Food Chemistry 414 (2023) 135645

Contents lists available at ScienceDirect

Food Chemistry
journal homepage: www.elsevier.com/locate/foodchem

Review

Biological and pharmacological aspects of tannins and potential

biotechnological applications
Luciana Fentanes Moura de Melo a, b, 1, Verônica Giuliani de Queiroz Aquino-Martins a, b, 1,
Ariana Pereira da Silva a, b, Hugo Alexandre Oliveira Rocha b, c, Katia Castanho Scortecci a, b, *
a
Departamento de Biologia Celular e Genética – Centro de Biociências, Universidade Federal do Rio Grande do Norte, Campus Universitário UFRN, 59072-970, Bairro
Lagoa Nova, Natal, RN, Brazil
b
Programa de Pós-Graduação em Bioquímica e Biologia Molecular, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Campus Universitário UFRN,
59078-970, Bairro Lagoa Nova, Natal, RN, Brazil
c
Departamento de Bioquímica – Centro de Biociências, Universidade Federal do Rio Grande do Norte, Campus Universitário UFRN, 59078-970, Bairro Lagoa Nova,
Natal, RN, Brazil

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

Keywords: Secondary metabolites are divided into three classes: phenolic, terpenoid, and nitrogenous compounds. Phenolic
Biomolecule compounds are also known as polyphenols and include tannins, classified as hydrolysable or condensed. Herein,
Oxidative stress we explored tannins for their ROS reduction characteristics and role in homeostasis. These activities are asso­
Metal complexation
ciated with the numbers and degree of polymerisation of reactive hydroxyl groups present in the phenolic rings
Nutraceutical
of tannins. These characteristics are associated with anti-inflammatory, anti-aging, and anti-proliferative health
Gut microbiome
Biotechnological application benefits. Tannins can reduce the risk of cancer and neurodegenerative diseases, such as cardiovascular diseases
and Alzheimer’s, respectively. These biomolecules may be used as nutraceuticals to maintain good gut micro­
biota. Industrial applications include providing durability to leather, anti-corrosive properties to metals, and
substrates for 3D printing and in bio-based foam manufacture. This review updates regarding tannin-based
research and highlights its biological and pharmacological relevance and potential applications.

1. Introduction other plants, such as phytoalexins, which are secondary metabolites

Plants produce numerous biomolecules in response to external
stimuli. Such compounds are produced in response to herbivore/
microorganism attacks (biotic stress) or environmental stresses, such as
drought, salinity, and temperature (abiotic stress) (Isah, 2019). Conse­
quently, plant cells transduce different stimuli (external and endoge­
nous) to internal messengers such as H2O2, reactive oxygen species
(ROS), Ca2+, or electrical signalling (Stein & Udasin, 2020; Szechyńska-
Hebda et al., 2022). These internal messengers promote a signal trans­
duction cascade that may be transmitted to different plant tissues, such
as leaves, stems, roots, flowers, and fruits. This in turn results in meta­
bolic changes and the production of biomolecules, such as secondary
metabolites, some of which are part of the plant’s defence mechanisms
(Choi et al., 2017).
In plants, biomolecules are often produced in response to pathogens.
These biomolecules may also have anti-germinative or toxic effects on
produced in response to biotic stress. Animals are directly or indirectly
affected by these biomolecules. They prevent oviposition by insects and
attract insects or birds for pollination (Erb & Kliebenstein, 2020).
These biomolecules are mainly used in traditional medicine and by
the pharmaceutical and chemical industries. In biotechnological and
food industries, these compounds have been employed for their many
biological effects, such as antioxidative (Cherubim et al., 2020; Pizzi,
2021), antimicrobial, antifungal (Khanzada et al., 2021), antiviral
(Montenegro-Landívar et al., 2021), and nutritional (Chang et al., 2019;
Rauf et al., 2019).
Therefore, secondary metabolites are organic compounds that are
not directly associated with plant development but play an essential role
in plant protection and environmental adaptation. These biomolecules
may also be sources of primary metabolites (Erb & Kliebenstein, 2020).
Based on their biosynthetic pathway, these compounds are divided
into three families: terpenoids, nitrogenous compounds (alkaloids), and

