Dietary Biomarkers


Dietary biomarkers are specific measurements within the body that accurately reflect the intake of a food constituent or food. These markers are measured in biofluids such as blood and urine, and include natural food constituents such as vitamins and fatty acids, in addition to certain food additives like iodine in milk or food contaminants like polychlorinated biphenyls in fatty fish. Dietary biomarkers can be used measure nutritional status and food intake, to find associations between diet and disease outcomes, and to monitor dietary changes in populations.

Accurate measurements of dietary exposures are required in order to evaluate compliance in dietary intervention studies, to find associations with disease outcomes, or to monitor dietary changes in populations. Traditionally, dietary exposure has been measured with self-reported methods, usually dietary recalls or food frequency questionnaires (). However, random and systematic errors such as recall bias and difficulty in assessing portion sizes are inherent in such methods and often result in inconsistencies (, ). As a result, efforts have been directed towards the application of dietary biomarkers as more objective measures of dietary exposure (). These biomarkers have been used to measure nutritional status and exposure to bioactive molecules in foods, as surrogate indicators of food intake, and also to validate measures of dietary intake (). Biomarkers are also useful when little or no data exist on food composition, as is often the case for bioactive molecules such as glucosinolates or food contaminants such as aflatoxins (, ).

Epidemiological studies have measured a variety of dietary biomarkers in plasma/serum (carotenoids, fatty acids, vitamins, polyphenols, food contaminants, and enzymes), red blood cells (fatty acids, carotenoids and haemoglobin adducts) and to a lesser extent in urine (polyphenols, vitamins, inorganic compounds and amino acids) (Table 1). Some of these biomarkers correspond to nutrients and bioactive compounds and have been utilized as surrogate biomarkers of food intake (Table 2): polyphenols, carotenoids and vitamin C for fruits and vegetables (, ), alkylresorcinols for wholegrain cereals (, ), isoflavones for soy (), amino acids and fatty acids for meat (, ), fatty acids for dairy products and fish (, ) and polyphenols for tea and wine (, ). Dietary biomarkers not only include natural food constituents but also certain food additives like iodine in milk () or food contaminants like polychlorinated biphenyls in fatty fish (), which are often specific of certain exposed populations. Other biomarkers are directly derived from the digestion and gut absorption of food constituents, or are endogenous metabolites that have been altered by exposure to specific nutrients.

Dietary biomarkers are not without their limitations, as they may be altered due to possible interactions with genetic factors, physiological or health status (i.e. age or obesity) (), dietary factors such as fats for lipophilic biomarkers (), and lifestyle factors such as alcohol intake or smoking (). Their levels also vary over time according to their pharmacokinetic properties and some have very short half-lives, thus are only useful in populations where their dietary sources are regularly and frequently consumed. Important qualities of dietary biomarkers include sufficient sensitivity to measure exposures within ranges commonly found in the populations of interest, and specificity for a particular food or food group.

Traditionally, single biomarkers have been utilised to characterize complex dietary exposures such as consumption of a whole food group or intake of a group of compounds with related biological activities. However, analytical approaches based on estimation of combinations of dietary constituents may provide more accurate measurements of dietary exposure. Metabolomics constitutes a comprehensive approach to identify new panels of biomarkers, specific or common to particular foods or food groups (Table 3). This should greatly improve the assessment of exposure to classes of food bioactive compounds, food groups or dietary patterns.

Table 1: Dietary biomarkers measured in various population studies for which some significant correlations with dietary intake were reported.
