Trends in Food Science & Technology 105 (2020) 347–362

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Trends in Food Science & Technology

journal homepage: www.elsevier.com/locate/tifs

A review on insoluble-bound phenolics in plant-based food matrix and their

contribution to human health with future perspectives
Bing Zhang a, b, Yujing Zhang a, Hongyan Li a, Zeyuan Deng a, **, Rong Tsao b, *
a
State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330047, China
b
Guelph Research & Development Centre, Agriculture and Agri-Food Canada, 93 Stone Road West, Guelph, ON N1G 5C9, Canada

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Diets rich in phenolics are associated with multiple health benefits. The majority of related studies
Insoluble-bound phenolics have focused nearly exclusively on soluble free and conjugated phenolics in plant-based foods, whereas a large
Bioaccessibility amount of insoluble phenolics bound to food matrix in the remaining solid residues are neglected. The fate of
Bioavailability
bound phenolics in human digestive tract and health implications are not well understood.
Bioactivity
Food matrix
Scope and approach: In this review, we provide a thorough literature review regarding the occurrence, chemistry
Intestinal health and potential health implications of the insoluble-bound phenolics in food matrix. Research gaps were identified
and future perspectives on insoluble-bound phenolics have been proposed.
Key findings and conclusions: Significant amount of phenolic compounds occurs in insoluble forms through
covalently binding to cell wall structural components in plant food matrix. These bound phenolics must be
released by various pretreatments such as hydrolysis by enzyme, alkali and acid, or other assisted technologies
before they can be identified and characterized, and there is no standard method currently. The health benefits of
insoluble-bound phenolics are not only largely governed by their intrinsic content in food matrix, but their
bioaccessibility and bioavailability in human body. Insoluble-bound phenolics obtained via hydrolysis possess
antioxidant and anti-inflammatory activities in vitro, and have been implicated in different health benefits.
Recent studies have suggested their involvement in modulating gut microbiota and intestinal immune response
as a dietary component; however, the roles of bound phenolics and phenolic metabolites in intestinal inflam­
mation and gut health and the interplay mechanisms are still poorly understood. This contribution provides an
update on the insoluble-bound phenolics in food matrix and new perspectives for future studies.

1. Introduction to their potential involvement in human health maintenance and disease

Phenolics are secondary metabolites found ubiquitously in plants
that have been found to possess important health beneficial effects
including antioxidant and anti-inflammatory activities. Phenolics play
an important role in plant by regulating growth as internal physiological
regulators or chemical messengers (Cheynier, Comte, Davies, Lattanzio,
& Martens, 2013). It has been reported that flavonols such as quercetin,
apigenin and kaempferol are capable of regulating plant architecture
and growth via interfering with the transport of polar auxin compounds
by binding to plasma membrane receptor (Shahidi & Yeo, 2016). Be­
sides, phenolics can protect plant tissues against mechanical injury,
pathogen infection, and UV radiation. However, phenolic compounds
have become the subject of tremendous number of research mainly due
prevention, particularly in lowering the risk of chronic diseases such as
cardiovascular diseases (CVD) and certain types of cancer (Fernan­
dez-Panchon, Villano, Troncoso, & Garcia-Parrilla, 2008). Dietary
phenolic compounds have been demonstrated to have the ability to
ameliorate endothelial damage, platelet reactivity, and oxidative dam­
age, among other processes that are relevant in the development of
chronic diseases. The CVD protective role of phenolic compounds from a
number of fruits and vegetable extracts have been shown in vitro for their
antiplatelet activity (Torresurrutia et al., 2011). Quercetin, a ubiquitous
polyphenol inhibited the action of metalloproteinase I (MMP-1) and
prevented the disruption of plaques (Lutz, Fuentes, Avila, Alarcon, &
Palomo, 2019). Phenolic compounds in barley significantly inhibited Cu
(II)-induced human LDL cholesterol oxidation (Madhujith & Shahidi,

* Corresponding author.
** Corresponding author.
E-mail addresses: zeyuandeng@hotmail.com (Z. Deng), rong.cao@canada.ca (R. Tsao).