* Corresponding author.
E-mail address: katia.scortecci@ufrn.br (K.C. Scortecci).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.foodchem.2023.135645
Received 11 July 2022; Received in revised form 29 January 2023; Accepted 4 February 2023
Available online 6 February 2023
0308-8146/© 2023 Elsevier Ltd. All rights reserved.
L.F.M. Melo et al. Food Chemistry 414 (2023) 135645

phenolics, also known as polyphenols. Depending on their chemical Table 1

family, they can used in the food, pharmaceutical, or biotechnology Phenolic compounds and their functions.
industries. For example, phenylpropanoids are used in the food industry Phenolic Activity References
as food supplements and in the pharmaceutical industry for skin pro­ compounds
tection and anti-ageing (Erb & Kliebenstein, 2020). These biomolecules Tannins; Bioactive compounds against (Borjan et al., 2020; Jin
have been associated with pleasant odours, tastes, and colours and are Flavonoids; ROS, et al., 2022; Kashi et al.,
found in fruits including currants, cherries, pomegranates, peaches, L-ascorbic acid; antihypertensive, 2019; Lyu et al., 2020)
plums, and apples. These properties also promote their use in beverages Chlorogenic antibacterial; prevents
acid; infections and
such as fruit juices, tea, coffee, and red wine (Bowtell & Kelly, 2019; Caffeic acid; degenerative diseases
Lara et al., 2020). Catechins
Terpenes are isoprene metabolites. These compounds are divided Trans-resveratrol; ROS reduction; antifungal (Shi et al., 2022; Simonetti
into monoterpenes, sesquiterpenes, diterpenes, sesterpenes, triterpenes, Resveratrol; et al., 2020)
Ellagic acid;
tetraterpenes, and polyterpenes. They have various biological functions
Flavan-3-ols;
with regard to the electron transport chain, pigments, and structural Quercetin,
elements. They may also interact with the cell membranes. Volatile Chlorogenic acid; Antifungal (Telles et al., 2017)
terpenes are found in different plant tissues such as roots, stems, leaves, Gallic acid;
fruits, seeds, and flowers, often providing the aroma associated with a Protocatechuic
acid.
particular fruit (Erb & Kliebenstein, 2020; Lara et al., 2020). Anthocyanins. Antitumour, cardiovascular (Di Lorenzo et al., 2021)
Alkaloids are nitrogen-containing compounds derived from amino disease and diabetes
acids. These compounds are classified into the following three types: 1) prevention
alkaloids with heterocyclic nitrogen, 2) protoalkaloids without cyclic Catechin; Anti-inflammatory; Anti- (Kagambega et al., 2022)
Epicatechin; Nociceptive.
nitrogen, and 3) pseudoalkaloids. These nitrogenous compounds may
Quercitrin.
act on lipid metabolism because enhanced de novo fatty acid synthesis in Condensed tannins Anti-helminthic. (Naumann et al., 2017;
cancer cells is mainly used for membrane formation, energy storage, and Oliveira et al., 2017)
signalling molecule production. In summary, lipid metabolism disorders
can cause severe diseases and health complications (Lara et al., 2020).
Tannins and the multiple functional groups, such as hydroxyls, of compounds are classified into two main groups: hydrolysable and non-
their chemical structure enable them to develop links to establish a hydrolysable tannins, also called CTs or proanthocyanidins (Bowtell &
stable reticulate association within different molecules, such as proteins Kelly, 2019; Durazzo et al., 2019; Erb & Kliebenstein, 2020; Jacobsen &
or carbohydrates. This unique feature allows their differentiation into Raguso, 2018; Lara et al., 2020; Pizzi, 2021). Different biological and
polyphenolic groups (Smeriglio et al., 2017). pharmacological activities have been associated with the composition
This review aims to present information about tannins concerning and function of tannins.
their chemical structure, biological activities, and application to pre­ For example, Marsh et al. (2020) worked with 628 eucalyptus sam­
vent/help in disease treatments and their biotechnological applications. ples from 515 eucalyptus species and observed differences among their
