Biomarkers of intake for coffee, tea, and sweetened beverages
- 3.3k Downloads
- 8 Citations
Abstract
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.
Keywords
Non-alcoholic beverages Coffee Tea Sugar-sweetened beverages Low-calorie-sweetened beverages Biomarkers IntakeAbbreviations
- AUC
Area under the curve
- BVO
Brominated vegetable oil
- C
Catechin
- CG
Catechin gallate
- EC
Epicatechin
- ECG
Epicatechin gallate
- EGC
Epigallocatechin
- EGCG
Epigallocatechin gallate
- EPIC
European Prospective Investigation into Cancer and Nutrition
- FFQ
Food frequency questionnaire
- GC
Gallocatechin
- GCG
Gallocatechin gallate
- GC-MS
Gas chromatography – mass spectrometry
- HFCS
High-fructose corn syrup
- LC-MS
Liquid chromatography – mass spectrometry
- LCS
Low-calorie sweeteners
- LCSB
Low-calorie-sweetened beverages
- NHDC
Neohesperidine dihydrochalcone
- NMR
Nuclear magnetic resonance
- ROC
Receiver operating characteristic
- SSB
Sugar-sweetened beverages
Background
Human adults consume about 3 to 4 l of water per day, which originate from plain water, solid foods, and other beverages like coffee, tea, soda, fruit juices, sport and energy drinks, milk, and alcoholic beverages [1]. Beside water, non-alcoholic beverages such as coffee and tea are also a source of other constituents like caffeine, chlorogenic acids, diterpenes, and diketopiperazines in coffee [2], theanine, catechins, theaflavins, thearubigins and flavonols in tea [3], sucrose or high-fructose corn syrup (HFCS) in sodas, and low-calorie sweeteners (LCSs) in low-calorie-sweetened beverages (LCSBs) which may influence health in a positive or negative way.
Although coffee drinking was initially thought to induce negative effects on health, for example, increasing blood pressure and the risk of cardiovascular disease risk in some cohorts [4, 5], the main interest in recent years is the potential for positive health effects. These include plausible reductions in risk of type 2 diabetes, Parkinson disease, Alzheimer’s disease, and liver and colorectal cancer [6, 7, 8, 9, 10]. Tea consumption has been associated with a reduction of the risk of chronic diseases and more particularly cardiovascular diseases, type 2 diabetes, cancers, and neurodegenerative diseases [11, 12, 13, 14]. Compounds like sugars in sodas may provide an excess of energy and increase the risk of obesity and associated diseases [15]. Given the overconsumption of free sugars, particularly from SSBs, the use of LCSBs has increased over the years as a strategy for reducing the free sugar content of the diet while maintaining palatability and research interest to date has focused on assessing the effect of LCSB consumption on a variety of health outcomes such as metabolic health, weight management, and renal impairment [16, 17].
Despite large efforts in unraveling these health effects of non-alcoholic beverages on health in epidemiological studies, some of these effects are not fully consistent between studies, and it has been suggested that this lack of agreement could be associated with the traditional methods used to assess beverage consumption [18]. Beverage consumption is most often measured with self-administered questionnaires, and these measurements are known to be prone to random or systematic errors which may prevent the detection of associations of intake with disease outcomes [19]. These errors are linked to limitations in the capacity of subjects to accurately describe their beverage intake and to difficulties in accounting for variations in the nature of the beverages consumed within or between populations. For example, concentrations of polyphenols in coffee and in tea vary with the type of coffee beans or tea leaves and with the method of coffee brewing or tea leaf infusion, information most often not recorded in dietary questionnaires.
In contrast to questionnaires, biomarkers are objective measures that provide estimates of beverage intake [20, 21, 22]. They are directly derived from beverage constituents absorbed in the gut during digestion. Thus, they provide more direct estimates of exposure to beverage constituents and are notably independent of the dilution of the beverages, or on any aspect of the recipes used for their preparation. Biomarkers of beverage intake can be identified using two separate approaches. Initially, biomarkers were hypothesized based on knowledge of beverage constituents and their metabolism. Beverages are fed to volunteers in controlled intervention studies and known metabolites of interest measured in biofluids to test for increases with intake. Until a few years ago, this targeted approach was the only viable method of biomarker discovery. More recently, metabolome profiling has taken precedence as a more comprehensive and agnostic approach. Rather than measuring known compounds only, biofluids are profiled to measure the relative intensities of as many signals as can be detected, either by nuclear magnetic resonance (NMR) or mass spectrometry coupled to liquid or gas chromatography (LC-MS or GC-MS). Signals associated with intake of the target food across the most possible subjects are retained as candidate biomarkers.
Initial metabolome profiling studies used an intervention design with a standardized dose and controlled diet, but more sensitive analytical techniques have enabled the analysis of biofluids from free-living subjects who have reported their beverage intakes via dietary questionnaires. This approach has some advantages and limitations. It encourages the discovery of biomarkers that are valid in the presence of interfering dietary factors and that also account for differences in the time period between beverage intake and biofluid collection. On the other hand, finding new biomarkers may be prevented by the limited accuracy of self-reported dietary intake data. Whatever the discovery approach, biomarkers can only be considered valid for the populations and biofluids in which they are discovered as different populations drink different brands or brews of a beverage with different compositions.
The purpose of this review is to describe the various biomarkers proposed to evaluate intake of some non-alcoholic beverages, including coffee, tea, sugar-sweetened beverages (SSBs), and LCSBs, all beverages that have raised much interest for being widely consumed worldwide and for their effects on the risk of various chronic diseases. Other non-alcoholic beverages such as fruit juices and milk are discussed in other chapters in this special volume. For each beverage, the main metabolites formed from their constituents and identified in blood or urine in human dietary intervention studies as putative biomarkers are first described. Their eventual detection in observational studies and respective value as intake biomarkers is then discussed.
Materials and methods
The reviewing process made was described in details recently [23] and use all elements of the PRISMA statement [24] that were relevant for a literature search on dietary biomarkers. Original research papers and reviews were searched for in PubMed, Scopus, and ISI Web of Knowledge using the following search terms: (biomarker* OR marker* OR metabolite* OR biokinetics OR biotransformation) AND (human* OR men OR women OR male OR female OR patient* OR volunteer* OR participant*) AND (urine OR plasma OR serum OR blood OR excretion) AND (intake OR meal OR diet OR ingestion OR consumption OR eating OR drink* OR administration) AND (‘name of beverage’). Name of beverages were (coffee), (tea), or (diet soda OR diet beverage* OR soft drink* OR artificial* sweet* beverage* OR low sugar beverage* OR low calorie sweet* beverage*).
The research was limited to papers in English language, and no restrictions were applied to publication date. End-date of search was April 2016, January 2017, June 2016, and December 2016 for coffee, tea, SSBs, and LCSBs, respectively. The research papers identifying or using potential biomarkers of intake for the foods were selected by one or more skilled researchers from the list of retrieved references in the process outlined in Additional file 1: Figure S1. Additional papers were identified from reference lists in these papers and from reviews or book chapters identified through the search. For each potential biomarker identified, an additional search was conducted with (“the name and synonyms of the compound” OR “the name and synonyms of any parent compound”) AND (biomarker* OR marker* OR metabolite* OR biokinetics OR biotransformation) to identify potential other foods containing the biomarker or its precursor. In this second step, Scifinder and Google Scholar were also used as search platforms, as well as the databases listed above. This second search was used to evaluate the apparent specificity of the marker.
Results and discussion
Biomarkers have been systematically searched for in the scientific literature independently for the four types of non-alcoholic beverages (coffee, tea, SSBs, and LCSBs). The literature was particularly abundant for biomarkers of coffee and tea intake (Additional file 1: Figure S1). Results are successively presented below.
Coffee biomarkers
Coffee metabolites in controlled intervention studies
Metabolites identified in human intervention studies on coffee
| Beverage | No. subjects | Sample type | Analytical method | Enzymatic hydrolysis | Discriminating metabolites/candidate biomarkers | Reference |
|---|---|---|---|---|---|---|
| Instant coffee (repeated intake) | 5 | Urine | HPLC | Yes | Ferulic, isoferulic, dihydroferulic, vanillic acids, 3-hydroxyhippuric acid | [25] |
| Instant coffee | 9 | Urine | LC-MS | Yes | Chlorogenic acid, caffeic acid, m-coumaric acid | [26] |
| Coffee | 13 | Urine | CE-MS | No | Coumaric acid, caffeic acid | [127] |
| Instant coffee | 11 | Plasma, urine | LC-MS | No | Ferulic and dihydroferulic acid sulfates (blood and urine), feruloylglycine (urine only) | [27] |
| Filter coffee | 9 | Urine | LC-MS | No | Trigonelline, N-methylpyridium | [35] |
| Filter coffee | 13 | Plasma | LC-MS | No | Trigonelline, dimethylxanthines, methylxanthines, dihydroferulic acid, dihydrocaffeic acid sulfate, ferulic acid glucuronide, ferulic acid sulfate, ferulic acid, dihydroferulic acid sulfate, dihydroferulic acid glucuronide, N- feruloylglycine | [29] |
| Instant coffee | 11 | Plasma, urine | LC-MS | No | 3-, 4- and 5-Feruloylquinic acid, 3 and 4-Caffeoylquinic acid lactone sulfate (urine and plasma), isoferulic acid-3-glucuronide (urine only) | [28] |
| Coffee (repeated intake) | 8 | Urine | 1H-NMR | No | 2-Furoylglycine | [30] |
Despite providing a wealth of information on potential markers of coffee intake, the main purpose of these controlled intervention studies was usually to investigate the metabolism of hydroxycinnamic acid derivatives rather than search for novel biomarkers of intake. Other authors have followed the appearance of a variety of coffee compounds in blood or urine in subjects administered a standardized dose of coffee [29]. Dihydroferulic acid conjugates, trigonelline, caffeine, and its primary metabolites were found to persist in plasma for long enough that they should never be fully cleared in individuals drinking three cups of coffee over a day. N-2-furoylglycine was identified as a promising biomarker of coffee intake after the untargeted NMR profiling of spot urine samples from five volunteers administered a dose of espresso coffee [30]. Highest concentrations were observed two hours after intake. N-2-furoylglycine is derived from furans formed during coffee roasting.