https://doi.org/10.1016/j.tifs.2020.09.029
Received 9 March 2020; Received in revised form 2 July 2020; Accepted 24 September 2020
Available online 28 September 2020
0924-2244/© 2020 Published by Elsevier Ltd.
B. Zhang et al.
2007). Phenolics in olive oil were found to decrease the oxidation of LDL
and triglyceride levels, and increase HDL levels in rats (Cicerale, Conlan,
Sinclair, & Keast, 2008). Most recent research has shown that the roles
and health benefits of dietary phenolics are beyond their antioxidant
activity; they are strong anti-inflammatory agents and effective modu­
lators of the immune system response. Phenolics inhibit the gene and
protein expressions of pro-inflammatory cytokines of cell signaling
pathways, modulate immune responses and positively alter the gut
microbiome (Espín, González-Sarrías, & Tomás-Barberán, 2017; Xing,
Zhang, Qi, Tsao, & Mine, 2019). In addition, these compounds may also
interact with indigestible fibers or their metabolites and synergistically
participate in the gut microbiota-low grade inflammation-metabolic
syndrome axis (Burcelin, 2016; Edwards et al., 2017).
Dietary source of phenolics are mainly from fruits, vegetables and
whole grains (Manach, Scalbert, Morand, Rémésy, & Jiménez, 2004).
Phenolic compounds not only exist in different classes according to their
structural feature, but are found in different forms depending on their
association with food matrix, e.g. soluble free, soluble esters or conju­
gated and insoluble-bound forms in plants (Arruda, Pereira, De Morais,
Eberlin, & Pastore, 2018; Bei, Liu, Wang, Chen, & Wu, 2017; Gulsuno­
glu, Karbanciogluguler, Raes, & Kilicakyilmaz, 2019). Soluble free
phenolics (SFP) present in free forms within the plant cell vacuole, while
soluble esters or conjugated phenolics are covalently bound or esterified
to sugars and other low molecular mass components such as fatty acids
(Shahidi & Yeo, 2016). In the past two decades, the majority of pub­
lished papers related to phenolics have on these two forms of phenolics
in foods including fruits, vegetables, legumes and cereal grains. Soluble
phenolics may appear in different names such as extractable poly­
phenols or phenolics, soluble free and conjugated phenolics (Hellström
& Mattila, 2008). These soluble phenolics are generally extracted from
food matrix using different combinations of aqueous and organic sol­
vents, as well as certain optimized techniques for specific soluble
phenolic fractions. However, a large amount of insoluble-bound phe­
nolics (ISBP) in the food matrix may still remain in the solid residues
after extractions by the above-mentioned methods, and their roles in
human health have not been closely examined until recently. Mean­
while, although ISBP in different foods have been reported, there lacks a
common understanding and comparable protocols for the extraction,
characterization and assessment of ISBP from different food matrices.
Their bioaccessibility, bioavailability and bioactivity are not clearly
understood because in most cases, ISBP are studied as part of an overall
research on (poly)phenolics. Although in general (poly)phenols are
known for their anti-inflammatory and immune modulatory effects and
their involvement in intestinal health, the specific role of ISBP in these
are not well established. Because ISBP is bound to cell wall components
i.e. the indigestible and fermentable dietary fibers, their release and
metabolism by the gut microbiota can play a key role in unlocking the
interactions among gut microbiota, intestinal inflammation and chronic
diseases. There is a need to study the specific involvements of ISBP in
modulating gut microbiome and intestinal immune response, and in
ameliorating chronic diseases such as metabolic syndrome.
This paper is a result of a literature search of relevant studies pub­
lished by Wiley, Springer and ScienceDirect and other major database in
the past 15 years by using the key words “insoluble bound phenolic” and
“unextractable phenolic”. We have reviewed the findings regarding the
occurrence, chemistry, bioaccessibility and bioavailability, and poten­
tial health implications of the insoluble-bound phenolics in food matrix.
It also identifies emerging research gaps in the area of insoluble-bound
phenolics and health benefits, especially in intestinal health and related
chronic diseases such as metabolic syndrome.
2. Definition of insoluble-bound phenolics
ISBP normally consist of several classes of phenolic compounds
including high-molecular-weight proanthocyanidins (PA, also well-
known as condensed tannins), hydrolyzable tannins, flavonoids and
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Trends in Food Science & Technology 105 (2020) 347–362
phenolic acids. ISBP are linked with the insoluble macromolecule sub­
strates of cell wall in plant food matrix through chemically covalent
bonds, hydrogen bonding and hydrophobic interactions (mainly with
structural proteins) (Fig. 1). PA are polymers of flavan-3-ols (e.g. cate­
chin, epicatechin), and have different structures based on their degree of
hydroxylation of the aromatic rings, carbon stereochemistry in the
middle ring (C ring), galloyl substituents, as well as the type of inter­
flavan linkages (Ayoub, de Camargo, & Shahidi, 2016). PA with a mean
degree of polymerization (mDP) over 25 could still be directly extracted
by organic solvent, and as the mDP increases, the extractability reduces
(Tarascou et al., 2010). The insoluble-bound characteristic of PA is not
because of its high-molecular-weight, but their linkage with other
components of the food matrix. Hydrolyzable tannins are polyesters of a
sugar moiety and an organic acid like as gallic acid or ellagic acid,
forming gallotannins and ellagitannins. Most of hydrolyzable tannins
are detected in water-organic extracts of food, but such extractions are
not exhaustive, leaving significant amount in the resulting solid residues
(Pérez-Jiménez & Torres, 2011). The chemistry of the ISBP and the
mechanisms of their association with food matrix are still not clearly
understood. In the early 1970s, the presence of ISBP, mainly determined
as PA, was first noted in the leaves of several species of the herbaceous
Leguminoseae family (Bate-Smith, 1973). A decade later, Krygier,
Sosulski, and Hogge (1982b) developed an accurate procedure to
determine soluble free, soluble conjugated and ISBP in rapeseed, cereal
and potato flours. However, ISBP has been largely neglected in the past
for their potential role in human health. It also comes with different
semantic terminologies such as non-extractable (Kristl, Slekovec,
Tojnko, & Unuk, 2011), unextractable (Hellström & Mattila, 2008),
cell-wall (Ma et al., 2014), insoluble (Nunes et al., 2016), bound (Pra­
deep & Sreerama, 2017) or insoluble-bound phenolics (Ayoub et al.,
2016). The concept of “non-extractable” or “unextractable phenolics”
mainly refers to their extractability in water-organic solvent system, but
they are phenolics that can be released and extracted after acid, alkaline
or enzymatic hydrolysis. “Insoluble phenolics” indicates the direct sol­
ubility of these phenolics in the extraction solvents, and is commonly
used to report phenolic complexes trapping in food matrix via hydrogen
bonding, hydrophobic and hydrophilic interactions, whereas the term
“bound phenolics” represents their linkage state with food matrix
components, and usually corresponds to phenolics linked to cell wall
components through covalent bonds. There is by far no clearly accepted
definition for the term “insoluble-bound phenolics”, but we intend to
widen the ISBP to cover both “Insoluble phenolics” and “bound phe­
nolics” or their combination.
3. Insoluble-bound phenolics in food matrix
3.1. Formation of insoluble-bound phenolics in food matrix
Phenolic compounds are initially synthesized in the cytoplasmic
surface of endoplasmic reticulum of the cells and then transferred to
other cell organelles (Shahidi & Yeo, 2016). Although the mechanism
for their transfer and subsequent formation of ISBP in the cell wall is still
unclear, available information show that such transfer of phenolics
occur in the cell wall matrix (Grotewold, 2004; Zhao & Dixon, 2010).
The synthesized phenolics are first transported into the vacuole as SFP or
cell wall matrix as ISBP mainly via the membrane-mediated transport
and vesicle transfer system (Grotewold, 2004; Zhao & Dixon, 2010). The
latter includes cytoplasmic and Golgi vesicles that are a lipid bilayer
system, which facilitates the migration of phenolics into the cell wall
matrix (Meyer, Pajonk, Micali, O’Connell, & Schulze-Lefert, 2009). The
transported phenolic compounds are bound to macromolecules such as
structural proteins, cellulose and pectin through covalent bonding via
ether, ester and carbon-carbon (C–C) bonds in the cell wall matrix,
forming the ISBP (Wong, 2006). For instance, phenolic acids hydrox­
ybenzoic and hydroxycinnamic acids can form ester bonds with hy­
droxyl groups of cell wall substances via their carboxylic groups, or form
B. Zhang et al.
Fig. 1. Representative chemically covalent bonds and hydrogen bond found in the insoluble-bound phenolics entrapped in food matrix.
ether linkages with the hydroxyl groups in the aromatic ring, or directly
yield C–C bonds between carbon atoms of the phenolics and that of the
cell wall substances (Bhanja, Kumari, & Banerjee, 2009; Liu, 2007;
Liyana-Pathirana & Shahidi, 2006; McLusky et al., 1999). These ISBP are
important in connecting cell wall substances and enhancing the struc­
tural rigidity, and in protecting cells with antibacterial, antifungal and
antioxidant activities (Liu, 2007; Sancho, Bartolomé, Gómez-Cordovés,
Williamson, & Faulds, 2001). Some phenolics of the ISBP are “trapped”
inside the matrix via hydrogen bonds or hydrophobic interactions (Le
Bourvellec, Bouchet, & Renard, 2005; Tarascou et al., 2010).
3.2. Insoluble-bound phenolics content in food matrix
ISBP are widely distributed in various food matrix such as fruits,
vegetables, legumes, cereal grains and other seeds. Vegetables and fruits
were reported to have most phenolics in the soluble free or soluble
conjugated forms, whereas those in insoluble-bound form only
accounted for an average of 24% of the total phenolic content in food
matrix (Sun, Chu, Wu, & Liu, 2002). Table 1 summarizes the composi­
tions and contents of ISBP in selected vegetables and fruits reported in
recent years. The most abundant ISBP in vegetables and fruits are
phenolic acids. Kapoor and Dharmesh (2016) isolated pectic poly­
saccharides (PPs) and pectic oligosaccharides (POs) of tomatoes and
identified their ISBP to be mainly gallic acid, protocatechuic acid,
chlorogenic acid, gentisic acid, caffeic acid, vanillic acid, syringic acid,
p-coumaric acid, ferulic acid and cinnamic acid. Similarly, 5 cell
wall-bound phenolic acids i.e. vanillic acid, p-coumaric acid, sinapic
acid, trans-ferulic acid and cis-ferulic acid, and p-hydroxybenzaldehyde
and vanillin were identified in two cruciferous vegetables, with higher
ISBP concentrations found in the leaf blade than in the leaf stalk (Har­
baum, Hubbermann, Zhu, & Schwarz, 2008). Vanillic acid (158.63
mg/100 g DW (dry weight)) and coumaric acid (245.94 mg/100 g DW)
were also the most abundant ISBP in roots and leaves of red radish,
respectively (Goyeneche et al., 2015). Red pepper was also shown to
contain significant amount of ISBP (Oboh & Rocha, 2007). ISBP is also
found in fruits particularly in peels and seeds, suggesting bound phe­
nolics may be a significant contributor in addition to the extractable
phenolics to the higher potential of health benefits (Luo, Zhang, Li, &
Shah, 2016). Ellagic acid and its derivatives have received great atten­
tion in recent years due to the production of urolithin and its
anti-inflammatory potential (Lorenzo et al., 2019). The major ISBP
identified in the pomegranate peel was ellagic (199.00 mg/100 g DW)
and gallic acids (7.71 mg/100 g DW), whereas ellagic acid was the main
hydrolysable tannin in bound form in pomegranate seed (Ambigaipalan,
De Camargo, & Shahidi, 2017; Gulsunoglu et al., 2019). While phenolic
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Trends in Food Science & Technology 105 (2020) 347–362
acids were the most abundant ISBP of commonly consumed vegetables
and fruits, flavonoids including rutin, (+)-catechin, isoquercitrin,
quercitrin and quercetin were found as ISBP in tropical or subtropical
fruits or their leaves. Epicatechin was found at a significantly higher
concentration (7697.95 μg/g DW) than gallic acid (2424.90 μg/g DW) in
the ISBP fraction of the leaves of mango (Mangifera indica). Quercitrin
was found to be the main ISBP in leaves of Diospyros Kaki L. (1773.01
μg/g DW) in the same study (Chen, Zhang, Chen, Han, & Gao, 2017). In
mango fruits, however, the ISBP were found to be associated with the
fiber, with gallic acid, protocatechuic acid, syringic acid and ferulic acid
to be the major phenolic acids, and kaempferol (10.29–52.73 mg/g
extract) and quercetin (5.84–56.83 mg/g extract) and rutin (0.49–3.76
mg/g extract) the main flavonoids (Ajila & Rao, 2013). Only phenolic
acids i.e. gallic acid, chlorogenic acid, p-coumaric acid and ferulic acid
were found in the ISBP fraction of olive fruit and leaf, with the latter
having approximately 2-fold higher concentration than that of the fruit
(Xie, Huang, Zhang, & Zhang, 2015).
Cereal grains and legumes are an excellent source of ISBP. Table 2
summarizes the ISBP content reported in most recent literatures. Ben­
zoic acid derivatives (gallic, p-hydroxybenzoic and vanillic acids) and
cinnamic acid derivatives (caffeic, chlorogenic, ferulic, sinapic and p-
cumaric acids) were found in the ISBP extract of whole millet, with
ferulic acid (83.72–121.02 μg/g of defatted meal) and p-coumaric acid
(70.36–196.62 μg/g of defatted meal) to be the major ISBP. In addition
to the phenolic acids, the same study also identified several ISBP fla­
vonoids including quercetin, kaempferol, myricetin, apigenin, luteolin,
catechin, naringenin and daidzein, among them luteolin (36.80–44.57
μg/g of defatted meal), quercetin (86.73–94.47 μg/g of defatted meal),
apigenin (23.52–125.16 μg/g of defatted meal) and kaempferol
(38.45–107.50 μg/g of defatted meal) were the principal flavonoids. An
isoflavone daidzein (7.17–9.35 μg/g of defatted meal) was also reported
for the first time as ISBP for millet (Lamuel-Raventos & Onge, 2017).
Phenolic acids were also the major ISBP in rice brans, although indi­
vidual phenolic acid compositions varied significantly among the brans
of white, red and black rice (Pang et al., 2018). Similarly phenolic acids
were the main ISBP in maize, however, these compounds were found to
be unevenly distributed in the kernel; the majority of these ISBP
phenolic acids were found in the endosperm, whereas fewer types and
less quantity were found in the germ and the pericarp. In the same study
cyanidin 3-O-glucoside and, quercetin were the main ISBP flavonoids
found only in the germ, but not in the endosperm portion (Das & Singh,
2015). Our recent study on quinoa seeds also showed that in addition to
phenolic acids such as ferulic acid, catechin (16.28 μg/g DW), quercetin
(47.2 μg/g DW) and kaempferol (30.4 μg/g DW) were also identified in
the ISBP fractions (Tang et al., 2016). In another study, we showed that
B. Zhang et al. Trends in Food Science & Technology 105 (2020) 347–362

Table 1
Insoluble-bound phenolics in vegetables and fruits.
Sources Quantitative unit Hydrolysis methods Insoluble-bound phenolics Ref.

