Critical Reviews in Food Science and Nutrition

2023, VOL. 63, NO. 22, 5953–5966

https://doi.org/10.1080/10408398.2022.2026291

Review

Current knowledge of anthocyanin metabolism in the digestive tract:

absorption, distribution, degradation, and interconversion
Hailong Guia,b, Lijun Sunc, Ruihai Liua,d, Xu Sia,b, Dongnan Lia,b , Yuehua Wanga,b, Chi Shua,b, Xiyun
Suna,b, Qiao Jianga,b, Yanyan Qiaoa,b, Bin Lia,b and Jinlong Tiana,b
a
College of Food Science, Shenyang Agricultural University, Shenyang, Liaoning, China; bKey Laboratory of Healthy Food Nutrition and
Innovative Manufacturing, Shenyang, Liaoning, China; cCollege of Food Science and Engineering, Northwest A & F University, Yangling,
Shaanxi, China; dDepartment of Food Science, Cornell University, Ithaca, NY, USA

ABSTRACT KEYWORDS
Potential roles for anthocyanins in preventing various chronic diseases have been reported. These Anthocyanins;
compounds are highly sensitive to external conditions and are susceptible to degradation, which metabolism;
increases the complexity of their metabolism in vivo. This review discusses anthocyanin metabolism absorption;
in the digestive tract, phase I and II metabolism, and enterohepatic circulation (EHC), as well as distribution;
interconversion
their distribution of anthocyanins in blood, urine, and several organs. In the oral cavity, anthocyanins
are partly hydrolyzed by microbiota into aglycones which are then conjugated by glucuronidase.
In stomach, anthocyanins are absorbed without deglycosylation via specific transporters, such as
sodium-dependent glucose co-transporter 1 and facilitative glucose transporters 1, while in small
intestine, they are mainly absorbed as aglycones. High polymeric anthocyanins are easily degraded
into low-polymeric forms or smaller phenolic acids by colonic microbiota, which improves their
absorption. Anthocyanins and their derivatives are modified by phase I and II metabolic enzymes
in cells and are released into the blood via the gastrovascular cavity into EHC. Notably, interconversion
can be occurred under the action of enzymes such as catechol-O-methyltransferase. Taking together,
differences in anthocyanin absorption, distribution, metabolism, and excretion largely depend on
their glycoside and aglycone structures.

1. Introduction clarified. This review aims to summarize the existing evi-

As secondary metabolites, anthocyanins are found in many
flowers, fruits, roots, stalks, leaves and seeds, accounting for
a large proportion of natural blue, purple, orange, and red
hues. The types and concentrations of anthocyanins vary
between different locations, seasons, and specific conditions
(De Rosas et al. 2019). Anthocyanins are known to possess
health benefits, including antioxidation, anti-inflammatory,
anti-obesity, antidiabetic, antihypertensive, anti-cardiovascular
disease, anticancer, and neuroprotective properties, mediated
via effects on gene expression, cell signaling, hormone secre-
tion, and enzyme activity (Tian et al. 2019a; Si et al. 2021).
Although the daily intake of anthocyanins is generally
sufficient, many studies have demonstrated their low bio-
availability which means that they cannot be fully absorbed
or utilized. The properties and applications of anthocyanins
have been thoroughly investigated for nearly a century (De
Rosas et al. 2019; Rusishvili et al. 2019; Zang et al. 2021).
Researchers have studied the metabolic processing of antho-
cyanins in the human body to explain the cause of their
low bioavailability and mechanisms of their health benefits,
aiming to determine and maximize these advantageous prop-
erties (Lila et al. 2016; Kalt 2019; Li et al. 2020). However,
many aspects of anthocyanin metabolism remain to be
dence and provide a comprehensive knowledge-base of
anthocyanin metabolism, in order to improve the under-
standing of these compounds and guide future research.
2. Structural features of anthocyanins
Anthocyanins are derived from the oxidation of
2-phenylbenzopyrylium or flavylium salts of polyhydroxyl-
ated or polymethoxylated glycosides or acylglycosides (Mazza
and Miniati 1993). Anthocyanins mainly exist as glycosides
linked with aglycone anthocyanidin-chromophores and com-
mon sugar moieties (including glucose, galactose, arabinose,
rutinose, rhamnose and xylose) bound as mono-, di-, or
trisaccharides and acylated with phenolic or aliphatic sub-
stituents (Mazza and Miniati 1993). Anthocyanidins with
different hydroxyl and methoxyl groups on the B-ring have
been found in nature, the six most common being cyanidin
(Cy), pelargonidin (Pg), peonidin (Pn), delphinidin (Dp),
petunidin (Pt), and malvidin (Mv) (Xie et al. 2018). These
B-ring substituents account for the natural pigmentation of
the aglycones, with increased hydroxyl and methoxyl groups
favoring the blue and red ends of the spectrum, respectively
(Rusishvili et al. 2019) (Figure 1a). In liquid, anthocyanins

CONTACT Bin Li libinsyau@163.com; Jinlong Tian 2017500015@syau.edu.com

Hailong Gui and Lijun Sun made the equal contribution to the article.
© 2022 Taylor & Francis Group, LLC
5954 H. GUI ET AL.

Figure 1. (a) Six common anthocyanidins and their glucoside forms with different substituent groups (in red dotted frames). The corresponding colors of the
anthocyanidins are shown in the background. (b) Anthocyanin metabolism in the human oral cavity according to Mallery et al. (2011). Anthocyanins and
derivatives: C3S, cyanidin-3 sambubioside; C3XR, cyanidin 3-xylosylrutinoside; PCA-G, glucuronidated protocatechuic acid; C3S-G, glucuronidated cyanidin-3
sambubioside. Enzymes: β-glucosidase, LPH, lactase phlorizin hydrolase; UGTs, UDP-glucuronosyl transferases; COMT, catechol-O-methyltransferase; UDP-Glu-DH,
UDP-glucose-dehydrogenase. Transporters: BCRP, breast cancer resistance protein; SGLT1 sodium dependent glucose co-transporter1. Supra enzymes and trans-
porters distribute granual layers, apinous layers, oral muscosa, and terminal ducts of the salivary glands.

present as the flavylium cation under acidic conditions, with
the hemiketal, cis-, and trans-chalcone species appearing at
higher pH when the hydroxyl substituents deprotonate and
yield the respective anionic base. In basic conditions the
different forms can coexist and interconvert to maintain an
equilibrium at different pH levels (Oliveira et al. 2019a).
3. Metabolism of anthocyanins
3.1. Oral cavity: the initial site of anthocyanin
metabolism
Digestion of food, including anthocyanins, begins in the oral
cavity. During the incubation of human saliva, the degradation
of anthocyanins in various berries (blueberry, chokeberry, and
strawberry) ranged from 8 to 90%, with the mean exceeding
10% within 5 min (Kamonpatana et al. 2012, 2014). Losses of
anthocyanins from fluids were relatively low while semisolid
and solid foods with high viscosity, which are retained for
longer in the oral cavity, had higher losses. In a recent study,
intact anthocyanins and their metabolites were detected in
blood a few minutes after administration, implying they were
absorbed from the oral cavity (Braga et al. 2018). Some clinical
studies have demonstrated that absorption of drugs is more
efficient from the oral cavity than the intestinal tract (Cury
et al. 2021). The metabolism of anthocyanins in the oral cavity
requires clarification.
Factors impacting anthocyanin metabolism in the oral
cavity may include interference by proteins, cells, and
microbiota. In oral models (including oral cells, saliva and
mucosal pellicle), anthocyanins had greater interaction with
oral constituents than flavanols (Soares et al. 2020). Following
acetonitrile extraction, additional anthocyanins (1–3% initial
amounts) were detected in oral proteins, but much less than
the total loss (>10%) (Kamonpatana et al. 2012). After heat
inactivation or cell-free treatment, anthocyanin degradation
in saliva decreased significantly compared with a control
group (Kamonpatana et al. 2012). Therefore, most anthocy-
anins were lost via hydrolysis by β-glycosidase secreted from
bacteria and oral epithelial cells, as proven by antimicrobial
treatment (Mallery et al. 2011; Kamonpatana et al. 2012).
Aglycones decreased to varying degrees in enzyme-free arti-
ficial saliva: Pt (10%), Dp (30%), Cy (40%), Pn (50%), and
Mv (50%), depending on their structural instability
(Kamonpatana et al. 2012). The -OH and -OCH3 substituents
in the B-ring of aglycones determine their stability and affect
their degradation in the oral cavity. The degradation rate of
Pg3G was much higher than Pg3R and C3G in saliva, while
C3R was higher than trisaccharide (Kamonpatana et al.
2014). As for the glucoside moiety of anthocyanins, degra-
dation of monosaccharide conjugation was significantly
higher than for di- and trisaccharides (Kamonpatana et al.
2014). Moreover, hexose conjugates had a higher degradation
rate than pentose conjugates in saliva (Kamonpatana et al.
2012). In summary, anthocyanin degradation in saliva appears
to be affected by the aglycone and glycoside moieties.
Anthocyanins had been detected at high levels in saliva
in the oral cavity and can cross the buccal layer to reach

