Biomarkers of Berry Intake: Systematic Review Update: Access

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Biomarkers of Berry Intake: Systematic Review Update

Hamza Mostafa, Alex Cheok, Tomás Meroño, Cristina Andres-Lacueva,* and Ana Rodriguez-Mateos*
Cite This: J. Agric. Food Chem. 2023, 71, 11789−11805 Read Online
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sı Supporting Information
ABSTRACT: Berries are rich in (poly)phenols, and these compounds may be beneficial to human health. Estimating berry
consumption through self-reported questionnaires has been challenging due to compliance issues and a lack of precision. Estimation
via food-derived biomarkers in biofluids was proposed as a complementary alternative. We aimed to review and update the existing
evidence on biomarkers of intake for six different types of berries. A systematic literature search was performed to update a previous
systematic review on PubMed, Web of Science, and Scopus from January 2020 until December 2022. Out of 42 papers, only 18
studies were eligible. A multimetabolite panel is suggested for blueberry and cranberry intake. Proposed biomarkers for blueberries
include hippuric acid and malvidin glycosides. For cranberries, suggested biomarkers are glycosides of peonidin and cyanidin
together with sulfate and glucuronide conjugates of phenyl-γ-valerolactone derivatives. No new metabolite candidates have been
found for raspberries, strawberries, blackcurrants, and blackberries. Further studies are encouraged to validate these multimetabolite
panels for improving the estimation of berry consumption.
KEYWORDS: Berries, Blueberry, Cranberry, Raspberry, Strawberry, Blackberry, Blackcurrant, BFIs
1. INTRODUCTION these metabolites are ubiquitous and can be found in many

Berries are fruits that are common in healthy dietary patterns types of foods such as nuts, red grapes, and red wine.
as they are rich in phytochemicals, fiber, and micronutrients.1,2 Therefore, they cannot be used as single biomarkers due to the
Berries may play an important role in the prevention and lack of specificity coupled with their abundance in a habitual
treatment of chronic diseases such as cardiovascular diseases diet. Similarly, phenolic acids are present in berries and they
(CVD), cancer, diabetes mellitus (DM), and age-related are also formed in the colon via the gut microbial metabolism
cognitive decline according to an increasing number of of anthocyanins and other berry (poly)phenols; however, they
randomized controlled trials (RCTs) and epidemiological are also abundant in many foods, such as coffee, tea, bread, and
studies.3−5 However, to understand the relationship between other fruits and vegetables. A potential solution to this is to use
berries and health, it is essential to be able to quantify their multibiomarker panels, which have been previously proposed
consumption accurately. The development of novel dietary to be more advantageous than the single biomarker
assessment methods to estimate food consumption is a current approach.18 In the past few years, a number of studies have
focus of nutrition research. Recent studies aim to discover and provided additional information on the berry metabolome;
validate biomarkers of food intake (BFIs) in biofluids, typically therefore, in this work, we aimed to update a previous
in the blood and urine. BFIs can be effectively used to (i) systematic review of biomarkers of berry intake19 to capture
validate dietary intake questionnaires, (ii) study physiological additional candidates beside the previously proposed metab-
and pathological responses to food and food components, (iii) olite panels.
provide information on interindividual variability in food
responses, and (iv) help to formulate personalized dietary 2. METHODOLOGY
recommendations.6−8 However, only a very limited number of We conducted the current systematic review according to the
biomarkers for specific foods have been proposed. Currently, PRISMA statement (Preferred Reporting Items for Systematic
there are no validated biomarkers for berries. Reviews and Meta-Analysis) as detailed in Supplementary
The most abundant phytochemicals in berries are (poly)- Table 1. Our review employed an extensive search using the
phenols, in particular anthocyanins, ellagitannins, flavonols, following keywords (Fruit name* OR botanical name), AND
flavan-3-ols, and phenolic acids.9 A large number of circulating (urine or plasma or serum or excretion or blood) AND
metabolites, including phase II and gut microbial metabolites (human* OR men OR women OR patient* OR volunteer*
derived from these compounds have been reported after the
consumption of different types of berries in human
intervention studies.10−12 Previous studies have proposed Received: February 22, 2023
ellagitannins and their gut microbial metabolites, urolithins Revised: July 8, 2023
(Uros), as biomarkers of strawberry and raspberry intake;13,14 Accepted: July 10, 2023
aromatic compounds like furaneol as biomarkers of strawberry Published: July 27, 2023
intake;15 and anthocyanins (ACN) like malvidin and its
derivatives as biomarkers of blueberry intake.16,17 However,
© 2023 The Authors. Published by
American Chemical Society https://doi.org/10.1021/acs.jafc.3c01142
11789 J. Agric. Food Chem. 2023, 71, 11789−11805
Journal of Agricultural and Food Chemistry pubs.acs.org/JAFC Review
Figure 1. Study selection bibliography search flow diagram.
OR participant*) AND (biomarker* OR marker* OR in Table 1. All included studies performed analysis without
metabolite* OR biokinetics OR biotransformation OR enzymatic treatment with glucuronidase and sulfatase.
pharmacokinetics OR bioavailability OR ADME) AND (intake 3.2. Biomarkers of Berry Intake. 3.2.1. Blueberries. A
OR meal OR diet OR ingestion OR administration OR total of 22 studies investigating the metabolic fate of
consumption OR eating OR drink) across three electronic (poly)phenols after blueberry intake were included in the
databases: PubMed, Web of Science, and Scopus. The previous systematic review of Ulaszewska et al.16,17,20−38 They
search covered published literature until December 2019. To concluded that the major ACN found in blood and urine
extend upon that, our systematic search included trials was delphinidin and malvidin glycosides. Various phenolic
published in English only that were conducted only on berries metabolites were also found after acute and chronic intake of
between January 2020 and December 2022. Short- and long- blueberries such as benzoic, ferulic, catechol, hippuric, and
term human intervention studies conducted on berry intake phenyl valeric acids and phenyl-γ-valerolactone (ph-γ-VL)
were selected for this review. As detailed in Figure 1, the main derivatives. However, these metabolites were not specific to
exclusion criteria were animal and in vitro studies and papers blueberry intake and can also be produced after the intake of
assessing irrelevant diets. Two investigators independently many other fruits and vegetables. Thus, there were no
performed the study selection and data extraction. metabolites identified as BFIs for blueberry, and it was
suggested that more trials were needed. In our systematic
3. RESULTS AND DISCUSSION search, 5 additional studies that investigated plasma or urine
metabolites after blueberry consumption were identified.39−43
We found 41 papers in PubMed, 67 in Web of Science, and Two of them were acute, single-dose studies, while the rest
101 in Scopus. Duplicated papers or papers found to be were long-term trials. One study administered a drink, while 4
irrelevant to our objective were excluded from the review. studies used reconstituted freeze-dried powder. Only one study
From there, only 42 articles fulfilled the inclusion and detected ACN in plasma namely cyanidin-3-galactoside (cya-3-
exclusion criteria of this review. After full-text screening, 18 galac), cyanidin-3-glucoside (cya-3-glu), malvidin-3-galactoside
papers were selected and analyzed, as detailed in Figure 1 and (mal-3-galac), peonidin-3-xyloside (peo-3-xyl), peonidin-3-
Table 1. glucuronide (peo-3-gluc), and petunidin-3-glucoside (pet-3-
3.1. Description of the Selected Trials. Among the 18 glu).41 Phenolic acid derivatives and small low molecular
studies, 8 studies had a berry drink as an intervention (in the weight compounds were found in all 5 studies, including
form of juices, nectars, or frozen juices), 2 studies used extract syringic acid, isovanillic acid, ferulic acid, benzoic acid,
capsules, 1 study used frozen berries, and 7 studies used freeze- catechol, and their derivatives, 3-caffeoylquinic acid,
dried powder dissolved in water. Twelve studies included only hydroxyphenylpropionic acid sulfate (OH-ph-PrA-S), 2,6-
healthy participants. The age of the participants across all of dimethoxyphenol (2,6-dimeO-phenol), and 3,4-dihydroxy-
the studies included in this review ranged from 21 to 75 years, phenylacetic acid (3,4-diOH-PA) (Table 1). Hippuric acid
except for one study, which was conducted on children (7−10 was the only common metabolite found in all of the studies
years old). Two studies had female participants only; while five regardless of the type of biofluid, study design or trial duration.
studies had only male participants. There were 5 studies In Lapo Renai et al.,42 12 metabolites were identified in serum
classified as acute interventions (single dose) while the long- using untargeted metabolomics after a single dose of Vaccinium
term interventions were between 21 days and 90 days as shown myrtillus and Vaccinium corymbosum supplements (bilberry and
11790 https://doi.org/10.1021/acs.jafc.3c01142
J. Agric. Food Chem. 2023, 71, 11789−11805
Table 1. List of the Studies Included for the Assessment of Biomarkers of Berry Intakea
Reference Intervention Study characteristics Analytical method Candidate biomarkers (blood) Candidate biomarkers (urine)
Blueberries (BB)
39 50g freeze-dried powder. Double-blind parallel RCT Targeted metabolomics LC-MS/MS Increased
analysis
Phytochemical content not reported Duration: 8 w Plasma samples (w0 and w8) - HA
49 participants 6 identified metabolites Decreased
- At risk of MetS - Ornithine
- 55% females - Hypoxanthine
- Age: 22−53 y - Diacylglycerol
Compliance: 92.7% - Indoxyl sulfate
- Ceramide
40 26 g freeze-dried powder containing 1243 mg of total (poly)phenols Double-blind parallel RCT UPLC-MS/MS analysis - 2,6-dimeO-phenol - Phloroglucinaldehyde
Duration: Acute single dose Serum samples (30, 60, 90, 120, 180, - 3-(4-OH-3- meO-ph)-PrA - 3-(3,4-diOH-ph)-PrA
360 min and 24 h), Urine samples (24
h)
45 participants 21 identified metabolites - 3-OH-4-meO-PA - 3-OH-HA
Journal of Agricultural and Food Chemistry
- With MS - 3-meO-PA-4-S - Syringic acid