Phenolic acids Flavonoids other phenolics

Vegetables
Pectic of Tomatoes μg/g 1 M sodium hydroxide gallic acid (0.25–5.5), Kapoor et al.
(2 cultivars with containing 0.5% sodium protocatechuic acid (0.02–15.5), (2016)
unripe and ripe) borohydride under nitrogen for chlorogenic acid (0–3.8), gentisic
2h acid (0–11.5), caffeic acid
(0.1–13.5), vanillic acids (1.7–15.5),
syringic acids (0.5–6.0), p-coumaric
acids (0.4–6.0), ferulic acids
(1.4–18.5), cinnamic acids (0–6.5)
Red pepper mg Gallic acid 4 M sodium hydroxide at room 42.5 (total phenolic content) Oboh and
equivalent/100 temperature for 1 h Rocha (2007)
g fresh weight
Pak choi (2 cultivars)
•Leaf blade μg/g cell wall Isolation of cell wall material vanillic acid (9.1–11.8), p-coumaric p- Harbaum et al.
and hydrolyzed with 1 M acid (5.2–5.9), sinapic acid hydroxybenzaldehyde (2008)
sodium hydroxide under N2 for (3.8–4.5), trans-ferulic acid (12.6–12.7), vanillin
96 h (48.4–51.1), cis-ferulic acid (46.5–54.0)
(8.9–9.0)
•Leaf stalk vanillic acid (9.5–10.4), p-coumaric p-
acid (1.6–2.1), sinapic acid Hydroxybenzaldehyde
(2.1–3.8), trans-ferulic acid (3.7–4.4), vanillin
(18.1–18.3), cis-ferulic acid (31.6–35.4)
(2.5–3.5)
Leaf mustard (2
cultivars)
•Leaf blade vanillic acid (7.8–8.4), p-coumaric p-
acid (5.2–5.9), sinapic acid Hydroxybenzaldehyde
(3.8–4.5), trans-ferulic acid (7.6–11.6), vanillin
(48.4–51.1), cis-ferulic acid (40.5–53.5)
(8.9–9.0)
•Leaf stalk μg/g cell wall vanillic acid (8.0–11.6), p-coumaric p-
acid (2.9–4.8), sinapic acid Hydroxybenzaldehyde
(2.5–6.3), trans-ferulic acid (7.6–8.1), vanillin
(7.0–12.0), cis-ferulic acid (1.0–2.0) (46.8–57.0)
Red Radish
•Roots mg/100 g d.m 4 M sodium hydroxide at room vanillic acid (158.63), coumaric acid Goyeneche
temperature for 4 h (52.32), caffeic acid (7.11) and et al. (2015)
trans-ferulic acid (34.40)
•Leaves vanillic acid (155.99), coumaric acid
(245.94) and trans-ferulic (98.13)
Fruits
Apple
•Peel mg Gallic acid 4 M sodium hydroxide at room 113.53 (total phenolic content) Luo et al.
•Flesh equivalent/100 temperature under N2 for 4 h 21.98 (total phenolic content) (2016)
g wet weight
14 Fruit leaves
•Peach μg/g DW 4 M sodium hydroxide at room gallic acid (27.41), protocatechuic (+)-catechin (G.-L. Chen
temperature under N2 for 4 h acid (28.62), caffeic acid (567.54), (75.34), rutin et al., 2017)
syringic acid (23.43), p-coumaric (44.17),
acid (492.96), ferulic acid (167.60) isoquercitrin
(330.00),
quercitrin
(108.90),
quercetin
(179.52)
•Jackfruit gallic acid (144.92), protocatechuic (+)-catechin
acid (33.19), vanillic acid (39.13), (202.22),
caffeic acid (142.61), p-coumaric epicatechin
acid (72.21), ferulic acid (117.73) (427.78) rutin
(272.99),
isoquercitrin
(202.63),
quercitrin
(286.47)
•Carambola gallic acid (223.68), protocatechuic (+)-catechin
acid (85.93), caffeic acid (24.19), p- (103.57),
coumaric acid (708.94), ferulic acid epicatechin
(174.33) (61.63), rutin
(177.76),
isoquercitrin
(179.14),
quercitrin
(265.68),
(continued on next page)

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Table 1 (continued )
Sources Quantitative unit Hydrolysis methods Insoluble-bound phenolics Ref.

Phenolic acids Flavonoids other phenolics

quercetin
(374.62)
•Pomelo gallic acid (24.83), vanillic acid (+)-catechin
(35.19), caffeic acid (26.76), p- (40.01), rutin
coumaric acid (264.62), ferulic acid (125.36),
(181.20) isoquercitrin
(237.04),
quercitrin
(140.34),
quercetin
(102.06)
•Wampee gallic acid (22.47), caffeic acid (+)-catechin
(92.86), syringic acid (21.64), p- (40.86),
coumaric acid (849.92), ferulic acid epicatechin
(329.13) (42.45), rutin
(336.68),
isoquercitrin
(165.79),
quercitrin
(101.85),
quercetin
(438.46)
•Longan rutin (49.71),
quercitrin
(35.87),
•Persimmon gallic acid (510.36), caffeic acid (+)-catechin
(22.30), p-coumaric acid (124.60), (41.70), rutin
ferulic acid (44.62) (735.46),
isoquercitrin
(66.56),
quercitrin
(1773.01),
quercetin
(186.76)
•Loquat gallic acid (21.73 ± 0.64), (+)-catechin
protocatechuic acid (34.56), caffeic (40.96),
acid (111.82), p-coumaric acid epicatechin
(167.89), ferulic acid (192.28) (44.25), rutin
(69.52),
isoquercitrin
(42.70),
quercitrin
(136.11),
quercetin
(41.15)
•Litchi gallic acid (40.83), protocatechuic (+)-catechin
acid (28.90), vanillic acid (38.76), (76.52),
caffeic acid (23.68), syringic acid epicatechin
(24.10), p-coumaric acid (84.17), (58.92), rutin
ferulic acid (39.45) (137.17),
isoquercitrin
(116.29),
quercitrin
(125.52),
quercetin
(31.54)
•Mango gallic acid (2424.90), (+)-catechin
protocatechuic acid (53.11), vanillic (257.23),
acid (59.23), caffeic acid (30.87), epicatechin
syringic acid (27.54), p-coumaric (7697.95),
acid (58.64), ferulic acid (44.98) rutin (977.63),
isoquercitrin
(605.60),
quercitrin
(308.73),
quercetin
(73.46)
•Banana (Musa gallic acid (21.47), vanillic acid rutin (86.98),
basjoo Sieb. et (38.58), caffeic acid (23.42), p- isoquercitrin
Zucc. (ba jiao)) coumaric acid (87.79), ferulic acid (47.74),
(386.23) quercitrin
(31.70),
quercetin
(36.00)
(continued on next page)

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Table 1 (continued )
Sources Quantitative unit Hydrolysis methods Insoluble-bound phenolics Ref.

Phenolic acids Flavonoids other phenolics

•Banana (Musa gallic acid (25.74), protocatechuic rutin (37.77),

nana Lour.) acid (24.31), vanillic acid (55.55), isoquercitrin
caffeic acid (28.66), p-coumaric acid (58.52),
(77.87), ferulic acid (797.99) quercitrin
(68.20),
quercetin
(31.99)
•Banana (Musa gallic acid (26.11), vanillic acid rutin (266.77),
sapientum L. (fen (39.40), caffeic acid (23.18), p- isoquercitrin
jiao)) coumaric acid (102.95), ferulic acid (62.06),
(753.60) quercitrin
(40.43),
quercetin
(49.25)
•Guava (Psidium gallic acid (2872.09), (+)-catechin
guajava L.) protocatechuic acid (150.27), caffeic (378.60), rutin
acid (108.90), p-coumaric acid (853.68),
(249.18), ferulic acid (148.70) isoquercitrin
(397.51),
quercetin
(597.12)
Dietary fiber of mg/g extract Isolation of dietary fiber and gallic (4.54–16.60), protocatechuic kaempferol Ajila and Rao
Mango peel (2 hydrolyzed with 1 M sodium (0.39–1.23), syringic acids (10.29–52.73), (2013)
cultivars with hydroxide containing 0.5% (1.42–4.88), ferulic acid (0.94–3.57) quercetin
raw and ripe) sodium borohydride under (5.84–56.83),
nitrogen rutin
(0.49–3.76)
Olive
•Fruit mg/g 4 M sodium hydroxide at room gallic acid (0.099), chlorogenic acid Xie et al.
temperature under N2 for 4 h (0.43), p-coumaric acid (0.09), (2015)
ferulic acid (0.40)
•Leaf gallic acid (0.21), chlorogenic acid
(0.89), p-coumaric acid (0.11),
ferulic acid (0.68)
pomegranate mg/100 g dry 2 M sodium hydroxide in a (
Peel weight probe-sonicated water bath at gallic acid (7.71), Ellagic acid (199) Ambigaipalan
Seed 100% amplitude at 60 ◦ C for gallic acid (0.44–0.959), et al., 2017;
30 min; 4 M NaOH (1:1, v/v) Protocatecheuic acid (0.079), Ellagic Gulsunoglu
under nitrogen for 4 h at room acid (0.029–14.62) et al., 2019)
temperature

