science source

In the paper

“Some of the biomarkers listed in Table 1 have half-lives that do not exceed 24 h [polyphenols, alkylresorcinols, and amino acids (34,35)].”

What the sources say

• Not checked yetcites [34] Manach, 2005, Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies, Am J Clin Nutr source
• Not checked yetcites [35] Söderholm, 2009, Plasma pharmacokinetics of alkylresorcinol metabolites: new candidate biomarkers for whole-grain rye and wheat intake, Am J Clin Nutr source

In the paper

“noticeable differences in human metabolomes could be detected that appeared to depend strongly on diet, sex, health status, genetics, kinetics, physiology, and age-with diet being most important (59)(60)(61)(62).”

What the sources say

• Not checked yetcites (59)(60)(61)(62)

In the paper

“The yield of phase I/II reactions are often very high (68,71), and host-transformed metabolites retain many of the features of their parent compounds.”

What the sources say

• Not checked yetcites [68] Testa, 2012, Foundation review: reactions and enzymes in the metabolism of drugs and other xenobiotics, Drug Discov Today source
• Not checked yetcites [71] Silberberg, 2006, The bioavailability of polyphenols is highly governed by the capacity of the intestine and of the liver to secrete conjugated metabolites, Eur J Nutr source

In the paper

“The human body maintains a complex defense system consisting of dozens of enzymes and membrane transporters to recognize these foreign and potentially toxic chemicals and to neutralize them by rapid biotransformation and/or elimination.”

In the paper

“Food compounds that are not useful for basic metabolism or that do not correspond to familiar endogenous metabolites are treated as”

In the paper

“Biomarkers such as vitamin C or selenium in erythrocyte glutathione peroxidase show saturable effects and may not be suitable for use at high levels of exposure (29,42).”

What the sources say

• Not checked yetcites [29] Crews, 2001, A critical assessment of some biomarker approaches linked with dietary intake, Br J Nutr source
• Not checked yetcites [42] Levine, 1996, Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance, Proc Natl Acad Sci USA source

In the paper

“Food constituents can be metabolized in 3 different ways: 1) they can be digested in the mouth, stomach, and small intestine into simple nutrients that can be absorbed through the gut barrier; 2) they can be further transformed by host tissues, especially the liver and kidney; or 3) they can be processed by the gut microbiota in the large intestine.”

In the paper

“Classically, the biotransformation process consists of 2 types of chemical reactions, phase I and phase II transformations, both of which occur primarily in the liver, kidney, and intestine.”

In the paper

“Microbes have a very different set of enzymes from mammals, and given that there are .1000different species of microbes in the human gut (72) there is an enormous diversity of enzymatic processes that act on foodderived compounds.”

What the sources say

• Not checked yetcites [72] Peris-Bondia, 2011, The active human gut microbiota differs from the total microbiota, PLoS ONE source

In the paper

“Minimally, the human metabolome contains 50,000 different detectable compounds (9,63), but as instrument sensitivity and separation technologies improve, this number is expected to increase.”

What the sources say

• Not checked yetcites [9] Wishart, 2013, HMDB 3.0—the Human Metabolome Database in 2013, Nucleic Acids Res
• Not checked yetcites [63] Smith, 2005, METLIN—a metabolite mass spectral database, Ther Drug Monit source

In the paper

“They may be altered because of possible interactions with genetic factors, physiologic or health status (ie, age or obesity) (30), dietary factors such as fats for lipophilic biomarkers (31), and lifestyle factors such as alcohol intake or smoking (32).”

What the sources say

• Not checked yetcites [30] Vioque, 2007, Plasma concentrations of carotenoids and vitamin C are better correlated with dietary intake in normal weight than overweight and obese elderly subjects, Br J Nutr source
• Not checked yetcites [31] Brown, 2004, Carotenoid bioavailability is higher from salads ingested with full-fat than with fat-reduced salad dressings as measured with electrochemical detection, Am J Clin Nutr source
• Not checked yetcites [32] Albanes, 1997, Effects of supplemental beta-carotene, cigarette smoking, and alcohol consumption on serum carotenoids in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, Am J Clin Nutr source

In the paper

“In explorative science there is no fixed rule for the acceptability level of the FDR, and any level from 5% to 50% may be useful, depending on further data analysis steps.”