Biomarkers of coffee intake in observational studies
Biomarkers of coffee intake discovered in observational studies
| Beverage | No. subjects | Sample type | Analytical method | Enzymatic hydrolysis | Discriminating metabolites/candidate biomarkers (HMDB ID if available) | Association with | Reference |
|---|---|---|---|---|---|---|---|
| Coffee | 111 | Urine (24 h) | GC-MS | Yes | Isoferulic acid (HMDB0000955) | FFQ | [32] |
| Coffee | 344 | Urine (24 h) | GC-MS | Yes | Isoferulic acid (HMDB0000955) | 24-HDR | [32] |
| Coffee | 53 | Urine (24 h and spot) | LC-MS | Yes | Chlorogenic acid (HMDB0003164), caffeic acid (HMDB0001964) | 2-Day dietary record | [33] |
| Coffee | 68 | Urine (24 h) | FIA-MS | Yes | Dihydrocaffeic acid (not in HMDB), dihydrocaffeic acid 3-glucuronide (HMDB0041720) | FFQ | [36] |
| Coffee | 39 | Urine (morning spot) | LC-MS | No | Atractyligenin glucuronide (not in HMDB), cyclo(isoleucylprolyl) (not in HMDB), trigonelline (HMDB0000875), paraxanthine (HMDB0001860), theobromine (HMDB0002825), theophylline (HMDB0001889), 1-methylxanthine (HMDB0010738), hippuric acid (HMDB0000714), trimethyluric acid (HMDB0002123), 3-hydroxyhippuric acid (HMDB0006116), 5-acetylamino-6-formylamino-3-methyluracil (AFMU) (HMDB0011105), 1,3 or 3,7 dimethyluric acid (HMDB0001857, HMDB0001982), caffeine (HMDB0001847) | FFQ | [38] |
| Coffee | 502 | Serum | LC-MS, GC-MS | No | Trigonelline (HMDB0000875), quinic acid (HMDB0003072), 1-methylxanthine (HMDB0010738), paraxanthine (HMDB0001860), N-2-furoylglycine (HMDB0000439), catechol sulfate (not in HMDB) | FFQ | [39] |
| Coffee | 498 | Serum | LC-MS | No | Trigonelline (HMDB0000875), quinic acid (HMDB0003072), paraxanthine (HMDB0001860), N-2-furoylglycine (HMDB0000439), catechol sulfate (not in HMDB), caffeine (HMDB0001847), 1-methylxanthine (HMDB0010738), theophylline (HMDB0001889), trimethyluric acid (HMDB002123), hydroxyhippuric acid (HMDB0006116), 1,7-dimethyluric acid (HMDB0011103), 1-methyluric acid (HMDB0003099), cyclo(leu-pro) (HMDB0034276), 4-vinylphenol sulfate (HMDB0062775), hydroxyphenylpropionate (HMDB0000375), theobromine (HMDB0002825), cinnamoylglycine (HMDB0011621) | FFQ | [10] |
| Coffee | 475 | Urine (24 h) | LC-MS | No | Dihydroferulic acid sulfate (HMDB0041724), guaiacol glucuronide (not in HMDB), feruoylquinic acid (HMDB0030669), ferulic acid sulfate (HMDB0029200), feruoylquinic acid glucuronide (not in HMDB), 3-caffeoylquinic acid (HMDB0003164), p-coumaric acid sulfate (not in HMDB), caffeic acid sulfate (HMDB0041706), ferulic acid glucuronide (HMDB0041733), hydroxyhippuric acid (HMDB0006116), dihydrocaffeic acid sulfate (HMDB0041721), m-coumaric acid sulfate (not in HMDB), dihydroferulic acid glucuronide (HMDB0041723), p-hydroxyphenyllactic acid (HMDB0000755), guaiacol sulfate (not in HMDB), ethylcatechol glucuronide (not in HMDB) | 24-HDR | [37] |
Later, metabolomic studies found novel markers of coffee intake in observational studies using untargeted approaches. In a first such study, N-methylpyridinium and trigonelline, products of the coffee roasting process, were found to best distinguish coffee drinkers from non-coffee drinkers (after analysis of urine by LC-MS) [35]. Both compounds remained elevated in urine for at least 2 days after coffee consumption and were thus proposed as stable biomarkers of intake. N-methylnicotinamide also distinguished the two groups, although it was not considered specific to coffee intake, being a metabolite of niacin found in a wide range of foods. In another study, dihydrocaffeic acid and its 3-glucuronide, measured in 24-h urine by LC-MS, was found to discriminate groups of high- and low-coffee consumers (identified with a food frequency questionnaire) with high sensitivity and specificity [36]. A later cross-sectional study in 481 subjects of the EPIC cohort, also using 24-h urine samples, showed significant correlations between concentrations of 16 phenolic acids, mostly glucuronide or sulfate esters, with acute coffee intake as estimated with 24-h dietary recalls [37]. Dihydroferulic acid sulfate concentrations correlated most strongly with coffee intake whether assessed by FFQ (r = 0.62) or 24-h dietary recall (r = 0.52). Dihydroferulic acid sulfate, feruloylquinic acid glucuronide, ferulic acid sulfate, and guaiacol glucuronide were the metabolites whose measured intensities best classified subjects into the highest or lowest quintiles of coffee intake, with a receiver operating characteristic (ROC) area under the curve (AUC) for the predictive model > 94%. Non-phenolic metabolites were not investigated in this study.
The use of 24-h urine samples yields the widest range of potential biomarkers, as all coffee metabolites accumulate in urine after coffee intake regardless of metabolite pharmacokinetics. Biomarkers identified in 24-h urine samples cannot be assumed to be effective markers when measured in spot urine or in blood samples taken at a single time point since many food-derived metabolites are excreted rapidly after absorption. A few authors have searched for markers of coffee intake in spot urine or blood collections (Table 2). For example, biomarkers of coffee intake were searched for in morning spot urines of French subjects from the SUVIMAX cross-sectional study [38]. The intensities of several coffee-derived metabolites accurately classified consumers into high- and low-intake groups (respectively 183–540 and vs. 0 mL/day, as measured with repeated 24-h dietary recalls and a food frequency questionnaire). The most effective of these were the diterpene atractyligenin glucuronide (r = 0.534, ROC AUC = 0.98), the cyclic amino acid cyclo(isoleucylprolyl) (r = 0.543, ROC AUC = 0.969) and the caffeine metabolite 1-methylxanthine (r = 0.561, ROC AUC = 0.965). Also, urinary concentrations of 1,7-dimethyluric acid, 1-methyluric acid, and trigonelline each classified subjects with an excellent sensitivity and specificity (ROC AUC > 0.9). Combining cyclo(isoleucylprolyl), 1-methylxanthine, and trigonelline concentrations as a single biomarker increased classification performance relative to any one single compound. Hippuric acid was elevated in the urine of coffee consumers, while caffeoylquinic acid-derived metabolites were not reported as discriminants in this study.
Two further studies have identified biomarkers of coffee intake in blood. Trigonelline, 1-methylxanthine, and paraxanthine were identified as serum biomarkers of coffee intake when comparing high- (> 2.5 cups/day) and low- (< 2.5 cups/day) coffee drinkers in an American-nested case-control study, along with N-2-furoylglycine and catechol sulfate [39]. A more detailed study on coffee in the same cohort additionally reported that plasma trigonelline (partial r = 0.608) and quinic acid (partial r = 0.59) concentrations best correlated with coffee intake as reported by FFQ [10]. In contrast, concentrations of unmetabolized caffeine correlated moderately with coffee intake (partial r = 0.327).
The studies described above proposed biomarkers of intake exclusively in urine, plasma, or serum. A small number of studies have considered coffee-derived metabolites in other biospecimens. For example, after a dose of coffee, a Japanese group was able to measure caffeine and three isomers of dimethylxanthine in fingerprints [40]. Also, pyridine was found to increase in breath after consumption of a large cup of espresso [41]. Such techniques may not be applicable to epidemiological studies at present but represent possible future alternatives to measuring biomarkers of coffee intake in blood and urine.
In summary, many exogenous blood and urinary metabolites have been proposed as coffee intake markers but their validity depends on study design, study population, biofluid, and analytical method. In intervention studies where urine or blood samples are taken shortly after the administration of coffee, hydroxycinnamic acid derivatives such as caffeic and dihydroferulic acid (and their phase II conjugates) have been most commonly proposed as biomarkers of coffee intake. Most recent studies in free-living subjects suggest that several phenolic acids (ferulic, isoferulic, dihydroferulic, caffeic, and dihydrocaffeic acids and their glucuronides and sulfate esters), alkaloids (caffeine, trigonelline, and their metabolites), cyclo(isoleucylprolyl), and atractyligenin glucuronide, measured in urine, are the most sensitive and specific biomarkers of coffee intake. Fewer studies in free-living subjects were conducted on blood and trigonelline, and quinic acid were found to best correlate with coffee intake.
Still, it will be important to check the specificity of these biomarkers in the populations where implemented as the levels of coffee intake and the impact of possible confounders may vary between populations. Indeed, some of these biomarkers like caffeine or ferulic acid may also arise from other dietary sources such as tea or soft drinks for caffeine or wholegrain cereals for ferulic acid. Trigonelline and cyclo(isoleucylprolyl) or their precursors may be preferred considering their high specificity for coffee.