phenolic acids such as gallic acid (4.79–6.64 μg/g DW, protocatechuic
acid (3.68–8.67 μg/g DW), 3-hydroxycinnamic acid (1.09–2.19 μg/g
DW), and flavonoids catechin (2.16–19.51 μg/g DW) and epicatechin
(3.25–6.45 μg/g DW) were the main ISBP for raw lentils of 4 cultivars
with domestic cooking process significantly reduced the amount (Zhang,
et al., 2014). This was confirmed by others who examined the ISBP of six
lentil cultivars (Alshikh, de Camargo, & Shahidi, 2015). Other pulses
such as cranberry beans were also found to contain p-hydroxybenzoic
(4.4–71.2 μg/g), p-coumaric (4.9–18.4 μg/g), ferulic (11.0–41.7 μg/g),
sinapic acid (0.03–3.55 μg/g), and kaempferol (0.2–0.3 μg/g) in the
ISBP fraction (Chen et al., 2015). Cereal grains and legumes such as
whole rice, barley, buck wheats, oats, red bean, chickpea, kidney bean
and mung beans are good sources of ISBP (Bei et al., 2017; Li et al., 2016;
Pająk, Socha, Gałkowska, Rożnowski, & Fortuna, 2014; Sumczynski,
Kotásková, Družbíková, & Mlček, 2016; Wang et al., 2016; Zhu et al.,
2015).
Other seeds including sesame, camelina and sophia seeds have also
been reported to contain high amount of ISBP. The total phenolic con­
tent of the ISBP fraction of white sesame seeds was 91.9–261.94 mg
GAE/100 g DW in six cultivars, although their phenolic compositions
were not analyzed (Lin et al., 2017). However, in camelina and sophia
seeds high levels of trans-sinapic acid, catechin and quercetin-hexoside
concentrations were found in the ISBP fraction (Rahman, Costa de
Camargo, & Shahidi, 2018). Although information on the contents and
compositions of ISBP in regular foods are available in the literature,
caution must be exercised when referring to these data; the accuracy of
these results can be questionable because the methodologies employed
to release and assess the ISBP are often destructive and inefficient.
Depending on the methods used, they may cause degradation or
incomplete releasing of these bound-forms of phenolics, resulting in
underestimated values. Considering the newly found and significant role
of ISBP in health, novel approaches such as enzyme-based methods and
emerging extraction techniques should be developed or adapted for
complete assessment of ISBP in different food matrices. These new
technologies are discussed below.
4. Extraction of insoluble-bound phenolics from food matrix
ISBP are normally covalently linked or entrapped into the macro­
molecules of food matrix through ester, ether or carbon-carbon bonding,
and to a certain degree by hydrophobic interactions and hydrogen
bonding. Therefore, a thorough and effective extraction method should
be developed around dissociation of these compounds from such
bonding in food matrix. Currently, chemical, biochemical and physico­
chemical methods including acid and alkaline hydrolysis, enzymatic
hydrolysis, microwave, ultrasound-assisted hydrolysis, and pressurized
solvent/liquid extractions (PLE) have been applied.
4.1. Alkaline and acid hydrolysis
Alkaline hydrolysis is the most widely employed chemical method
for extracting the ISBP from food matrix, followed by acid hydrolysis.
Alkaline hydrolysis usually uses a wide range of concentrations of so­
dium hydroxide (1–4 M) and different hydrolysis time (15 min to

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Table 2
Insoluble-bound phenolics in cereal grains, legumes and other seeds.
Sources Quantitative unit Hydrolysis methods Insoluble-bound phenolics Ref.

Phenolic acids Flavonoids

Cereal grains
Whole millet μg/g of defatted 2 M sodium hydroxide for 4 h gallic acid (0.85–2.54), p- quercetin (86.73–94.47), kaempferol Pradeep and
(2 cultivars) meal at room temperature hydroxybenzoic acid (1.06–1.32), (38.45–107.50), myricetin Sreerama
vanillic acid (23.51–31.93), caffeic (14.18–17.85), apigenin (23.52–125.16), (2017)
(1.29–2.03), chlorogenic (2.53–3.21), luteolin (36.80–44.57), catechin
ferulic (83.72–121.02), sinapic acid (12.51–31.65), naringenin
(2.59–4.13), p-cumaric acid (13.46–28.14), daidzein (7.17–9.35)
(70.36–196.62)
Rice
•Black（5 mg/kg 4 M sodium hydroxide for 2 h gallic acid (1.3–5.4), protocatechuic acid catechin (7.6–30.8), rutin (0.9–1.4), Sumczynski
types） at room temperature (1.9–7.1), vanillic acid (11.9–45.9), quercetin (12.6–38.9) et al. (2016)
caffeic (1.3–6.5), syringic acid (1.2–3.2),
trans-p-coumaric acid (0.1–10.6), m-
coumaric acid (2.3–8.3), ferulic
(115.8–198.0), cinnamic acid (0.8–1.7)
•Red（4 gallic acid (2.7–3.6), protocatechuic acid catechin (7.5–9.2), rutin (0.7–1.1),
types） (0.9–2.0), vanillic acid (12.1–12.3), quercetin (20.2–28.0)
caffeic (0.8–2.0), syringic acid
(22.3–22.6), trans-p-coumaric acid
(15.7–17.4), m-coumaric acid (1.1),
ferulic (63.0–110.6), cinnamic acid
(0.7–1.2)
Rice bran
•White (7 μg/g 4 M sodium hydroxide for 2 h gallic acid (0–3.95), p-hydroxybenzoic Pang et al.
cultivars) at room temperature acid (0.63–1.25), vanillic acid (2018)
(0.70–1.22), syringic acid (0.36–0.82), p-
coumaric acid (24.28–70.74), ferulic acid
(118.34–172.52), sinapic acid
(2.22–5.45), isoferulic acid (0.19–6.42)
•Red (4 gallic acid (1.25–3.05), protocatechuic
cultivars) acid (0–2.69), 2,5-dihydroxybenzoic acid
(2.02–9.74), p-hydroxybenzoic acid
(0.83–1.64), vanillic acid (0.73–27.84),
syringic acid (0.36–0.64), p-coumaric
acid (12.36–42.40), ferulic acid
(61.89–141.03), sinapic acid
(1.92–5.04), isoferulic acid (1.88–5.43)
•Black (7 gallic acid (6.36–10.58), protocatechuic
cultivars) acid (1.57–10.78), 2,5-dihydroxybenzoic
acid (5.54–12.78), p-hydroxybenzoic
acid (0.68–1.94), vanillic acid
(17.58–45.37), syringic acid (0.32–0.67),
p-coumaric acid (9.69–28.52), ferulic
acid (98.03–146.34), sinapic acid
(3.43–9.50), isoferulic acid (1.37–3.33)
Maize (2
cultivars)
•Pericarp μg/g of dry methanol/H2SO4 90:10 (v/v) vanillic acid (1328.4–1349.5), syringic cyanidin 3-o-glucoside (12.6–36.8), Das and Singh
sample at 85 ◦ C for 20 h acid (272.7–558.9), p-hydroxybenzoic quercetin (0–35.9) (2015)
(0–299.0), protocatechuric acid
(443.9–756.4), caffeic acid (0-31), p-
coumaric (123.3–136.5), ferulic
(1823.1–2730.4)
•Germ vanillic acid (450.3–497.2), syringic acid quercetin (0–12.0)
(248.8–510.5), caffeic acid (27.8–59.8),
p-coumaric (68.2–250.8), ferulic
(332.2–2324.9)
•Endosperm syringic acid (166.9–200.4), p-coumaric
(0–0.45), ferulic (5.1–22.9)
Barley (4 mg phenolics/ 2 M sodium hydroxide for 4 h protocatechuic acid (0–0.52), catechin (2.58–4.78) Zhu et al.
cultivars) 100 g grain at room temperature chlorogenic acid (17.83–41.84), caffeic (2015)
acid (1.80–3.07), p-coumaric
(0.78–1.59), ferulic (348.14–67.53)
Quinoa seeds μg/g of dry 2 M HCl at 85 ◦ C for 1 h; 2 M protocatechuic acid (0–49.39), 2,4-dihy­ catechin (0–16.28), quercetin (0–47.2) Tang et al.
weight sodium hydroxide for 4 h at droxybenzoic acid (0–111.52), vanillin and kaempferol (0–30.4) (2016)
room temperature; xylanase, (0–71.16), 4-hydroxybenzoic acid
pectinase, and feruloyl esteras (0–46.54), caffeic acid (0–20.64),
vanillic acid (0–52.96), syringic acid
(0–21.22), p-coumaric acid (0–16.28),
ferulic acid (0.62–231.01), sinapic acid
(0–30.60), o-coumaric acid (0–7.72), 8,5-
diferulic acid (0–60.22), rosmarinic acid
(0–20.28), chlorogenic acid (0–51.32)
(continued on next page)

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Table 2 (continued )
Sources Quantitative unit Hydrolysis methods Insoluble-bound phenolics Ref.