- 64% males - 4-OH-HA - 4-OH-BA
- Age: 63.4 ± 7.4 y - HA - Isovanillic acid-gluc
- HA-S - Benzoylglutamic acid
- OH-meO-BA-S - 3-Caffeoylquinic acid
- 3-(3-meO-ph)-PrA - HA
- Methoxy-PA-gluc - BA-4-S
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- 3,4-OH-BA-3/4-S
- DOPAC
41 24g freeze-dried powder containing 36 mg/g of total (poly)phenols Double-blind parallel RCT UPLC-QQQ-MS analysis - HA
Duration: 90 d Plasma samples (0, 2 h) - Phloroglucinaldehyde
38 participants (d0, d45, d90) - Syringic acid
- Healthy 11 identified metabolites - Ferulic acid-gluc
- 68% females - Cya-3-galac
- Age: 60−75 y - Cya-3-glu
Compliance: 99.2% - Mal-3-galac
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- Mal-3-glu
- Peo-3-xyl
- Peo-3-gluc
- Pet-3-glu
42 25 g of (Vaccinium myrtillus (VM)) Single-blind parallel Untargeted metabolomics LC-HRMS After VM consumption:
randomized trial analysis
25 g of (Vaccinium Corymbosum (VC)) supplements in a capsule Duration: Acute single dose Serum samples (30, 60, 120, 240, and - Uric acid
containing 39 mg of catechin equivalent/g (total (poly)phenols∼ 360 min)
1 g) 20 participants 12 identified metabolites - Inosine
- Healthy - α-Hydroxyhippuric acid
- 1 male, 9 females - Catechol-S
- Age: 25−60 y - me-catechol-S
- Abscisic acid glucuronide
- Azelaic acid
Review
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https://doi.org/10.1021/acs.jafc.3c01142
Table 1. continued
Blueberries (BB)
- OH-ph-PrA-S
After VC consumption:
- Caprylic acid (hydroxyl octanone)
- Tetrahydro-me-ß-carboline dicarboxylic
- Octahydro-methyl-ß-carboline dicarboxylic
- Citric acid for both VM and VC.
43 13.3 g blueberry juice daily, containing 766 mg of total (poly) Single-blind between-groups UHPLC-Q-TOF-MS analysis - HA
phenols trial
Duration: 4 w Urine samples (24 h) - Dihydrocaffeic acid-3-S
15 participants 2 identified metabolites
- Healthy
- 7 males, 8 females
- Age: 7−10 y
Cranberries (CB)
10 Cranberry juice containing 375, 716, 1131, 1396, 1741 mg of total Double-blind six-arm Targeted UHPLC-ESI-QqQ-MS/MS - 5-(diOH-ph)-γ-VL-gluc (3′,4′,5′) - 5-(5′−OH-ph)-γ-VL-3′-gluc
flavan-3-ols crossover RCT analysis
Duration: Acute single dose Plasma samples (0, 1, 2, 4, 6, 8 and 24 - 5-(5′- OH-ph)-γ-VL-3′-gluc - 5-ph-γ-VL-4′-gluc
h), Urine samples (0, < 8, 8−24 h)
10 participants 22 identified metabolites - 5-(3′,5′-diOH-ph)-γ-VL - 5-(3′−OH-ph)-γ-VL-4′-gluc
- Healthy - 5-(diOH-ph)-γ-VL-S (3′,4′,5′) - 5-ph-γ-VL-S-gluc isomer
(3′,4′)
11792
- Males - 5-ph-γ-VL-4′-gluc - 5-(4′−OH-ph)-γ-VL-3′-gluc
- Age: 18−35 y - 5-(3′−OH-ph)-γ-VL-4′-gluc - 5-(3′,4′-diOH-ph)-γ-VL
- 5-ph-γ-VL-S-gluc isomer (3′,4′) - 5-(5′−OH-ph)-γ-VL-3′-S
- 5-(4′−OH-ph)-γ-VL-3′-gluc - 5-ph-γ-VL-meO-gluc isomer
(3′/4′)
- 4-OH-5-(OH-ph)-VA-S (3′/4′) isomer 1 - 5-ph-γ-VL-3′-gluc
- 4-Hydroxy-5-(OH-ph)-VA-gluc (3′/4′) - 5-(OH-ph)-γ-VL-S (3′,4′
isomers)
- 5-(5′−OH-ph)-γ-VL-3′-S - 5-ph-γ-VL-meO-S (3′,4′)
isomer 1
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- 5-ph-γ-VL-meO-gluc isomer (3′/4′) - 5-ph-γ-VL-3′-S