Chemical classBiomarkers
Amino acids1-Methylhistidine, 3-methylhistidine
Organic acidsTaurine
Aliphatic acyclic compoundsUrea
Chemical elementsNitrogen, 15N/14N
Fatty acids9-cis-Linoelaidic acid, α-linolenic acid, arachidonic acid, cis-docosapentaenoic acid, cis-octadecenoic acid, cis-palmitoleic acid, DHA, DPA, eicosadienoic acid, eicosenoic acid, elaidic acid, EPA, lauric acid, linoelaidic acid, linoleic acid, linolenic acid, myristic acid, myristoleic acid, oleic acid, ω-3 PUFAs, ω-6-PUFA, palmitic acid, petroselaidic acid, phytanic acid, phytanic acid, rumenic acid, stearic acid, tetradecenoic acid, trans-hexadecenoic acids, trans-octadecadienoic acid, trans-octadecenoic acid, vaccenic acid
VitaminsVitamins B1, B2, B5, B6, B12, C, D, E, K1, folic acid, nicotinamide
Inorganic compoundsIodine, phosphorus, potassium, selenium, sodium, zinc, iron
Carotenoidsα-Carotene, β-carotene, β-cryptoxantin, lutein, lycopene, zeaxanthin
Polyphenols4-O-Methylgallic acid, 5-heneicosylresorcinol, 5-heptadecylresorcinol, 5-nonadecylresorcinol, 5-tricosylresorcinol, apigenin, caffeicacid, chlorogenicacid, daidzein, DHBA, DHPPA, dihydrodaidzein, dihydrogenistein, enterodiol, enterolactone, equol, eriodictyol, gallic acid, genistein, glycitein, hesperetin, isorhamnetin, kaempferol, luteolin, m-coumaricacid, naringenin, ODMA, phloretin, quercetin, resveratrol, tamarixetin
Food contaminantsAflatoxins, mercury, PCBs
Cooking productsAcrylamide, 1-hydroxypyrene glucuronide
Endogenous metabolites and enzymes5-Hydroxytryptophol / 5-Hydroxyindole-3-acetic acid, ALAT, ASAT, GGT
Table 2: Biomarkers used as surrogate indicators of consumption of foods and food groups.
Food categoryFoodBiomarkers
FruitsAppleKaempferol, isorhamnetin, m-coumaric acid, phloretin
OrangeCaffeic acid, hesperetin, proline betaine
GrapefruitNaringenin
Citrus fruitsAscorbic acid, β-cryptoxanthin, hesperetin, naringenin, proline betaine, vitamin A, zeaxanthin
Fruits (total)4-O-Methylgallic acid, β-cryptoxanthin, carotenoids (mix), flavonoids (mix), gallic acid, hesperetin, isorhamnetin, kaempferol, lutein, lycopene, naringenin, phloretin, vitamin A, vitamin C, zeaxanthin
VegetablesCarrotα-Carotene
TomatoCarotenoids (mix), lycopene, lutein
Vegetables, leafyAscorbic acid, beta-carotene, carotenoid (mix)
Vegetables, rootAscorbic acid, α-Carotene, β-carotene
Vegetables (total)Ascorbic acid, α-carotene, β-carotene, β-cryptoxanthin, carotenoids (mix), enterolactone, lutein, lycopene
Fruit & vegetablesFruit & vegetables (total)α-Carotene, apigenin, ascorbic acid, β-carotene, β-cryptoxanthin, carotenoids (mix), eriodictyol, flavonoids(mix), hesperetin, hippuric acid, lutein, lycopene, naringenin, phloretin, phytoene, zeaxanthin
Cereal productsWholegrain rye5-Heptadecylresorcinol, 5-pentacosylresorcinol, 5-tricosylresorcinol
Wholegrain wheat5-Heneicosylresorcinol, 5-tricosylresorcinol, alkylresorcinols (mix)
Wholegrain cereals (total)5-Heneicosylresorcinol, 3,5-dihydroxybenzoic acid, 3-(3,5-dihydroxyphenyl)-1-propanoic acid), 5-pentacosylresorcinol, 5-tricosylresorcinol, alkylresorcinols (mix)
SeedsSoy productsDaidzein, genistein, isoflavones (mix), O-desmethylangolensin
MeatsMeat1-Hydroxypyrene glucuronide, 1-methylhistidine,
Meat, beefPentadecylic acid
Animal productsAnimal products (total)1-Methylhistidine, 3-methylhistidine, margaric acid, pentadecylic acid, phytanic acid
Dairy productsMilk, dairy productsIodine, margaric acid, pentadecylic acid, phytanic acid
FishFish, fattyDHA, EPA, long chain ω-3 PUFAs, PCB toxic equivalents, pentachlorodibenzofuran, polychlorinated biphenyl 126, polychlorinated biphenyl 153, ω-3 PUFAs
Fish, leanLong chain ω-3 PUFAs
Beverages (non-alcoholic)Tea4-O-Methylgallic acid, gallic acid, kaempferol
CoffeeChlorogenic acid
Beverages (alcoholic) Wine4-O-Methylgallic acid, caffeic acid, gallic acid, resveratrol metabolites
Beverages (alcoholic) (total)5-Hydroxytryptophol / 5-hydroxyindole-3-acetic acid, carbohydrate-deficient transferrin, ethyl glucuronide, γ-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase
Table 3: Tentative dietary biomarkers identified through untargeted metabolomic approaches in human dietary intervention studies and cross sectional studies.