Tea biomarkers
Tea metabolites in controlled intervention studies
Metabolites identified in human intervention studies on tea
| Type of beverage | No. subjects | Sample type | Analytical method | Enzymatic hydrolysis | Discriminating metabolites/candidate biomarkers | Reference |
|---|---|---|---|---|---|---|
| Green tea, black tea | 18 | Urine | LC-ECD | Yes | Epicatechin, epigallocatechin | [49] |
| Green tea, black tea | 20 | Urine | GC-MS | Yes | 4-O-Methylgallic acid | [128] |
| Black tea | 10 | Plasma, urine | HPLC | ? | 4-O-Methylgallic acid, gallic acid | [55] |
| Green tea, black tea (extracts) | 17 | Urine | LC-MS | No | Hippuric acid | [129] |
| Green tea, black tea (decaffeinated) | 133 | Urine | LC-ECD | Yes | (−)-Epigallocatechin | [60] |
| Green tea, black tea | 30 | Plasma | LC-ECD | Yes | (−)-Epicatechin, (−)-epicatechin-3-gallate, (−)-epigallocatechin, (−)-epigallocatechin-3-gallate | [61] |
| Green tea | 10 | Plasma, urine | LC-MS | No | (−)-Epicatechin-3’-O-glucuronide, (epi)catechin-O-sulfates, 3’-O-methyl-(epi)catechin-O-sulfates, 4’-O-methyl-(epi)catechin-O-sulfate, (epi)gallocatechin-O-glucuronide, 4’-O-methyl-(epi)gallocatechin-O-sulfates (urine and plasma); (−)-epicatechin-3-O-gallate, 4’-O-methyl-(epi)gallocatechin-O-glucuronide, (−)-epigallocatechin-3-O-gallate (plasma only); (epi)gallocatechin-O-sulfates (urine only) | [42] |
| Green tea | 20 | Urine | LC-MS | No | (Epi)catechin glucuronide, (epi)catechin sulfate, (epi)catechin sulfoglucuronide, methyl(epi)catechin sulfate, (epi)gallocatechin glucuronide,(epi)gallocatechin sulfate, methyl(epi)gallocatechin glucuronide, methyl(epi)gallocatechin sulfate, methyl(epi)gallocatechin sulfoglucuronide, 5-(hydroxyphenyl)-γ-valerolactone glucuronide, 5-(hydroxyphenyl)-γ-valerolactone glucuronide sulfate, 5-(3′,5′-dihydroxyphenyl)-γ-valerolactone glucuronide,5-(3′,5′-dihydroxyphenyl)-γ-valerolactone glucuronide disulfate, 5-(4′,5′-dihydroxyphenyl)-γ-valerolactone glucuronide, 5-(4′,5′-dihydroxyphenyl)-γ-valerolactone glucuronide disulfate, 5-(4′,5′-dihydroxyphenyl)-γ-valerolactone glucuronide sulfoglucuronide, methyl-5-(4′,5′-dihydroxyphenyl)-γ-valerolactone glucuronide, 5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone glucuronide, 5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone glucuronide sulfate, methyl-5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone glucuronide, methyl-5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone sulfate | [43] |
| Black tea | 4 | Urine | LC-MS | No | (Epi)catechin sulfate, O-methylcatechin sulfate, O-methyl(epi)catechin sulfates, O-methyl(epi)gallocatechin sulfates, di-O-methyl(epi)gallocatechin sulfates, dihydronaringenin sulfates, 3’-O-methyl-5-(3′,4′-dihydroxyphenyl)-γ-valerolactone 4’-O-glucuronide, 4’-O-methyl-5-(3′,4′-dihydroxyphenyl)-γ-valerolactone 3’-O-glucuronide, 5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone 3’-O-glucuronide, 4’-O-glucuronide, 3’-O-sulfate, 4’-O-sulfate and sulfoglucuronide, O-methyl-5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone 3′- or 4’-O-glucuronides, 3′ or 5’-O-glucuronide and O-sulfate, 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone 3’-O-glucuronide, 4’-O-glucuronide and sulfates, 5-(3′,5′-dihydroxyphenyl)-γ-valerolactone 3’-O-glucuronide and 3’-O-sulfate, O-methyl-5-(3′,5′-dihydroxyphenyl)-γ-valerolactone glucuronides and sulfates, 5-(3′-hydroxyphenyl)-γ-valerolactone 3’-O-glucuronide, 4’-O-glucuronide, 5-(hydroxyphenyl)-γ-valerolactone sulfate, O-methyl-4-hydroxy-5-(3′,4′,5′-trihydroxyphenyl)valeric acid glucuronides, 4-hydroxy-5-(3′,4′-dihydroxyphenyl)valeric acid glucuronides, O-methyl-4-hydroxy-5-(3′,4′-dihydroxyphenyl)valeric acid glucuronides, 4-hydroxy-5-(3′,5′-dihydroxyphenyl)valeric acid glucuronide, O-methyl-4-hydroxy-5-(3′,5′-dihydroxyphenyl)valeric acid glucuronides, 4-hydroxy-5-(3′-hydroxyphenyl)valeric acid 3’-O-sulfate and 4’-O-sulfate, O-methyl-4-hydroxy-5-(dihydroxyphenyl)valeric acid sulfates, 4-hydroxy-5-(dihydroxyphenyl)valeric acid sulfates, O-methyl-4-hydroxy-5-(hydroxyphenyl)valeric acid sulfate, 4-hydroxy-5-(phenyl)valeric acid glucuronides and sulfates, hippuric acid, indole-3-acetic-acid glucuronide, indole-3-carboxylic acid glucuronide, p-cresol sulfate and glucuronide, pyrogallol 2-O-glucuronide, 1-O-sulfate and 2-O-sulfate, urolithin A-3-O-glucuronide, 8-O-glucuronide and sulfoglucuronide, urolithin B-O-glucuronide, vanilloylglycine, vanillic acid-4-O-glucuronide and 4-O-sulfate, phenylacetylglycine | [130] |
| Green tea (extract) | 14 | Urine | LC-MS | Yes | Catechin,, epicatechin, 3’-O-methylepicatechin, 4’-O-methylepicatechin, epicatechin-3-O-gallate, gallocatechin, gallocatechin gallate, epigallocatechin, 3’-O-methylepigallocatechin, 4’-O-methylepigallocatechin, epigallocatechin-3-O-gallate, 5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone, 5-(3′,4′-dihydroxyphenyl)valerolactone, 5-(3′,5′-dihydroxyphenyl)valerolactone, gallic acid, 3-O-methyl gallic acid, 3-hydroxybenzoic acid, syringic acid, benzoic acid, hippuric acid | [131] |
| Black tea (extract) | 12 | Plasma | LC-MS | No | (Epi)catechin sulfate, O-methyl(epi)catechin sulfates, di-O-methyl(epi)catechin sulfate, O-methyl(epi)gallocatechin sulfate, (epi)catechin gallate sulfate and sulfoglucuronide, O-methyl(epi)catechin gallate sulfate and sulfoglucuronide, (epi)gallocatechin gallate, (epi)gallocatechin gallate sulfate, O-methyl(epi)gallocatechin gallate sulfate, δ-(3′,4′-dihydroxyphenyl)-γ-valerolactone) 3′-O-glucuronide, 4′-O-glucuronide, 3′-O-sulfate and sulfoglucuronide, 5-(3′-hydroxyphenyl)-γ-valerolactone 3′-O-glucuronide and 3′-O-sulfate, 5-(4′-hydroxyphenyl)-γ-valerolactone 4′-O-glucuronide, 5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone 3′-O-glucuronide, 4′-O-glucuronide, 3′-O-sulfate and sulfoglucuronide, O-methyl-5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone 3′/4′-O-glucuronide, 3′/5′-O-glucuronide and O-sulfates, 5-(3′,5′-dihydroxyphenyl)-γ-valerolactone 3′-O-glucuronide and 3′-O-sulfate, O-methyl-5-(3′,5′-dihydroxyphenyl)-γ-valerolactone 3′-O-glucuronide and 3′-O-sulfate, 4-hydroxy-5-(dihydroxyphenyl)valeric acid sulfates, O-methyl-4-hydroxy-5-(hydroxyphenyl)valeric acid sulfates, 4-hydroxy-5-(3′,4′-dihydroxyphenyl)valeric acid glucuronides, 4-hydroxy-5-(3′,5′-dihydroxyphenyl)valeric acid glucuronide, O-methyl-4-hydroxy-5-(3′,5′-dihydroxyphenyl)valeric acid glucuronide, O-methyl-4-hydroxy-5-(3′,4′,5′-trihydroxyphenyl)valeric acid glucuronide, kaempferol glucuronide, O-methylgallic acid sulfates, pyrogallol 2-O-glucuronide and 2-O-sulfate, O-methylcatechol sulfates, resorcinol glucuronide and sulfate, hippuric acid | [54] |
| Black tea (extract) | 19 | Plasma | LC-MS | Yes | (−)-Catechin, (−)-epicatechin, (−)-(epi)catechin gallate, (−)-epigallocatechin, (−)-epigallocatechin gallate, isorhamnetin, 3/4-O-methylgallic acid, 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone, 5-(3′-methoxy-4′-hydroxyphenyl)-γ-valerolactone | [56] |
| Black tea (extract) | 12 | Plasma | GC-MS | Yes | 4-O-Methylgallic acid, gallic acid, hippuric acid, pyrogallol | [57] |
| Green tea, black tea | 93 | Urine | LC-ECD | Yes | (−)-Epicatechin, (−)-epigallocatechin, 4’-O-methylepigallocatechin | [62] |
Catechins not absorbed in the small intestine reach the colon where they can be degraded by the microbiota into low-molecular weight metabolites such as hydroxyphenylvalerolactones, hydroxyphenylvaleric acids, phenolic acids, and hippuric acid. These metabolites show longer elimination half-lives in urine where they persist for 48 h after tea intake [43].
Most studies showed a linear relationship between plasma concentrations or urine excretion of tea catechins and the ingested dose [44, 45, 46, 47, 48] although concentrations of some catechins were also shown to reach a plateau at a high level of intake in some studies [49, 50].
Many untargeted metabolomic studies have been conducted to elucidate additional candidate biomarkers of tea intake [51, 52, 53]. In a placebo-controlled cross-over intervention study based on high-resolution mass spectrometry, 12 male subjects consumed a single capsule of tea extract (2.65 g) or a placebo after 1 day of a polyphenol-poor diet [54]. Fifty-nine polyphenol metabolites were identified and increased in concentration after black tea ingestion. These metabolites were catechins, phenolic acids, valerolactones, and simple phenols, most in the form of glucuronides and sulfate esters. The highest concentrations in plasma were observed within 1–4 h (catechins, kaempferol, gallic acid) or 5–10 h (microbial metabolites such as phenylvalerolactones, pyrogallol, and hippuric acid), suggesting that they would be better indicators of tea intake if measured in 24-h urine samples rather than spot urine samples.
Some markers may be used to differentiate intake of green and black tea. In particular, 4-O-methylgallic acid, formed by O-methylation of gallic acid, has frequently been reported in both urine and plasma after black tea intake [55, 56, 57]. This metabolite is also detected in urine after green tea intake but in much lower concentrations [58]. This difference in concentrations is explained by the low content of gallic acid in green tea when compared to black tea. Measurement of 4-O-methylgallic acid in urine or plasma could thus be useful to differentiate consumption of black and green tea, particularly if used in combination with catechins more abundant in green tea than in black tea [59] and present at higher concentrations in plasma or urine after consumption of green tea when compared to black tea [49, 60, 61, 62]. Theaflavins and thearubigins are abundant in black tea and absent from green tea; however, their high molecular weight considerably limits or prevents their absorption in the gut [63] and they therefore cannot be used as biomarkers of black tea intake.
Catechin metabolites formed by the gut microbiota are, in comparison with catechins or gallic acid, less useful as biomarkers of tea intake. Some of these metabolites (some phenolic acids and hippuric acid) were present in plasma in the absence of tea consumption [54]. This is explained by the existence of precursors of these metabolites in other dietary sources such as coffee, cocoa, fruits, or vegetables beside tea [64, 65, 66]. Other metabolites derived from tea catechins such as 5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone, 5-(3′,4′-dihydroxyphenyl)- γ-valerolactone, and/or 5-(3′,5′-dihydroxyphenyl)- γ-valerolactone may be more specific for tea intake [48, 67]. However, formation of these metabolites from catechins shows high interindividual variations, compromising their potential use as biomarkers of intake [68]. Similarly, other tea constituents such as quercetin or caffeine may also be of limited utility as biomarkers due to their abundance in other foods and beverages [69, 70].
Biomarkers of tea intake in observational studies
As previously highlighted, observational studies allow the investigation of biomarker sensitivity and specificity. In the Shanghai Cohort Study, EGC, 4′-O-methyl-EGC, EC, and two phenylvalerolactones measured in urine were significantly associated with self-reported tea intake [71, 72]. In another study carried out in 481 subjects from the EPIC cohort, metabolic profiles were compared in 24-h pooled urine samples by high-resolution MS in tea consumers and non-consumers (identified with 24-h dietary recalls) [37]. Several phenolic compounds were found to be associated with recent tea intake as assessed with a 24-h dietary recall. The compound that best distinguished non- and high consumers was found to be 4-O-methylgallic acid (ROC AUC = 0.84). 4-O-Methylgallic acid was also associated with habitual tea intake as assessed with a FFQ despite its short-elimination half-life, and this was explained by frequent tea intake in this population. However, some confounding with red wine intake was also observed. Other polyphenol metabolites were also found to be associated with tea intake in the same study (methyl(epi)catechin sulfate, dihydroxyphenyl-γ-valerolactone sulfate, hydroxyphenylvaleric acid glucuronide, and pyrogallol sulfate), but they may not be more specific for tea than 4-O-methylgallic acid, as other dietary sources of the same polyphenol metabolites are also known. Excretion of catechin metabolites in urine were also found to be correlated with intake of chocolate products, apples, and pears. Pyrogallol sulfate has also been identified in plasma after intake of nuts [73] or mixed berry fruit [74]. In another cross-sectional study, 24-h urinary kaempferol was correlated with tea intake (r = 0.41; p < 0.01) [75], but kaempferol was also found to be correlated with onion in another study [76]. Therefore, most of these markers associated with tea intake may not be specific enough for tea, depending on the possible consumption of confounding foods in the population considered.