oral cells with a downward trend. (Ugalde et al. 2009). In
alkaline conditions, anthocyanins transform into hemiacetal
and chalcone forms (Fernandes et al. 2015). Chalcone glu-
cosides were detected in saliva during the incubation of
C3G, demonstrating the cleavage of the heterocyclic C-ring
of anthocyanin glycosides prior to their deglycosylation
(Kamonpatana et al. 2012). After deglycosylation by β-D-ga-
lactosidase and β-D-glucosidase from microbiota, anthocy-
anins produced aglycones which were automatically
degraded into phloroglucinol aldehyde (PGA) and proto-
catechuic acid (PCA) (Han et al. 2021). Derived from Cy
rather than C3G, PCA was readily detected in saliva and
its glucuronide form appeared after absorption by oral epi-
thelium, as cyanidin-3 sambubioside (Mallery et al. 2011).
In IHC (immunohistochemistry) analyses, catechol-O-meth-
yltransferase (COMT), UDP-glucuronosyl transferases
(UGTs), UDP-glucose-dehydrogenase (UDP-Glu-DH), breast
cancer resistance protein (BCRP), β-glucosidase, lactase
phlorizin hydrolase (LPH), and sodium-dependent glucose
co-transporter 1 (SGLT 1) were found at the end of the
salivary ducts and stratified squamous surface epithelia
(Mallery et al. 2011), suggesting that the glucuronidation,
methylation or glutathionylation of anthocyanins might
occur in the mucosa. Additionally, arylsulfatase and
β-glucuronidase, two key enzymes responsible for deglucu-
ronidation in phase II metabolism of anthocyanins, were
also detected in human saliva (Mallery et al. 2011). The
identification of these transporters and enzymes shows that
anthocyanin metabolism in the oral cavity is more compli-
cated than previously thought and involves a series of com-
pounds. The possible pathway involved is schemed in
Figure 1b.
The degradation of anthocyanins in the oral cavity is
primarily attributed to enzymatic hydrolysis (especially bac-
terial) and varies with their aglycone/glycoside structures.
After enzymatic hydrolysis, anthocyanin aglycones are more
lipophilic and orally absorbable, and automatically break-
down into PCA due to their instability. LPH and β-glucosidase
(enzymes distributed in oral epithelium, mucosa, and saliva)
catalyze the transformation of anthocyanins into aglycones
except for cyanidin-3 sambubioside whose absorption
depends on transportation by SGLT1. In oral cells, UGTs
induce the glucuronidation of aglycones, anthocyanins, and
PCA, and some products return into the cavity via BCRP
efflux. These glucuronidated compounds undergo deglucu-
ronidation by arylsulfatase and β-glucuronidase in saliva,
producing compounds for next circulation. The existence of
these various transporters and enzymes implies that oral
anthocyanins undergo not just degradation but also absorp-
tion, transportation, derivatization, and EHC. Although sep-
arated by the oral-gut barrier, oral microbiota could reach
the intestinal mucosa when the barrier malfunctions, while
gut-to-oral microbial transmission could happen due to
inter- and intrapersonal manners (Lira-Junior and Boström
2018; Park et al. 2021). Thus, the oral and gut microbial
profiles are likely to have some similarities, leading to sim-
ilar anthocyanin metabolism in the oral cavity and intestinal
tract. Furthermore, the prerequisite of anthocyanin metab-
olites (enzymes and transporters) in oral cells has been
Critical Reviews in Food Science and Nutrition 5955
confirmed in IHC analysis, revealing metabolites appearing
within 5 min. Thus, anthocyanin metabolites are directly
generated in the oral cavity by a combination of oral cells
and microbiota. The transmission of gut metabolites in bio-
logical fluids needs to be verified. The metabolic pathway
of anthocyanins is complicated and, although many products
have been detected, further research in this area is
still needed.
3.2. Stomach: a route for intact anthocyanin
absorption
The acidic gastric juices in the stomach are a favorable
environment for anthocyanin stability and absorption.
Anthocyanins could be rapidly absorbed without hydrolysis
(20–25%) in the stomach and appear in the plasma within
30 min of intake (Mueller et al. 2017). Peak plasma concen-
trations were reached within 0.5–2 h, which was consistent
with the time for emptying the stomach, implying that slow-
ing the gastric emptying rate could significantly improve
anthocyanin absorption (Passamonti et al. 2009). Although
p-hydroxybenzoic acid was detected in rat stomach, this
was due to unstable pelargonidin rather than the action of
the stomach (El Mohsen et al. 2006). In a gastric cell model
(MKN-28, moderately differentiated adenocarcinoma stom-
ach cell), the absorption of anthocyanins was independent
of pH variation and a proton gradient (Fernandes et al.
2012). In the same cell model, anthocyanin transport rates
from jambo, jamelão, and jaboticaba varied over 3 h and
the diglucoside of Cy was in line with Mv but higher than
Dp and Pt, due to differences in stability and initial con-
centration (Marques Peixoto et al. 2016). Among the agly-
cones, Cy is more stable than Dp and Pt due to its fewer
hydroxyl groups, which enhances transportation. The sugar
moiety might play a crucial role in anthocyanin transport
in a gastric cell model, but not the position of additional
glucose residue (Oliveira et al. 2019b). This also explains
the insignificant difference in transport rates between
malvidin-3,5-O-diglc and malvidin- 3,5-O-diglcCoum, as
well as between malvidin-3-O-glc and malvidin-3,5-O-diglc
(Han et al. 2020). In addition, the lower transport efficiency
of malvidin-3-O-glucur showed that the carboxyl group at
the C6” position of the glucose could impede the recognition
of transporters for sugar moiety (Han et al. 2020).
Interestingly, the transport of anthocyanins in extracts was
significantly lower than the purified forms, and the addi-
tional sugar slowed down the transport of anthocyanin. This
demonstrated that there was a competitive relationship
between anthocyanins (or with other compounds) for com-
mon transporters (Oliveira et al. 2015; Han et al. 2020).
Fernandes et al. (2012) concluded that the transport of
anthocyanin in MKN-28 cells was time-consuming and
saturable.
Due to hydrophilicity and size (Mw ≈ 500 g/mol),
anthocyanins are unable to cross the gastric epithelium
via para-cellular absorption. At pH 2, anthocyanins mainly
existed as polar flavylium cations, which impeded their
passive diffusion in the gastric mucosa (Mueller et al.
5956 H. GUI ET AL.

2017). Bilitranslocase, an organic anion carrier, is widely
expressed in the epithelia of the stomach, small intestine,
liver, kidney, and vascular endothelium. This carrier binds
to glycosides of anthocyanins, improving the direct absorp-
tion of the intact molecules. The transport efficiency via
bilitranslocase was related to its affinity with the antho-
cyanin, which particularly depends on the structure of
the anthocyanin’s glycoside portion (Passamonti et al.
2003, 2009). Except for acylated anthocyanins, mono- and
di-glucosylated forms were good ligands for bilitranslocase
(Novotny, Clevidence, and Kurilich 2012). Anthocyanin
absorption from the stomach clearly involves glucose
transporters, as evidenced by the transport rate decreasing
following the genetic silencing of facilitative glucose trans-
porters 1 and 3 (GLUT1, 3) (Han et al. 2020). Other
related transporters had also been detected, including
SGLT1, organic cation transporter 1 (OCT1), organic
anion transporter 2 (OAT2), and sodium/monocarboxylate
transporters (SMCT1, 2) (Fernandes et al. 2012; Oliveira
et al. 2015).
Anthocyanins are stable in the acidic gastric juices (pH
1.5–4), except for the most active types like pelargonidin.
Their absorption is mediated by transporters with rates
depending on the interaction which is influenced by the
anthocyanin structure. In addition, absorption from the
stomach is time-dependent, which means the mitigation of
gastric emptying is a feasible way to increase anthocyanin
absorption and improve their bioavailability.
3.3. Small intestine: the major location of anthocyanin
absorption
As the longest part of the digestive tract, the small intestine
plays a major role in the absorption of nutrients from food.
According to pharmacokinetic data, anthocyanin absorption
was greatest from the jejunum, less from the duodenum,
and negligible from the ileum (Talavéra et al. 2004). In an
intestinal cell model (Caco-2 cells), anthocyanin transport
rates varied among various fruits and anthocyanins, and
bioavailability was low (Liu et al. 2014).
The absorption of anthocyanins from the small intestine
is related to their stability and hydrophobicity, which are
determined by their structure. Differences in their B-ring
substituents (Figure 1) are reflected in their absorption:
Dp has two -OH groups, Mv has two -OCH 3 groups and
Pn has one, which makes Dp more hydrophilic than the
others. The transport rate of hydrophobic anthocyanins
was higher than hydrophilic ones (Liu et al. 2014). The
sugar moiety was crucial for anthocyanin absorption in
cell models, but the position of the glucoside residue was
not (Oliveira et al. 2019b). For instance, the transport
rates of Cy-3,5-O-diglu and C3G in Caco-2 cells were not
significantly different after 2 h (Marques Peixoto et al.
2016), as were malvidin-3-O-glucoside and malvidin-3,
5-O-diglucoside from red wine (Han et al. 2020). The
hydrophilic flavonoid glycosides were hydrolyzed to more
hydrophobic aglycones, which could cross the phospholipid
bilayer cell membranes via passive diffusion or specific
transporter (Chen et al. 2014). LPH from enterocytes
could hydrolyze anthocyanins, releasing the more hydro-
phobic aglycones, which facilitated their absorption by
passive diffusion (Rodriguez-Mateos et al. 2014). The two
main hexose transporters (SGLT1 and GLUT2) had also
been proven to be involved in the absorption of C3G by
Caco-2 cells (Zou et al. 2014). Following treatment of
Caco-2 cells with red grape skin anthocyanins, the expres-
sion of GLUT2 increased and glucose uptake decreased,
which illustrated the competition between anthocyanins
and glucose for the same transporter (Faria et al. 2009).
Hence, enzymes and transporters are both involved in
anthocyanin absorption in intestinal models, facilitating
their entry into enterocytes.
Having entered the enterocytes, aglycones underwent
phase II metabolism, mainly producing glucuro- and
sulpho-conjugates (Manach et al. 2005) with decreased
transmembrane capability. In a study by Chen et al. (2014),
associated transporters mediated the translocation of fla-
vonoids across the cell membrane (Figure 2). ATP-binding
cassette (ABC) transporters played a vital role in the dis-
tribution of many conjugated flavonoids, and ABCC2, sit-
uated on the enterocytes, transported conjugates back to
the gut lumen. Some well-known drug transporters, includ-
ing multidrug resistance-associated proteins (MRPs), BCRP,
organic anion transporters (OATs), organic anion trans-
porting polypeptides (OATPs), P-glycoprotein (P-gp), and
peptide transporters (PEPTs), were extensively distributed
in the small intestine and liver (DeGorter et al. 2012).
Following the translocation of MRPs and P-gp, some
metabolites are returned to the lumen while others travel
to the liver via the bloodstream for further phase II metab-
olism (Dreiseitel et al. 2009). As a result, anthocyanin
conjugates are transported in different directions with spe-
cific transporters in enterocytes. It should be noted that
Figure 2. Schematic representation of anthocyanin derivatization and transport
in the stomach, small intestine, colon, liver, and kidney based on the compre-
hensive knowledge of anthocyanin metabolism.