Dietary factorStudy typeNumber of subjectsComparisonDietary assessment toolBiospecimenAnalytical techniqueBiomarkersReferences
Fruits, fruit juices
Mixed fruit mealAI8Consumers/CtrlNAU (spot)NMRProline betaine
Citrus fruitsCS499Consumers/non-consumers24-HDRU (24-hr)NMRProline betaine
Citrus fruitsCS12H/M/LFFQU (fasting)FIE-FTICR-MSProline betaine, 4-hydroxyproline betaine
Orange juiceAI4Consumers/CtrlNAU (kinetics)LC-ESI-QTof; LTQ-OrbitrapProline betaine, limonene-8,9-diol-Gluc*, nootkatone-13,14-diol-Gluc*, hesperetin-3'-Gluc, hydroxyproline betaine , N-methyltyramine-Sulf*, naringenin-7-O-Gluc
Orange juiceSMTI12Consumers/CtrlNAU (24-hr)LC-ESI-QTof; LTQ-Orbitrap
Citrus fruitsCS80H/LFFQ & 24-HDRU (spot)LC-ESI-QTof; LTQ-Orbitrap
RaspberriesSMTI24Consumers/CtrlNAU (kinetics)FIE-FTICR-MS, GC-Tof-MSCaffeic acid-Sulf, methylepicatechin-Sulf
Vegetables
VegetablesCS160H/M/LFood diaryU (fasting)NMRPhenylacetylglutamine
BroccoliSMTI24Consumers/CtrlNAU (kinetics)FIE-FTICR-MSTetronic acid*, xylonate/lyxonate*, threitol/erythritol*
Cruciferous vegetablesSMTI20Before/AfterNAU (kinetics)NMRS-Methyl-L-cysteine sulfoxide
Cruciferous vegetablesAI17Consumers/CtrlNAU (kinetics)LC-ESI-QTofSulforaphane N-acetyl-cysteine, N-Acetyl-(NÕ-benzylthiocarbamoyl)-cysteine, Sulforaphane N-cysteine*, N-acetyl-S-(N-3-methylthiopropyl)cysteine*, N-acetyl-S-(Nallylthiocarbamoyl)cysteine*, Iberin N-acetyl-cysteine*, 4-iminopentylisothiocyanate*, Erucin N-acetyl-cysteine*
Cereals
Wholegrain rye breadSMTI20Consumers/CtrlNAU (24-hr)LC-ESI-QTof3-(3,5-Dihydroxyphenyl)-1-propanoic acid-Sulf* and -Gluc*, enterolactone-Gluc*, azelaic acid*, 2-aminophenol-Sulf*, 2,4-dihydroxy-1,4-benzoxazin-3-one*, 2-aminophenol-Sulf*, 2-4-dihydroxy-1,4-benzoxazin-3-one-Sulf*, indolylacryloylglycine*, ferulic acid-Sulf*, 3,5-dihydroxyphenylethanol-Sulf*, 3,5-dihydroxycinnamic acid-Sulf*
Meat & fish
Red meatCS160H/M/LFood diaryU (fasting)NMRO-Acetylcarnitines
SalmonSMTI24Consumers/CtrlNAU (kinetics)FIE-FTICR-MSAnserine, methylhistidine, trimethylamine-N-oxide
Oily fishCS68H/M/LFFQU (spot, 24-hr, fasting)FIE-FTICR-MS Methylhistidine
Beverages
CoffeeCS18Comsumers/non-consumersU (fasting)LC-QTof-MSN-Methylpyridinium, trigonelline
CoffeeAI9Before/AfterNAU (kinetics)LC-QTof-MSN-Methylpyridinium, trigonelline
CoffeeCS68H/M/LFFQU (spot, 24-hr, fasting)FIE-FTICR-MSDihydrocaffeic acid
Chamomile teaSMTI14Before/AfterNAU (spot)NMRHippuric acid*
Black teaAI3Before/AfterNAU (24-hr)NMRHippuric acid*, gallic acid, 1,3-dihydroxyphenyl-2-O-Sulf*