- 5-OH-ph -γ-VL-meO-gluc (3′,4′,5′) - 5-ph-γ-VL-meO-S (3′,4′)
- 5-ph-γ-VL-3′-gluc isomer 2
- 4-OH-5-(OH-ph)-VA-S (3′/4′) isomer 2
- 5-(OH-ph)-γ-VL-meO-S (3′,4′,5′)
- 5-(OH-ph)-γ-VL-S (3′,4′ isomers)
- 5-ph-γ-VL-4′-S
- 5-ph-γ-VL-meO-S (3′,4′) isomer 1
- 5-ph-γ-VL-3′-S
- 5-ph-γ-VL-meO-S (3′,4′) isomer 2
64 9 g whole cranberry freeze-dried powder containing 525 mg of total Double-blind parallel RCT Targeted quantitative UPLC-MS - 1 Flavonol - 5 Flavonols
(poly)phenols analysis
Duration: 1 month Plasma samples (0, 2 h) (d1, 1 month), - 2 Benzene diols and triols - 7 Benzene diols and triols
Urine samples (24 h) (d1, 1 month)
Review
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Table 1. continued
Cranberries (CB)
45 participants 130 identified metabolites - 2 BAL - 3 BAL
- Healthy - 5 HAs - 5 HAs
- Males - 11 BAs - 14 BAs
- Age: 25 ± 3 y - 12 CAs - 15 CAs
- 6 PAs - 6 PAs
- 12 ph-PrAs - 11 ph-PrAs
- 5 ph-γ-VLs and ph-VAs - 8 ph-γ-VLs and ph-VAs
Increased after 2 h: Increased after 1 day:
13 in plasma 13 in urine
Increased after 1 month: Increased after 1 month:
4 in plasma 13 in urine
65 6 bottles/3 d (250 mL per bottle, twice a day) of 54% cranberry Crossover RCT Untargeted UHPLC-Q-orbitrap- - Quinic acid
juice containing 913 ± 7 mg of total (poly)phenols Mean ± SD HRMS-based metabolomics analysis
Duration: 3 d Spot urine samples (d0, after d3) - Coumaric acid
15 participants 16 identified metabolites - 4-OH-5-(OH-ph)-VA-S

- Healthy - 5-(diOH-ph)-γ-VL-S
- Females - Diphenol-gluc
- Age: 21−29 y - 3,4-diOh-ph-PA
- 3-(OH-ph)-PA
- 4-me-gallic acid,
11793
- triOH-BA
- 1,3,5-trimeO-benzene
- Homocitric acid
- HA
- 3-OH-3-carboxy-me-adipic
acid
- (2)3-isopropylmalate
- Pimelic acid
- N-acetyl-L-glutamate 5-
semialdehyde
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66 6 bottles/21 d (250 mL per bottle, twice a day) of 54% cranberry Double-blind crossover RCT UPLC-MS untargeted metabolomics - Quinic acid ⧺
juice Duration: 21 d analysis - 3-(OH-ph)-PA ⧺
16 participants - (S)-Homostachydrine
- Healthy - et-(methylthio)methyl disulfide
- Females - Catechol-S ⧺
- Age: 21−29 y - Vanilloloside ⧺
Compliance: 100% - S-acetyl dihydroasparagusic acid
- Pyrocatechol
- Guaiacol
- HA ⧺
- Glycerol 3-phosphate
- diOH-quinoline ⧺
- OH-pyruvic acid
Review
- 3,4-diOH-ph-glycol
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Table 1. continued
Cranberries (CB)
- Guanidoacetic acid
- 2-Chloromaleylacetate
- 2-Phenylacetamide
- Tyrosine ⧺
- 3-Isopropylmalate
- 2-Chloromaleylacetate
- Lanthionine ketimine
- Prolyl-Hydroxyproline
- Tyramine-O-S
containing 913 ± 7 mg of total (poly)phenols Mean ± SD Plasma samples (d0, d3, d21) - (3,4,5,6-tetrahydroxyoxan-2-yl)me-4-OH-
benzoate
25 identified metabolites - {4-[2,3-dioxo-3-(2,4,6-trihydroxy-3-meO-
ph)propyl]-2-OH-6-meO-ph}
oxidanesulfonic acid
⧺
Identified in a previous study111