In this study, 123 articles were reviewed, out of which 95.94 % have polyphenol profiles. Consequently, the oxidative activity, protein pre­
been published during the last 7 years (118 articles from 2016 to 2022), cipitation capacity, and the ability to reduce digestibility in herbivores
whereas the remaining 4.06 % articles were published for more than showed interesting differences (Marsh et al., 2020), highlighting the
seven years (5 articles before 2016). The terms more commonly importance of in-depth research into these compounds.
searched in the PubMed database were tannins, hydrolysed tannins,
condensed tannins (CTs), metabolism, nutrition, nutraceuticals, 1.2. Composition and structure of tannins
biotechnology, and axis gut/brain/microbiota.
Tannins were chosen as the main subjects of this review because they
1.1. Polyphenols are relevant phenolic compounds. They are natural compounds present
in fruits, vegetables, cereals, and seeds and have wide applications in
Polyphenols are found in fruits, vegetables, tea, coffee, cereals, wine, human health, plant defence, development, and plant growth (Erb &
and chocolates. In addition, their presence in human diets may help Kliebenstein, 2020; Fraga et al., 2019; Kashi et al., 2019; Lara et al.,
prevent cardiovascular diseases, diabetes, and cancers, improving in­ 2020; Smeriglio et al., 2017). One essential characteristic of tannins is
testinal microbiota and cognition (Fraga et al., 2019; Kashi et al., 2019). their ability to interact with proteins denaturing them in vertebrate
The mode of action of polyphenols is associated with antioxidation of herbivores, which is the basis of astringent, ROS reduction, anti­
ROS, signalling, regulation of transcription factors, and modulation of mutagenic, antiviral, and antimicrobial properties. Astringency is the
inflammation (Table 1) (Bowtell & Kelly, 2019; Durazzo et al., 2019; sensation of dryness, tightness, and wrinkling of the oral cavity. It occurs
Fraga et al., 2019). when there is a precipitation of glycoproteins from the mucous secre­
Polyphenols have two or more hydroxyl groups in their structure that tions of the salivary glands following increased interactions between
are attached to one or more benzene rings. They can be divided into two tannins and salivary proteins rich in proline amino acids (Soares et al.,
main groups: flavonoid and non-flavonoid (phenolic acids, stilbenes, 2020). This interaction is probably due to a sum of secondary forces,
lignans, and tannins) polyphenols. Flavonoids have a chemical structure prevalence of both ionic and covalent bonds, interaction between tan­
consisting of phenylbenzopyran with a C6-C3-C6 carbon skeleton; that nins and proteins (amino groups of the non-skeletal side chains of amino
is, they consist of two aromatic rings interconnected by a 3-carbon acids and the phenolic hydroxyl groups of tannin), and by esterification
chain, usually in the form of an oxygenated heterocycle with three or of the groups of side chains of the carboxylic acid of amino acids (Pizzi,
more hydroxyl (OH) groups. They may occur as aglycones or may be 2021). This interaction depends on the molecular weight, protein size,
conjugated to sugars, organic acids, and glycans. These compounds can structure, and enzymatic reaction conditions, such as temperature, re­
be subdivided into subclasses based on the oxidation degree of the action time, and pH (Marsh et al., 2020). Proline-rich proteins (PRPs)
heterocyclooxygenate, including flavonols, flavanols, flavanones, fla­ have a lubricating function. When these interact with tannins, they
vones, isoflavones, and anthocyanidins (Bowtell & Kelly, 2019; Durazzo inhibit lubrication, causing a sensation of astringency (Dufourc, 2021).
et al., 2019; Erb & Kliebenstein, 2020; Fraga et al., 2019). This aggregate may cause the precipitation of salivary proteins by
Tannins are polyphenols containing aromatic rings. These tannins, which may reduce the lubricative properties, possibly because a