Biomarkers of tea intake discovered in observational studies
| Type of beverage | No. subjects | Sample type | Analytical method | Enzymatic hydrolysis | Discriminating metabolites/candidate biomarkers (HMDB ID if available) | Association with | Reference |
|---|---|---|---|---|---|---|---|
| Black tea | 232 | Urine (24 h) | GC-MS | Yes | 4-O-Methylgallic acid (HMDB0013198) | 24-HDR | [132] |
| Black tea | 53 | Urine (24 h and spot) | LC-MS | Yes | Gallic acid (HMDB0005807), 4-O-methylgallic acid (HMDB0013198) | 2-Day dietary record | [33] |
| Green tea | 968 | Urine | LC-MS | Yes | Epicatechin (HMDB0001871), (−)-epigallocatechin (HMDB0038361), 4’-O-methylepigallocatechin (not in HMDB), 5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone (HMDB0041691), 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone (HMDB0029185) | FFQ | [71] |
| Green tea, black tea | 119 | Urine (24 h) | LC-MS | Yes | Kaempferol (HMDB0005801) | FFQ, 4-day food diary | [75] |
| Green tea | 660 | Urine (spot, non-fasting) | HPLC | Yes | Epicatechin (HMDB0001871), (−)-epigallocatechin (HMDB0038361), 4’-O-methylepigallocatechin (not in HMDB), 5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone (HMDB0041691), 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone (HMDB0029185) | FFQ | [72] |
| Tea | 191 | Urine (24 h, overnight) | LC-MS | Yes | Kaempferol (HMDB0005801) | FFQ | [133] |
| Tea | 476 | Urine (24 h) | LC-MS | No | Methyl(epi)catechin sulfate (not in HMDB), hydroxyphenylvaleric acid glucuronide (not in HMDB), dihydroxyphenyl-γ-valerolactone glucuronide and sulfate (HMDB0041693, HMDB0029191), 4-O-methylgallic acid (HMDB0013198), methylgallic acid sulfate(HMDB0060005), pyrogallol sulfate (HMDB0060016) | 24-HDR | [37] |
Sugar-sweetened beverage biomarkers
Identification and validation of markers reflecting the consumption of SSBs are an important task to better assess the association between the consumption of SSBs and related health effects. Major challenges to identify such biomarkers are linked to the broad definition of what a SSB is and to the variability of their composition. One major point is the nature of the caloric sweeteners used. Beverages containing added caloric sweeteners such as sucrose or high-fructose corn syrup (HFCS) are the main types of SSB. These beverages form a very heterogeneous group comprising soft drinks, fruit drinks, sports drinks, energy drinks, flavored water drinks, and iced teas [81, 82, 83]. Given this diversity of products and their different composition, having specific markers that reflect the intake of individual products or the total daily consumption of SSBs is challenging.
The dominating ingredient in all SSBs is, by definition, the added sugar. Exposure markers for the intake of sugar have been described using two different approaches, either through the measurement of the carbon isotope ratio 13C/12C (expressed as δ13C value) or through the determination of sugars in urine. The first approach is based on the different discrimination against carbon dioxide formed from the 13C and 12C isotopes in plants. Crop species have been classified as C3 and C4 plants depending on their photosynthetic pathway. The photosynthetic pathway of C3 plants like sugar beet discriminates against 13CO2 compared with 12CO2, and thus, the resulting plant mass carbon has a lower 13C/12C ratio than atmospheric CO2. In contrast, the C4 pathway is almost non-discriminating against 13C, resulting in a plant mass higher in 13C compared to C3 plants. Sugarcane and corn, the main sources for sugar production in the USA, are C4 crops. As a consequence, sugar from these crops is enriched in 13C, compared to sugar produced by C3 plants. This enrichment can be seen in whole human biospecimens or specific metabolites in these biospecimens after consumption of sugars from C4 plants.
Biomarkers of intake for sugar-sweetened beverages discovered in observational studies
| No. subjects | Analytical method | Sample type | Discriminating metabolites/candidate biomarkers (HMDB ID) | Association with | Reference |
|---|---|---|---|---|---|
| 144 | IRMS | Serum | δ13C | 24-HDR (× 2) | [86] |
| 60 | IRMS | Blood | δ13C | 4-day dietary record | [85] |
| 68 | GC-IRMS | Red blood cells | δ13C of alanine (HMDB0000161) | 24-HDR (× 2) | [84] |
| 68 | IRMS | Red blood cells, plasma, hair | δ13C | 24-HDR | [87] |
| 68 | IRMS | Fasting plasma | δ13C of glucose (HMDB0000122) | 24-HDR | [87] |
| 257 | IRMS | Blood | δ13C | 24-HDR (× 3), 4-day dietary record | [91] |
| 565 | 1H-NMR | Urine | Formate (HMDB0000142), citrulline (HMDB0000904), taurine HMDB0000251, isocitrate (HMDB0000193) | 4-day dietary record | [95] |
The second approach for calculating sugar intake uses urinary sucrose and fructose as exposure markers [93, 94]. Details on the different intervention studies and surveys were recently reviewed [93]. For this exposure marker, no information on its applicability for SSBs is currently available.
Both approaches, the carbon isotope ratio of different biospecimens and urinary fructose and sucrose, show promise as exposure markers for sugar and sucrose intake. However, sugar alone does not appear suitable as an exposure marker for SSB consumption because it is also contained in hundreds of other food items and is thus not specific. The use of an exposure marker for sugars in combination with additional substances used as ingredients might prove to be more specific. However, ingredients used in SSBs vary depending upon the type of SSB. Citric acid is added to many types of widely distributed SSBs as acidity regulator. However, citric acid seems not suitable as a marker for SSB consumption since it is produced in large quantities in the human metabolism. Moreover, it also naturally occurs in large concentrations in fruits and fruit juices. Other typical ingredients in SSBs are natural or artificial flavors such as ginger extract for ginger ale or caffeine for cola type beverages. Using these compounds or their metabolites as markers would consequently only cover specific subgroups of SSBs. Their specificity should also be carefully assessed as some of these substances may also be ingested with other foods, like coffee in case of caffeine.
A more reliable approach to reach a high specificity when assessing intake of a whole food group such as SSBs might be to use a combination of exposure markers as described by Gibbons et al. [95]. In this study, a subcohort of 565 participants from the National Adult Nutrition Survey was divided into four quartiles. Four metabolites detected by NMR spectroscopy in urine—formate, citrulline, taurine, and isocitrate—showed concentration levels that differed significantly between SSB consumers (n = 146) and non-consumers (n = 391) as identified via a 4-day semi-weighed food record. Levels of these same four metabolites also showed transient and modest increase in an acute intervention study (n = 10) after the consumption of one can of cola. The authors detected all four markers in the cola drink used for the acute intervention study. Although found in the cola drink, none of these compounds are normally added in a pure form so that they would most likely originate from added flavor extracts. It also remains questionable whether these markers are indicative of intake of the whole group of SSBs or cola consumption only. So-called energy drinks often contain taurine, a sulfur-containing amino acid. Thus, taurine might serve as a marker for this specific type of beverage. However, it is unlikely that taurine is present in all types of SSB. Furthermore, other sources of taurine cannot be excluded. Taurine is formed in human metabolism from methionine and cysteine with an endogenous average daily synthesis of 0.4–1.0 mmol (50–125 mg) [96]. Meat and seafood are significant dietary sources of this amino acid [93]. Similarly, isocitrate is an intermediate of the citric cycle—like citrate—and, therefore, occurs in all humans, animals, and plants. These examples demonstrate that the urinary excretion of these compounds can have different origins that interfere with their use as markers of exposure for SSBs. Further validation of the proposed panel of biomarkers in other populations is still necessary. Furthermore, more research is needed to identify new markers or marker panels with higher specificity and selectivity.
In summary, biomarkers of sugar intake would not be ideal biomarkers of SSB intake due the diversity of dietary sources of sugar. One exception may be the 13C/12C isotope ratio in countries where sugarcane and corn sugar is more specifically used as SSB sugar. Other SSB ingredients or combinations of ingredients might be used as biomarkers of intake for SSBs or for specific types of SSB. However, none of these biomarkers have yet been validated in population studies.
Low-calorie-sweetened beverage biomarkers
No studies were identified which specifically aimed to identify biomarkers of LCSB intake. Rather, many of the studies investigated the impact of LCSB consumption on health via the measurement of effect biomarkers in relation to metabolic syndrome [97], blood pressure [98], and glycemic control [99, 100]. LCSB consumption was found to influence the concentration of various compounds including urinary hippuric acid excretion [101], serum uric acid concentrations [102], and plasma free fatty acid concentrations [103]. However, these biomarkers are not specific to LCSBs; hippuric acid is a potential marker of toluene exposure, as well as fruit and vegetable intake, and serum uric acid and plasma free fatty acids are endogenous compounds influenced by factors other than LCSB intake. Therefore, utilization of these biomarkers is unlikely to provide useful information on LCSB intake owing to a lack of specificity. Several advanced glycation end products were found to be present in regular and, to a lesser extent, in diet cola drinks. They are normally excreted via the urine, but they are also confounded by other more significant dietary sources of these compounds [104]. Brominated vegetable oil (BVO) is used in North America as a clouding agent in some soft drinks but is not permitted for use in many other areas, including the European Union, owing to concerns about bromine toxicity. Bendig et al. assessed the BVO content of commonly consumed soft drinks, and BVO was detected in only three out of the ten drinks investigated indicating that tissue bromine concentrations would not serve as a reliable biomarker of LCSB intake [105]. Eisner et al. assessed the citrate and malate content of diet beverages in the context of the treatment of nephrolithiasis (kidney stones) [106], but these two organic acids are not specific for LCSBs and may be directly influenced by other dietary and non-dietary factors or may not be relevant for all LCSBs.
Given that the term LCSB encompasses an array of products including carbonated beverages, fruit cordials, sweetened dairy products, and flavored teas, all of which are likely to differ significantly in their composition, the identification of a specific biomarker of intake which is specific to all LCSBs as a single food group is likely to be challenging. The low-calorie sweeteners (LCSs) themselves, common to a large diversity of LCSBs, may prove to be the most useful biomarkers of LCSB intake. There are eleven LCSs currently approved for use on the European market (Additional file 2: Table S1), and their use extends to a wide range of foods other than LCSBs, as well as non-dietary products such as oral hygiene products and e-cigarette fluids [107]. Although this may complicate the use of LCSs as valid markers of LCSB intake, LCSBs are widely considered to be the primary source of LCSs in the diet; and therefore, measurement of these as biomarkers may provide a viable option for assessing LCSB intake.