Tea (black and green)STI17Consumers/CtrlNAU (24-hr)NMRHippuric acid*, 1,3-dihydrophenyl-2-O-Sulf*
Green teaAI8Before/AfterNAU (B/A)NMRHippuric acid*
Black teaAI20Consumers/CtrlNAU (kinetics)NMRHippuric acid*, 4-hydroxyhippuric acid*, 1,3-dihydrophenyl-2-O-Sulf*, gallic acid, 4-O-methylgallic acid*
Mixed Red Wine-Grape Juice ExtractsSMTI35Consumers/CtrlNAU (24-hr)"GC-MS, LC-MS"Hippuric acid*, 3-hydroxyhippuric acid*, 4-hydroxyhippuric acid*, 4-hydroxybenzoic acid*, 1,2,3-trihydroxybenzene*, vanillic acid*, isovanillic acid*, syringic acid*, 3-hydroxyphenylacetic acid*, 4-hydroxymandelic acid*, vanilmandelic acid*, ferulic acid*, 3-hydroxyphenylpropionic acid*, 3,4-dihydroxyphenylpropionic acid*, 3-(3-hydroxyphenyl)-3-hydroxypropionic acid*, catechol*, pyrogallol*, citrate*, betaine*,
WineSMTI61Consumers/CtrlNAU (24-hr)NMRTartrate*, 4-hydroxyphenylacetate*, mannitol*, ethanol*
Other foods
Cocoa PowderAI10Consumers/CtrlNAU (kinetics)LC-ESI-QTofVanilloylglycine*, 6-amino-5-[N-methylformylamino]-1-methyluracil*, 3-methyluric acid*, 7-methyluric acid*, 3-methylxanthine*, 7-methylxanthine*, dimethyluric acid*, theobromine, caffeine, trigonelline*, hydroxynicotinic acid*, tyrosine, 3,5-diethyl-2-methylpyrazine*, hydroxyacetophenone*, diketopiperazines*, epicatechin-Sulf*, O-methylepicatechin*, vanillic acid*, phenylvaleric acid* and phenylvalerolactone* derivatives, furoylglycine*, xanthurenic acid*
Cocoa PowderSMTI20Consumers/Ctrl & Before/AfterNAU (24-hr)LC-ESI-QTofHydroxynicotinic acid*, 6-amino-5-[N-methylformylamino]-1-methyluracil*, 7- and 3-methyluric acid*, 7- and 3-methylxanthine*, 3,7-dimethylruric acid*, cyclo(propylalanyl)*, 3,5-diethyl-2-methylpyrazine*, theobromine*, vanillic acid-Gluc* and -Sulf-Gluc*, vanilloylglycine*, 4-hydroxy-5-(dihydroxyphenyl)-valeric acid-Glucs* and -Sulf*, 3«-methoxy-4«-hydroxyphenylvalerolactone*, 4«-hydroxy-5-(hydroxymethoxyphenyl)valeric acid-Gluc*, 5-(3«,4«-dihydroxyphenyl)-g-valerolactone-Gluc* and -Sulf* and -SulfGluc*, (epi)catechin-Gluc* and -SulfGluc*, methyl-(epi)catechin-Sulf*, N-[4«-hydroxy-3«-methoxy-E-cinnamoyl]-L-aspartic acid*, N-[4«-hydroxycinnamoyl]-L-aspartic acid*, methoxyhydroxyphenylvalerolactone-Glucs*, hydroxyphenylvalerolactone-Gluc* and -Sulf*, 5-(hydroxymethoxyphenyl)valeric acid-Sulf*, 4-hydroxy-5-(phenyl)valeric acid-Sulf*