2
L.F.M. Melo et al. Food Chemistry 414 (2023) 135645

decrease in viscosity or sensation of the precipitate itself could increase

friction perception, explaining the astringency (Brossard et al., 2020).
Tannins are natural polyphenolic compounds generated during sec­
ondary metabolism. The shikimic acid pathway is one of the routes of
biosynthesis of most plant phenolic compounds, along with the meva­
lonic acid pathway, which needs previous reactions to synthesise
phenolic compounds (Gómez-Martínez et al., 2021; Sogvar et al., 2020)
(Fig. 1).
Tannins are flavonoids, oligomers, or polymers that are highly
reactive and form intermolecular and intramolecular hydrogen bonds,
which means that they might interact with macromolecules such as
carbohydrates and proteins (Smeriglio et al., 2017). These compounds
can be classified as hydrolysable or condensed (Chung et al., 1998).
Hydrolysable tannins are formed by several phenolic acid molecules and
classified as gallotannins and ellagitannins when producing hydrolysed
gallic acid and ellagic acid, respectively (Fig. 2). These molecules are
hydrolysable because their ester bonds quickly undergo hydrolysis by
acids or high temperatures (Durazzo et al., 2019; Li & Duan, 2019;
Smeriglio et al., 2017).
By contrast, CTs are more resistant to fragmentation, and they are the
products of the flavonoid biosynthetic pathway. These molecules have
two phenol rings connected by a central pyral ring (Fig. 2).
CTs are polymers of flavan-3-ols, including procyanidins (PC), which
have two OH groups, and prodelfinidines (PD), which have three OH
groups. Two examples of PCs are catechins and epicatechins, whereas
epigallocatechin is a type of PD (Fig. 3).
Plants synthesising tannins have a mixture of PCs and PDs, making
their isolation difficult (Del Bianco et al., 2021). Some plants, such as Fig. 2. Tannin structure. Schematic representation of (A) gallotannin and (B)
broad beans, beans, barley, blackcurrant, cinnamon, and black tea, ellagitannins examples from hydrolysable tannins, and (C) n monomers of
specialise in the production of PC or PD in their roots, bark, shoots, flavan-3-ols where R, in general, can represent a procyanidin (represented by
flowers, and seeds and may be excellent tannin sources (Del Bianco H) or prodelphinidin (represented by OH), examples from condensed tannins.
et al., 2021; Rauf et al., 2019; Smeriglio et al., 2017). This figure was drawn using ACD/ChemSketch software (Freeware) 2020.2.1.
When these compounds are heated in an acidic medium, they give

Fig. 1. Phenolic compound biosynthesis and the shi­

kimic acid pathway. The biotransformation pathway
of hydrolysable and condensed tannins, originating
from CO2 carbons that, when photosynthesized,
generate phosphorylated sugars that enter the shiki­
mic acid pathway to generate several phenolic com­
pounds that form gallic acid, ellagic acid and
hydrolysable tannins. Another way, after the shikimic
acid route generates phenylalanine, cinnamic acid,
and simple phenolic compounds that may form lignin.