Metabolic fates of low-calorie sweeteners approved in the European Union (adapted from [107])
| Sweetener (CAS registry no.) | Metabolic fate | Route(s) of excretiona | References |
|---|---|---|---|
| Saccharin (81-07-2) | Not metabolised, excreted unchanged. | Urine | |
| Acesulfame-K (55589-62-3) | Not metabolised, excreted unchanged. | Urine | [108] |
| Aspartame (22839-47-0) | Hydrolysed to aspartic acid, phenylalanine and methanol. | N/A | |
| Cyclamate (139-05-9) | 80% of the population do not metabolise cyclamate. In 20%, it undergoes partial hydrolysis in the gut to cyclohexylamine. Extent of hydrolysis varies between and within individuals. | Faeces, urine | [113] |
| Thaumatin (53850-34-3) | Undergoes normal protein digestion. | N/A | [123] |
| NHDC (20702-77-6) | Metabolised by gut microflora to similar metabolites to naturally occurring flavonoids. | Urine | [124] |
| Salt of aspartame-acesulfame (106372-55-8) | Dissociates to individual sweeteners in digestive fluids and undergoes same metabolic fates. | See information for acesulfame-K and aspartame | [134] |
| Sucralose (56038-13-2) | Not metabolised, excreted mainly unchanged but 2% of absorbed portion excreted as conjugates. | Faeces, urine | |
| Steviol glycosides† | Bacterial hydrolysis in the gut to steviol which is then absorbed and excreted as steviol glucuronide. | Urine | |
| Advantam (714229-20-6) | Converted to advantame acid and mainly excreted as such with 2 minor metabolites. | Faeces, urine | [120] |
Other LCSs, namely aspartame, neohesperidine dihydrochalcone (NHDC), and thaumatin, undergo extensive metabolism into metabolites commonly found in the diet or in the body, which suggests that no obvious specific biomarkers of intake exist for these LCSs. Aspartame is broken down to its three constituents, aspartic acid, phenylalanine, and methanol, all of which are often present in greater quantities in other dietary sources [121, 122]. Thaumatin, a naturally occurring protein complex, undergoes normal protein digestion; and therefore, identification of a specific biomarker of intake is not likely to be possible [123]. Finally, NHDC has a similar structure to naturally occurring flavonoids with similar metabolites; and for this reason, specificity of any putative biomarker is likely to be problematic [124].
In summary, a biomarker approach for assessing intake of specific LCSs used in LCSBs may prove useful as several of them are excreted unchanged in urine following ingestion. Expected biomarkers should be based on LCSs most commonly used in LCSBs. However, considering the range of LCSs used in different types of LCSBs, the geographical differences and the evolving nature of LCS use by manufacturers, further work is required to ensure the specificity of the putative biomarkers. This work may take the form of comprehensive and international label surveys along with biomarker validation studies for specific LCSBs. As such, more work will be needed to validate their use as biomarkers of LCSB intake, considering all these factors, and to identify possible confounding by other foods containing the same LCSs.
Conclusions
A wide diversity of biomarkers has been proposed to estimate the consumption of non-alcoholic beverages. Metabolism of major constituents of non-alcoholic beverages has been studied in a large number of controlled intervention studies, and many metabolites were identified mainly in blood and urine (Tables 1 and 2). Participants in these studies have usually consumed a high amount of a particular beverage with a fully controlled diet after a proper washout period. These studies are useful for identification of putative biomarkers of intake, but provide limited evidence of their potential value as biomarkers of intake in a population and more particularly of their sensitivity and specificity.
Several of these candidate biomarkers have been further studied in observational studies with individuals following their own diet and their sensitivity and specificity as indicators of coffee, tea, and SSB intake evaluated (Tables 1, 2, and 3). Various compounds including phenolic acids, alkaloids, and terpenes measured in urine or plasma samples were shown to accurately predict coffee intake in various populations, and EGC and 4-O-methylgallic acid were also shown to be good indicators of tea intake. These two last biomarkers could also possibly be used to differentiate intake of green and black tea. Several biomarkers have been proposed to estimate SSB intake but none for LCSB intake. Difficulties met in finding biomarkers for these two last classes of beverages are explained by the lack of constituents that would be at the same time characteristic of each of these two groups of beverages and absent in all other foods.
Controlled intervention studies and observation studies are complementary. The first ones provide direct evidence of the causality of the associations between beverage intake and the biomarker and allow establishing the dose-effect relationship. Observational studies, although relying on self-reported estimate of beverage intake that are liable to errors, allow to study the sensitivity and selectivity of a biomarker and to identify potential confounders.
Combinations of biomarkers may be needed to assess intake of SSBs and LCSBs. Combinations of biomarkers may also allow the estimation of intake of different types of beverages within a particular group, as suggested for green and black tea. Combination of a generic biomarker for coffee with caffeine should help assess relative intake of caffeinated and decaffeinated coffee. Panels of biomarkers of intake have been proposed, but none has yet been validated.
The new biomarkers, identified through metabolomics or other approaches, will need to be validated in populations sharing similar lifestyle and diet to the ones where these biomarkers will be used. All possible confounders (e.g., foods containing the same biomarker or a precursor transformed into the biomarker in the body) will need to be carefully considered [37]. More extensive food composition data for these compounds, often scattered across a large number of publications and not easily analyzed, will have to be collected and made easily accessible in new databases such as those developed for polyphenols or for caffeine [59, 125]. Biomarkers with long elimination half-lives should be preferred particularly to assess intakes of foods more episodically consumed [126] although this may be less important for beverages like coffee or tea most often consumed on a daily basis [37]. Finally, the practicality of biomarkers will need to be assessed, including their performance according to the type of biospecimens (e.g., urine vs. blood, fasting vs. non-fasting blood samples or 24-h urine samples vs. spot urine samples), performance of analytical methods, and cost of analyses.
Overall, biomarkers should help estimate intake of non-alcoholic beverages and this may be particularly useful in overcoming some of the limitations met with dietary questionnaires. It is expected that these biomarkers will be increasingly used in cohort studies to evaluate the effects of non-alcoholic beverages on disease risk. However, it will also be important to carefully evaluate the respective advantages of biomarkers and questionnaires, an evaluation that has not been done yet.
Notes
Funding
FoodBAll is a project funded by the BioNH call (grant number 529051002) under the Joint Programming Initiative, “A Healthy Diet for a Healthy Life.” The project is funded nationally by the respective Research Councils; the work was funded in part by a grant from the Danish Innovation Foundation (#4203-00002B) and a Semper Ardens grant from the Carlsberg Foundation to LOD; a grant from the China Scholarship Council (201506350127) to QG; a postdoc grant from the University of Rome La Sapienza (“Borsa di studio per la frequenza di corsi o attività di perfezionamento all’estero” erogata ai sensi della legge 398/89) to GP; a grant from the Spanish National Grants from the Ministry of Economy and Competitiveness (MINECO) (PCIN-2014-133-MINECO Spain), an award of 2014SGR1566 from the Generalitat de Catalunya’s Agency AGAUR, and funds from CIBERFES (co-funded by the FEDER Program from EU) to CAL; a grant from the German Federal Ministry of Food and Agriculture (BMEL) through the Federal Office for Agriculture and Food (BLE) (grant number 2814ERA03E).
Authors’ contributions
JAR, FMG, MGA, CAL, CL, AMG, CM, SEK, QG, GP, LOD, and AS wrote the manuscript. AS was responsible for final content. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable
Consent for publication
Not applicable
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary material
References
- 1.Drewnowski A, Rehm CD, Constant F. Water and beverage consumption among adults in the United States: cross-sectional study using data from NHANES 2005–2010. BMC Public Health. 2013;13:1068.PubMedPubMedCentralCrossRefGoogle Scholar
- 2.Ludwig IA, Clifford MN, Lean MEJ, Ashihara H, Crozier A. Coffee: biochemistry and potential impact on health. Food Funct. 2014;5:1695–717.PubMedCrossRefGoogle Scholar
- 3.Sang SM, Lambert JD, Ho CT, Yang CS. The chemistry and biotransformation of tea constituents. Pharmacol Res. 2011;64:87–99.PubMedCrossRefGoogle Scholar
- 4.Noordzij M, Uiterwaal CSPM, Arends L, Kok F, Grobbee D, Geleijnse JM. Blood pressure response to chronic intake of coffee and caffeine: a meta-analysis of randomized controlled trials. J Hypertens. 2005;23:921–8.PubMedCrossRefGoogle Scholar
- 5.Cornelis MC, El-Sohemy A. Coffee, caffeine, and coronary heart disease. Curr Opin Clin Nutr Metab Care. 2007;10:745–51.PubMedCrossRefGoogle Scholar