Raspberries (RB)
77 - 250 g frozen raspberries containing 203.6 ± 11.1 mg/meal of total Single-blind three-arm UHPLC-QTOF analysis - Cya-3-sop
(poly)phenols Mean ± SD crossover RCT
Duration: Acute single dose Plasma samples (0, 0.5, 1, 2, 4, 6, 7, 8, - Cya-3-glu
and 24 h)
32 participants 24 identified metabolites - Cya glucosylrutinoside
11794
- 12 preDM-IR and 11 healthy - Cya-3-rut
- 15 males, 17 females - Pel-3-sop
- Age: 34 ± 12 - Pel-3-glu
- me-cya-sop
- me-cya-3-glu
- 8-OH-Uro-3-gluc
- Uro-3-gluc
- 4′−OH-CA
- OH-CA
- CA-gluc
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- 4′−OH-3′-meO-CA
- OH-meO-CA
- meO-CA-gluc isomer 1
- etO-CA-gluc isomer 2
- 2,4,6-triOH-BAL
- 3,4-diOH-BA
- 2,3- diOH-BA
- 4-OH-PA
- diOH-ph-PA isomer
- HA
- 125 g frozen raspberries containing 101.8 ± 5.6 mg/meal of total - HA-gluc
(poly)phenols Mean ± SD
78 Frozen raspberry drink containing 388.4 ± 3.3 mg of total (poly) Single-blind crossover RCT UHPLC-QQQ analysis - 13 ACN derivatives Increased:
Review
phenols Mean ± SD
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Table 1. continued
Raspberries (RB)
Duration: 4 w Plasma samples (0, 0.5, 1, 2, 3, 4, 24h), - 7 Uros derivatives - Total Uros
Urine samples (0, 1,2,3,4, 24h)
35 participants: 123 identified (poly)phenolic - 9 ph-γ-VLs derivatives - Total ph-γ-VL
- 25 preDM-IR and 10 healthy metabolites - 94 Phenolic acid derivatives:
- 17 males, 18 females - 10 BALs
- Age: 34 ± 3 - 24 CAs
- 19 ph-PrA
- 17 PAs
- 16 BAs
- 8 HAs
Increased:
- Total Uros
- Total ph-γ-VL
- Select PA(CAs, ph-PrAs and HAs)
Decreased:
- Total ACN
79 280 g frozen raspberries Two-arm parallel RCT Targeted metabolomics analysis using - Cholesterol 1-pentadecanoate
MxP Quant 500 kit
No phytochemical content reported Duration: 8 w Plasma samples (w0, w4, w8) - 1-Palmitoyl-2-palmitoyl-3-docosahexaenoyl-
glycerol
48 participants 10 identified metabolites - 1-Octadecanoyl-2-(9Z-hexadecenoyl)-3-
11795
(9Z-tetradecenoyl)-glycerol
- Obese - 1-Palmitoleoyl-2-palmitoleoyl-3-linoleoyl-
glycerol
- 16 males, 32 females - 1-Arachidonyl-2-docosapentaenoyl-sn-
glycero-3-phosphocholine
- Age: 18−60 y - 1-Octadecanoyl-2-octadecanoyl-3-(9Z-
tetradecenoyl)-glycerol
Compliance: 92.8% - β-Alanine
- Trimethylamine N-oxide
- Deoxycholic acid glycine conjugate
pubs.acs.org/JAFC
- Hexosylceramide
80 - 10 g or 20 g Raspberry nectar (containing 17 mg and 46 mg of ETs Five-arm parallel RCT UPLC/MS/MS analysis - Uro A - Uro A
respectively)
- 10 g or 20 g Raspberry confection (containing 25 mg and 50 mg of Duration: 4 w Plasma samples, Urine (spot and 24 h) - Uro C - Uro B
ETs respectively) 40 participants 5 identified metabolites - Uro C
- Healthy - Uro D
- Male - dime-ellagic acid
- Age: 60.2 ± 7 y
Compliance: 100%
Strawberries (SB)
84 50 g strawberry freeze-dried powder containing 450.7 mg of total Double-blind crossover RCT UPLC-QQQ analysis Decreased:
(poly)phenols Duration: 4 w Plasma (w0, w4) - Secondary BAs
34 participants 37 identified bile acids (BA) species - Deoxycholic acid
Review
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Table 1. continued
Strawberries (SB)
- Obese - Lithocholic acid (and their glycine
conjugates)
- 17 males, 17 females - Glycoursodeoxycholic acid
- Age: 52.6 ± 7.1 y
82 50g whole strawberry freeze-dried powder containing 450.7 mg of Double-blind crossover RCT Targeted metabolomics UHPLC-ESI- 8 increased:
total (poly)phenols MS/MS analysis
Duration: 4 w Plasma samples (0, 1 h) - 3-meO-BA-4-S
34 participants 17 identified phenolic metabolites - 3-meO-PA
- With MHC - 3-OH-ph-γ-VL-4-S
- 17 males, 17 females - 4-OH-PA
- Age: 53 ± 1 y - 4-OH-3-meO-BA-me ester
- 3-(4-OH-ph)-PA-3-S
- OH-CA-O-gluc
- 4-OH-3,5-dimeO-PA
4 decreased:
- 4-meO-CA
- 3-me-HA
- OH-BAL-O-gluc
- 3-(4-meO-ph)-PA-3-gluc
83 - 26 g strawberry freeze-dried powder + Beige diet daily One-arm parallel trial LCMS/MS analysis - Pel-3-gluc - Pel-3-gluc
- Beige diet only Duration: 4 w for (Beige diet Serum samples (w0, w4, w6), Urine - Uro A-gluc
11796
+ SB), 2 w for Beige diet samples (24 h) (w0, w4, w6)
only
No phytochemical content reported 15 participants 4 identified metabolites - dime-ellagic acid-gluc
- Healthy
- Age: 18−55 y
Blackcurrants (BC)
95 300 mg blackcurrant extract capsule coontains 105 mg of ACN One-arm trial Reversed-phase HPLC analysis - Gallic acid
Duration: acute single dose Plasma samples (0, 1, 1.5, 2, 3, 4, 5, 6 h) - PCA
pubs.acs.org/JAFC
20 participants 2 identified metabolites