some anthocyanins in the upper gastrointestinal tract (pH
5.0– 6.5) converted to a combination of hemiketal, qui-
nonoidal, and chalcone forms, which were mainly degraded
to PCA and 2, 4, 6-trihydroxybenzaldehyde via ring fission
(Chen et al. 2019). However, the metabolites of bilberry
anthocyanins in ileal effluent were phloroglucinol aldehyde,
syringic acid, vanillic acid, and 3-O-methylgallic acid
(Mueller et al. 2017). C3G loss and its degradation prod-
ucts were not notably different in the presence and absence
of Caco-2 cells, indicating that the major loss of C3G was
attributable to chemical degradation rather than cellular
action (Faria et al. 2009).
Anthocyanins are absorbed in their intact forms from
the small intestine via glucose transporters or hydrolyzed
into aglycones to facilitate their entry into enterocytes. Some
may be degraded into small phenolic acids under alkaline
conditions. In the enterocytes, anthocyanins and their agly-
cones undergo phase II metabolism and their conjugates
are partly pumped out by efflux transporters (ABCC2,
MRPs, and P-gp) while other hydrophilic and hydrophobic
metabolites move with the help of transporters (ABC, BCRP,
OATs, OATPs, and PEPTs) into capillaries and/or lymph
vessels, for further transport (Kalt 2019).
3.4. Phase I and II metabolism and enterohepatic
circulation of anthocyanins
3.4.1. Phase I and II metabolism of anthocyanins
Most compounds including anthocyanins, undergo metabolic
transformation in vivo (particularly in the liver), involving
phase I (demethylation, hydrolysis) and phase II (glucuro-
nidation, sulfation, methylation) metabolism. Metabolic
enzymes, including cytochrome P450 1 A (CYP1A), UGTs,
COMT, and sulfotransferases (SULTs) are highly expressed
in the liver and small intestine. UGTs produced glucuronic
conjugates with improved hydrophilicity facilitating their
excretion in urine and bile (Rowland, Miners, and Mackenzie
2013). SULTs also increased the hydrophilicity of substrates
via sulfation and were regulated by low concentrations of
flavonoids in vivo (while UGTs are not) (Huang et al. 2009).
Unlike the above enzymes, COMT increased the lipophilicity
of its substrates, enhancing their accumulation in tissues
(Chen et al. 2014). Conjugations via glucuronidation was
very common for anthocyanins, with products being iden-
tified at a high concentration in the circulatory system.
Methylation could convert C3G into Pn3G (the methylic
form of C3G) after a high intake of C3G (Talavéra et al.
2003; Fornasaro et al. 2016). In contrast to glucuronidation
and methylation, sulfation had been less reported, with fewer
sulfated metabolites being identified (Straßmann, Passon,
and Schieber 2021). Phase I metabolism is less important
than phase II in the distribution of flavonoids. Mediated by
CYPs, phase I metabolism oxidized flavonoids via demeth-
ylation and hydroxylation, creating additional reactive sites
for phase II conjugation (Chen et al. 2014). CYPs were
widely spread in tissues, especially in liver. CYP1A2 mainly
modulated the hydroxylation and demethylation of flavo-
noids at positions 3′ and 4′ of the B-ring, respectively
(DeGorter et al. 2012). However, this CYP metabolism was
Critical Reviews in Food Science and Nutrition 5957
only detectable after consumption of a high dose flavonoids
or when administered intravenously, which could saturate
the phase II enzymes (Chen et al. 2014).
After absorption, anthocyanins and their aglycones were
conjugated in phase I and II metabolism by various enzymes,
changing their hydrophilicity for elimination or accumula-
tion. These conjugations are affected by the saturation level
of anthocyanin. The quantity and quality of anthocyanin
derivatives are related to both their concentration and mode
of administration. Derivatives from anthocyanins commonly
appeared as glucuronide, methyl- and sulfoconjugates in
urine, blood, intestinal epithelia, liver, and kidney (Kay,
Mazza, and Holub 2005; Di el al 2017; Tian et al. 2019b;
Netzel, Wright, and Sultanbawa 2020). Conjugates were gen-
erally more abundant than their native compounds in vivo,
showing their health benefits were associated with antho-
cyanins (Williamson and Clifford 2010). Studies of this
aspect of anthocyanin metabolism are limited and further
exploration of these mechanisms are needed.
3.4.2. Enterohepatic circulation of anthocyanins
As described above, a proportion of anthocyanin conjugates
within enterocytes are pumped out by efflux transporters
and then are transported to the liver via the bloodstream
where they undergoe EHC. Radiolabeling techniques have
demonstrated the participation of anthocyanins in EHC by
detecting them in bile. Furthermore, the jejunum (the main
site of EHC) had also been shown to be a major site of
anthocyanin absorption (Verediano et al. 2021).
Pharmacokinetic studies show that EHC was crucial for
compounds to amplify their bioactivity by increasing their
distribution and prolonging the half-life of their glucuronide
and sulfated metabolites (Zhou et al. 2019). Bile acids could
be recycled over 20 times via EHC and anthocyanins in
bile could be retained for a long time, repeatedly undergoing
phase II metabolism (Lila et al. 2016). Some anthocyanins
generate multiple derivatives are retained for varying lengths
of time. Di-, tri-, and higher conjugated derivatives have
been detected in many studies, indicating that they have
been conjugated and recycled during repeated EHC
(Fornasaro et al. 2016). Anthocyanins are translocated into
enterocytes via transporters, are conjugated by enzymes like
UGTs, and some products are returned to the lumen via
efflux transporters (this is termed enteroenteric circulation).
The remaining metabolites enter the venous system along
with anthocyanins from the stomach, bind with serum albu-
min, and travel to the liver for further conjugation (Cahyana
and Gordon 2013). Following conjugation, anthocyanin
derivatives could leave the hepatocytes with the help of
efflux transporters, and were excreted into the bile. Some
were hydrolyzed to aglycones which could be directly reab-
sorbed by the small intestine or degraded to low molecular
weight aromatic acids under the action of colonic microbiota
(Banaszewski et al. 2013). The rest are ultimately excreted
via the urine. This process is illustrated in Figure 3.
Under EHC, different doses of anthocyanins activate
phase I and II enzymes to differing degrees, resulting in
different products and conjugates after recycling many times.
5958 H. GUI ET AL.
Figure 3. Simple schematic representation of anthocyanin metabolism in the
digestive system.
Compared with pharmaceutical drugs undergoing EHC,
anthocyanins are more susceptible to degradation and deri-
vatization, which increases the analytical challenge. However,
EHC is indispensable for anthocyanins to perform their
functions at low concentrations over extended periods.
3.5. Colon: the primary site of anthocyanin
degradation
The colon (the distal gastrointestinal tract) is the major
habitat for microbiota in the human body, with more than
a trillion microorganisms having a symbiotic relationship
with their host (Kataoka 2016). Equipped with large amounts
of enzymes, the gut microbiota has a powerful capacity to
degrade and absorb nutrients. Some anthocyanins in food
matrices are hard to degrade and/or absorb in the upper
gastrointestinal tract but easy for gut microbiota to decom-
pose into small, absorbable phenolic acids. It has long been
speculated that the colon had a major role in anthocyanin
metabolism (Selma et al. 2020).
The initial action of gut microbiota on anthocyanins was
deglycosylation (producing aglycones) catalyzed by α-L-rham-
nosidase and β-D-glucosidase and was dependent upon the
type of glycoside (Ozdal et al. 2016). At neutral pH, antho-
cyanins with multiple glycosides were first degraded into
mono-glycoside forms, then into aglycones which were auto-
matically transformed into quinoid bases and to an aldehyde
and a phenolic acid via an α-diketone intermediate (Kay,
Kroon, and Cassidy 2009; Nagar, Okun, and Shpigelman
2020). In vivo, gut microbiota not only hydrolyzed the gly-
cosylated group of anthocyanins, but also cleaved the antho-
cyanidin heterocycle (from C-ring), producing benzoic acids
(from B-ring) and phloroglucinol derivatives (from A-ring)
(Fernandes et al. 2015). Thus, different combinations of
anthocyanin monomer could decompose into various phenolic
acids and aldehyde metabolites (Tian et al. 2019b). The main
metabolites produced by intestinal probiotics from cyanidin
glycosides were 2,4,6-trihydroxybenzaldehyde, ρ-coumaric,
protocatechuic, vanillic acids, and phenolic conjugates (e.g.,
hippuric, phenylacetic, and phenylpropenoic acids) (Ludwig
et al. 2015; Mueller et al. 2017), while delphinidin-based
anthocyanins yielded 2,4,6-trihydroxybenzaldehyde, gallic, and
syringic acids. The main metabolites of malvidin, pelargonidin,
and peonidin glucosides were syringic, 4-hydroxybenzoic, and
vanillic acids, respectively (Eker et al. 2019; Dharmawansa,
Hoskin, and Rupasinghe 2020). Some phenolic acids could
be converted further by gut microbiota. For example, esters
of caftaric acid, chlorogenic acid, and caffeic acid were con-
verted to 3-(3′-hydroxyphenyl) propionic acid and benzoic
acid (Ozdal et al. 2016). These microbial metabolites could be
reabsorbed for further metabolism or excreted via the urine.
Large numbers of anthocyanin metabolites have greater
chemical and microbial stability than their parent com-
pounds, along with antioxidant and other physiological
properties. It had been proven that some anthocyanin
metabolites produced by colonic microbiota possessed higher
bioavailability and bioactivity than their parents (Chen et al.
2017; Nagar, Okun, and Shpigelman 2020). Additionally, the
interaction between gut microbiota and anthocyanins and
their derivatives is a “win-win” situation—nutrient metab-
olism is enhanced and the composition of the microflora
is modulated by the promotion of beneficial bacteria and
suppression of detrimental bacteria. For instance, anthocy-
anins from black raspberry induced the growth of
Eubacterium rectale, Faecalibacterium prausnitzii and
Lactobacillus, and the inhibition of Desulfovibrio spp. and
Enterococcus spp. (Chen et al. 2017). Moreover, gut metab-
olites from anthocyanins stimulated macrophage reverse
cholesterol transport and prevented atherosclerotic lesions
in gut, indicating that some bio-functions of anthocyanins
were mediated by the microbiota (Tian et al. 2019b).
Consequently, the metabolism of colonic microbiota is vital
for the bioavailability and bioactivity of anthocyanins and
their health benefits.
However, the health benefits of anthocyanins can be
unpredictable due to several uncontrollable points including
human individuality (genetic makeup, physiological status,
etc.), lifestyle (physical activity, dietary pattern, etc.), meth-
odological approach, evaluation system (trial designs, ana-
lytical protocols, measurement procedure, etc.), and the
interactions of microflora and anthocyanins (Cortés-Martín
et al. 2020). These factors combine to affect the quality and
quantity of gut metabolites, resulting in variable health