- 6.van Dam RM, Willett WC, Manson JE, Hu FB. Coffee, caffeine, and risk of type 2 diabetes––a prospective cohort study in younger and middle-aged US women. Diabetes Care. 2006;29:398–403.PubMedCrossRefGoogle Scholar
- 7.Zhang R, Wang Y, Song B, Jørgensen HS, Xu Y. Coffee consumption and risk of stroke: a meta-analysis of cohort studies. Cent Eur J Med. 2012;7:310–6.Google Scholar
- 8.Butt MS, Sultan MT. Coffee and its consumption: benefits and risks. Crit Rev Food Sci Nutr. 2011;51:363–73.PubMedCrossRefGoogle Scholar
- 9.Aleksandrova K, Bamia C, Drogan D, Lagiou P, Trichopoulou A, Jenab M, Fedirko V, et al. The association of coffee intake with liver cancer risk is mediated by biomarkers of inflammation and hepatocellular injury: data from the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr. 2015;102:1498–508.PubMedPubMedCentralCrossRefGoogle Scholar
- 10.Guertin KA, Loftfield E, Boca SM, Sampson JN, Moore SC, Xiao Q, Huang W-Y, et al. Serum biomarkers of habitual coffee consumption may provide insight into the mechanism underlying the association between coffee consumption and colorectal cancer. Am J Clin Nutr. 2015;101:1000–11.PubMedPubMedCentralCrossRefGoogle Scholar
- 11.Yang CS, Hong J. Prevention of chronic diseases by tea: possible mechanisms and human relevance. Annu Rev Nutr. 2013;33:161–81.PubMedCrossRefGoogle Scholar
- 12.Yang W-S, Wang W-Y, Fan W-Y, Deng Q, Wang X. Tea consumption and risk of type 2 diabetes: a dose-response meta-analysis of cohort studies. Br J Nutr. 2014;111:1329–39.PubMedCrossRefGoogle Scholar
- 13.Onakpoya I, Spencer E, Heneghan C, Thompson M. The effect of green tea on blood pressure and lipid profile: a systematic review and meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2014;24:823–36.PubMedCrossRefGoogle Scholar
- 14.Yuan J-M, Sun C, Butler LM. Tea and cancer prevention: epidemiological studies. Pharmacol Res. 2011;64:123–35.PubMedPubMedCentralCrossRefGoogle Scholar
- 15.Hu FB, Malik VS. Sugar-sweetened beverages and risk of obesity and type 2 diabetes: epidemiologic evidence. Physiol Behav. 2010;100:47–54.PubMedPubMedCentralCrossRefGoogle Scholar
- 16.Nettleton JA, Lutsey PL, Wang Y, Lima JA, Michos ED, Jacobs DR Jr. Diet soda intake and risk of incident metabolic syndrome and type 2 diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care. 2009;32:688–94.PubMedPubMedCentralCrossRefGoogle Scholar
- 17.Lin J, Curhan GC. Associations of sugar and artificially sweetened soda with albuminuria and kidney function decline in women. Clin J Am Soc Nephrol. 2011;6:160–6.PubMedPubMedCentralCrossRefGoogle Scholar
- 18.Arab L, Il'yasova D. “The epidemiology of tea consumption and colorectal cancer incidence.” J Nutr. 2003;133(10):3310s–3318s.Google Scholar
- 19.Rosner B, Willett WC, Spiegelman D. Correction of logistic regression relative risk estimates and confidence intervals for systematic within-person measurement error. Stat Med. 1989;8:1051–69. discussion 71–3PubMedCrossRefGoogle Scholar
- 20.Potischman N, Freudenheim JL. Biomarkers of nutritional exposure and nutritional status: an overview. J Nutr. 2003;133:873S–4S.PubMedCrossRefGoogle Scholar
- 21.Jenab M, Slimani N, Bictash M, Ferrari P, Bingham SA. Biomarkers in nutritional epidemiology: applications, needs and new horizons. Hum Genet. 2009;125:507–25.PubMedCrossRefGoogle Scholar
- 22.Gao Q, Practico G, Scalbert A, Vergeres G, Kolehmainen M, Manach C, Brennan L, et al. A scheme for a flexible classification of dietary and health biomarkers. Genes Nutr. 2017;12:34.PubMedPubMedCentralCrossRefGoogle Scholar
- 23.Practico G, Gao Q, Scalbert A, Vergeres G, Kolehmainen M, Manach C, Brennan L, et al. Guidelines for Food Intake Biomarker Reviews (FIBRev): how to conduct an extensive literature search for food intake biomarker discovery. Genes Nutr. 2017; in pressGoogle Scholar
- 24.Moher D, Liberati A, Tetzlaff J, Altman DG, Grp P. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.PubMedPubMedCentralCrossRefGoogle Scholar
- 25.Rechner AR, Spencer JP, Kuhnle G, Hahn U, Rice-Evans CA. Novel biomarkers of the metabolism of caffeic acid derivatives in vivo. Free Radic Biol Med. 2001;30:1213–22.PubMedCrossRefGoogle Scholar
- 26.Ito H, Gonthier M-P, Manach C, Morand C, Mennen L, Rémésy C, Scalbert A. Polyphenol levels in human urine after intake of six different polyphenol-rich beverages. Br J Nutr. 2005;94:500–9.PubMedCrossRefGoogle Scholar
- 27.Stalmach A, Mullen W, Barron D, Uchida K, Yokota T, Cavin C, Steiling H, et al. Metabolite profiling of Hydroxycinnamate derivatives in plasma and urine after the ingestion of coffee by humans: identification of biomarkers of coffee consumption. Drug Metab Dispos. 2009;37:1749–58.PubMedCrossRefGoogle Scholar
- 28.Stalmach A, Williamson G, Crozier A. Impact of dose on the bioavailability of coffee chlorogenic acids in humans. Food Funct. 2014;5:1727–37.PubMedCrossRefGoogle Scholar
- 29.Lang R, Dieminger N, Beusch A, Lee YM, Dunkel A, Suess B, Skurk T, et al. Bioappearance and pharmacokinetics of bioactives upon coffee consumption. Anal Bioanal Chem. 2013;405:8487–503.PubMedCrossRefGoogle Scholar
- 30.Heinzmann SS, Holmes E, Kochhar S, Nicholson JK, Schmitt-Kopplin P. 2-Furoylglycine as a candidate biomarker of coffee consumption. J Agric Food Chem. 2015;63:8615–21.PubMedCrossRefGoogle Scholar
- 31.Clifford MN. Chlorogenic acids and other cinnamates––nature, occurence and dietary burden. J Sci Food Agric. 1999;79:362–72.CrossRefGoogle Scholar
- 32.Hodgson JM, Chan SY, Puddey IB, Devine A, Wattanapenpaiboon N, Wahlqvist ML, Lukito W, et al. Phenolic acid metabolites as biomarkers for tea- and coffee-derived polyphenol exposure in human subjects. Br J Nutr. 2004;91:301–6.PubMedCrossRefGoogle Scholar
- 33.Mennen L, Sapinho D, Ito H, Galan P, Hercberg S, Scalbert A. Urinary flavonoids and phenolic acids as biomarkers of intake for polyphenol-rich foods. Br J Nutr. 2006;96:191–8.PubMedCrossRefGoogle Scholar
- 34.Zamora-Ros R, Achaintre D, Rothwell JA, Rinaldi S, Assi N, Ferrari P, Leitzmann M, et al. Urinary excretions of 34 dietary polyphenols and their associations with lifestyle factors in the EPIC cohort study. Sci Rep. 2016;6:26905.PubMedPubMedCentralCrossRefGoogle Scholar
- 35.Lang R, Wahl A, Stark T, Hofmann T. Urinary N-methylpyridinium and trigonelline as candidate dietary biomarkers of coffee consumption. Mol Nutr Food Res. 2011;55:1613–23.PubMedCrossRefGoogle Scholar
- 36.Lloyd AJ, Beckmann M, Haldar S, Seal C, Brandt K, Draper J. Data-driven strategy for the discovery of potential urinary biomarkers of habitual dietary exposure. Am J Clin Nutr. 2013;97:377–89.PubMedCrossRefGoogle Scholar
- 37.Edmands WM, Ferrari P, Rothwell JA, Rinaldi S, Slimani N, Barupal DK, Biessy C, et al. Polyphenol metabolome in human urine and its association with intake of polyphenol-rich foods across European countries. Am J Clin Nutr. 2015;102:905–13.PubMedCrossRefGoogle Scholar
- 38.Rothwell JA, Fillâtre Y, Martin J-F, Lyan B, Pujos-Guillot E, Fezeu L, Hercberg S, et al. New biomarkers of coffee consumption identified by the non-targeted Metabolomic profiling of cohort study subjects. PLoS One. 2014;9:e93474.PubMedPubMedCentralCrossRefGoogle Scholar
- 39.Guertin KA, Moore SC, Sampson JN, Huang W-Y, Xiao Q, Stolzenberg-Solomon RZ, Sinha R, et al. Metabolomics in nutritional epidemiology: identifying metabolites associated with diet and quantifying their potential to uncover diet-disease relations in populations. Am J Clin Nutr. 2014;100:208–17.PubMedPubMedCentralCrossRefGoogle Scholar
- 40.Kuwayama K, Tsujikawa K, Miyaguchi H, Kanamori T, Iwata YT, Inoue H. Time-course measurements of caffeine and its metabolites extracted from fingertips after coffee intake: a preliminary study for the detection of drugs from fingerprints. Anal Bioanal Chem. 2013;405:3945–52.PubMedCrossRefGoogle Scholar
- 41.Berchtold C, Meier L, Steinhoff R, Zenobi R. A new strategy based on real-time secondary electrospray ionization and high-resolution mass spectrometry to discriminate endogenous and exogenous compounds in exhaled breath. Metabolomics. 2013;10:291–301.CrossRefGoogle Scholar
- 42.Stalmach A, Troufflard S, Serafini M, Crozier A. Absorption, metabolism and excretion of Choladi green tea flavan-3-ols by humans. Mol Nutr Food Res. 2009;53 Suppl 1:S44–53.PubMedCrossRefGoogle Scholar
- 43.Calani L, Del Rio D, Luisa Callegari M, Morelli L, Brighenti F. Updated bioavailability and 48 h excretion profile of flavan-3-ols from green tea in humans. Int J Food Sci Nutr. 2012;63:513–21.PubMedCrossRefGoogle Scholar
- 44.Nakagawa K, Okuda S, Miyazawa T. Dose-dependent incorporation of tea catechins, (−)-epigallocatechin-3-gallate and (−)-epigallocatechin, into human plasma. Biosci Biotechnol Biochem. 1997;61:1981–5.PubMedCrossRefGoogle Scholar
- 45.August DA, Landau J, Caputo D, Hong J, Lee MJ, Yang CS. Ingestion of green tea rapidly decreases prostaglandin E2 levels in rectal mucosa in humans. Cancer Epidemiol Biomark Prev. 1999;8:709–13.Google Scholar
- 46.Kimura M, Umegaki K, Kasuya Y, Sugisawa A, Higuchi M. The relation between single/double or repeated tea catechin ingestions and plasma antioxidant activity in humans. Eur J Clin Nutr. 2002;56:1186–93.PubMedCrossRefGoogle Scholar
- 47.Luo H, Cox SB, Gao W, Yu J, Tang L, Wang J-S. Metabolic profiling in validation of plasma biomarkers for green tea polyphenols. Metabolomics. 2006;2:235–41.CrossRefGoogle Scholar
- 48.Wu AH, Spicer D, Stanczyk FZ, Tseng C-C, Yang CS, Pike MC. Effect of 2-month controlled green tea intervention on lipoprotein cholesterol, glucose, and hormone levels in healthy postmenopausal women. Cancer Prev Res (Phila). 2012;5:393–402.CrossRefGoogle Scholar
- 49.van het Hof KH, Wiseman SA, Yang CS, Tijburg LB. Plasma and lipoprotein levels of tea catechins following repeated tea consumption. Proc Soc Exp Biol Med. 1999;220:203–9.PubMedCrossRefGoogle Scholar