-Healthy
- Age: 28 ± 7 y
Blackberries (BLB)
103 400 mL of commercial blackberry nectar containing 100 mg of Cya- One-arm trial LC-IMS-QTOF-MS and LC-LIT-MS - Two sulfated cya derivatives
3-glu analysis
Duration: acute single dose Urine samples (24 h) - One sulfated cya-3-gluc
Two participants 2 identified metabolites
- Healthy
- Age and sex: unreported
a
Data are presented as Mean ± SD. Study compliance only reported for long-term interventions when data was available. BB: blueberries, CB: cranberries, RB: raspberries, SB, strawberries, BC:
blackcurrants, BLB: blackberries, VM: Vaccinium myrtillus, VC: vaccinium corymbosum, RCT: randomized controlled trial, preDM-IR: prediabetes and insulin resistance, MHC: moderate
Review
hypercholesterolemia, MetS: metabolic syndrome, HPLC: high pressure liquid chromatography, UPLC: ultra performance liquid chromatography, QQQ: triple quadrupole, MS: mass spectrometry,
J. Agric. Food Chem. 2023, 71, 11789−11805

blueberry, respectively), including some phenolic compounds,
hydroxybenzoic acid, DOPAC: 3,4-dihydroxyphenylacetic acid, BA: benzoic acid, CA: cinnamic acid, 4-OH-BA: 4-hydroxybenzoic acid, 3,4-OH-BA: 3,4-Hydroxybenzoic acid-3/4-sulfates, BAL:
benzaldehydes, Cya-3-galac: cyanidin-3-galactosdie, Cya-3-glu:cyanidin-3-glucoside, Mal-3-galac: malvidin-3-galactoside, Mal-3-glu: malvidin-3-glucoside, Peo-3-xyl: peonidin-3-xyloside, Peo-3-gluc:
IMS: ion mobility separation, HRMS: high resolution mass spectrometry, LIT: linear ion trap, ESI: electrospray ionization, QTOF: quadrupole time-of-flight, HA: hippuric acid, 4-OH-BA: 4-
PCA: protocatechuic acid, PrA: propionic acid, ph-PrA: phenylpropionic acid, PA: phenylacetic acid, 4-OH-PA: 4-hydroxyphenylacetic acid, me: methyl, dime: dimethyl, meO: methoxy, dimeO:
peonidin-3-glucoronide, Pet-3-glu: petunidin-3-glucoside, Pel-3-gluc: pelargonidin-3- glucuronide, OH-ph: hydroxyphenyl, diOH-ph: dihydroxyphenyl, ph: phenyl, VL: valerolactones, VA: valeric acid,
uric acid, inosine, and abscisic acid glucuronide (Table 1). Five
of those metabolites were associated with blueberry con-
sumption for the first time (citric acid, azelaic acid, caprylic
acid, and two derivatives of ß-carboline dicarboxylic acid).
However, the authors concluded, in agreement with previous
dimethoxy, meO-ph: methoxyphenyl, et: ethyl, etO: ethoxy, ETs: ellagitannins, Uros: urolithins, Uro A: urolithin A, Uro B: urolithin B, Urol C: urolithin C, Uro D: urolithin D. data, that these metabolites are not specific to blueberry intake
as they might be biomarkers of other fruits and vegetable
consumption, as well as alcohol, coffee and fructose
intake.44−47 Some endogenous metabolites such as inosine,
uric acid, ornithine, and hypoxanthine were increased or
decreased in blood samples after the intake of blueberry in
several studies (Table 1). Nevertheless, endogenous metabo-
lites could be affected by numerous intrinsic factors, hence
disqualifying them as specific biomarkers for blueberry intake.
In line with the result from the previous review, we suggest that
the simultaneous presence of hippuric acid with malvidin
glycosides could be an indicator of blueberry intake. This could
potentially be used to assess compliance in human studies.
However, they may not specific enough to be considered BFIs
of blueberries within the overall diet of an individual, as there
are many other anthocyanin-rich foods containing malvidin
glycoside, and hippuric acid is a metabolite found after the
consumption of many different types of (poly)phenols and also
part of other endogenous pathways.48,49 In addition, intact
anthocyanins are not an optimal biomarker of intake due to
their instability and low concentration in biofluids.50
3.2.2. Cranberries. Thirteen studies51−63 using untargeted
and targeted metabolomic approaches in plasma and urine
after cranberry consumption were included in Ulaszewska et al.
systematic review,19 revealing that the most abundant ACN
found were the arabinoside, glucoside and galactoside
derivatives of peonidin and cyanidin. In addition, various
phenolic metabolites were identified after cranberry intake
such as sulfate conjugates of catechols, ferulic acid, coumaric
acid, and ph-γ-VL derivatives alongside other metabolites such
as hippuric acid, citramalic acid, and derivatives of terpenes
and iridoids. Nevertheless, these metabolites are not specific
BFIs for cranberry intake, as they are also metabolites formed
after the consumption of many other (poly)phenol-rich foods.
In this work, we identified 4 additional studies10,64−66
exploring the plasma and urine metabolome after cranberry
consumption. Two studies10,64 used targeted analysis, whereas
the other 2 used untargeted analysis.65,66 All of them are RCTs
with interventions ranging from a single dose10 up to a 4 week
daily consumption. Only one study administered reconstituted
cranberry powder,64 while the rest used cranberry juices.
Following up with previous work 58 using untargeted
metabolomics for cranberry intake biomarker discovery, Liu
et al. have proposed newly identified exogenous discriminant
metabolites, including 4-hydroxy-5-(hydroxyphenyl)-valeric
acid sulfate, 5-(dihydroxy-ph)-γ-VL sulfate, pyrocatechol,
guaiacol, (S)-homostachydrine, ethyl (methylthio)methyl
disulfide, and S-acetyl dihydroasparagusic acid.65,66 However,
these compounds have been found in biofluids after the
consumption of many other foods,67,68 so unlikely to be good
Table 1. continued
BFIs. Additional endogenous metabolites such as glycerol 3-