benefits. Polyphenol-related metabotypes may well reflect
the character of the microflora impacting on health.
Metabotype was an effective way to predict the status of
gut microbiota and achieve the clustering of subjects, thus
avoiding the interference from individual variations in the
verification of bioactive compounds (Cortés-Martín et al.
2020). Although the major phenolic acids arising from some
aglycones had been confirmed, these may also be derived
from other compounds in vivo. Anthocyanins are susceptible
to external derivers and give rise to a huge number of
metabolites which are subject to mutual transformation by
enzymes and microbiota (Figure 4). The metabolic pathway
of anthocyanins is, therefore, more complex than other phe-
nolic acids. Some complex interactions between microbiota
and phenolic metabolites may be clarified by the application
of “big data” analyses and developing “-omics” approaches.
However, it is almost certain that conversion pathways have
been oversimplified (Williamson, Kay, and Crozier 2018).
Multiple factors influence the production of metabolites,
from the profile of the gut microbiota to the chemical struc-
tures of the anthocyanins, and much research is still required
to clearly elucidate these pathways.
3.6. Distribution of anthocyanins and derivatives in
tissues
3.6.1. Distribution in tissues
Although the bioavailability of anthocyanins is very low,
their accumulation in tissues is detectable. After a four-week
Figure 4. Proposed pathways for the conversion of cyanidin-based anthocyanins to phenolic acids and related compounds. Compounds in red are major
components in 0–24 h urine. Based on published data (Borges et al., 2018; Czank et al. 2013; De Ferrars et al. 2014a; González-Barrio, Edwards, and Crozier
2011; Jaganath et al. 2006; Ludwig et al. 2015; Nurmi et al. 2009; Ottaviani et al. 2016; Pereira-Caro et al. 2014a, 2014b, 2015, 2016, 2017).
Critical Reviews in Food Science and Nutrition 5959
diet including blueberry, anthocyanins were detected in
pig plasma, urine, and tissues (eyes, liver, cortex, and cer-
ebellum at 1.58, 1.30, 0.88, and 0.66 pmol/g, respectively)
(Kalt et al. 2008). Unexpectedly, anthocyanins were also
detected in the control group on a grain diet (equivalent
to 0.0002% blueberry powder). The glucuronide forms of
Cy, Mv, Pn, Dp, and Pt were detected in different regions
of the pig brain after eight weeks on the blueberry diet
(Milbury and Kalt 2010). Pn3G, C3G and galactosides of
Cy, Mv, Dp, and Pt accumulated in young swine tissues in
a dose-dependent manner during a three-week bilberry diet
(Chen et al. 2015). Following a fifteen-day blackberry diet,
anthocyanins appeared in various organs of rats (jejunum,
stomach, kidney, liver, brain, and even bone tissues), and
their methylated and glucuronidated forms were partic-
ularly concentrated in the jejunum (Talavéra et al. 2005;
Janle et al. 2010). It is noteworthy that the anthocyanins
were most concentrated in the kidney and bladder, then
in the liver, even cross the blood-brain barrier (some in
glycoside forms), but were not found in the retroperito-
neal fat (Kirakosyan et al. 2015). When equilibrium of
anthocyanin levels in plasma and liver was achieved, con-
centrations in kidney were almost three times higher than
in plasma, indicating the reabsorption of anthocyanins by
the kidney (Vanzo et al. 2008). Cy was the most abundant
anthocyanidin, and C3G was more widely distributed than
other anthocyanins in nature (Bendokas et al. 2020). C3G
preferred peripheral spaces to systemic circulation and had
a long residence time in rats. Its derivatives include Cy,
Pn, Pn3G, and their glucuronide and methyl conjugates
5960 H. GUI ET AL.
(Czank et al. 2013; Fornasaro et al. 2016). Mv contains
two methoxy groups and is the largest and most hydro-
phobic aglycone of the six common anthocyanidins. After
drinking blueberry juice, 75% of the anthocyanins in vol-
unteer urine were glycosides of Mv while the rest were
methyl and glucuronide conjugates of common aglycones
(Kalt et al. 2017). Compared with other aglycones, Dp has
the highest antioxidant activity due to its three hydroxyl
groups on the B-ring (Ali, Almagribi, and Al-Rashidi 2016).
Glucuronidation of anthocyanins is common in vivo. Mv
and Dp glucuronides were 6–48 times more abundant than
Cy, Pn, and Pt glucuronides in various regions of the brain
(Milbury and Kalt 2010). Dp3G was more prone to con-
version to glucuronic forms and accumulation in the brain
(Milbury and Kalt 2010).
The accumulation of anthocyanins and conjugates in vivo
follows time- and dose-dependent patterns. Generally, the
order of anthocyanin concentrations in tissues is consist
with metabolic pathways (Figure 5a). At equilibrium, con-
centrations of anthocyanin in plasma are proportional to
those in kidney, liver, and brain. Moreover, anthocyanin
distribution (especially glucuronides and methyl conjugates)
varies with aglycone status, due to their different binding
capabilities in vivo.
3.6.2. Concentrations in circulating blood
Generally, anthocyanins appear rapidly in the blood.
Maximum concentrations were reached within 0.5 h and
ranged from 1.4 to 592 nmol/L over 0.5 to 4 h. The max-
imum in urine (202.74 ± 85.06 µg) appeared after
3.72 ± 0.83 h (Kay, Mazza, and Holub 2005). Almost one
third of anthocyanins in blood and urine were in their
parent form and the rest were conjugated forms (Kay,
Mazza, and Holub 2005), including aglycones, methylated,
sulfated, and glucuronidated forms (Czank et al. 2013;
Wiczkowski, Szawara-Nowak, and Romaszko 2016; Kasote
et al. 2019).
Figure 5. (a) The order of anthocyanin elimination and accumulation in vivo according to published data. (b) Schematic representation of anthocyanin inter-
conversion in vivo based on Fornasaro et al. (2016).
After administrating 13C-labeled C3G, over half the
labeled compounds remained in the human body after 48 h
with the rest being excreted in urine (5.4%), breath (6.9%
exhaled as CO2), and feces (32.1%) (Czank et al. 2013). The
profile of C3G metabolites distributed in serum, urine, and
feces is shown in Table S1 (Czank et al. 2013). Phenolic
products in blood were more likely to be conjugated via
glucuronidation or sulfation than their parent anthocyanins.
The glucuronide and methylated anthocyanins in urine
demonstrate their participation in phase II metabolism. In
feces, the disappearance of some conjugates and the appear-
ance of phenolic acids derived from breakdown of the A-
and B-rings suggest that some metabolites may be reabsorbed
via EHC or degraded by gut microbiota in the colon. For
instance, after oral administration of Pg3R, demethylated
Pg3R (from the action of gut microflora) was much higher
than Pg3R-monoglucuronide and hydroxylated Pg3R in
plasma (Xu et al. 2021).
In a study by De Ferrars et al. (2014b), some acids
appeared in urine rather than plasma while some were
detected in plasma but not urine, indicating they under-
went further metabolism in tissues or were eliminated via
the biliary route or catabolized by colonic microbiota to
be reabsorbed or excreted. Although some metabolites,
such as hippuric acid, 2-, 3- and 4-hydroxybenzoic acid,
and benzoic acid-4-glucuronide, may be derived from other
endogenous sources, they are still regarded as urinary bio-
markers in anthocyanin metabolism (Khanal, Howard, and
Prior 2014; Liu et al. 2020). Parts of the metabolic pathway
of certain anthocyanins may differ due to specific struc-
tural differences. Based on the current information, the in
vivo pathways of anthocyanin derivatization are summa-
rized in Figure 4. Significantly, some anthocyanin deriva-
tives have more potential as health treatments than their
parent forms due to their superior absorption, size, and
stability. Considering the powerful antioxidant properties
of anthocyanins and the advantages of their being safe,
natural pigments, researchers improve anthocyanin

bioavailability with food ingredients (protein, peptides,
polysaccharides and lipids) via non-covalent bonding.
3.6.3. Anthocyanin interconversion in vivo
The addition and removal of -OH and -OCH3 substituents
are common in vivo and can facilitate the interconversion
of anthocyanins. The production of Pn from Cy is com-
mon in many studies but other anthocyanin interconver-
sions are rare. Fornasaro et al. (2016) gave rats 668 nmol
C3G intravenously and observed the appearance of Pn3G
and M3G after a rapid decrease of C3G in plasma. Dp3G
appeared transiently after 2 min with small amounts of
Pt3G at 5 min while Pg3G remained throughout the trial.
The AUC ranking was C3G > M3G > Pn3G > Pg3G in
plasma, and C3G > Pt3G > Pn3G in brain. Despite these
differing profiles, C3G concentration in plasma correlated
linearly with brain. In another study, metabolites of Pg,
which was not common in blueberry, were detected in
urine after drinking blueberry juice (Kalt et al. 2017). In
a metabolic study of pelargonidin-based anthocyanins, Xu
et al. (2021) detected higher levels of demethylated metab-
olites than their hydroxylated and monoglucuronide forms.
These results imply the existence of anthocyanin inter-
conversion in vivo, which could be achieved via enzymatic
reaction. The corresponding products appear so rapidly
that gut microflora with the capacity for dehydroxylation
and demethylation may not be responsible for this inter-
conversion. Except for the role of microbiota in upper
gastrointestinal tract, the mammalian CYP enzymes dis-
cussed above are responsible for the hydroxylation and
demethylation of flavonoids at positions 3′ and 4′ of the
B-ring and COMT is responsible for the methylation of
anthocyanins. This may be sufficient to account for antho-
cyanin interconversion. A possible pathway of intercon-
version is illustrated in Figure 5b.
4. Challenges and opportunities for metabolic
studies
Anthocyanin metabolism has been studied for a hundred
years, but several challenges still remain. Firstly, availability
of anthocyanin monomer is limited. To date, more than 700
anthocyanins have been identified in nature and the mix-
tures commonly encountered in research studies severely
hinder the elucidation of their mechanisms. Anthocyanins
are mainly extracted and isolated from plant tissues, which
is time consuming, labor intensive, and difficult on an
industrial scale. In metabolic studies, a large number of
anthocyanin monomer is required, but only the common
anthocyanin C3G can satisfy this. Engineered bacteria could
be an alternative source of anthocyanins offering fast,
high-yield, controllable, and stable production (Zha et al.
2018). For example, Cress et al. (2017) optimized the pro-
duction of up to 56 mg/L peonidin 3-O-glucoside in E. coli
by increasing the availability of S-adenosyl-L-methionine.
Lim et al. (2015) maximized production of (+)-catechin and
UDP-glucose (a key metabolic limiting factor) and
Critical Reviews in Food Science and Nutrition 5961
optimizing culture and induction conditions, obtaining a
final C3G titer of 350 mg/L. Anthocyanin biosynthesis using
engineered bacteria is a promising route, but has, so far,
been limited to production of derivatives by E. coli. (Zha
et al. 2018). There is a long way to go to achieve
industrial-scale production of anthocyanin monomers. The
second challenge is the various factors that may impact
anthocyanin metabolism. Human studies offer limited sam-
ple types (blood, urine, and feces) and anthocyanin bio-
availability was affected by food matrix, food processing,
metabolizing enzymes and gut microbiota (Eker et al. 2019).
Furthermore, methodological approaches and evaluation
systems can be incompatible resulting high inter and
intra-individual variation, and even contradictory results in
some studies. General pharmaceutical studies demonstrate
that greater numbers of comparable subjects are required
in treatment groups to avoid these drawbacks. In vivo ani-
mal experiments allow greater control of anthocyanin metab-
olism, but although input dosages are lower than in human
studies, it is still difficult to recover practical quantities of
anthocyanin monomers. Furthermore, animal studies can
be expensive, time-consuming, and laborious. Model systems
utilizing cell lines such as MKN-28 cells and Caco-2 cells
are now commonly applied in anthocyanin studies to replace
in vivo tissues. Japanese scientists have also established a
repeatable way to create multi-cellular human liver organoids
that can be used for in vitro drugs efficiency testing (Ouchi
et al. 2019). Notably, human embryonic stem cells have the
potential to differentiate into every cell type found in the
body. Researchers have utilized this unique potential to
replace damaged or missing cells, aiding the healing of some
diseases (Klimanskaya, Kimbrel, and Lanza 2014).
Furthermore, 3 D printing has made cell culture possible in
complex three-dimensional biomimetic structures that
enhanced cell behavior and function (Zhu et al. 2016). This
technology has been successfully applied in the simulation
of human intestinal tissues (Madden et al. 2018) and bone
(Bandyopadhyay, Mitra, and Bose 2020). The combination
of cell culture and 3 D printing is a promising route for the
urgently needed construction of simulated human tissues
and organs. In vitro experiments using commercially avail-
able digestive enzymes and buffers are a suitable alternative
approach for the study of low concentration compounds
like the anthocyanins. For the development of in vitro exper-
iments that avoid low physiological relevance and incom-
parable results, a standardized digestion protocol is available
based on available physiological data, covering parameters
such as electrolytes, enzymes, bile, dilutions, pH, and diges-
tion time (Brodkorb et al. 2019). Researchers are continually
extending the capabilities of the techniques used to inves-
tigate the mechanisms and maximize the efficacy of these
functional substances in the hope of matching the break-
throughs made in related fields.
The third challenge for metabolic studies of the antho-
cyanins is that they are highly sensitive to physiological
conditions, including pH, chemicals, enzymes, and other
bioactive compounds. The different stages of digestion with
their varied pH impact anthocyanin stability and degrada-
tion. Numerous anthocyanin derivatives are widely dispersed
5962 H. GUI ET AL.