In the paper

“Metabolite identification in metabolomic studies relies on the comparison of generated spectra with those in curated metabolite databases.”

In the paper

“The gut microbiota also processes indigestible carbohydrates through a variety of fermentative pathways yielding short-chain fatty acids such as butyric acid and propionic acid.”

In the paper

“As with any experimentally based analytic method, multiple variables can substantially affect the final data set.”

In the paper

“In principle, untargeted metabolomics provides a wider coverage and is likely to show the presence of new metabolites in biofluids and tissues.”

In the paper

“These phenolic acids can be further conjugated to glycine as in hippurate.”

In the paper

“Briefly, NMR is robust, nondestructive, and quantitative but has a relatively low sensitivity, which narrows its coverage of the food metabolome to predominant nutrients, sugars, and microbial metabolites present at millimolar to micromolar concentrations.”

What the sources say

• Not checked yetcites [111] Theodoridis, 2008, LC-MS-based methodology for global metabolite profiling in metabonomics/metabolomics, Trends Analyt Chem source
• Not checked yetcites [112] Scalbert, 2009, Mass-spectrometry-based metabolomics: limitations and recommendations for future progress with particular focus on nutrition research, Metabolomics source
• Not checked yetcites [113] Issaq, 2009, Analytical and statistical approaches to metabolomics research, J Sep Sci source

In the paper

“Supervised multivariate analysis is commonly the next step in many data analysis methods but has a strong tendency to overfit the data.”

In the paper

“There are a large number of supervised methods (120, 127), with the most commonly used analysis for comparing 2 groups being partial least-squares discriminant analysis (PLS-DA) (132) or one of its several variants.”

What the sources say

• Not checked yetcites [120] Sugimoto, 2012, bioinformatics tools for mass spectroscopy-based metabolomic data processing and analysis, Current Bioinformatics source
• Not checked yetcites [127] Worley, 2013, Utilities for quantifying separation in PCA/PLS-DA scores plots, Anal Biochem source
• Not checked yetcites [132] Wold, 1983, The multivariate calibration problem in chemistry solved by the PLS methods source

In the paper

“It is crucial to align the different sample profiles, which do not match exactly because of small variations in retention times, masses, or chemical shifts.”

In the paper

“These include data preprocessing, data alignment, data normalization, and signal correction followed by the analysis through various statistical methods.”

What the sources say

• Not checked yetcites [119] Katajamaa, 2007, Data processing for mass spectrometry-based metabolomics, J Chromatogr A source
• Not checked yetcites [120] Sugimoto, 2012, bioinformatics tools for mass spectroscopy-based metabolomic data processing and analysis, Current Bioinformatics source

In the paper

“The features associated with any pattern can be shown by the loadings in a PCA plot; however, PCA is generally not well suited to identify the most prominent part of the pattern.”

In the paper

“Certain microbial metabolites can be useful as food biomarkers, although there is a complex relation between the food source, the predominant gut microbial species, and the resulting food metabolites (73).”

What the sources say

• Not checked yetcites [73] Moco, 2012, A metabolomics view on gut microbiome modulation by polyphenol-rich foods, J Proteome Res source

In the paper

“First, it comprises a much greater chemical diversity than any other part of the metabolome (see Food metabolome and metabolite databases section).”

In the paper

“The main current limitation of MS is the very challenging and burdensome task of the structural elucidation of the detected ions (see below).”

In the paper

“Direct flow injection-MS has also been used (82,114), which offers the advantage of high-throughput analysis, as would be required for large-scale epidemiologic studies.”

What the sources say

• Not checked yetcites [82] Lloyd, 2011, Use of mass spectrometry fingerprinting to identify urinary metabolites after consumption of specific foods, Am J Clin Nutr source
• Not checked yetcites [114] Beckmann, 2013, Hydroxylated phenylacetamides derived from bioactive benzoxazinoids are bioavailable in humans after habitual consumption of whole grain sourdough rye bread, Mol Nutr Food Res source

In the paper

“MS is by far the most sensitive technique and the only method able to cover the nonnutrient metabolites of the food metabolome occurring at low concentrations in biological samples.”