Phenolic acids Flavonoids

Oats mg/kg 2 M sodium hydroxide for 4 h gallic acid (2.5), sinapic acid (2.67), kaempferol (2.5) Bei et al.
at room temperature ferulic acid (2.5) (2017)
Buckwheat g/100gDW 2 M sodium hydroxide for 1.5 caffeicacidhexos (11.91), chlorogenic catechin-glucoside (7.23), myricetin Li et al. (2016)
h at room temperature acid (13.48), protocatechuic acid (2.28) (35.12), rutin (414.85)
legumes
Cranberry μg/g 2 M sodium hydroxide for 16 h p-hydroxybenzoic acid (4.4–71.2), p- kaempferol (0.2–0.3) Chen et al.
beans (4 at room temperature coumaric acid (4.9–18.4), ferulic acid (2015)
cultivars) (11.0–41.7), sinapic acid (0.03–3.55)
Lentils (6 μg/g 4 M sodium hydroxide for 4 h gallic (0.0–1.8), protocatechuic catechin (15.0–78.4), epicatechin Alshikh et al.
cultivars) at room temperature with (0.0–4.4), p-coumaric (0.0–3.1), ferulic (0.5–7.9), (+)-catechin-3-glucoside (2015)
stirring under nitrogen. acid (0.0–0.3) (0.0–122.0), luteolin 3′ -7-diglucoside
(0.0–49.3)
Lentils (4 2 M sodium hydroxide at room
cultivars) temperature overnight
•Raw μg/g DW gallic acid (8.54–19.18, protocatechuic catechin (14.19–71.04), epicatechin (Zhang, et al.,
acid (6.39–11.09), 3-hydroxycinnamic (7.70–9.72) 2014)
acid (2.03–2.82)
•Cooked gallic acid (4.79–6.64, protocatechuic catechin (2.16–19.51), epicatechin
acid (3.68–8.67), 3-hydroxycinnamic (3.25–6.45)
acid (1.09–2.19)
Red bean μg/g 4 M sodium hydroxide under gallic acid (65.91), protocatechuic acid rutin (89.58) Wang et al.
N2 for 4 h at room temperature (130.91), ferulic acid (72.89) (2016)
Kidney bean protocatechuic acid (138.41), vanillic (+)-catechin (107.34),
acid (75.83), ferulic acid (92.40)
Chickpea gallic acid (82.85), protocatechuic acid
(110.98)
Mung bean mg/100gDW 10 ml of deionised water and 5 gallic acid (0.54), caffeic acid (1.29), p- quercetin (1.09) and luteolin (0.36) Pająk et al.
ml of 10 M sodium hydroxide coumaric acid (1.06), and sinapicacid (2014)
(containing 2% ascorbic acid (22.46)
and 13.4 mM EDTA) for 16 h at
room temperature
other seeds
White sesame mg Gallic acid 4 M sodium hydroxide for 1.5 91.9–261.94 (total phenolic content) Lin et al.
seeds (6 equivalent/100 h at room temperature (2017)
cultivars) g, dry weight
Camelina μg/g 4 M sodium hydroxide for 4 h p-hydroxybenzoic acid (16.60), catechin (12.49), quercetin-hexoside Rahman et al.
seeds under nitrogen protocatechuic acid (31.11), gallic acid (48.49), myricetin (5.45), procyanidin (2018)
(8.86), trans-caffeic acid (7.19), cis- dimer b3 (5.29)
hydroxycaffeic acid (5.08), trans-sinapic
acid (172.02), ellagic acid (3.54)
Sophia seeds protocatechuic acid (17.24), gallic acid catechin (8.78), quercetin-hexoside
(4.79), cis-hydroxycaffeic acid (2.86), (3.01), proanthocyanidins (6.22)
trans-sinapic acid (70.48), rosmarinic
acid (31.03)

overnight) at room temperature (Stalikas, 2007; White, Howard, &
Prior, 2010). Our early study indicated that alkaline hydrolysis was
better than acid hydrolysis in the extraction of ISBP from wheat bran
because of the higher yield of phenolic acids especially hydroxycin­
namic acids e.g. ferulic acid, syringic acid, p-coumaric acid, whereas
acid hydrolysis was less significant and released mainly hydroxybenzoic
acids e.g. vanillic acid and p-hydroxybenzoic acid (Kim, Tsao, Yang, &
Cui, 2006). In the same study, we also found that when both hydrolysis
methods were sequentially applied to the same sample, significantly
higher yield of phenolic acids was only observed in the method that
started with alkaline hydrolysis and followed by acid hydrolysis, the
yield was very low for the alkaline hydrolysis after the same sample was
first acid hydrolyzed, suggesting that acidic conditions might cause
instability of ISBP. A subsequent study by Verma et al. confirmed the
effectiveness of alkaline hydrolysis by examining the ISBP of wheat bran
of six cultivars; they found that alkaline hydrolysis released nearly twice
the amount of phenolics as acid hydrolysis, particularly in releasing
vanillic, cis-ferulic and sinapic acids. p-Coumaric acid was determined at
very high levels in the alkaline hydrolysis fraction, whereas syringic acid
and caffeic acid were only detectable in the acid hydrolysis fraction
(Verma, Hucl, & Chibbar, 2009). It was also found that alkaline hy­
drolysis can minimized the degradation of ferulic acid in corn to 4.8%
loss compared to 78% by acid hydrolysis (Krygier, Sosulski, & Hogge,
1982a). The majority of the phenolic acids of dry beans were also most
released by alkaline hydrolysis compared to other extraction and hy­
drolysis methods (Ross, Beta, & Arntfield, 2009). This is because alka­
line hydrolysis is effective in breaking both ether and ester bonds linking
phenolics to the cell wall substances, particularly the polysaccharides in
food matrix (Acosta-Estrada, Gutiérrez-Uribe, & Serna-Saldívar, 2014).
In contrast, acid hydrolysis mainly breaks glycosidic bonds of solubi­
lizing sugars, and generally leaves ester bonds of ISBP intact (Fazary &
Ju, 2007). The higher effectiveness and advantage in releasing
matrix-bound phenolics by alkaline hydrolysis is evident thus widely
adapted for extracting ISBP from different food matrices such as cereal
grains, legumes and other seeds (Alshikh et al., 2015; Ti et al., 2014).
Despite the wide acceptance of alkaline hydrolysis, others have
found that the amounts of phenolics in the acidic hydrolysates were
higher than those in alkaline hydrolysates (Arranz & Saura Calixto,
2010). Acid hydrolysis might also have some unique advantages, for
example, the extracted bound phenolics can be directly injected into a
chromatographic system for further analyses after neutralization and
filtration, whereas alkaline hydrolysis requires additional extraction
procedure using diethyl ether, (Arranz, Saura-Calixto, Shaha, & Kroon,
2009; Arranz & Saura Calixto, 2010; Saura-Calixto, Serrano, & Goñi,
2007). Decisions on which of the two chemical hydrolysis methods to
use may largely depend on the food matrix under investigation. For
example, one of our recent studies indicated that acid hydrolysis was
more vigorous than alkaline hydrolysis in the extraction of ISBP of black