phosphate, dihydroxyquinoline, and guanidoacetic acid were
also found in this work (Table 1); however, they should not be
considered as BFIs due to their susceptibility to changes by
many other factors. Another study detected 56 and 74
(poly)phenols metabolites in plasma and urine respectively
via a targeted approach64 after participants consumed 9 g of
J. Agric. Food Chem. 2023, 71, 11789−11805
reconstituted cranberry powder daily for a month. Overall, 13 structurally unstable and readily degrade into smaller phenolic
metabolites were found to have increased in plasma as well as metabolites, making them problematic as BFIs. There are also
13 in urine samples. However, these are mainly derivatives of no specific ACN for each individual berry, and ACN are largely
ph-γ-VLs, phenylvaleric acids (ph-VAs), cinnamic acids (CAs) common across red and purple foods such as red grapes, red
and benzoic acids (BAs) which were previously excluded as wine, red apples, red onions, aubergines, or plums. One study79
BFIs in the previous systematic review, as these are metabolites performed targeted metabolomics in participants with obesity
of many other flavan-3-ol rich foods. Another study from the after 8 weeks of frozen raspberry consumption. They reported
same team10 performed a targeted analysis of 22 ph-γ-VLs and changes in 10 plasma metabolites (4 endogenous and 6
ph-VAs in plasma and urine after an increasing dose (375− exogenous). The exogenous metabolites were made up of
1741 mg) of total flavan-3-ols. The ph-γ-VLs in both plasma triacylglycerols, glycerophospholipids, and cholesterol esters
and urine showed a linear dose−response with the glucuronide (Table 1). These compounds are omnipresent and can be
and sulfate derivatives of 5-(3′,4′-dihydroxyph)-γ-VL being the found across a wide range of animal and plant-based products
most dominant metabolites. Although 5-(3′,4′-dihydroxyph)-γ- rendering them ineffective BFIs. Lastly, Roberts et al.80 focused
VL and some of its derivatives were previously ruled out as on metabolism of ellagitannins in male individuals upon 4 w
BFIs in Ulaszewska M. et al.,19 here the authors suggested that consumption of raspberry products and quantified Uro A-D
its sulfate and glucuronide conjugates could serve as a and dimethylellagic acid (DMEA) in plasma and urine. They
biomarker for the intake of cranberry flavan-3-ols in the reported an increase in all urolithins in urine, but only Uro A
context of controlled clinical trials, as they are not specific and C increased in plasma. In addition to Uro A, the author
enough for being biomarkers of general cranberry intake. supports the consideration of DMEA as a good biomarker for
These gut microbial metabolites have been proposed as ellagitannins exposure. Although DMEA may be specific to
biomarkers of flavan-3-ol intake in previous studies, and have ellagitannins, it is still difficult to propose DMEA as the sole
been successfully used in an epidemiological study investigat- BFI for raspberry intake due to the ubiquitous nature of
ing associations between flavan-3-ol intake and blood ellagitannins across many Rubus species, strawberry, walnuts,
pressure.69,70 Taken together, these conjugates cannot be and many other foods widely abundant in the diet. As for Uros,
considered as specific BFIs of cranberries. Perhaps they could they have been previously proposed as strong candidates as
be used as indicators for intake when they appear alongside part of a multimetabolite panel for raspberry due to their
some ACN associated with cranberry intake, possibly as a specificity. These Uros include Uro A, Uro A glucuronide,
collective multibiomarker panel. Further studies are warranted Isouro A, Isouro A glucuronide, Uro B, Uro B glucuronide, and
to confirm this. Uro C. However, Uro A and its derivatives are more likely to
3.2.3. Raspberries. Seven studies12,71−76 investigating be good biomarkers as they are produced by the majority of
circulating raspberry metabolites were considered in the the population, while Isouro A and uro B are only produced by
previous systematic review.19 Various ACN, phenolic, and some people.81 The combination of Uros with raspberry
ellagitannins metabolites were found in low concentrations in ketone metabolites as part of a multimarker panel may be
plasma and urine such as cya-3-glu, hippuric acid, ferulic acid, specific enough to distinguish raspberry consumption from
phenyl acetic acid, Uros and ellagic acid derivatives; however, other foods such as strawberries. More efforts are needed to
these metabolites are not specific to raspberry consumption. investigate the presence and metabolic fate of raspberry
Some animal models detected the formation of raspberry ketones in humans and to determine whether they may be
ketone 4-(phenylhydroxyphenyl)-2-butanone and its deriva- suitable biomarkers for raspberry intake.
tives 4-(4-hydroxyphenyl)butan-2-ol and 4-OH-PA in urine 3.2.4. Strawberries. Twenty papers were included inves-
and they have been proposed as BFIs for raspberries.75 These tigating biomarkers of strawberry intake in the review of
ketones can be rapidly absorbed from the gastrointestinal tract Ulaszewska et al.19 Pelargonidin and Uros derivatives were
and are found exclusively in raspberries. To date, raspberry suggested as BFIs of strawberry. Besides, aromatic compounds
ketone metabolites have been detected in animal models but such as furaneol and mesifurane were also proposed to be used
not in humans. Nevertheless, due to the widespread use of as BFIs for strawberries. However, all of these metabolites lack
raspberry ketone as a food additive, it is not suitable to be used specificity. A multi-BFIs including pelargonidin glucuronides,
as single biomarkers for raspberry consumption. The use of Uros, furaneol, or mesifurane derivatives was proposed as an
raspberry ketones along with other raspberry-derived metab- adequate biomarker for strawberry intake. One drawback of
olites such as Uros has been proposed as a multi-BFIs for this proposed approach is the lack of commercially available
raspberry intake in the previous systematic review. The authors standards for pelargonidin glucuronide. In this review, 3
concluded that human studies are needed to validate these additional studies investigating biomarkers of strawberry intake
metabolites for use as BFIs of raspberries.19 Our systematic were found.82−84 All were chronic interventions (≥4 w) that
review captured 4 new publications investigating the raspberry used reconstituted freeze-dried strawberry powder (25−26 g)
metabolome.77−80 Two studies from the same research as treatment. In Zhao et al.,84 a total of 81 bile acids were
group77,78 collectively measured up to 123 (poly)phenolic analyzed in plasma, urine and feces collectively after 4 w of