Almond skin extractAI24Before/AfterNAU (kinetics)LC-QTof-MScatechin-Sulf*, O-methyl-(epi)catechin-Sulf*, naringenin-O-Gluc*, 5-(hydroxyphenyl)-_-valerolactone-Gluc* and -Sulf*, 5-(dihydroxyphenyl)-_-valerolactone-Gluc*, -SulfGluc* and -Sulf*, 5-(trihydroxyphenyl)-_-valerolactone-Gluc*, 5-(hydroxymethoxyphenyl)-_-valerolactone-Gluc* and Sulf*, 4-hydroxy-5-(dihydroxyphenyl)-valeric acid-Gluc* and Sulf*, 4-hydroxy-5-(hydroxymethoxyphenyl)valeric acid-Gluc*, 4-hydroxy-5-(methoxyphenyl)valeric acid-Gluc*, 4-hydroxy-5-(hydroxyphenyl)valeric acid-Gluc and -Sulf*, 4-hydroxy-5-(phenyl)valeric acid-Sulf*, 2-(dihydroxyphenyl)acetic acid-Gluc*, -SulfGluc* and -Sulf*, 2-(hydroxymethoxyphenyl)acetic acid-Gluc*, 2-(hydroxyphenyl)acetic acid-Sulf*, 3-(hydroxyphenyl)propionic acid-Gluc*, 3-(dihydroxyphenyl)propionic acid-Sulf*, vanillic acid-Gluc*, hydroxyhippuric acid*, ferulic acid-Gluc*
NutsSMTI42Consumers/CtrlNAU (24-hr)LC-QTof-MS; LTQ-Orbitrap10-Hydroxydecene-4,6-diynoic acid-Sulf*, tridecadienoic/tridecynoic acid-Gluc*, dodecanedioic acid*, 1,3-dihydroxyphenyl-2-O-Sulf*, p-coumaroyl alcohol-Gluc* and -Sulf*, N-acetylserotonine-Sulf*, 5-hydroxyindoleacetic acid*, Urolitin A-Gluc, Sulf*and SulfGluc*
Nutrients
Dietary FibreSMTI77H/LDietary recordU (24-hr)NMRHippuric acid*
Dietary FibreSMTI25Consumers/CtrlNAP (fasting)LC-QTof2-Aminophenol-Sulf, 2,6-dihydroxybenzoic acid, hydroxynuategenin-Gluc*
Diets
Omnivorous DietSMTI12Consumers/CtrlNAU (24-hr)NMRTaurine*, carnitine*, acetylcarnitine*, 1-methylhistidine*, 3-methylhistidine*, trimethylamine-N-oxide*
Vegetarian DietSMTI12Consumers/CtrlNAU (24-hr)NMRp-Hydroxyphenylacetate*
Meat Protein dietSMTI24Before/AfterNAU (24-hr)NMRTrimethylamine-N-oxide*, histidine*
SeafoodsAI17Consumers/CtrlNAU (kinetics)LC-ESI-QTofTrimethylamine-N-oxide
Milk Protein dietSMTI24Before/AfterNAS (fasting)NMRShort chain fatty acids*
Omnivorous DietCS161Consumers/CtrlQuestionnaireU (fasting)NMRTrimethylamine-N-oxide*, dimethylamine*, phenylalanine*, methylhistidine*
Lacto-vegetarian DietCS161Consumers/CtrlQuestionnaireU (fasting)NMRCitrate*
Phytochemical-rich diet (citrus, crucifer veg., soy)SMTI10Consumers/CtrlNAU (spot)LC-FTMSSulforaphane*, proline betaine*, hippuric acid*, genistein*, daidzein*, equol*, glycitein*, O-desmethylangolensin*, enterolactone*, trigonelline*
Phytochemical-rich diet (citrus, crucifer veg., soy)CS60H/LDietary recordU (spot)LC-FTMSProline betaine*

References
For more information see: Scalbert A, Brennan L, Manach C, Andres-Lacueva C, Dragsted LO, Draper J, Rappaport SM, van der Hooft JJ, Wishart DS. The food metabolome: a window over dietary exposure. Am J Clin Nutr. 2014 Jun;99(6):1286-308. doi: 10.3945/ajcn.113.076133. Epub 2014 Apr 23. 24760973
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