3
L.F.M. Melo et al.
Fig. 3. Schematic representation of catechin subunits in (A) catechin, (B)
epicatechin, (C) gallocatechin, and (D) epigallocatechin. These figures were
drawn using ACD/ChemSketch software (Freeware) 2020.2.1.
rise to proanthocyanidins (derived from acid hydrolysis of anthocyani­
dins) by a Bate–Smith reaction (Mannino et al., 2021). In plants, these
molecules exist as oligomers and high-molecular-weight polymers. The
molecules may be formed from only one subunit type (only (-) - epi­
catechin, for example), or they may contain several unit types and
interflavanic bonds (C4–C6 or C4–C8) and exist as complex structures
(Durazzo, Lucarini, Souto, et al., 2019; Del Bianco et al., 2021; Li &
Duan, 2019; Ogawa & Yazaki, 2018; Zeng et al., 2020).
1.3. Biological and pharmacological activities of tannins
CTs, also called procyanidins, are more common in the human diet
than hydrolysable tannins. These CTs are found in grapes, apples, red
fruits, fruit-derived beverages, and cocoa (Rauf et al., 2019; Smeriglio
et al., 2017; Pizzi, 2021). However, hydrolysable tannins in wine may be
of exogenous origin once the wood from barrels used in fermentation
and ageing processes is usually rich in those tannins, especially ellagi­
tannins (Li & Duan, 2019).
CTs are also present in roots, bark, stems, leaves, and green and
unripe fruits (Rauf et al., 2019; Smeriglio et al., 2017), endowing them
with an astringent character, which protects vegetables and fruits from
herbivores (Isah, 2019; Lara et al., 2020). Astringency is an organoleptic
characteristic caused by exposure to certain substances, such as tannins.
It evokes different palatable responses, such as roughness and dryness
(lack of lubrication or moisture causing attrition or friction between the
various oral surfaces) and constriction (tightening and contraction
sensation in the tissues of the mouth, lips, and inner cheeks) (Li & Duan,
2019; Ma et al., 2018; Merrell et al., 2018; Soares et al., 2019).
Furthermore, the tannin content of the fruit depends on the cultivar and
ripening stage (Lara et al., 2020; Simonetti et al., 2020).
The activity of tannins against ROS may be associated with protein
complexes, and these biomolecules may interact with ROS to protect
membranes from lipid peroxidation and DNA damage (Chung et al.,
1998; Habib et al., 2022; Isah, 2019; Rodríguez-Pérez et al., 2019;
Smeriglio et al., 2017). Therefore, this interaction plays a vital role in
maintaining a balance between ROS production, degradation, and cell
homeostasis. Any imbalance may result in oxidative stress, which may
be associated with organelle degradation and lead to cell death. In some
cases, these imbalances have been associated with diseases such as
rheumatoid arthritis, heart disease, asthma, cancer, inflammation of the
gastrointestinal tract, and early cellular ageing (Lara et al., 2020).
The link between some tannins and proteins has been extensively
studied and probably occurs through hydrogen bonds between the
phenolic groups of tannins and specific sites on the proteins, inhibiting
digestive enzymes and making them unpalatable through astringency.
4
Food Chemistry 414 (2023) 135645
They also have an anti-nutritional effect, negatively interacting with
food proteins or neutralizing endogenous enzymes (Chung et al., 1998;
Brossard et al., 2016; Marchand et al., 2020). This mode of action also
means that tannins, in some cases, may act against microorganisms by
inhibiting enzymes or substrates, inactivating membrane-bound pro­
teins, inhibiting oxidative phosphorylation by acting as ionophores,
inhibiting the electron transport system, and chelating metal ions (e.g.,
iron and zinc) (Guil-Guerrero et al., 2016).
Other plants rich in total polyphenols, flavonoids, and tannins with
ROS reduction activity are Camellia sinensis (Ethiopian green tea,
Bizuayehu et al., 2016) and Acacia mearnsii (Acacia). A correlation has
also been observed between tannin concentration and anti-microbial
activity against fungi, bacteria, cyanobacteria, enzyme inhibition, and
other activities (Ogawa & Yazaki, 2018). Cheesman et al. (2021) also
observed that extracts from Hamamelis virginiana L., another species rich
in those active compounds, inhibited the growth of Streptococcus and
Staphylococcus spp.
In addition, Fraga-Corral et al. (2021) proposed that tannin-rich
extracts may have ROS reduction and anti-proliferative activities.
These activities may be associated with the phenol ring, which possibly
interacts with ROS, consequently reducing lipid peroxidation effects
(Bowtell & Kelly, 2019; Kashi et al., 2019).
Tannins may also play an important role as ROS reduction activity in
food by preventing or slowing the oxidation responsible for altering
sensory and nutritional characteristics and the possible production of
compounds detrimental to health (Chung et al., 1998; Chang et al.,
2019; Fraga et al., 2019; Lara et al., 2020). Lopez-Corona et al. (2022)
observed that Rubus idaeus (raspberry) extracts showed excellent ac­
tivity ROS reduction, anti-inflammatory and cytotoxic activity due to