at low concentrations (ng–μg) and most are undetectable disciplines offers unique benefits to scientific progress. The
by current detection technologies. Radioisotope tracer tech- utilization of engineered bacteria, the combining of embry-
niques were first applied to anthocyanin metabolism by onic stem cell and 3 D printing technologies, and improve-
Czank et al. (2013). However, the complex reaction pathways ments to detection techniques will greatly expand our
in vivo makes the data difficult to interpret. Recently devel- knowledge of anthocyanin metabolism, and help to maxi-
oped comprehensive analysis called “omics” (genomics, tran- mize the use and health benefits of these, and similar,
scriptomics, proteomics, metabolomics, etc.) have been compounds.
applied to the analysis of complicate “big data”, making
many remarkable advances in bioinformatics, especially in
the analysis of gut microbiota. In summary, the study of Acknowledgments
anthocyanins (and other similar compounds) faces several
challenges: shortage of anthocyanin monomers, many exter- We are grateful to Dr. Jian Dai for her valuable comments and careful
nal and internal factors influencing their metabolism, and examination on this manuscript.
limitations of the detection technology. The current pace of
technological development suggests these problems can
be solved. Author’s contributions
Hailong Gui contributed to writing – original draft, Lijun Sun contributed
to writing – original draft, Ruihai Liu contributed to conceptualization,
5. Conclusions and perspectives Xu Si contributed to editing, Qiao Jiang contributed to editing and super-
vision, Yanyan Qiao contributed to grammar, Bin Li contributed to con-
The stability of anthocyanins varies with their structure ceptualization, funding acquisition, and writing – review and editing, and
(aglycone or glycoside), environmental pH (7.0 in the oral Jinlong Tian contributed to writing – review and editing.
cavity, 2–3 in the stomach, 7–8 in the small intestine), and
catalytic impact of the microbiota. Major time-dependent
breakdown of the anthocyanins by microbiota occurs in the Disclosure statement
oral cavity. Unexpectedly, their glucuronide forms, which
The authors declare no conflicts of interest.
involve the enzymes UGTs, arylsulfatase and β-glucuronidase
are also detectable in the oral cavity. Prior to absorption in
vivo, some anthocyanins are deglycosylated by LPH and Funding
β-glucosidase enzymes while others are absorbed directly
via specific transporters (bilitranslocase, SGLT1, GLUT1, −2 This work was supported by the National Natural Science Foundation
and −3, OCT1, OAT2, and SMCT1 and −2), depending on of China (U21A20273), China Agriculture Research System of MOF
and MARA (CARS-29), and the First Batch of Liaoning “Unveiling
their glycoside moiety. Anthocyanin aglycones with more
Leader” Scientific and Technological Projects (2021JH1/10400036).
–OH rather than –CH3 groups have lower hydrophobicity
and stability, resulting in low absorption and high degra-
dation. After passing through the acidic stomach and ORCID
alkalescent small intestine, unabsorbed anthocyanins are
metabolized by gut microbiota into small phenolic acids Dongnan Li http://orcid.org/0000-0001-8499-5022
Bin Li http://orcid.org/0000-0002-7393-2111
and absorbed in the colon. After absorption, anthocyanins
and their derivatives are conjugated by cellular enzymes
(UGTs, SULTs, COMT, and CYP1A), pumped in and out
by transporters (ABC, BCRP, OATs, OATPs, PEPTs, ABCC2, Abbreviations
MRPs, and P-gp), and begin EHC after being transported ABC ATP-binding cassette
the liver via the bloodstream. During EHC the compounds BCRP Breast cancer resistance protein
are further conjugated and maintained low concentrations C3G Cyanidin-3-O-glucoside
over extended periods. As a result of this circulation, antho- C3Gal Cyanidin-3-O- galactoside
C3R Cyanidin-3-O- rutinoside
cyanin derivatives are detectable and unevenly distributed
COMT Catechol-O-methyltransferase
in nondigestive tissues (eyes, liver, cortex, cerebellum, kid- Cy Cyanidin
ney, and even brain). Interconversion of anthocyanins occurs Cy3R Cyanidin-3-O-rutinoside
and is modulated by enzymes (COMT and CYP) whose CYP1A Cytochrome P450 1A
mechanisms need further exploration. Anthocyanin metab- Dp Delphinidin
olism is dependent on their chemical structure and is Dp3G Delphinidin-3-O-glucoside
reflected in their derivatives, absorption, distribution, metab- Dp3R Delphinidin-3-O-rutinoside
EHC Enterohepatic circulation
olism, and excretion. Based on recent findings concerning
GLUT 1, 3 Facilitative glucose transporters 1 and 3
competition during transportation, conjugation sequencing, LPH Lactase phlorizin hydrolase
variations in microflora and the effects of other food com- MRPs Multidrug resistance-associated proteins
ponents, factors including anthocyanin dosage, intake pat- Mv Malvidin
tern, duration, digestion environment, and food matrices Mv3G Malvidin-3-O-glucoside
should also be considered. Cooperation between research OAT2 Organic anion transporter 2