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soybean (Peng, Li, Li, Deng, & Zhang, 2017). However, the disadvan­
tages of acid hydrolysis are also obvious. Like our early study showed,
the acidic pH and high temperature might cause degradation of some
phenolic compounds (Kim et al., 2006). Others have also attributed the
lack of detection of phenolic acids in acid hydrolysates (compared to the
alkaline hydrolysates) to the degradation of some phenolic compounds
under heated acid conditions (Sani, Iqbal, Chan, & Ismail, 2012).
Moussa-Ayoub et al. found that acid hydrolysis caused partially degra­
dation of flavonols from Opuntia ficus indica prickly fruit (Mous­
sa-Ayoub, El-Samahy, Kroh, & Rohn, 2011). Consider the pros and cons
of the two chemical hydrolysis regimes, and the complexity of different
food matrices, it is the authors’ opinion that to fully assess the ISBP, both
acid and alkaline hydrolyses should be deployed. Fig. 2 provides a
methodological schematic for the extraction of ISBP by both acid and
alkaline hydrolysis. In choosing which protocol to be first when the two
hydrolysis methods are conducted sequentially, stability of ISBP of a
particular food matrix in acid and alkaline should be considered. For
instance bound anthocyanins are more stable in acidic pH, acidolysis
followed by alkaline hydrolysis is more suitable if focus of the study is on
these compounds. Sequential hydrolysis with both methods assures
complete assessment of ISBP. Our recent study showed that almost all
the ISBP in black soybean can be released after both acid and alkaline
hydrolysis (Peng et al., 2017).
4.2. Enzymatic hydrolysis
Enzymatic hydrolysis is a biochemical process, and a highly specific
and efficient method for the extraction of ISBP from food matrix. Given
food matrix is largely made of cell wall materials, e.g. cellulose, hemi­
cellulose, pectin and glucans, carbohydrate-hydrolyzing enzymes or
carbohydrases including cellulase, hemicellulase, pectinase, amylase
and glucanase that can depolymerize and disintegrate these components
are widely used to release the associated ISBP. Carbohydrases contain­
ing arabinases, cellulases, β-glucanases, hemicellulases and xylanases
were shown to improve the contents of p-coumaric, ferulic and caffeic
acids, by 8, 4, and 32 folds, respectively, in the extraction of ISBP
Fig. 2. Methodological schematic for the extraction of insoluble-bound phenolics by sequential acid/alkaline or alkaline/acid hydrolyses.
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Trends in Food Science & Technology 105 (2020) 347–362
fraction from unripe apples (Zheng, Hwang, & Chung, 2009). The
enzymatic hydrolysis requires mild conditions thus avoids loss or
degradation of phenolics due to extreme pH or high temperature.
However, the ability of carbohydrases in releasing ISBP has been found
to be significantly lower than chemical hydrolyses. A commercial
enzyme mixture UltrafloL containing β-glucuronidase and xylanase, was
found to be most efficient in releasing bound ferulic and p-coumaric
acids of barley spent grain, but only at a fraction of what was by alkaline
hydrolysis (Bartolomé & Gómez-Cordovés, 1999). In addition to the
carbohydrases, esterases have also been studied for their ability to
release phenolic acids from ester bonds with the fibers or other polymers
of plant cells. The ISBP content released by a mixture of pectinase,
protease, cellulase, and esterase from apple was also much lower than
those obtained by the butanol-HCl method (Pérez-Jiménez, Arranz, &
Saura-Calixto, 2009). Recently, we used pectinase, xylanase and feruloyl
esterase, an enzyme specific for hydrolyzing ferulic acid esters, to study
the ISBP from quinoa seeds, and found that the amounts released were
also significantly lower than that by both acid and alkaline extractions
(Tang et al., 2016). The efficiencies of enzymes on releasing ISBP vary
significantly depending on the type and structure of the substrates in
food matrix. Selection of a specific enzyme or a combination of different
enzymes for specific food matrix might be a good strategy for enhancing
the hydrolysis efficiency of ISBP. It should be cautioned that even
though commercial preparations may contain similar enzymes, their
efficacies in hydrolysis and releasing ISBP may be different. Some
commercial enzyme preparations may also contain native phenolics of
yeasts that were used in production. While genetic engineering of en­
zymes has been explored in many areas, designing enzymes by changing
the sequence of amino acids through recombinant DNA mutation for
effective release of ISBP remains an untapped area of research. Powerful
enzymes developed from such approaches might not only shed new
lights on the composition, but also help unlock the mystery of the health
promoting roles of food ISBP. Enzymatic hydrolysis has also been used in
combination with chemical hydrolysis to acquire additional informa­
tion. Kapasakalidis et al. developed a protocol in which black currant
pomace was first treated with cellulase (C013L) and then by acid
B. Zhang et al.
hydrolysis, and determined both bound hydroxybenzoic and hydrox­
ycinnamic acids (Kapasakalidis, Rastall, & Gordon, 2009). An
enzyme-assisted supercritical fluid extraction has been developed
recently for efficient release of ISBP from black tea leftover as an
eco-friendly method (Mushtaq et al., 2017). The authors found that
hydrolysis of black tea leftover with 2.9% (w/w) kemzyme at 45 ◦ C and
pH 5.4 for 98 min combined with supercritical carbon dioxide and
ethanol had 5-fold higher extract yield (g/100 g) compared with the
conventional solvent extraction. In another study on rice grains, com­
bined enzymatic hydrolysis and alkaline extraction resulted in a signif­
icantly higher yield of all phenolic acids in bound form than direct
alkaline treatment alone (Zhou, Robards, Helliwell, & Blanchard, 2004).
These results indicated that a single hydrolytic regime is probably
inadequate in the extraction and for full assessment of ISBP. A combi­
nation of different treatments may provide more complete picture of the
ISBP of different food matrices.
4.3. Physicochemical and assisted hydrolysis
Physicochemical extraction methods such as microwave-assisted
(MAE), ultrasound-assisted (UAE), far-infrared radiation (FIR)-assis­
ted, pulsed electric field (PEF)-assisted, PLE and electron-beam irradi­
ation-assisted extractions have been studied for the extraction of ISBP in
recent years. MAE is made possible because microwaves can penetrate to
the interior of the plant cells or food matrix, and heat the in-situ water
throughout its volume, whereas conventional heating is from exterior
and requires contact with hot surface. During microwave irradiation, the
immediate internal change causes an increase of pressure inside the
plant cells, thus further disrupting the cell walls and releasing the target
substances (Vinatoru, Mason, & Calinescu, 2017). Generally, the MAE
technique is combined with alkaline hydrolysis to extract ISBP from food
matrix. Chiremba et al. performed MAE in 2 M NaOH to improve the
release of insoluble-bound phenolic acids from sorghum and maize
(Chiremba, Rooney, & Beta, 2012). Similarly, microwave-assisted
autohydrolysis was applied to extraction of ISBP from Prunus mume
stone by partial degradation of its hemicelluloses and lignins via mi­
crowave treatment (Tsubaki, Ozaki, & Azuma, 2010). These studies
show that MAE is viable approach to assistant extraction of ISBP by
other hydrolysis methods.
Sonication of the extraction mixture causes acoustic cavitation that
produces a great number of collapsing bubbles that constantly impacts
the food matrix particles. This process significantly improves the
transfer of phytochemicals from plant matrix to the extractant, thus
increases the extraction yield (Vinatoru et al., 2017). UAE is believed to
release phenolic compounds faster than conventional methods, and has
been mostly used to extract soluble free and conjugated phenolics from
foods (Erşan, Güçlü Üstündağ, Carle, & Schweiggert, 2017; Kumari,
Tiwari, Hossain, Rai, & Brunton, 2017). However, combining ultrasound
with other hydrolysis approaches such as alkaline hydrolysis and su­
percritical fluid extraction has been reported to be more effective in
releasing ISBP than any other single extraction method (Gonzales,
Smagghe, Raes, & Van Camp, 2014).
FIR ray is an electromagnetic wave longer than 4 μm but shorter than
microwave (k > 0.1 cm) that could transfer heat to the center of food
matrix and enable breaking of the covalent bonds of ISBP, thus
enhancing solvent extraction efficiency from food matrix (Niwa, Kanoh,
Kasama, & Negishi, 1988). FIR treatment has been applied to effectively
release ISBP from rice bran and husk (Wanyo, Meeso, & Siriamornpun,
2014). Peanut hulls treated with FIR also yielded higher total phenolic
content, possibly due to the enhanced release of ISBP (Lee et al., 2006).
Other physicochemical technologies have also been applied to
enhance the extraction efficiency of ISBP. Electron beam irradiation was
found to significantly improve the extraction yield of phenolic com­
pounds in almond skin due to enhanced release of bound phenolics from
the matrix (Teets, Minardi, Sundararaman, Hughey, & Were, 2009). PLE
with water as the solvent showed significantly higher amounts of ferulic
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Trends in Food Science & Technology 105 (2020) 347–362
acid and vanillin from flax shives, wheat bran and corn bran than
non-pressurized alkaline hydrolysis (Buranov & Mazza, 2009). PEF uses
high voltage to increase porosity of plant cells, enhancing the release of
ISBP. PEF treatment has been found to enhance the extraction of phe­
nolics orange juice, grapes and soybeans, resulting in increased anti­
oxidant activities (Corrales, Toepfl, Butz, Knorr, & Tauscher, 2008;
Guderjan, Töpfl, Angersbach, & Knorr, 2005; Sánchez-Moreno et al.,
2005; Soliva-Fortuny, Balasa, Knorr, & Martín-Belloso, 2009). It also
enhanced the total phenolic content of orange juice due to increased
extraction of ISBP from intracellular materials (Agcam, Akyıldız, &
Akdemir Evrendilek, 2014). PEF with mild intensity significantly
increased the release of ISBP from sorghum flour and apple pomace
compared to the control, and increased ISBP extraction also led to higher
antioxidant activity (Lohani & Muthukumarappan, 2016).
As discussed above, methodologies that aid the release and extrac­
tion of ISBP are key factors affecting accurate and thorough assessment
of the amount and composition of food matrix-bound phenolics. While
different chemical (acid, alkaline) and biochemical (enzymatic) hydro­
lyses, as well as physicochemical treatments (MAE, UAE, FIR, PLE, PEF)
have been used in the studies of ISBP in various foods or agri-food by-
products, owing to the complexity of food matrices, and the different
forms of bonding by which the ISBP are associated, it is highly chal­
lenging to reach any consensus on a single standardized method that fits
all types of food matrices. These methods have been developed and
studied separately, and often not available at the same time, making it