In the paper

“Overall, the field of metabolomics is rich with data analysis options, and the challenge in the future will be to optimally apply these to food metabolomic studies.”

In the paper

“The use of food-frequency questionnaires may directly lead to the identification of biomarkers of habitual dietary exposure, but the lower accuracy and lower number of foods documented may limit their value for such discovery studies (105).”

What the sources say

• Not checked yetcites [105] May, 2013, Metabolomic profiling of urine: response to a randomised, controlled feeding study of select fruits and vegetables, and application to an observational study, Br J Nutr source

In the paper

“The reason for this is partly technical because of the higher concentrations of food-derived metabolites in urine as compared with blood and because of the lack of interfering proteins.”

In the paper

“This provides an objective assessment of the principal patterns in the data set (eg, intake or no intake of a specific food component or diet).”

In the paper

“Statistical analysis of untargeted metabolomic data is often an initial step in the biomarker discovery process that should not be confused with hypothesis testing, because there is no a priori hypothesis.”

In the paper

“These include the mode of sample preparation, method of chromatography, mode of detection, and the choice of data reduction methods (116, 117).”

What the sources say

• Not checked yetcites [116] Barri, 2012, Metabolic fingerprinting of high-fat plasma samples processed by centrifugation- and filtration-based protein precipitation delineates significant differences in metabolite information coverage, Anal Chim Acta source
• Not checked yetcites [117] Gika, 2010, Does the mass spectrometer define the marker? A comparison of global metabolite profiling data generated simultaneously via UPLC-MS on two different mass spectrometers, Anal Chem source

In the paper

“The metabolic profile of raw data generated by the spectrometric analysis of biological samples can be analyzed in several steps (119, 120).”

What the sources say

• Not checked yetcites [119] Katajamaa, 2007, Data processing for mass spectrometry-based metabolomics, J Chromatogr A source
• Not checked yetcites [120] Sugimoto, 2012, bioinformatics tools for mass spectroscopy-based metabolomic data processing and analysis, Current Bioinformatics source

In the paper

“However, ion suppression effects, due to inefficient ionization of certain ions in complex matrices and the inability to discriminate between isomers, limit the use of this approach.”

In the paper

“Multivariate analysis is most commonly used for explorative analysis of metabolic profiling data (127).”

What the sources say

• Not checked yetcites [127] Worley, 2013, Utilities for quantifying separation in PCA/PLS-DA scores plots, Anal Biochem source

In the paper

“In cross-sectional studies this large contrast seldom applies, but approximate dose-response relations from food-frequency questionnaires may help in the identification of food intake biomarkers.”

In the paper

“In dietary intervention studies with single foods, the contrast observed for a good biomarker can be large, sometimes even infinite, making it possible to work robustly with small sample sets and discriminate potential intake biomarkers from more subtle changes in endogenous metabolites (126).”

What the sources say

• Not checked yetcites [126] Kristensen, 2012, LC-MS metabolomics top-down approach reveals new exposure and effect biomarkers of apple and apple-pectin intake, Metabolomics source

In the paper

“As opposed to univariate analysis, multivariate analysis can be performed in an unsupervised manner (ie, without including information on group assignment for the analysis).”

In the paper

“All of these discriminatory biomarkers point to dietary sources, sometimes in combination with cometabolism by gut microbiota.”

In the paper

“Although they are not specific to the food metabolome, these resources are useful for metabolite identification because fragmentation data or NMR signals of known metabolites can be compared with the unknown query to gain structural information.”

In the paper

“In fact, MWASs can be regarded as a special case of the exposome-wide association study, which investigates disease associations with all exposures to low-and high-molecular-weight compounds (167).”

What the sources say

• Not checked yetcites [167] Rappaport, 2012, Biomarkers intersect with the exposome, Biomarkers source

In the paper

“Recently, a large number of food compounds have been added to the HMDB, which makes searches on the basis of their accurate masses possible (9); however, to date it contains few mass fragmentation spectra useful for food metabolite identification.”

What the sources say

• Not checked yetcites [9] Wishart, 2013, HMDB 3.0—the Human Metabolome Database in 2013, Nucleic Acids Res

In the paper

“The alternative untargeted approach makes no a priori assumptions regarding sources of exposure that are causal for a particular disease but instead relies on comparisons of comprehensive profiles of metabolomic features between cases and controls to find discriminating exposure biomarkers.”