OATPs Organic anion transporting polypeptides
OATs Organic anion transporters
OCT 1 Organic cation transporter 1
PCA Protocatechuic acid
PEPTs Peptide transporters
Pg Pelargonidin
Pg3G Pelargonidin-3-O-glucoside
Pg3R Pelargonidin-3-O-rutinoside
PGA Phloroglucinol aldehyde
P-gp P-glycoprotein
Pn Peonidin
Pn3G Peonidin-3-O-glucoside
Pt Petunidin
Pt3G Petunidin -3-O-glucoside
SGLT 1 Sodium-dependent glucose co-transporter 1
SMCT 1, 2 Sodium/monocarboxylate transporters 1 and 2
SULTs Sulfotransferases
UDP-Glu-DH UDP-glucose-dehydrogenase
UGTs UDP-glucuronosyl transferases 500
References
Ali, H. M., W. Almagribi, and M. N. Al-Rashidi. 2016. Antiradical
and reductant activities of anthocyanidins and anthocyanins,
structure-activity relationship and synthesis. Food Chemistry
194:1275–82. doi: 10.1016/j.foodchem.2015.09.003.
Banaszewski, K., E. Park, I. Edirisinghe, J. C. Cappozzo, and B. M.
Burton-Freeman. 2013. A pilot study to investigate bioavailability
of strawberry anthocyanins and characterize postprandial plasma
polyphenols absorption patterns by q-tof lc/ms in humans. Journal
of Berry Research 3 (2):113–26. doi: 10.3233/JBR-130048.
Bandyopadhyay, A., I. Mitra, and S. Bose. 2020. 3D printing for bone
regeneration. Current Osteoporosis Reports 18 (5):505–14. doi:
10.1007/s11914-020-00606-2.
Bendokas, V., V. Stanys, I. Mažeikienė, S. Trumbeckaite, R. Baniene,
and J. Liobikas. 2020. Anthocyanins: From the field to the antiox-
idants in the body. Antioxidants 9 (9):819. doi: 10.3390/an-
tiox9090819.
Borges, G., J. I. Ottaviani, J. J. Van Der Hooft, H. Schroeter, and A.
Crozier. 2018. Absorption, metabolism, distribution and excretion
of (−)-epicatechin: A review of recent findings. Molecular Aspects
of Medicine 61:18–30. doi:10.1016/j.mam.2017.11.002.
Braga, A., D. Murador, L. de Souza, and V. V. de Rosso. 2018.
Bioavailability of anthocyanins: Gaps in knowledge, challenges and
future research. Journal of Food Composition and Analysis 68:31–40.
doi: 10.1016/j.jfca.2017.07.031.
Brodkorb, A., L. Egger, M. Alminger, P. Alvito, R. Assunção, S.
Ballance, T. Bohn, C. Bourlieu-Lacanal, R. Boutrou, F. Carrière,
et al. 2019. INFOGEST static in vitro simulation of gastrointestinal
food digestion. Nature Protocols 14 (4):991–1014. doi: 10.1038/
s41596-018-0119-1.
Cahyana, Y., and M. Gordon. 2013. Interaction of anthocyanins with
human serum albumin: Influence of pH and chemical structure on
binding. Food Chemistry 141 (3):2278–85. doi: 10.1016/j.food-
chem.2013.05.026.
Chen, Y., H. Chen, W. Zhang, Y. Ding, T. Zhao, M. Zhang, G. Mao,
W. Feng, X. Wu, and L. Yang. 2019. Bioaccessibility and biotrans-
formation of anthocyanin monomers following in vitro simulated
gastric-intestinal digestion and in vivo metabolism in rats . Food &
Function 10 (9):6052–61. doi: 10.1039/C9FO00871C.
Chen, T.-Y., J. Kritchevsky, K. Hargett, K. Feller, R. Klobusnik, B. J.
Song, B. Cooper, Z. Jouni, M. G. Ferruzzi, and E. M. Janle. 2015.
Plasma bioavailability and regional brain distribution of polyphenols
from apple/grape seed and bilberry extracts in a young swine mod-
el. Molecular Nutrition & Food Research 59 (12):2432–47. doi:
10.1002/mnfr.201500224.
Chen, Y., Q. Li, T. Zhao, Z. Zhang, G. Mao, W. Feng, X. Wu, and L.
Yang. 2017. Biotransformation and metabolism of three mulberry
Critical Reviews in Food Science and Nutrition 5963
anthocyanin monomers by rat gut microflora. Food Chemistry
237:887–94. doi: 10.1016/j.foodchem.2017.06.054.
Chen, Z., S. Zheng, L. Li, and H. Jiang. 2014. Metabolism of flavonoids
in human: A comprehensive review. Current Drug Metabolism 15
(1):48–61. doi: 10.2174/138920021501140218125020.
Cortés-Martín, A., M. V. Selma, F. A. Tomás-Barberán, A.
González-Sarrías, and J. C. Espín. 2020. Where to look into the
puzzle of polyphenols and health? The postbiotics and gut micro-
biota associated with human metabotypes. Molecular Nutrition &
Food Research 64 (9):e1900952. doi: 10.1002/mnfr.201900952.
Cress, B. F., Q. D. Leitz, D. C. Kim, T. D. Amore, J. Y. Suzuki, R. J.
Linhardt, and M. A. Koffas. 2017. CRISPRi-mediated metabolic
engineering of E. coli for O-methylated anthocyanin production.
Microbial Cell Factories 16 (1):10. doi: 10.1186/s12934-016-0623-3.
Cury, B. S. F., A. B. Meneguin, F. G. Prezotti, F. I. Boni, and V. M.
de Oliveira Cardoso. 2021. Nanocarriers for oral drug delivery. In
Nanocarriers for drug delivery, nanomedicine and nanotoxicology.
concepts and applications, ed. J. O. Eloy, J. P. Abriata, and J. M.
Marchetti, 127–51. Switzerland, Cham: Springer.
Czank, C., A. Cassidy, Q. Zhang, D. J. Morrison, T. Preston, P. A.
Kroon, N. P. Botting, and C. D. Kay. 2013. Human metabolism and
elimination of the anthocyanin, cyanidin-3-glucoside: A (13)C-tracer
study. The American Journal of Clinical Nutrition 97 (5):995–1003.
doi: 10.3945/ajcn.112.049247.
De Ferrars, R., A. Cassidy, P. Curtis, and C. Kay. 2014a. Phenolic
metabolites of anthocyanins following a dietary intervention study
in post-menopausal women. Molecular Nutrition & Food Research
58 (3):490–502. doi: 10.1002/mnfr.201300322.
De Ferrars, R., C. Czank, Q. Zhang, N. P. Botting, P. Kroon, A. Cassidy,
and C. Kay. 2014b. The pharmacokinetics of anthocyanins and their
metabolites in humans. British Journal of Pharmacology 171
(13):3268–82. doi: 10.1111/bph.12676.
De Rosas, M. I., L. Deis, L. Martínez, M. Durán, E. Malovini, and J.
B. Cavagnaro. 2019. Anthocyanins in nutrition: Biochemistry and
health benefits. In Psychiatry and neuroscience update: from trans-
lational research to a humanistic approach-volume III, ed. P. Á.
Gargiulo and H. L. Mesones Arroyo, 143–52. Cham: Springer
International Publishing.
DeGorter, M. K., C. Xia, J. J. Yang, and R. B. Kim. 2012. Drug trans-
porters in drug efficacy and toxicity. Annual Review of Pharmacology
and To x i c o l o g y 52:249–73. doi: 10.1146/
annurev-pharmtox-010611-134529.
Dharmawansa, K., D. W. Hoskin, and H. Rupasinghe. 2020.
Chemopreventive effect of dietary anthocyanins against gastrointes-
tinal cancers: A review of recent advances and perspectives.
International Journal of Molecular Sciences 21 (18):6555. doi: 10.3390/
ijms21186555.
Dreiseitel, A., B. Oosterhuis, K. V. Vukman, P. Schreier, A. Oehme, S.
Locher, G. Hajak, and P. G. Sand. 2009. Berry anthocyanins and
anthocyanidins exhibit distinct affinities for the efflux transporters
BCRP and MDR1. British Journal of Pharmacology 158 (8):1942–50.
doi: 10.1111/j.1476-5381.2009.00495.x.
Edwards, C. A., M. Serafini, A. Crozier, and W. Mullen. 2008.
Bioavailability of pelargonidin-3-O-glucoside and its metabolites in
humans following the ingestion of strawberries with and without
cream. Journal of Agricultural and Food Chemistry 56 (3):713–9.
doi: 10.1021/jf072000p.
Eker, M. E., K. Aaby, I. Budic-Leto, S. R. Brnčić, S. N. El, S. Karakaya,
S. Simsek, C. Manach, W. Wiczkowski, and S. Pascual-Teresa. 2019.
A Review of factors affecting anthocyanin bioavailability: Possible
implications for the inter-individual variability. Foods 9 (1):2. doi:
10.3390/foods9010002.
El Mohsen, M. A., J. Marks, G. Kuhnle, K. Moore, E. Debnam, S.
Kaila Srai, C. Rice-Evans, and J. P. E. Spencer. 2006. Absorption,
tissue distribution and excretion of pelargonidin and its metabolites
following oral administration to rats. The British Journal of Nutrition
95 (1):51–8. doi: 10.1079/BJN20051596.
Faria, A., D. Pestana, J. Azevedo, F. Martel, V. de Freitas, I. Azevedo,
N. Mateus, and C. Calhau. 2009. Absorption of anthocyanins
through intestinal epithelial cells - Putative involvement of GLUT2
5964 H. GUI ET AL.
. Molecular Nutrition & Food Research 53 (11):1430–7. doi: 10.1002/
mnfr.200900007.
Felgines, C., O. Texier, P. Garcin, C. Besson, J. L. Lamaison, and A.
Scalbert. 2009. Tissue distribution of anthocyanins in rats fed a
blackberry anthocyanin-enriched diet. Molecular Nutrition & Food
Research 53 (9):1098–103. doi: 10.1002/mnfr.200800323.
Fernandes, I., A. Faria, V. de Freitas, C. Calhau, and N. Mateus. 2015.