- 50.Renouf M, Marmet C, Guy PA, Beaumont M, Lepage M, Williamson G, Dionisi F. Dose-response plasma appearance of green tea catechins in adults. Mol Nutr Food Res. 2013;57:833–9.PubMedCrossRefGoogle Scholar
- 51.Daykin CA, Van Duynhoven JP, Groenewegen A, Dachtler M, Van Amelsvoort JM, Mulder TP. Nuclear magnetic resonance spectroscopic based studies of the metabolism of black tea polyphenols in humans. J Agric Food Chem. 2005;53:1428–34.PubMedCrossRefGoogle Scholar
- 52.Van Dorsten FA, Daykin CA, Mulder TPJ, Van Duynhoven JPM. Metabonomics approach to determine metabolic differences between green tea and black tea consumption. J Agric Food Chem. 2006;54:6929–38.PubMedCrossRefGoogle Scholar
- 53.van Velzen EJ, Westerhuis JA, van Duynhoven JP, van Dorsten FA, Grun CH, Jacobs DM, Duchateau GS, et al. Phenotyping tea consumers by nutrikinetic analysis of polyphenolic end-metabolites. J Proteome Res. 2009;8:3317–30.PubMedCrossRefGoogle Scholar
- 54.van Duynhoven J, van der Hooft JJJ, van Dorsten FA, Peters S, Foltz M, Gomez-Roldan V, Vervoort J, et al. Rapid and sustained systemic circulation of conjugated gut microbial catabolites after single-dose black tea extract consumption. J Proteome Res. 2014;13:2668–78.PubMedCrossRefGoogle Scholar
- 55.Shahrzad S, Aoyagi K, Winter A, Koyama A, Bitsch I. Pharmacokinetics of gallic acid and its relative bioavailability from tea in healthy humans. J Nutr. 2001;131:1207–10.PubMedCrossRefGoogle Scholar
- 56.van Velzen EJJ, Westerhuis JA, Grun CH, Jacobs DM, Eilers PHC, Mulder TP, Foltz M, et al. Population-based nutrikinetic modeling of polyphenol exposure. Metabolomics. 2014;10:1059–73.CrossRefGoogle Scholar
- 57.van der Pijl PC, Foltz M, Glube ND, Peters S, Duchateau GSMJE. Pharmacokinetics of black tea-derived phenolic acids in plasma. J Funct Foods. 2015;17:667–75.CrossRefGoogle Scholar
- 58.Hodgson JM, Morton LW, Puddey IB, Beilin LJ, Croft KD. Gallic acid metabolites are markers of black tea intake in humans. J Agric Food Chem. 2000;48:2276–80.PubMedCrossRefGoogle Scholar
- 59.Neveu V, Perez-Jiménez J, Vos F, Crespy V, du Chaffaut L, Mennen L, Knox C, et al. Phenol-explorer: an online comprehensive database on polyphenol contents in foods. Database. 2010;2010:bap024.PubMedPubMedCentralCrossRefGoogle Scholar
- 60.Hakim IA, Harris RB, Brown S, Chow HH, Wiseman S, Agarwal S, Talbot W. Effect of increased tea consumption on oxidative DNA damage among smokers: a randomized controlled study. J Nutr. 2003;133:3303s–9s.PubMedCrossRefGoogle Scholar
- 61.Henning SM, Niu Y, Lee NH, Thames GD, Minutti RR, Wang H, Go VL, et al. Bioavailability and antioxidant activity of tea flavanols after consumption of green tea, black tea, or a green tea extract supplement. Am J Clin Nutr. 2004;80:1558–64.PubMedCrossRefGoogle Scholar
- 62.Henning SM, Wang P, Said JW, Huang M, Grogan T, Elashoff D, Carpenter CL, et al. Randomized clinical trial of brewed green and black tea in men with prostate cancer prior to prostatectomy. Prostate. 2015;75:550–9.PubMedCrossRefGoogle Scholar
- 63.Mulder TP, van Platerink CJ, Wijnand Schuyl PJ, van Amelsvoort JM. Analysis of theaflavins in biological fluids using liquid chromatography-electrospray mass spectrometry. J Chromatogr B Biomed Sci Appl. 2001;760:271–9.PubMedCrossRefGoogle Scholar
- 64.Urpi-Sarda M, Monagas M, Khan N, Lamuela-Raventos RM, Santos-Buelga C, Sacanella E, Castell M, et al. Epicatechin, procyanidins, and phenolic microbial metabolites after cocoa intake in humans and rats. Anal Bioanal Chem. 2009;394:1545–56.PubMedCrossRefGoogle Scholar
- 65.Krupp D, Doberstein N, Shi L, Remer T. Hippuric acid in 24-hour urine is a potential biomarker for fruit and vegetable consumption in healthy children and adolescents. J Nutr. 2012;142:1314–20.PubMedCrossRefGoogle Scholar
- 66.Madrid-Gambin F, Garcia-Aloy M, Vázquez-Fresno R, Vegas-Lozano E, de Villa Jubany MCR, Misawa K, Hase T, et al. Impact of chlorogenic acids from coffee on urine metabolome in healthy human subjects. Food Res Int. 2016;89:1064–70.CrossRefGoogle Scholar
- 67.Del Rio D, Calani L, Cordero C, Salvatore S, Pellegrini N, Brighenti F. Bioavailability and catabolism of green tea flavan-3-ols in humans. Nutrition. 2010;26:1110–6.PubMedCrossRefGoogle Scholar
- 68.Perez-Jimenez J, Hubert J, Ashton K, Hooper L, Cassidy A, Manach C, Williamson G, et al. Urinary metabolites as biomarkers of polyphenol intake in humans—a systematic review. Am J Clin Nutr. 2010;92:801–9.PubMedCrossRefGoogle Scholar
- 69.Hertog MGL, Hollman PCH, Katan MB, Kromhout D. Intake of potentially anticarcinogenic flavonoids and their determinants in adults in The Netherland. Nutr Cancer. 1993;20:21–9.PubMedCrossRefGoogle Scholar
- 70.Bispo MS, Veloso MC, Pinheiro HL, De Oliveira RF, Reis JO, De Andrade JB. Simultaneous determination of caffeine, theobromine, and theophylline by high-performance liquid chromatography. J Chromatogr Sci. 2002;40:45–8.PubMedCrossRefGoogle Scholar
- 71.Yuan JM, Gao YT, Yang CS, Yu MC. Urinary biomarkers of tea polyphenols and risk of colorectal cancer in the Shanghai Cohort Study. Int J Cancer. 2007;120:1344–50.PubMedCrossRefGoogle Scholar
- 72.Inoue-Choi M, Yuan JM, Yang CS, Van Den Berg DJ, Lee MJ, Gao YT, Yu MC. Genetic association between the COMT genotype and urinary levels of tea polyphenols and their metabolites among daily green tea drinkers. Int J Mol Epidemiol Genet. 2010;1:114–23.PubMedPubMedCentralGoogle Scholar
- 73.Tulipani S, Llorach R, Jáuregui O, López-Uriarte P, Garcia-Aloy M, Bullo M, Salas-Salvadó J, et al. Metabolomics unveils urinary changes in subjects with metabolic syndrome following 12-week nut consumption. J Proteome Res. 2011;10:5047–58.PubMedCrossRefGoogle Scholar
- 74.Pimpao RC, Ventura MR, Ferreira RB, Williamson G, Santos CN. Phenolic sulfates as new and highly abundant metabolites in human plasma after ingestion of a mixed berry fruit puree. Br J Nutr. 2015;113:454–63.PubMedCrossRefGoogle Scholar
- 75.Brantsaeter AL, Haugen M, Rasmussen SE, Alexander J, Samuelsen SO, Meltzer HM. Urine flavonoids and plasma carotenoids in the validation of fruit, vegetable and tea intake during pregnancy in the Norwegian Mother and Child Cohort Study (MoBa). Public Health Nutr. 2007;10:838–47.PubMedCrossRefGoogle Scholar
- 76.de Vries JH, Hollman PC, Meyboom S, Buysman MN, Zock PL, van Staveren WA, Katan MB. Plasma concentrations and urinary excretion of the antioxidant flavonols quercetin and kaempferol as biomarkers for dietary intake. Am J Clin Nutr. 1998;68:60–5.PubMedCrossRefGoogle Scholar
- 77.Meng X, Lee MJ, Li C, Sheng S, Zhu N, Sang S, Ho CT, et al. Formation and identification of 4′-o-methyl-(−)-epigallocatechin in humans. Drug Metab Dispos. 2001;29:789–93.PubMedGoogle Scholar
- 78.Manach C, Williamson G, Morand C, Scalbert A, Remesy C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr. 2005;81:230S–42S.PubMedCrossRefGoogle Scholar
- 79.Landberg R, Aman P, Friberg LE, Vessby B, Adlercreutz H, Kamal-Eldin A. Dose response of whole-grain biomarkers: alkylresorcinols in human plasma and their metabolites in urine in relation to intake. Am J Clin Nutr. 2009;89:290–6.PubMedCrossRefGoogle Scholar
- 80.Linko-Parvinen AM, Landberg R, Tikkanen MJ, Adlercreutz H, Penalvo JL. Alkylresorcinols from whole-grain wheat and rye are transported in human plasma lipoproteins. J Nutr. 2007;137:1137–42.PubMedCrossRefGoogle Scholar
- 81.Bleich SN, Wang YC, Wang Y, Gortmaker SL. Increasing consumption of sugar-sweetened beverages among US adults: 1988–1994 to 1999–2004. Am J Clin Nutr. 2009;89:372–81.PubMedCrossRefGoogle Scholar
- 82.Bremer AA, Auinger P, Byrd RS. Relationship between insulin resistance-associated metabolic parameters and anthropometric measurements with sugar-sweetened beverage intake and physical activity levels in US adolescents: findings from the 1999–2004 National Health and Nutrition Examination Survey. Arch Pediatr Adolesc Med. 2009;163:328–35.PubMedPubMedCentralCrossRefGoogle Scholar
- 83.Wang YC, Ludwig DS, Sonneville K, Gortmaker SL. Impact of change in sweetened caloric beverage consumption on energy intake among children and adolescents. Arch Pediatr Adolesc Med. 2009;163:336–43.PubMedCrossRefGoogle Scholar
- 84.Choy K, Nash SH, Kristal AR, Hopkins S, Boyer BB, O'Brien DM. The carbon isotope ratio of alanine in red blood cells is a new candidate biomarker of sugar-sweetened beverage intake. J Nutr. 2013;143:878–84.PubMedPubMedCentralCrossRefGoogle Scholar
- 85.Davy BM, Jahren AH, Hedrick VE, Comber DL. Association of delta C-13 in fingerstick blood with added-sugar and sugar-sweetened beverage intake. J Am Diet Assoc. 2011;111:874–8.PubMedPubMedCentralCrossRefGoogle Scholar
- 86.Fakhouri TH, Jahren AH, Appel LJ, Chen L, Alavi R, Anderson CA. Serum carbon isotope values change in adults in response to changes in sugar-sweetened beverage intake. J Nutr. 2014;144:902–5.PubMedPubMedCentralCrossRefGoogle Scholar
- 87.Nash SH, Kristal AR, Hopkins SE, Boyer BB, O’Brien DM. Stable isotope models of sugar intake using hair, red blood cells, and plasma, but not fasting plasma glucose, predict sugar intake in a Yup’ik study population. J Nutr. 2014;144:75–80.PubMedCrossRefGoogle Scholar
- 88.Schoeller DA. A novel carbon isotope biomarker for dietary sugar. J Nutr. 2013;143:763–5.PubMedCrossRefGoogle Scholar
- 89.Jahren AH, Bostic JN, Davy BM. The potential for a carbon stable isotope biomarker of dietary sugar intake. J Anal At Spectrom. 2014;29:795–816.CrossRefGoogle Scholar
- 90.Starch_Europe_(European_Starch_Industry_Association) Facts about sugar. http://www.starch.eu/wp-content/uploads/2015/05/Facts-about-sugars-Brochure.pdf. Accessed 13 Jun 2016.