In the paper

“biomarkers were identified, namely alanine, which was directly correlated with blood pressure, and formate and hippurate, both of which were inversely correlated with blood pressure.”

What the sources say

• Not checked yetcites [59] Holmes, 2008, Human metabolic phenotype diversity and its association with diet and blood pressure, Nature source
• Not checked yetcites [166] Bictash, 2010, Opening up the “black box”: metabolic phenotyping and metabolome-wide association studies in epidemiology, J Clin Epidemiol source

In the paper

“These associations were tentatively explained by either different amounts of dietary intake or differential fatty acid metabolism in cases and controls.”

In the paper

“The most comprehensive and best-curated chemical (commercial) database is currently SciFinder, which includes many food metabolome compounds collected from the literature (151).”

What the sources say

• Not checked yetcites [151] American Chemical Society. SciFinder. Available from: https://scifinder.cas.org (cited 3 September 2013).

In the paper

“The human metabolome database has recently expanded to include compounds found in common foods because these are, at least initially before metabolism, also present within the human body (9).”

What the sources say

• Not checked yetcites [9] Wishart, 2013, HMDB 3.0—the Human Metabolome Database in 2013, Nucleic Acids Res

In the paper

“A number of loci associated with variations in the concentration of endogenous metabolites could be identified in genome-wide analysis studies, and many of these genes were coding for metabolic enzymes (180-182).”

What the sources say

• Not checked yetcites [180] Suhre, 2011, Human metabolic individuality in biomedical and pharmaceutical research, Nature source
• Not checked yetcites [181] Illig, 2010, A genome-wide perspective of genetic variation in human metabolism, Nat Genet source
• Not checked yetcites [182] Kettunen, 2012, Genome-wide association study identifies multiple loci influencing human serum metabolite levels, Nat Genet source

In the paper

“The Metabolomics Standards Initiative (MSI) launched by the Metabolomics Society is an example of such an initiative, and the MSI has already had significant impact on reporting formats in metabolomics (110, 188).”

What the sources say

• Not checked yetcites [110] Sumner, 2007, Proposed minimum reporting standards for chemical analysis, Metabolomics source
• Not checked yetcites [188] Fiehn, 2007, The Metabolomics Standards Initiative (MSI), Metabolomics source

In the paper

“For example, many studies have been conducted with oranges (Table 3), but a broad coverage of all citrus and many other fruit as well as kinetic studies have been necessary to interpret proline betaine as a short-term marker of citrus that is dominated by orange and orange juice intake (80).”

What the sources say

• Not checked yetcites [80] Heinzmann, 2010, Metabolic profiling strategy for discovery of nutritional biomarkers: proline betaine as a marker of citrus consumption, Am J Clin Nutr source

In the paper

“Some commercial software exists for the pharmaceutical area (192,193) and covers many phase I and II reactions.”

What the sources say

• Not checked yetcites [192] T’Jollyn, 2011, Evaluation of three state-of-the-art metabolite prediction software packages (Meteor, MetaSite, and StarDrop) through independent and synergistic use, Drug Metab Dispos source
• Not checked yetcites [193] Piechota, 2013, pragmatic approaches to using computational methods to predict xenobiotic metabolism, J Chem Inf Model source

In the paper

“They should also significantly contribute to a better understanding of the complex interactions between diet and human health.”

In the paper

“The MSI, initiated by the Metabolomics Society, has already issued several reference articles on good practice for metabolomic research.”

What the sources say

• Not checked yetcites [189] Metabolomics Standards Initiative. Homepage. Available from: http://msi-workgroups.sourceforge.net/ (cited 3 September 2013).

In the paper

“Some proof-of-principle studies have established the feasibility of metabolomic approaches to identify novel dietary biomarkers and suggest that these approaches could greatly expand the field of molecular nutritional epidemiology and contribute to future progress in nutrition research.”

In the paper

“Several training workshops on metabolomics and nutrition were supported by the Nutrigenomics Organization (112).”

What the sources say

• Not checked yetcites [112] Scalbert, 2009, Mass-spectrometry-based metabolomics: limitations and recommendations for future progress with particular focus on nutrition research, Metabolomics source