Multiple-approach studies to assess anthocyanin bioavailability.
Phytochemistry Reviews 14 (6):899–919. doi: 10.1201/9781351069700.
Fernandes, I., F. Nave, R. Gonçalves, V. Freitas, and N. Mateus. 2012.
On the bioavailability of flavanols and anthocyanins:
Flavanol-anthocyanin dimers. Food Chemistry 135 (2):812–8. doi:
10.1016/j.foodchem.2012.05.037.
Fornasaro, S., L. Ziberna, M. Gasperotti, F. Tramer, U. Vrhovsek, F.
Mattivi, and S. Passamonti. 2016. Determination of cyanidin
3-glucoside in rat brain, liver and kidneys by UPLC/MS-MS and
its application to a short-term pharmacokinetic study. Scientific
Reports 6 (1):22815. doi: 10.1038/srep22815.
González-Barrio, R., C. Edwards, and A. Crozier. 2011. Colonic ca-
tabolism of ellagitannins, ellagic acid, and raspberry anthocyanins:
In vivo and in vitro studies. Drug Metabolism and Disposition 39
(9):1680–8. doi: 10.1124/dmd.111.039651.
Han, H., C. Liu, W. Gao, Z. Li, G. Qin, S. Qi, H. Jiang, X. Li, M. Liu,
F. Yan, et al. 2021. Anthocyanins are converted into anthocyanidins
and phenolic acids and effectively absorbed in the jejunum and
ileum. J Agric Food Chem 69 (3):992–1002. doi: 10.1021/acs.
jafc.0c07771.
Han, F., H. Oliveira, N. F. Brás, I. Fernandes, L. Cruz, V. De Freitas,
and N. Mateus. 2020. In vitro gastrointestinal absorption of red
wine anthocyanins - Impact of structural complexity and phase II
metabolization. Food Chemistry 317:126398. doi: 10.1016/j.food-
chem.2020.126398.
Huang, C., Y. Chen, T. Zhou, and G. Chen. 2009. Sulfation of dietary
flavonoids by human sulfotransferases. Xenobiotica; the Fate of
Foreign Compounds in Biological Systems 39 (4):312–22. doi:
10.1080/00498250802714915.
Jaganath, I., W. Mullen, C. Edwards, and A. Crozier. 2006. The relative
contribution of the small and large intestine to the absorption and
metabolism of rutin in man. Free Radical Research 40 (10):1035–46.
doi: 10.1080/10715760600771400.
Janle, E. M., M. A. Lila, M. Grannan, L. Wood, A. Higgins, G. G.
Yousef, R. B. Rogers, H. Kim, G. S. Jackson, L. Ho, et al. 2010.
Pharmacokinetics and tissue distribution of 14C-labeled grape poly-
phenols in the periphery and the central nervous system following
oral administration. Journal of Medicinal Food 13 (4):926–33. doi:
10.1089/jmf.2009.0157.
Kalt, W. 2019. Anthocyanins and their C6-C3-C6 metabolites in hu-
mans and animals. Molecules 24 (22):4024. doi: 10.3390/mole-
cules24224024.
Kalt, W., J. B. Blumberg, J. E. McDonald, M. R. Vinqvist-Tymchuk, S.
A. E. Fillmore, B. A. Graf, J. M. O’Leary, and P. E. Milbury. 2008.
Identification of anthocyanins in the liver, eye, and brain of
blueberry-fed pigs. Journal of Agricultural and Food Chemistry 56
(3):705–12. doi: 10.1021/jf071998l.
Kalt, W., J. McDonald, Y. Liu, and S. A. E. Fillmore. 2017. Flavonoid
metabolites in human urine during blueberry anthocyanin intake.
Journal of Agricultural and Food Chemistry 65 (8):1582–91. doi:
10.1021/acs.jafc.6b05455.
Kamonpatana, K., M. Failla, P. Kumar, and M. Giusti. 2014. Anthocyanin
structure determines susceptibility to microbial degradation and
bioavailability to the buccal mucosa. Journal of Agricultural and
Food Chemistry 62 (29):6903–10. doi: 10.1021/jf405180k.
Kamonpatana, K., M. Giusti, C. Chitchumroonchokchai, M.
MorenoCruz, K. Riedl, P. Kumar, and M. Failla. 2012. Susceptibility
of anthocyanins to ex vivo degradation in human saliva. Food
Chemistry 135 (2):738–47. doi: 10.1016/j.foodchem.2012.04.110.
Kasote, D. M., G. J. Duncan, M. Neacsu, and W. R. Russell. 2019.
Rapid method for quantification of anthocyanidins and anthocyanins
in human biological samples. Food Chemistry 290:56–63. doi:
10.1016/j.foodchem.2019.03.109.
Kataoka, K. 2016. The intestinal microbiota and its role in human
health and disease. The Journal of Medical Investigation: JMI 63
(1–2):27–37. doi: 10.2152/jmi.63.27.
Kay, C., P. Kroon, and A. Cassidy. 2009. The bioactivity of dietary
anthocyanins is likely to be mediated by their degradation products.
Molecular Nutrition & Food Research 53 (S1):S92–S101. doi: 10.1002/
mnfr.200800461.
Kay, C., G. Mazza, and B. Holub. 2005. Anthocyanins exist in the
circulation primarily as metabolites in adult men. The Journal of
Nutrition 135 (11):2582–8. doi: 10.1093/jn/135.11.2582.
Khanal, R., L. R. Howard, and R. L. Prior. 2014. Urinary excretion of
phenolic acids in rats fed cranberry, blueberry, or black raspberry
powder. Journal of Agricultural and Food Chemistry 62 (18):3987–96.
doi: 10.1021/jf403883r.
Kirakosyan, A., E. M. Seymour, J. Wolforth, R. McNish, P. Kaufman,
and S. Bolling. 2015. Tissue bioavailability of anthocyanins from
whole tart cherry in healthy rats. Food Chemistry 171:26–31. doi:
10.1016/j.foodchem.2014.08.114.
Klimanskaya, I., E. A. Kimbrel, and R. Lanza. 2014. Embryonic stem
cells. In Principles of tissue engineering, ed. R. Lanza, R. Langer,
and J. Vacanti 4th ed., 565–79. Salt Lake: Academic Press.
Li, B., Z. Cheng, X. Sun, X. Si, E. Gong, Y. Wang, J. Tian, C. Shu, F.
Ma, D. Li, et al. 2020. Lonicera caerulea L. polyphenols alleviate
oxidative stress-induced intestinal environment imbalance and
lipopolysaccharide-induced liver injury in HFD-fed rats by regulat-
ing the Nrf2/HO-1/NQO1 and MAPK pathways. Molecular Nutrition
& Food Research 64 (10):1901315. doi: 10.1002/mnfr.201901315.
Lila, M., B. Burton-Freeman, M. Grace, and W. Kalt. 2016. Unraveling
anthocyanin bioavailability for human health. Annual Review of
Food Science and Technology 7:375–93. doi: 10.1146/
annurev-food-041715-033346.
Lim, C. G., L. Wong, N. Bhan, H. Dvora, P. Xu, S. Venkiteswaran,
and M. A. Koffas. 2015. Development of a recombinant escherich-
ia coli strain for overproduction of the plant pigment anthocyanin.
Applied and Environmental Microbiology 81 (18):6276–84. doi:
10.1128/AEM.01448-15.
Lira-Junior, R., and E. A. Boström. 2018. Oral-gut connection: One
step closer to an integrated view of the gastrointestinal tract?
Mucosal Immunology 11 (2):316–8. doi: 10.1038/mi.2017.116.
Liu, H., T. J. Garrett, Z. Su, C. Khoo, S. Zhao, and L. Gu. 2020.
Modifications of the urinary metabolome in young women after
cranberry juice consumption were revealed using the
UHPLC-Q-orbitrap-HRMS-based metabolomics approach. Food &
Function 11 (3):2466–76. doi: 10.1039/c9fo02266j.
Liu, Y., D. Zhang, Y. Wu, D. Wang, Y. Wei, J. Wu, and B. Ji. 2014.
Stability and absorption of anthocyanins from blueberries subjected
to a simulated digestion process. International Journal of Food Sciences
and Nutrition 65 (4):440–8. doi: 10.3109/09637486.2013.869798.
Ludwig, I. A., P. Mena, L. Calani, G. Borges, G. Pereira-Caro, L.
Bresciani, D. Del Rio, M. E. Lean, and A. Crozier. 2015. New in-
sights into the bioavailability of red raspberry anthocyanins and
ellagitannins. Free Radical Biology & Medicine 89:758–69. doi:
10.1016/j.freeradbiomed.2015.10.400.
Madden, L. R., T. V. Nguyen, S. Garcia-Mojica, V. Shah, A. V. Le, A.
Peier, R. Visconti, E. M. Parker, S. C. Presnell, D. G. Nguyen, et al.
2018. Bioprinted 3D primary human intestinal tissues model aspects
of native physiology and ADME/tox functions. iScience 2:156–67.
doi: 10.1016/j.isci.2018.03.015.
Mallery, S. R., D. E. Budendorf, M. P. Larsen, P. Pei, M. Tong, A. S.
Holpuch, P. E. Larsen, G. D. Stoner, H. W. Fields, K. K. Chan, et al.
2011. Effects of human oral mucosal tissue, saliva, and oral micro-
flora on intraoral metabolism and bioactivation of black raspberry
anthocyanins. Cancer Prevention Research (Philadelphia, Pa.) 4
(8):1209–21. doi: 10.1158/1940-6207.CAPR-11-0040.
Manach, C., G. Williamson, C. Morand, A. Scalbert, and C. Rémésy.
2005. Bioavailability and bioefficacy of polyphenols in human. I.
Review of 97 bioavailability studies. The American Journal of Clinical
Nutrition 81 (1):230S–42S. doi: 10.1093/ajcn/81.1.230S.
Marques Peixoto, F., I. Fernandes, A. C. M. S. Gouvêa, M. C. P. A.
Santiago, R. Galhardo Borguini, N. Mateus, V. Freitas, R. L. O.