difficult to compare results from different groups. Putnik et al. adapted
“extraction rate” as a dependent variable to optimize the high hydro­
static pressure extraction parameters on the recovery of anthocyanins
from the grape skin pomace (Putnik et al., 2018). This may possibly be
adopted as an index to compare the results of various extraction ap­
proaches. Establishment of standardized protocols for analyzing ISBP of
specific food matrix are therefore necessary.
5. Bioaccessibility and bioavailability of insoluble-bound
phenolics in human digestive tract
Bioaccessibility refers to the amount of bioactive compounds
potentially absorbable from the gut lumen (Putnik et al., 2019). After
consumption, foods containing phenolics may undergo a series of
enzymatic reactions, resulting in altered physiochemical properties in
the digestive tract. Soluble phenolic compounds in free and conjugated
forms can be released from the food matrix into the digestive fluids of
the stomach and small intestine. Hence, the bioaccessibility of these
released phenolics also depends on their stability during digestion in the
gastrointestinal (GI) tract. Bioavailability is defined as the extent to
which bioactive components are absorbed into the blood circulation
system so that they can exert bioactivity at target tissues and organs
(Putnik et al., 2019). As such, bioavailability strictly depends on bio­
accessibility, whereas the biological activities of phenolic compounds
are subjected to the release–absorption process. The soluble phenolics
and those released in the stomach are absorbed in the small intestine,
however, only 5–10% of such phenolics are absorbed, and the remaining
90–95% including the non-absorbed soluble phenolics and ISBP
continue to pass down to the colon, where they are subjected to mi­
crobial metabolism and degradation by the gut microbiota. While the
bioavailability of phenolics is low, once they are absorbed, they may be
further metabolized by phase I and II enzymes and reach systemic cir­
culation. It is unlikely that the intrinsic phenolic compounds alone, in
the aglycone or various other conjugated forms, are responsible for the
bioactivities in vivo, their metabolites and conjugates may contribute in
significant ways to the biological activities. Pimpao et al. detected and
identified the phase II metabolites of phenolic acids after ingestion of a
phenolic-rich berry puree, and found several metabolites such as
4-O-methylgallic acid-3-O-sulphate, gallic acid-O-glucuronide, cat­
echol-O-sulphate and –O-glucuronide and 4-methylcatechol-O-sulphate
and -O-glucuronide in human urine after ingestion of (poly)phenols,
B. Zhang et al.
which represent possible biomarkers for phenolics intake (Pimpao et al.,
2014). These phenolic metabolites were quantified at physiological
levels ranging from 0.3 to 12 μM in plasma (Pimpão, Ventura, Ferreira,
Williamson, & Santos, 2015). These phenolic sulfates could across
blood-brain barrier endothelial cells and exert neuroprotective effect at
circulating concentrations (Figueira et al., 2017). The large intestine
(colon) is where the non-absorbed phenolics and cell wall bound ISBP (e.
g. those bound to cellulose, hemicellulose, structural protein and pectin)
are released and metabolized to simple phenolic compounds under the
action of digestive enzymes or colon microbiota (Chandrasekara &
Shahidi, 2012). Fig. 3 depicts the absorption and metabolic pathways of
ISBP in the GI tract where chemical and biochemical hydrolyses (low pH
in the stomach; hydrolytic enzymes) and microbial transformations
occur. Absorption of phenolics can take place by passive diffusion and
active transport by transporters. Both anthocyanins and their degraded
products phenolic acids can be transported through the intestinal
epithelium via passive diffusion or active transporters, such as hexose
transporter, ATP-binding cassette transporters and monocarboxylic acid
transporters (Han et al., 2019). Anson et al. reported that bioavailability
of phenolic compounds such as ferulic acid in cereal grain is dependent
on their bioaccessibility (Anson et al., 2009). Different forms of phe­
nolics i.e. soluble free, soluble conjugated and ISBP in the GI tract have
been reported to follow different pathways. Colonic microorganisms
such as Bifidobacterium spp. and Lactobacillus spp. produce a variety of
extracellular enzymes such as carbohydrases, proteases, esterases and
other types of enzymes, leading to disruption of the food matrix and
hydrolysis of the covalent bonds of ISBP to release phenolics (Shahidi &
Yeo, 2016). Kroon et al. reported that more than 95% of feruloyl groups
associated with wheat fiber were released by enzymes (esterase and
xylanase activities) during fermentation in the colon, whereas only 2.6%
of ferulic acid was released by gastric and small intestinal treatments
(Kroon, Faulds, Ryden, Robertson, & Williamson, 1997). Flavonoids can
also be metabolized, through ring cleavage, to simpler phenolic com­
pounds by gut microbiota (Selma, Espín, & Tomás-Barberán, 2009).
Fig. 3. Absorption pathways and metabolism of insoluble-bound phenolic compounds in the gastrointestinal tract.
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Trends in Food Science & Technology 105 (2020) 347–362
Esterases are not only secreted by colon microflora, but also existing
in the mucosa epithelial cells of the small intestine (Fig. 3). It has been
proposed that the release and in vivo absorption of insoluble-bond
hydroxycinnamic acid is probably initiated by hydrolysis of covalent
bonds by esterases in the small intestine (Andreasen, Kroon, Williamson,
& Garcia-Conesa, 2001). Similarly, Nardini et al. demonstrated that the
plasma level of caffeic acid increased after coffee consumption, possibly
due to the release and absorption of caffeic acid from insoluble-bound
chlorogenic acid (Nardini, Cirillo, Natella, & Scaccini, 2002). Despite
these findings, the bioavailability of insoluble-bound phenolic acids is
generally very low in vivo. One of the major reasons is that the structure
of food matrix severely hinders the hydrolysis of insoluble-bound
phenolic acids by esterases in the human GI tract, resulting in
extremely low bioaccessibility and bioavailability (release and absorp­
tion). For instance, the urinary recovery level of ferulic acid was
determined to be as low as 3.9% in rats and 3.1% in humans after wheat
bran consumption (Adam et al., 2002; Kern, Bennett, Mellon, Kroon, &
Garcia-Conesa, 2003), whereas only 0.4–0.6% was found in the urine of
rats fed corn bran, which was attributed to the more complex food
matrix structure of the latter (Zhao, Egashira, & Sanada, 2005). Our
recent study showed that although intrinsic phenolic acids were found in
green pea hulls, none of these compounds or their metabolites were
found in the plasma and urine samples of rats fed these hulls (Guo et al.,
2019). Although a large number of metabolites are formed during
microflora fermentation, only a few of them have been documented to
be absorbed in the colon, such as water, some salts, sodium and potas­
sium ions, vitamin K, vitamin B12, thiamin, riboflavin, short-chain fatty
acids and some small molecules (Shahidi & Yeo, 2016). The absorption
mechanism of ISBP released in the colon has not yet been well studied,
despite the colonic epithelium is considered the main site of in vivo ab­
sorption of phenolic acids in the microbiota. Absorption of phenolic
acids such as chlorogenic acid, ferulic acid and p-coumaric acid have
been demonstrated to be mediated by monocarboxylic acid transporter
(MCT) using Caco-2 cell monolayers (Konishi & Kobayashi, 2004),
B. Zhang et al.
which was affirmed in vivo (Konishi, Hitomi, & Yoshioka, 2004; Konishi,
Zhao, & Shimizu, 2006). Using a cell model consisting of co-cultured
Caco-2 and mucus-producing HT29-MTX cells, ferulic acid was shown
to be efficiently transported as the free form through a with only a small
amount transported as feruloyl-glucuronide or sulphate, together with
some free dihydroferulic acid (Poquet, Clifford, & Williamson, 2008).
Colonic phenolic acids, which can be assumed as catabolites of the gut
microbiota from unabsorbed soluble or conjugated polyphenols, or ISBP
released by colonic fermentation, may also have local roles in regulating
immune system response at the epithelial level or modulating micro­
biome to activate short chain fatty acids (SCFA) excretion and promote
gut health (Kawabata, Yoshioka, & Terao, 2019). As phenolic acids and
other small phenolics derived from ISBP are important colonic metab­
olites, it would be beneficial to conduct more in-depth studies on their
absorption and bioactivities in the intestinal epithelium and contribu­
tion to the systemic actions. Meanwhile, currently there are no widely
acceptable analytical methods for distinguishing the colonic ISBP from
other simple phenolic metabolites in the colon that are derived from
unabsorbed multiple (poly)phenol parent compounds. High resolution
mass spectrometry and metabolomics approach have been successfully
used in studies of urine and plasma metabolites (Guo et al., 2019;
Pimpao et al., 2014; Pimpão et al., 2015). Such methods have also been
applied to analysis of colonic fermentation metabolites (Chen et al.,
2018); however, due to many technical challenges such as sample sta­
bility and low concentration, more sensitive and specific methods need
to be developed. One approach that might warrant further study is the
use of stable isotope labelling, in which case a standard matrix of
phenolic compounds or ISBP labeled with carbon 13 (13C) and/or
deuterium (2H) may be used in metabolomics and health related studies.
6. In vitro and in vivo biological activity of insoluble-bound
phenolics in food matrix
While various bioactivities of food-based phenolics have been re­
ported, unlike the soluble free and conjugated phenolics, it is difficult to
directly determine the bioactivities of ISBP using in vitro assays due to
the insoluble nature of the bound phenolics. Most studies on charac­
terization of ISBP are carried out by first performing acid, alkaline or
enzymatic hydrolysis of food samples followed by extraction of the
phenolics released from the insoluble-bound state in food matrix into
proper solvents, and then identification of the compounds and assess­
ment of their various bioactivities in similar manners to those for the
soluble free and conjugated phenolics. For example, ISBP was extracted
from different food sources after alkaline hydrolysis, and then evaluated
for their antioxidant potentials against oxidative damage using in vitro
assays such as copper-induced LDL-cholesterol oxidation and super­
coiled plasmid DNA strand breakage inhibition (Ayoub et al., 2016;
Jayaram & Dharmesh, 2011). We have also studied the antioxidant ac­
tivities of ISBP from black soybean, lentil, quinoa seeds and cranberry
beans by first performing acid, alkaline or enzymatic hydrolysis, char­
acterizing the composition and then evaluated their contribution to the
antioxidant activities (Chen et al., 2015; Peng et al., 2017; Tang et al.,
2016; Zhang, et al., 2014). Additionally, released single phenolics