metabolites in plasma and urine of individuals with prediabetes strawberry consumption. Several secondary bile acids,
after a single-dose and after a month of daily raspberry deoxycholic acid, lithocholic acid (and their glycine con-
consumption. Their targeted analyses revealed that several jugates), and glycoursodeoxycholic acid decreased upon
metabolite groups including ACN, Uros, ph-γ-VLs and intervention. While interesting, it is difficult to recommend
phenolic acids were significantly changed after raspberry primary bile acids as BFIs due to them being internally
consumption. Cya-3-sophoroside (cya-3-sop), cya-3-rut, and synthesized.85 Even though secondary bile acids are regarded
cya-3-glu were found as the major ACN. Despite ACN being as bacterial metabolites of the gut microbiota,86 they still lack
established as the most abundant (poly)phenols in berries, specificity due to their endogenous nature. After 4 weeks of
they inherently suffer from low bioavailability. They are also intake, Huang et al. identified 17 plasma phenolic metabolites
J. Agric. Food Chem. 2023, 71, 11789−11805
in patients with hypercholesterolemia.82 These included clinical trials on blackcurrants and BFIs. In our review, only
various phenolic acid groups and their derivatives (Table 1) one additional study explored the bioavailability of plasma
which have already been ruled out as candidates in the phenolic acids after an acute single-dose intake of black-
previous review for being common metabolites for many fruits currant.95 In this study, gallic acid (GA) and protocatechuic
and vegetables. In the last study,83 pelargonidin-3-glucuronide acid (PCA) increased in plasma after blackcurrant con-
(pel-3-gluc) found in both plasma and urine further reinforces sumption. However, the participants in this trial were not
its standing as a strong BFI candidate for strawberries as asked to follow a restricted low (poly)phenol diet during the
proposed in the previous review alongside Uro A detected in trial, and GA and PCA were also detected in their baseline
urine samples. In summary, no additional strawberry BFI plasma. GA and PCA are phenolics compounds that appears in
candidates were found to fit the proposed multimetabolite biofluid samples as a result of gut microbiota metabolism after
panel. Generally, the copresence of Uros and ACN derivatives the consumption of many other (poly)phenol-rich fruits and
in plasma and urine could be considered as an indicator of foods.96,97 In line with the previous review, specific BFIs for
strawberry and/or raspberry intake. However, the timing of blackcurrant intake are still lacking. Further studies are much
sample collection should be taken into consideration, as Uros encouraged to identify new candidates for blackcurrant intake.
and ACN have very different half-lives in blood and urine. As 3.2.6. Blackberries. Five studies98−102 were included in the
mentioned previously, ACN can rapidly degrade and disappear previous review to examine BFIs of blackberry intake. Like
from the circulation within 6h, while Uros have a Cmax of 24h other Rubus fruits, blackberries are rich in ellagitannins and
post consumption. Furthermore, the high interindividual ACN. The main metabolites detected in plasma and urine in
variability in the metabolism of Uros needs to be taken into these studies were derivatives of cyanidins and ellagitannins,
consideration, in particular for Uro B and Isouro A derivatives, such as cya-3-gluc, cya-3-glucoside, cya-3-rut, Uro A gluc, Uro
as it is estimated that in adulthood, only between 15% to 45% B gluc, and ellagic acid. Nevertheless, these metabolites are not
of the population produce such metabolites after ellagitannin specific to blackberries, as previously discussed for raspberries
consumption.81 This is an important limitation when they are and strawberries. The authors of the previous systematic
used as biomarkers of berry consumption. As it currently review suggested evaluating the Rubus fruits as a group and
stands, the panel consists of pelargonidin, pelargonidin considering ellagitannins that conjugated with the ester of
glucuronide, mesifurane sulfate, furaneol glucuronide, and sanguisorboyl group as BFI. In this systematic review, only one
furaneol sulfate. These metabolites are reasonably unique to small pilot study was found which evaluated the metabolic fate
strawberries and together with Uro A derivatives to form the of blackberry (poly)phenols on 2 participants who consumed a
proposed multi-BFIs for strawberries (Table 2). blackberry juice as single dose.103 They detected sulfated
cyanidin derivatives in 24 h urine that are not specific to
Table 2. Summary of Proposed Biomarkers of Berry Intakea blackberry. Thus, we still need more studies, ideally with
untargeted metabolomics, to discover the potential BFIs of
Berries Suggested BFIs blackberries.
Blueberries No specific BFIs 3.3. Final Remarks and Implications. This systematic
Suggested multibiomarker panel: review provides an update on the current knowledge on
Hippuric acid biomarkers of berry intake. The previous review established
Malvidin glycosides tentative multi-BFI panels for cranberries, raspberries, and
Cranberries No specific BFIs strawberries but failed to find suitable metabolite candidates
Suggested multibiomarker panel: for blackcurrants, blueberries, and blackberries. The results of
Peonidin and cyanidin glycosides our search are generally aligned with their findings. In addition,
ph-γ-VL- sulfate and glucuronide conjugates we propose a potential multi-BFI panel for blueberries
Raspberries No specific BFIs consisting of hippuric acid and malvidin glycosides. We
Suggested multibiomarker panel: however acknowledge the limitation of the use of intact
Raspberry ketone sulfate/glucuronide anthocyanins as biomarkers of intake due to their low
Uro A/Uro A gluc bioavailability in biofluids and their natural instability. Our
Strawberries No specific BFIs search confirms that BFIs specific to blackcurrants and
Suggested multibiomarker panel: blackberries have yet to be discovered. Figure 2 depicts a
Pel/Pel-3-gluc summary of our newly proposed BFIs on top of previous
Uro A/Uro A-gluc suggestions for intake of blueberries, cranberries, raspberries,
Furaneol glucuronide/Furaneol sulfate/Mesifurane sulfate and strawberries.
Blackcurrants No specific BFIs or multibiomarker panel available Berries can be consumed in different forms such as fresh,
Blackberries No specific BFIs or multibiomarker panel available freeze-dried, juiced, and frozen. Freeze-drying is a technique
a
ph-γ-VL: phenyl-γ-valerolactone, Uro A: urolithin A, Uro A gluc: that has shown to preserve (poly)phenols content without
urolithin A glucuronide, Pel: pelargonidin, Pel-3-gluc: pelargonidin-3- significant biotransformation.104 Although administering ber-