Godoy, and I. MPLVO. Ferreira. 2016. Simulation of in vitro diges-
tion coupled to gastric and intestinal transport models to estimate
absorption of anthocyanins from peel powder of jabuticaba, jamelao
and jamb fruits. Journal of Functional Foods 24:373–81. doi:
10.1016/j.jff.2016.04.021.
Mazza, G., and E. Miniati. 1993. Anthocyanins in Fruits. Vegetables
and grains. London: CRC Press.
Milbury, P., and W. Kalt. 2010. Xenobiotic metabolism and berry flavo-
noid transport across the blood-brain barrier. Journal of Agricultural
and Food Chemistry 58 (7):3950–6. doi: 10.1021/jf903529m.
Mueller, D., K. Jung, M. Winter, D. Rogoll, R. Melcher, and E. Richling.
2017. Human intervention study to investigate the intestinal acces-
sibility and bioavailability of anthocyanins from bilberries. Food
Chemistry 231:275–86. doi: 10.1016/j.foodchem.2017.03.130.
Nagar, E., Z. Okun, and A. Shpigelman. 2020. Digestive fate of poly-
phenols: Updated view of the influence of chemical structure and
the presence of cell wall material. Current Opinion in Food Science
31:38–46. doi: 10.1016/j.cofs.2019.10.009.
Netzel, G., O. Wright, and Y. Sultanbawa. 2020. Understanding the
metabolic fate and bioactivity of dietary anthocyanins. Proceedings
36:64. doi: 10.3390/proceedings2019036064.
Novotny, J. A., B. A. Clevidence, and A. C. Kurilich. 2012. Anthocyanin
kinetics are dependent on anthocyanin structure. The British Journal
of Nutrition 107 (4):504–9. doi: 10.1017/S000711451100314X.
Nurmi, T., J. Mursu, M. Heinonen, A. Nurmi, R. Hiltunen, and S.
Voutilainen. 2009. Metabolism of berry anthocyanins to phenolic
acids in humans. Journal of Agricultural and Food Chemistry 57
(6):2274–81. doi: 10.1021/jf8035116.
Oliveira, H., N. Basílio, F. Pina, I. Fernandes, V. de Freitas, and N.
Mateus. 2019a. Purple-fleshed sweet potato acylated anthocyanins:
Equilibrium network and photophysical properties. Food Chemistry
288:386–94. doi: 10.1016/j.foodchem.2019.02.132.
Oliveira, H., I. Fernandes, N. Bras, A. Faria, V. Freitas, C. Calhau, and
N. Mateus. 2015. Experimental and theoretical data on the mech-
anism by which red wine anthocyanins are transported through a
human MKN-28 gastric cell model. Journal of Agricultural and Food
Chemistry 63 (35):7685–92. doi: 10.1021/acs.jafc.5b00412.
Oliveira, H., R. Perez-Gregório, V. de Freitas, N. Mateus, and I.
Fernandes. 2019b. Comparison of the in vitro gastrointestinal bio-
availability of acylated and non-acylated anthocyanins: Purple-fleshed
sweet potato vs red wine. Food Chemistry 276:410–8. doi: 10.1016/j.
foodchem.2018.09.159.
Ottaviani, J., G. Borges, T. Momma, J. Spencer, C. Keen, A. Crozier,
and H. Schroeter. 2016. The metabolome of [2-(14)C](-)-epicatechin
in humans: Implications for the assessment of efficacy, safety, and
mechanisms of action of polyphenolic bioactives. Scientific Reports
6:29034. doi: 10.1038/srep29034.
Ouchi, R., S. Togo, M. Kimura, T. Shinozawa, M. Koido, H. Koike,
W. Thompson, R. A. Karns, C. N. Mayhew, P. S. McGrath, et al.
2019. Modeling steatohepatitis in humans with pluripotent stem
cell-derived organoids. Cell Metab 30 (2):374–84.e6. doi: 10.1016/j.
cmet.2019.05.007.
Ozdal, T., D. Sela, J. Xiao, D. Boyacioglu, F. Chen, and E. Capanoglu.
2016. The Reciprocal Interactions between polyphenols and gut
microbiota and effects on bioaccessibility. Nutrients 8 (2):1–36.78.
doi: 10.3390/nu80200:.
Park, S. Y., B. O. Hwang, M. Lim, S. H. Ok, S. K. Lee, K. S. Chun,
K. K. Park, Y. Hu, W. Y. Chung, and N. Y. Song. 2021. Oral-gut
microbiome axis in gastrointestinal disease and cancer. Cancers 13
(9):2124. doi: 10.3390/cancers13092124.
Passamonti, S., M. Terdoslavich, R. Franca, A. Vanzo, F. Tramer, E.
Braidot, E. Petrussa, and A. Vianello. 2009. Bioavailability of flavo-
noids: A review of their membrane transport and the function of
bilitranslocase in animal and plant organisms. Current Drug
Metabolism 10 (4):369–94. doi: 10.2174/138920009788498950.
Passamonti, S., U. Vrhovsek, A. Vanzo, and F. Mattivi. 2003. The
stomach as a site for anthocyanins absorption from food. 2003.
FEBS Letters 544 (1–3):210–3. doi: 10.1016/S0014-5793(03)00504-0.
Pereira Caro, G., J. Moreno-Rojas, N. Brindani, D. Del Rio, M. Lean,
Y. Hara, and A. Crozier. 2017. Bioavailability of black tea theaflavins:
Critical Reviews in Food Science and Nutrition 5965
Absorption, metabolism, and colonic catabolism. Journal of
Agricultural and Food Chemistry 65 (26):5365–74. doi: 10.1021/acs.
jafc.7b01707.
Pereira-Caro, G., G. Borges, I. Ky, A. Ribas, L. Calani, D. Del Rio, M.
N. Clifford, S. A. Roberts, and A. Crozier. 2014b. In vitro colonic
catabolism of orange juice (poly)phenols. Molecular Nutrition &
Food Research 59 (3):465–75. doi: 10.1002/mnfr.201400779.
Pereira-Caro, G., G. Borges, J. van der Hooft, M. N. Clifford, D. Del
Rio, M. E. J. Lean, S. A. Roberts, M. B. Kellerhals, and A. Crozier.
2014a. Orange juice (poly)phenols are highly bioavailable in humans.
The American Journal of Clinical Nutrition 100 (5):1378–84. doi:
10.3945/ajcn.114.090282.
Pereira-Caro, G., I. A. Ludwig, T. Polyviou, D. Malkova, A. García, J.
M. Moreno-Rojas, and A. Crozier. 2016. Identification of plasma
and urinary metabolites and catabolites derived from orange juice
(p oly)phenols: Analysis by high-p erformance liquid
chromatography-high-resolution mass spectrometry. Journal of
Agricultural and Food Chemistry 64 (28):5724–35. doi: 10.1021/acs.
jafc.6b02088.
Pereira-Caro, G., C. M. Oliver, R. Weerakkody, T. Singh, M. Conlon,
G. Borges, L. Sanguansri, T. Lockett, S. A. Roberts, A. Crozier, et al.
2015. Chronic administration of a microencapsulated probiotic en-
hances the bioavailability of orange juice flavanones in humans.
Free Radical Biology & Medicine 84:206–14. doi: 10.1016/j.freerad-
biomed.2015.03.010.
Rodriguez-Mateos, A., D. Vauzour, C. G. Krueger, D. Shanmuganayagam,
J. Reed, L. Calani, P. Mena, D. Del Rio, and A. Crozier. 2014.
Bioavailability, bioactivity and impact on health of dietary flavonoids
and related compounds: An update. Archives of Toxicology 88
(10):1803–53. doi: 10.1007/s00204-014-1330-7.
Rowland, A., J. Miners, and P. Mackenzie. 2013. The
UDP-glucuronosyltransferases: Their role in drug metabolism and
detoxification. The International Journal of Biochemistry & Cell
Biology 45 (6):1121–32. doi: 10.1016/j.biocel.2013.02.019.
Rusishvili, M., L. Grisanti, S. Laporte, M. Micciarelli, M. Rosa, R. J.
Robbins, T. Collins, A. Magistrato, and S. Baroni. 2019. Unraveling
the molecular mechanisms of color expression in anthocyanins.
Physical Chemistry Chemical Physics: PCCP 21 (17):8757–66. doi:
10.1039/C9CP00747D.
Selma, M. V., F. A. 2020. Tomás-Barberán, M. Romo-Vaquero, A.
Cortés-Martín, and J. C. Espín. Understanding polyphenols’ health
effects through the gut microbiota. In Dietary polyphenols: Their
metabolism and health effects, ed. F. A. Tomás-Barberán, A.
González-Sarrías, & R. García-Villalba,. 497–531. Brisbane: Wiley.
Si, X., J. Bi, Q. Chen, H. Cui, Y. Bao, J. Tian, C. Shu, Y. Wang, H.
Tan, W. Zhang, et al. 2021. Effect of blueberry anthocyanin-rich
extracts on peripheral and hippocampal antioxidant defensiveness:
The analysis of the serum fatty acid species and gut microbiota
profile. Journal of Agricultural and Food Chemistry 69 (12):3658–66.
doi: 10.1021/acs.jafc.0c07637.
Soares, S., S. Soares, E. Brandão, C. Guerreiro, N. Mateus, and V. de
Freitas. 2020. Oral interactions between a green tea flavanol extract
and red wine anthocyanin extract using a new cell-based model:
Insights on the effect of different oral epithelia. Scientific Reports
10 (1):12638. doi: 10.1038/s41598-020-69531-9.
Straßmann, S., M. Passon, and A. Schieber. 2021. Chemical hemisyn-
thesis of sulfated cyanidin-3-o-glucoside and cyanidin metabolites.
Molecules (Basel, Switzerland) 26 (8):2146. doi: 10.3390/mole-
cules26082146.
Talavéra, S., C. Felgines, O. Texier, C. Besson, A. Gil-Izquierdo, J.-L.
Lamaison, and C. Rémésy. 2005. Anthocyanin metabolism in rats
and their distribution to digestive area, kidney, and brain. Journal
of Agricultural and Food Chemistry 53 (10):3902–8. doi: 10.1021/
jf050145v.
Talavéra, S., C. Felgines, O. Texier, C. Besson, J. L. Lamaison, and C.
Rémésy. 2003. Anthocyanins are efficiently absorbed from the stom-
ach in anesthetized rats. The Journal of nutrition 133 (12):4178–82.
doi: 10.1093/jn/133.12.4178.
Talavéra, S., C. Felgines, O. Texier, C. Besson, C. Manach, J.-L.
Lamaison, and C. Rémésy. 2004. Anthocyanins are efficiently ab-
5966 H. GUI ET AL.
sorbed from the small intestine in rats. The Journal of Nutrition
134 (9):2275–9. doi: 10.1093/jn/134.9.2275.
Tian, J.-L., X.-J. Liao, Y.-H. Wang, X. Si, C. Shu, E.-S. Gong, X. Xie,
X.-L. Ran, and B. Li. 2019a. Identification of cyanidin-3-arabinoside
extracted from blueberry as a selective protein tyrosine phosphatase
1B inhibitor. Journal of Agricultural and Food Chemistry 67
(49):13624–34. doi: 10.1021/acs.jafc.9b06155.
Tian, L., Y. Tan, G. Chen, G. Wang, J. Sun, S. Ou, W. Chen, and W.
Bai. 2019b. Metabolism of anthocyanins and consequent effects on
the gut microbiota. Critical Reviews in Food Science and Nutrition
59 (6):982–91. doi: 10.1080/10408398.2018.1533517.
Ugalde, C. M., Z. Liu, C. Ren, K. K. Chan, K. A. Rodrigo, Y. Ling,
P. E. Larsen, G. E. Chacon, G. D. Stoner, R. J. Mumper, et al. 2009.
Distribution of anthocyanins delivered from a bioadhesive black
raspberry gel following topical intraoral application in normal
healthy volunteers. Pharmaceutical Research 26 (4):977–86. doi:
10.1007/s11095-008-9806-x.
Vanzo, A., M. Terdoslavich, A. Brandoni, A. Torres, U. Vrhovsek, and
S. Passamonti. 2008. Uptake of grape anthocyanins into the rat
kidney and the involvement of bilitranslocase. Molecular Nutrition
& Food Research 52 (10):1106–16. doi: 10.1002/mnfr.200700505.
Verediano, T. A., H. Stampini Duarte Martino, M. C. Dias Paes, and
E. Tako. 2021. Effects of anthocyanin on intestinal health: A sys-
tematic review. Nutrients 13 (4):1331. doi: 10.3390/nu13041331.
Wiczkowski, W., D. Szawara-Nowak, and J. Romaszko. 2016. The im-
pact of red cabbage fermentation on bioavailability of anthocyanins
and antioxidant capacity of human plasma. Food Chemistry 190:730–
40. doi: 10.1016/j.foodchem.2015.06.021.
Williamson, G., and M. N. Clifford. 2010. Colonic metabolites of
berry polyphenols: The missing link to biological activity? The British
Journal of Nutrition 104 (Suppl 3):S48–S66. doi: 10.1017/
S0007114510003946.
Williamson, G., C. Kay, and A. Crozier. 2018. The bioavailability,
transport, and bioactivity of dietary flavonoids: A review from a
historical perspective. Comprehensive Reviews in Food Science and
Food Safety 17 (5):1054–110. doi: 10.1111/1541-4337.12351.
Xie, L., H. Su, C. Sun, X. Zheng, and W. Chen. 2018. Recent advanc-
es in understanding the anti-obesity activity of anthocyanins and
their biosynthesis in microorganisms. Trends in Food Science &
Technology 72:13–24. doi: 10.1016/j.tifs.2017.12.002.
Xu, Y., Y. Li, J. Xie, L. Xie, J. Mo, and W. Chen. 2021. Bioavailability,
absorption, and metabolism of pelargonidin-based anthocyanins using
sprague-dawley rats and Caco-2 cell monolayers. Journal of Agricultural
and Food Chemistry 69 (28):7841–50. doi: 10.1021/acs.jafc.1c00257.
Zang, Z., S. Chou, J. Tian, Y. Lang, Y. Shen, X. Ran, N. Gao, and B.
Li. 2021. Effect of whey protein isolate on the stability and antiox-
idant capacity of blueberry anthocyanins: A mechanistic and in
vitro simulation study. Food Chemistry 336:127700. doi: 10.1016/j.
foodchem.2020.127700.
Zha, J., Y. Zang, M. Mattozzi, J. Plassmeier, M. Gupta, X. Wu, S.
Clarkson, and M. Koffas. 2018. Metabolic engineering of coryne-
bacterium glutamicum for anthocyanin production. Microbial Cell
Factories 17 (1):143. doi: 10.1186/s12934-018-0990-z.
Zhou, X., K. C. Cassidy, L. Hudson, M. A. Mohutsky, G. A. Sawada,
and J. Hao. 2019. Enterohepatic circulation of glucuronide metab-
olites of drugs in dog. Pharmacology Research & Perspectives 7
(4):e00502. doi: 10.1002/prp2.502.
Zhu, W., X. Ma, M. Gou, D. Mei, K. Zhang, and S. Chen. 2016. 3D
printing of functional biomaterials for tissue engineering. Current
Opinion in Biotechnology 40:103–12. doi: 10.1016/j.copbio.2016.03.014.
Zou, T., D. Feng, G. Song, H. Li, H. Tang, and W. Ling. 2014. The
role of sodium-dependent glucose transporter 1 and glucose trans-
porter 2 in the absorption of cyanidin-3-O-β-glucoside in Caco-2
cells. Nutrients 6 (10):4165–77. doi: 10.3390/nu6104165.