including phenolics acids and flavonoids have been extensively exam­
ined for their biological activities against diabetes, cardiovascular dis­
ease, neurodegenerative disease and cancers in cell culture and in vivo
models (Eitsuka et al., 2014; Liao et al., 2016; Narasimhan, Chinnaiyan,
& Karundevi, 2015; Nirmala & Ramanathan, 2011). It is apparently
challenging to assess the contribution of ISBP in a food form to health
benefits. Recently, efforts in finding ways to release the insoluble-bound
phenolics from food matrix before consumption have been made. Ap­
proaches such as solid state fermentation can enhance the release of
phenolic contents and antioxidant activities (Bhanja Dey, Chakraborty,
Jain, Sharma, & Kuhad, 2016).
The chemical and enzymatic hydrolyses in the laboratory provide
important compositional information on potential ISBP in food,
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Trends in Food Science & Technology 105 (2020) 347–362
however, the released phenolics may differ significantly from those
released in vivo. Similarly, the various in vitro bioactivities may not truly
reflect the actual in vivo effects. Release of ISBP in vivo is more complex
than that by a single chemical or enzymatic reaction, factors such as food
matrix and intestinal microorganisms can all significantly impact on the
release and metabolism of ISBP. More importantly, the in vivo outcome
of health benefits also depend on the bioaccessibility and bioavailability
of all forms of phenolics in the diet. The interplay among free, conju­
gated and bound phenolics, food matrix and gut microbiome are highly
complex and are currently not fully understood (Manach et al., 2004).
The microbiota of the large intestine initially cleaves the glycosidic
linkage and breaks down the flavonoid structure of the unabsorbed
phenolics into smaller phenolic compounds (Cardona, Andrés-Lacueva,
Tulipani, Tinahones, & Queipo-Ortuño, 2013; van Duynhoven et al.,
2011). Different intestinal bacterial species including Bacteroides, Eu­
bacterium, Enterococcus and Blautia are engaged in this metabolic process
(Braune & Blaut, 2016; Martinez-Zapata et al., 2016). Polymeric
proanthocyanins are ISBP that can be metabolized by gut microbes to
phenolic acids and valerolactones (Lamuel-Raventos & Onge, 2017).
These microbial species or the microbiota could have different impacts
on the metabolic fate of dietary polyphenols including ISBP, resulting in
different degrees of bioaccessibility and bioavailability (Ozdal et al.,
2016), although bioavailability and physiological activities need to be
verified in vivo. The particular species of gut microbes involved in the
biotransformation and metabolism of polymeric proanthocyanins,
particularly in depolymerisation of these compounds in the gut also
warrant further investigation.
The majority of ISBP are associated with cell wall components
especially the dietary fibers. Fermentation of these fibers especially the
indigestible insoluble fibers by colonic bacteria including probiotics
such as Lactobacteria produce significant amount of which lowers the pH
in the colon, preventing the growth of pathogenic microorganisms.
These indigestible fibers are classic prebiotics. However, in recent years,
the unabsorbed phenolics and their metabolites including the ISBP
released in the colon have been found to have “prebiotic-like” effects
(Espín et al., 2017). Although a thorough discussion on such effect is
beyond the scope of this review, it is very intriguing that ISBP and other
phenolic metabolites in the colon are absorbed into the blood stream,
and can persist in human plasma for up to 3–4 days after the intake with
significant concentrations at which anti-inflammatory and anti-oxidant
effects have been observed. ISBP and other colonic metabolites may play
key bioactive roles, in both intestinal epithelium, endothelial cells, and
in systemic circulation, particularly as modulators of low-grade
inflammation and mediators of cell signaling pathway (Edwards et al.,
2017; González-Sarrías, Espín, & Tomás-Barberán, 2017; Vitaglione,
Napolitano, & Fogliano, 2008). Intestinal low-grade inflammation is
linked to immune system dysfunction and metabolic diseases such as
diabetes and cardiovascular disease, via the gut-low grade
inflammation-metabolic syndrome axis. It has been shown that people
with metabolic syndrome have different microbiota compositions which
affect the release of ISBP and catabolism of dietary phenolics. The
mechanisms of the metabolic disease have been linked to the trans­
location of low-grade inflammation in the epithelial layer of the gut to
tissues. Existing evidence in rodents also supports that an impaired in­
testinal immune system characterizes and causes the development of
metabolic disease, and strategies based on improving the interplay
among gut microbiota-host immune system-metabolic syndrome have
been proposed (Burcelin, 2016). The local and systemic antioxidant and
anti-inflammatory effects of ISBP and other phenolic metabolites and
their “prebiotic-like” activity strongly suggest that these compounds
may play a significant role in this crosstalk, and may offer a good
treatment strategy for intestinal and metabolic health.
Meanwhile, as mentioned above, colonic fermentation of dietary fi­
bers produces both SCFA and phenolic metabolites, which have been
implicated in suppression of intestinal inflammation. In addition, the
number and type of fermentable macromolecules and unabsorbed
B. Zhang et al.
phenolics reaching the human colon could significantly impact the
concentration and type of metabolites in the colon, and further affect the
health outcome. Aprikian et al. (2003) found that pectin acted as a
prebiotic that led to enhanced yield of phenolics metabolites during
colonic fermentation, probably due to increased bacterial activity.
However, whether the ISBP exert synergistic effects with macromole­
cules or their colonic fermentation products in human colon remains to
be properly investigated. A recent study showed that common bean diets
rich in dietary fiber and phenolics improved biomarkers of colon health
and reduced inflammation during colitis, and the effects were signifi­
cantly correlated to fecal SCFAs and total phenolic contents, and fecal
and serum antioxidant activities (Zhang et al., 2014). More recently,
Awika et al. reviewed the dietary fiber and polyphenols of cereal
grains/pulses and existing evidence of their anti-inflammatory and gut
health effects. They concluded that the anti-inflammatory effects of diets
rich in these two major constituents may act synergistically and
contribute in a complementary manner to chronic inflammation and gut
health (Awika, Rose, & Simsek, 2018). More interestingly SCFA have
also been shown to affect and enhance uptake of phenolic metabolites
(Van Rymenant et al., 2017). It was proposed that the slow and
continuous release of ISBP may favorably act in vivo, quenching the
soluble radicals that are continuously formed in the intestinal tract as
opposed to the soluble free phenolics that are rapidly absorbed and
metabolized in the gastrointestinal tract (Vitaglione et al., 2008). Un­
derstanding the roles of ISBP in intestinal health and modulation of
metabolic syndrome and the potential synergistic effects with indigest­
ible fibers and/or their colonic metabolites SCFA is a clear direction for
future research.
7. Concluding remarks and future perspectives
Phenolic compounds are ubiquitous in plant foods, and are the most
important dietary bioactives with significant role in reducing chronic
diseases, especially those induced by oxidative stress. Phenolics not only
exist in different chemical classes, but are in different forms depending
on their association with food matrix, e.g. soluble free, soluble conju­
gated and insoluble-bound phenolics. Past studies have accumulated
sufficient knowledge on the chemistry, biochemistry and potential
health benefits of soluble phenolics, but those of the ISBP have only
become a separate subject of research in recent years. For this reason,
current knowledge and information on ISBP’s occurrence, forms of
binding to the cell wall components, methods for extraction and char­
acterization, release and absorption in the intestinal tract, and ulti­
mately their implications on human health have been sporadic. This
review is not only a compilation of these existing information, but
intended also to be a guide for future research. The complex chemistry of
ISBP within the cell walls of plants and their association with food
matrices makes it a highly challenging task to fully understand and
characterize these bioactives. Current methodologies employed to
release and assess dietary ISBP are often destructive and ineffective.
They also lack the biological relevance to physiological behavior and in
vivo results. When chemical hydrolyses are used, we have proposed a
sequential extraction strategy for a complete and comprehensive eval­
uation of the ISBP composition (Fig. 2). While these chemical extraction
processes have limited use in assessing actual ISBP released from a diet
in the human digestive tract, they may serve as a standard extraction
method and provide a good reference for further studies on enzymatic
and microbial release of ISBP. As the role of ISBP and other (poly)
phenolic metabolites in modulation of the gut microbiome and intestinal
immune response becomes increasingly recognized, a standard matrix of
ISBP labeled with carbon 13 (13C) and/or deuterium (2H) may be used in
metabolomics and health related studies.
The health benefits of ISBP depend on many key factors: the type of
food matrix and their colonic fermentation products, the amount and
form of phenolic compounds, and the amount and type of ISBP released
by gut microbiome, as well as their synergistic effects, and cellular
359
Trends in Food Science & Technology 105 (2020) 347–362
uptake and absorption in systemic circulation, can all directly or indi­
rectly affect the local or systemic bioactivity and health benefits. In this
sense, more studies that address the bioavailability, metabolism and
mechanism of action of ISBP are required to better understand the
benefits of this important form of phenolics. It is our opinion that future
research on ISBP should focus on the following:
1. Establish a standard protocol for complete assessment of ISBP in
different food matrices
2. Create a standard matrix of ISBP labeled with carbon 13 (13C) and/or
deuterium (2H) for bioaccessibility, bioavailability and metab­
olomics studies.
3. Role of ISBP in the interplay between the gut microbiota-low grade
inflammation-metabolic syndrome axis
Declaration of competing interest
The authors declare that there are no conflicts of interest.
Acknowledgements
This project was supported by the A-base funding of Agriculture &
Agri-Food Canada (Project # J-001322.001.04, #J-002252.001.04), the
Ontario Research Fund (ORF), Canada (# RE-08-082), and the National
Natural Science Foundation of China (Grant No. 31701564), Natural
Science Foundation of Jiangxi Province (Grant No. 20171BAB214035)
and Key R&D Program of Jiangxi Province (Grant No.20181BBF60014).
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