- 91.Hedrick VE, Zoellner JM, Jahren AH, Woodford NA, Bostic JN, Davy BM. A dual-carbon-and-nitrogen stable isotope ratio model is not superior to a single-carbon stable isotope ratio model for predicting added sugar intake in Southwest Virginian adults. J Nutr. 2015;145:1362–9.PubMedPubMedCentralCrossRefGoogle Scholar
- 92.Nash SH, Kristal AR, Bersamin A, Hopkins SE, Boyer BB, O'Brien DM. Carbon and nitrogen stable isotope ratios predict intake of sweeteners in a Yup’ik study population. J Nutr. 2013;143:161–5.PubMedCrossRefGoogle Scholar
- 93.Tasevska N. Urinary sugars—a biomarker of total sugars intake. Nutrients. 2015;7:5816–33.PubMedPubMedCentralCrossRefGoogle Scholar
- 94.Tasevska N, Runswick SA, McTaggart A, Bingham SA. Urinary sucrose and fructose as biomarkers for sugar consumption. Cancer Epidemiol Biomark Prev. 2005;14:1287–94.CrossRefGoogle Scholar
- 95.Gibbons H, McNulty BA, Nugent AP, Walton J, Flynn A, Gibney MJ, Brennan L. A metabolomics approach to the identification of biomarkers of sugar-sweetened beverage intake. Am J Clin Nutr. 2015;101:471–7.PubMedCrossRefGoogle Scholar
- 96.Lourenco R, Camilo ME. Taurine: a conditionally essential amino acid in humans? An overview in health and disease. Nutr Hosp. 2002;17:262–70.PubMedGoogle Scholar
- 97.Crichton G, Alkerwi A, Elias M. Diet soft drink consumption is associated with the metabolic syndrome: a two sample comparison. Nutrients. 2015;7:3569–86.PubMedPubMedCentralCrossRefGoogle Scholar
- 98.Souza Bda S, Cunha DB, Pereira RA, Sichieri R. Soft drink consumption, mainly diet ones, is associated with increased blood pressure in adolescents. J Hypertens. 2016;34:221–5.PubMedCrossRefGoogle Scholar
- 99.de Koning L, Malik VS, Rimm EB, Willett WC, Hu FB. Sugar-sweetened and artificially sweetened beverage consumption and risk of type 2 diabetes in men. Am J Clin Nutr. 2011;93:1321–7.PubMedPubMedCentralCrossRefGoogle Scholar
- 100.Imamura F, O’Connor L, Ye Z, Mursu J, Hayashino Y, Bhupathiraju SN, Forouhi NG. Consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice and incidence of type 2 diabetes: systematic review, meta-analysis, and estimation of population attributable fraction. Br Med J. 2015;351:h3576.CrossRefGoogle Scholar
- 101.Christiani DC, Chang SH, Chun BC, Lee WJ. Urinary excretion of hippuric acid after consumption of nonalcoholic beverages. Int J Occup Environ Health. 2000;6:238–42.PubMedCrossRefGoogle Scholar
- 102.Choi JW, Ford ES, Gao X, Choi HK. Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: the third national health and nutrition examination survey. Arthritis Rheum. 2008;59:109–16.PubMedCrossRefGoogle Scholar
- 103.Bellet S, Kershbaum A, Roman L. Effect of cola drinks on serum free fatty acids. Arch Environ Health. 1968;17:803–6.PubMedCrossRefGoogle Scholar
- 104.Ahmed N, Mirshekar-Syahkal B, Kennish L, Karachalias N, Babaei-Jadidi R, Thornalley PJ. Assay of advanced glycation endproducts in selected beverages and food by liquid chromatography with tandem mass spectrometric detection. Mol Nutr Food Res. 2005;49:691–9.PubMedCrossRefGoogle Scholar
- 105.Bendig P, Maier L, Vetter W. Brominated vegetable oil in soft drinks—an underrated source of human organobromine intake. Food Chem. 2012;133:678–82.CrossRefGoogle Scholar
- 106.Eisner BH, Asplin JR, Goldfarb DS, Ahmad A, Stoller ML. Citrate, malate and alkali content in commonly consumed diet sodas: implications for nephrolithiasis treatment. J Urol. 2010;183:2419–23.PubMedCrossRefGoogle Scholar
- 107.Logue C, Dowey LC, Strain JJ, Verhagen H, Gallagher AM. The potential application of a biomarker approach for the investigation of low-calorie sweetener exposure. Proc Nutr Soc. 2016;75:216–25.PubMedCrossRefGoogle Scholar
- 108.Christ O, Rupp W. Human experiments with acetosulfam-14C. Pharmacokinetics after oral administration of 30 mg to three healthy male probands. Unpublished report. http://www.inchem.org/documents/jecfa/jecmono/v28je13.htm. Accessed 5 Jun 2015.
- 109.Byard JL, McChesney EW, Golberg L, Coulston F. Excretion and metabolism of saccharin in man. II. Studies with 14-C-labelled and unlabelled saccharin. Food Cosmet Toxicol. 1974;12:175–84.PubMedCrossRefGoogle Scholar
- 110.Ball LM, Renwick AG, Williams RT. The fate of [14C]saccharin in man, rat and rabbit and of 2-sulphamoyl[14C]benzoic acid in the rat. Xenobiotica. 1977;7:189–203.PubMedCrossRefGoogle Scholar
- 111.Sweatman TW, Renwick AG, Burgess CD. The pharmacokinetics of saccharin in man. Xenobiotica. 1981;11:531–40.PubMedCrossRefGoogle Scholar
- 112.Wilson LA, Wilkinson K, Crews HM, Davies AM, Dick CS, Dumsday VL. Urinary monitoring of saccharin and acesulfame-K as biomarkers of exposure to these additives. Food Addit Contam. 1999;16:227–38.PubMedCrossRefGoogle Scholar
- 113.Renwick AG, Thompson JP, O'Shaughnessy M, Walter EJ. The metabolism of cyclamate to cyclohexylamine in humans during long-term administration. Toxicol Appl Pharmacol. 2004;196:367–80.PubMedCrossRefGoogle Scholar
- 114.Grice HC, Goldsmith LA. Sucralose—an overview of the toxicity data. Food Chem Toxicol. 2000;38 Suppl 2:S1–6.PubMedCrossRefGoogle Scholar
- 115.Roberts A, Renwick AG, Sims J, Snodin DJ. Sucralose metabolism and pharmacokinetics in man. Food Chem Toxicol. 2000;38 Suppl 2:S31–41.PubMedCrossRefGoogle Scholar
- 116.Bopp BA, Sonders RC, Kesterson JW. Toxicological aspects of cyclamate and cyclohexylamine. CRC Crit Rev Toxicol. 1986;16:213–306.CrossRefGoogle Scholar
- 117.Geuns JM, Buyse J, Vankeirsbilck A, Temme EH. Metabolism of stevioside by healthy subjects. Exp Biol Med (Maywood). 2007;232:164–73.Google Scholar
- 118.Geuns JM, Buyse J, Vankeirsbilck A, Temme EH, Compernolle F, Toppet S. Identification of steviol glucuronide in human urine. J Agric Food Chem. 2006;54:2794–8.PubMedCrossRefGoogle Scholar
- 119.Wheeler A, Boileau AC, Winkler PC, Compton JC, Prakash I, Jiang X, Mandarino DA. Pharmacokinetics of rebaudioside A and stevioside after single oral doses in healthy men. Food Chem Toxicol. 2008;46 Suppl 7:S54–60.PubMedCrossRefGoogle Scholar
- 120.Ubukata K, Nakayama A, Mihara R. Pharmacokinetics and metabolism of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-alpha-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the rat, dog, and man. Food Chem Toxicol. 2011;49 Suppl 1:S8–29.PubMedCrossRefGoogle Scholar
- 121.Butchko HH, Stargel WW, Comer CP, Mayhew DA, Benninger C, Blackburn GL, de Sonneville LM, et al. Aspartame: review of safety. Regul Toxicol Pharmacol. 2002;35:S1–93.PubMedCrossRefPubMedCentralGoogle Scholar
- 122.Magnuson BA, Burdock GA, Doull J, Kroes RM, Marsh GM, Pariza MW, Spencer PS, et al. Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies. Crit Rev Toxicol. 2007;37:629–727.PubMedCrossRefPubMedCentralGoogle Scholar
- 123.Joint_FAO/WHO_Expert_Committee_on_Food_Additives_(JECFA) Thaumatin. WHO Food Additives Series 20. http://www.inchem.org/documents/jecfa/jecmono/v20je15.htm. Last Accessed 5 Jun 2015.
- 124.Borrego F, Montijano H. Neohesperidine dihydrochalcone. In: O'Brien Nabors L, editor. Alternative sweeteners. 3rd ed. New York: Marcel Dekker; 2001. p. 87–105.Google Scholar
- 125.U.S. Department of Agriculture, ARS. USDA National Nutrient Database for Standard Reference, Release 28. 2009:Nutrient Data Laboratory Home Page, http://www.ars.usda.gov/nutrientdata. Accessed 5 Jun 2015.
- 126.Scalbert A, Rothwell JA, Keski-Rahkonen P, Neveu V. The food metabolome and dietary biomarkers. In: Schoeller DA, Westerterp-Plantenga M, editors. Advances in the Assessment of Dietary Intake. Boca Raton: CRC Press; 2017. p. 259–82.Google Scholar
- 127.Allard E, Backstrom D, Danielsson R, Sjobberg JR, Bergquist J. Comparing capillary electrophoresis—mass spectrometry fingerprints of urine samples obtained after intake of coffee, tea, or water. Anal Chem. 2008;80:8946–55.PubMedCrossRefGoogle Scholar
- 128.Hodgson JM, Puddey IB, Croft KD, Burke V, Mori TA, Caccetta RA, Beilin LJ. Acute effects of ingestion of black and green tea on lipoprotein oxidation. Am J Clin Nutr. 2000;71:1103–7.PubMedCrossRefGoogle Scholar
- 129.Mulder TP, Rietveld AG, van Amelsvoort JM. Consumption of both black tea and green tea results in an increase in the excretion of hippuric acid into urine. Am J Clin Nutr. 2005;81:256S–60S.PubMedCrossRefGoogle Scholar
- 130.van der Hooft JJ, de Vos RC, Mihaleva V, Bino RJ, Ridder L, de Roo N, Jacobs DM, et al. Structural elucidation and quantification of phenolic conjugates present in human urine after tea intake. Anal Chem. 2012;84:7263–71.PubMedCrossRefGoogle Scholar
- 131.Rhodes LE, Darby G, Massey KA, Clarke KA, Dew TP, Farrar MD, Bennett S, et al. Oral green tea catechin metabolites are incorporated into human skin and protect against UV radiation-induced cutaneous inflammation in association with reduced production of pro-inflammatory eicosanoid 12-hydroxyeicosatetraenoic acid. Br J Nutr. 2013;110:891–900.PubMedCrossRefGoogle Scholar
- 132.Hodgson JM, Devine A, Puddey IB, Beilby J, Prince RL. Drinking tea is associated with lower plasma total homocysteine in older women. Asia Pac J Clin Nutr. 2006;15:253–8.PubMedGoogle Scholar
- 133.Krogholm KS, Bysted A, Brantsaeter AL, Jakobsen J, Rasmussen SE, Kristoffersen L, Toft U. Evaluation of flavonoids and enterolactone in overnight urine as intake biomarkers of fruits, vegetables and beverages in the Inter99 cohort study using the method of triads. Br J Nutr. 2012;108:1904–12.PubMedCrossRefGoogle Scholar
- 134.European_Commission Minutes of the 120th Meeting of the Scientific Committee on Food held on 8–9 March 2000 in Brussels. https://ec.europa.eu/food/sites/food/files/safety/docs/sci-com_scf_out57_en.pdf. Accessed 5 Jan 2017.
Copyright information
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.