glucuronide. ries in different formats may have a significant impact on
bioavailability due to the effects of the food structure and the
3.2.5. Blackcurrants. Eight studies17,87−94 investigating food matrix,105 this is unlikely to have meaningful effects on
blackcurrant biomarkers of intake were discussed in the the metabolism of berry (poly)phenols, although this needs to
previous review. Two main ACN (cya-3-rut and delp-3-rut) be confirmed in future studies. Another important aspect to
were identified in urine. In plasma, these two ACN were also consider when investigating biomarkers of intake in acute and
identified alongside cya-3-glu and del-3-glu. There were no chronic consumption studies is that changes in the gut
bioavailability studies conducted on other blackcurrant microbiota population or diversity due to continuous exposure
phytochemicals in humans, which warrants the need for future to berry (poly)phenols may lead to changes in gut microbial
J. Agric. Food Chem. 2023, 71, 11789−11805
Figure 2. Venn diagram illustrating previously proposed BFIs alongside the new BFIs suggested in the current systematic review.
metabolism and therefore changes in the metabolites found in burden for participants, but it is considered a viable alternative
biofluids. Therefore, both acute assessments, which have the for 24 h urine for dietary exposure biomarkers.107 While urine
advantage of a much better control over background diet, sampling does not capture (poly)phenols excreted through
coupled with sustained or long-term monitoring is recom-
alternative routes, combining plasma sampling with urine
mended.
In the current systematic review, 11 studies were conducted sampling may be the preferable approach for measuring
in healthy individuals while 7 were conducted in individuals at (poly)phenols as biomarkers of intake.
risk of chronic diseases or under medication. Currently, little is Many of the detected metabolites in the studies reviewed
known about how medication or pathological states may affect here were present in a conjugated form. The metabolism of
the metabolome upon consumption of berries and whether this (poly)phenols involves the conversion of (poly)phenols into
differs from healthy individuals. To maximize the general simple aglycones in the gastrointestinal tract, followed by phase
applicability of biomarkers of intake, it is crucial to validate
II metabolism with additional modifications such as methyl-
them in diverse study populations. Across the studies reviewed,
we also noticed a huge variation in the sampling interval used ation, sulfation, and glucuronidation. Enzymes like Catechol-
to collect biological samples. When optimizing detection of O-methyltransferase (COMT), sulfotransferases (SULT), and
(poly)phenols metabolites, it necessary to consider their uridine-5′-diphosphate glucuronosyltransferases (UGT) play
individual time to reach maximum concentration (Tmax) and essential roles in these processes, transferring methyl, sulfate,
half-life (T1/2). These are crucial points to help inform the and glucuronic acid groups to the aglycones, respectively.108,109
optimum sampling interval for maximizing detection and The specific conjugates formed can vary based on the
quantification. It can become challenging or problematic when
compound’s nature and available sites for conjugation.110
many metabolites are simultaneously being monitored
especially in a multi-BFI approach in which the sampling In conclusion, there is currently no singular biomarker that
interval for each metabolite has to be optimized. can be confidently linked to individual berries. The multi-
BFIs detected in this systematic review included both blood biomarker approach appears to be the best option for
and urine metabolites. The assessment of (poly)phenols estimating berry consumption, although concerns about the
metabolites excreted through urine is commonly used and specificity of current proposed panels still exist for all berries
typically consistent with the data obtained from plasma.106 investigated here. Untargeted metabolomic studies coupled to
However, 24-h urine sampling offers advantages over plasma
well conducted acute and chronic feeding studies using
measurements, providing a more accurate evaluation of total
(poly)phenols absorption and better tracking of (poly)phenols adequate biofluid sample collection in different study
with short and long half-lives.106 On the other hand, a study populations may help improve current knowledge in berry
suggested that spot urine not only provides a lower collection biomarker discovery.
J. Agric. Food Chem. 2023, 71, 11789−11805
■ ASSOCIATED CONTENT
* Supporting Information
sı
10.13039/501100011033 and CIBERFES, CB16/10/00269,
from the Instituto de Salud Carlos III all of them by “ERDF A
The Supporting Information is available free of charge at way of making Europe”, and La Marató de TV-3 (553/C/
https://pubs.acs.org/doi/10.1021/acs.jafc.3c01142. 2019). The Generalitat de Catalunya’s Agency AGAUR of
2021SGR00687. Maria de Maeztu Unit of Excellence grant
Systematic search was conducted using three electronic
(CEX2021−001234-M) funded by (MICIN/AEI/FEDER,
databases, in accordance with the PRISMA statement, to
UE). CAL thanks ICREA Academia Award. HM thanks the
identify relevant studies: details of the search strategy
scholarship and travel grants from the University of Barcelona
and the databases searched (PDF)
(APIF) and Institut de Nutrició i Seguretat Alimentària
■ AUTHOR INFORMATION
Corresponding Authors
(INSA) de la Universitat de Barcelona, for the scholarship and
travel grants.
Notes
Cristina Andres-Lacueva − Biomarkers and
Nutrimetabolomics Laboratory, Department of Nutrition, The authors declare no competing financial interest.
Food Sciences and Gastronomy, Nutrition and Food Safety
Research Institute (INSA), Facultat de Farmàcia i Ciències
de l’Alimentació, Universitat de Barcelona (UB), 08028
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1. INTRODUCTION these metabolites are ubiquitous and can be found in many

Figure 1. Study selection bibliography search flow diagram.

- With MS - 3-meO-PA-4-S - Syringic acid

J. Agric. Food Chem. 2023, 71, 11789−11805

- 5-ph-γ-VL-meO-gluc isomer (3′/4′) - 5-ph-γ-VL-3′-S

J. Agric. Food Chem. 2023, 71, 11789−11805

15 participants 16 identified metabolites - 4-OH-5-(OH-ph)-VA-S

J. Agric. Food Chem. 2023, 71, 11789−11805

Identified in a previous study111

J. Agric. Food Chem. 2023, 71, 11789−11805

J. Agric. Food Chem. 2023, 71, 11789−11805

20 participants 2 identified metabolites

J. Agric. Food Chem. 2023, 71, 11789−11805

blueberry, respectively), including some phenolic compounds,

BFIs. Additional endogenous metabolites such as glycerol 3-

(107) Wilson, T.; Garcia-Perez, I.; Posma, J. M.; Lloyd, A. J.;

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