the presence of ellagic acid, anthocyanins, and ellagitannins. Further­
more, Xie et al. (2020) observed that epigallocatechin-3-gallate (EGCG),
a component present in green tea, decreased the ROS level and it acti­
vated the Nrf2 transcription factor and antioxidant proteins. Further­
more, Luo et al. (2022) verified that corilagin (an ellagitannin) was able
to reduce the expression of inflammatory cytokines, to inhibit the
inflammasome of the NLR family, it reduced pyroptosis. All these
mechanisms reduced ROS production by mitochondria (Luo et al.,
2022).
Virgen-Carrillo et al. (2022), using an in silico approach evaluating
the energy interaction between molecules, proposed that phytochemi­
cals present in the West Mexican berries were able to inhibit enzymes
associated to obesity and diabetes. In addition, they observed their ROS
reduction potential and nitric oxide (NO) inhibition. Liao et al. (2020)
proposed that the NO reduction activity observed in ‘Navaho’, ‘Kiowa’,
and ‘Ouachita’ blackberry cultivars might be associated with the pres­
ence of ellagitannins. These two observations reinforce the hypothesis
that tannins might be involved in regulating NO levels.
Many hydrolysable and CTs have pharmacological applications,
including ROS reduction, antimicrobial, antifungal, cyanobacterial,
enzyme inhibition, anti-obesity, anti-diabetes, anti-helminthic, neph­
roprotective, and antiviral activities (Chung et al., 1998; Mahipal &
Pawar, 2017; Ogawa & Yazaki, 2018; Oliveira et al., 2017; Pizzi, 2021).
Tannins may decrease the risk of cardiovascular disease by reducing
ABCA1 gene expression. This gene is associated with high-density li­
poprotein (HDL) formation, promoting blood pressure, and total
cholesterol reduction (Nie & Stürzenbaum, 2019; Wang et al., 2020).
Dense lipoproteins, such as HDL, are central mediators of reverse
cholesterol transport (RCT), which occurs in several steps and results in
a network of cholesterol uptake from peripheral tissues back to the liver
using the plasma as a vehicle (Ben-Aicha et al., 2020; Ouimet et al.,
2019). Furthermore, diabetic cardiomyopathy is one of the main com­
plications of diabetes mellitus. Therefore, epigallocatechin gallate
(EGCG) was tested to alleviate diabetic and myocardial complications.
EGCG was found to decrease glucose, triglycerides, cholesterol, and LDL
levels and increase HDL levels. Additionally, it was able to lower the
cardiac index, improving its function. Thus, EGCG can improve
L.F.M. Melo et al.
metabolic syndrome, alleviate diabetic complications, and protect the
heart (Gui et al., 2022). The gene expression analysis revealed that genes
related to hepatic lipogenesis were repressed, including Srebp-1c,
gamma coactivator 1 beta (Pgc-1β), and Scd1. These changes in gene
expression were consistent with the observed reduction in hepatic
cholesterol after grape-seed proanthocyanindin extract (GSPE) admin­
istration and demonstrate that, in the presence of a lipogenic, fructose-
rich diet, GSPE can convert lipids to HDL cholesterol to maintain lipid
homeostasis in the liver.
Furthermore, tannins may positively inhibit or retard Alzheimer’s
disease (AD) onset (Snow et al., 2019), some cancers (Durazzo et al.,
2019), and ageing (Nie & Stürzenbaum, 2019). Digallic acid, the main
substance found in Phyllanthus emblica fruit extract, was able to atten­
uate lipid metabolism by decreasing the triglyceride accumulation by
down-regulating adiponectin (Balusamy et al., 2020).
Other pharmacological activities of CTs may be associated with their
ability to chelate metal ions, such as copper (Cu+2), zinc (Zn+2), and iron
(Fe2+). Chelation is an excellent mechanism for decreasing the toxicity
by metals, such as oxidative stress injury and toxic metal accumulation
in food. Iron complexation also reduces iron levels in patients with iron
metabolism problems, which leads to iron accumulation in the organism
(Zeng et al., 2019).
During in vivo calvarial analysis using adult male Sprague–Dawley
rats, it was observed that hydroxyapatite modified with tannic acid
(THA) was able to restore bone structure and promote osteogenesis and
angiogenesis better than treatment with hydroxyapatite alone (Tian
et al., 2020). In addition, a CT compound extracted from Fagopyrum
cymosum (trevir.) Meisn, known as the effect of Weimaining (WMN), has
been tested for effects on breast cancer tumour growth. In this experi­
ment, 4 T1-luc2 murine carcinoma cells were inoculated into BALB/c
animals. It was observed that this tannin increased the apoptosis index
and mRNA levels from caspase-3 mRNA and protein. These results
showed that tannin WMN suppressed tumour growth (Ke et al., 2021).
Using Zebrafish (AB strain) previously stressed with 300 μM H2O2,
Chen et al. (2021) treated one group with PCs (a type of polyphenols)
and observed an increase in ROS reduction enzymes, such as GSH-Px,
CAT, and SOD, with a consequent reduction in ROS and malondialde­
hyde (MDA) levels. They also reported the activation of nuclear factor-
erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE).
These results suggest that the treatment with procyanidins has a neu­
roprotective effect and decreased oxidative damage (Chen et al., 2021).
Another aspect of tannins evaluated was their association with car­
diac disease. Tao et al. (2021) observed that when minipigs were fed a
high-fat diet, they developed atherosclerosis in the common carotid
artery. Nevertheless, when the animals received corilagin (an ellagi­
tannin), significant reduction in the damage degree in the common ca­
rotid artery and a decrease in the number of lipid plaques was observed.
Furthermore, a downregulation in the expression of MMP-1, MMP-2,
and MMP-9, which were markers of oxidative stress and inflammation,
was noted.
The in vivo effect of persimmon-derived tannin, another CT, has also
been evaluated. This tannin was used to treat Syrian hamsters after
being orally inoculated with severe acute respiratory syndrome coro­
navirus 2 (SARS-CoV-2). The administration of tannin drastically re­
duces pneumonia severity and helps to maintain a low virus
concentration. These data suggest that this tannin may be an excellent
candidate for coronavirus disease treatment as it reduces complications
and transmission (Furukawa et al., 2021). Li et al. (2020) and Du et al.
(2021) observed that quebulagic acid and punicalagin were able to
affect the SARS-CoV-2 cycle by regulating the 3-like cysteine protease
enzyme-chymotrypsin (3CL pro). These molecules were previous known
to inhibit influenza infections. These in vitro and in vivo assessments
showed that tannins and polyphenols may have many applications in
preventive and curative medicine.
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Food Chemistry 414 (2023) 135645
1.4. Other tannin applications
Oliveira et al. (2017) working with extracts from three Brazilian
cerrado plants: Turnera ulmifolia L. (leaves and roots), Parkia platyce­
phala Benth (leaves and seeds), and Dimorphandra gardneriana Tul
(leaves and bark) observed in vitro anti-helminthic activity against
Haemonchus contort. In addition, tannins can interact with proteins from
the sheaths, cuticles, and larval fluid, and this interaction might be
associated with nematode death. Tannin-rich extracts were found to be
associated with the unsheathing process, which was related to the
presence of proline-rich proteins and hydroxyproline in the structures of
the nematode, then modifying the physical and chemical properties
from the nematode (Alonso-Díaz et al., 2011). In addition, Elumalai
et al. (2016) reported that extract rich in catechin exhibits larvicidal
activity against Aedes aegypti, Anopheles stephensi, and Culex
quinquefasciatus.
1.4.1. Biotechnological and industrial applications
Tannins are widely used in tanneries because they combine with the
positively charged –NH3+ from collagen, dehydrating the leather, con­
trolling bacterial growth, preventing foul odour, and strengthening the
leather (Fraga-Corral et al., 2020; Grenda et al., 2018).
Considering that tannins inhibit the growth of some microorganisms,
they may affect the ecosystem following excessive disposal through
wastewater from tanneries, where they represent the largest fraction of
organic matter in effluents. Therefore, these wastes should be treated
before being discharged into the rivers. To solve this problem, Prigione
et al. (2018) investigated some species of fungi adapted to grow on
specific substrates and if they can function as bioremediation agents
acting against different types of tannins: the hydrolysable ellagitannins
of chestnut, gallotannins of Tara, and CTs from Quebracho and Acacia.
Additionally, they verified the following two possible mechanisms of
action: 1) formation of tannic acid by the hydrolysis of ester bonds,
catalysed by tannases, into hydrolysable tannins, releasing glucose and
gallic acid or 2) the ability to activate a secondary metabolism to convert
tannins as a carbon source. These results show that despite the possi­
bility of disturbing the ecosystem when released as effluents, tannins
have fungal biodegradability by commonly occurring fungi (Prigione
et al., 2018).
Tannin and sucrose were mixed to form a composite adhesive and
used to prepare plywood. The results showed that the tannin-sucrose
adhesive had a high solids content (70 %) and low viscosity. The
macromolecular structure of the tannins provided sufficient cohesive
strength for the adhesive system, and the acidic tannins could more
efficiently promote the crosslinking reaction between tannins and su­
crose (Xiao et al., 2022). In addition, CTs obtained from Acacia mearnsii
showed better efficiency in removing anionic and cationic dyes from
effluents (Grenda et al., 2020). CTs also have applications in 3D printing.
Liao et al. (2020) observed that approximately 20 % acetylated-
condensed tannin in polylactic acid (PLA) and tannin filament com­
posites provided good print quality with better tensile properties (Liao
et al., 2020).
Chemically self-expanding rigid foam formulations based on tannin
extracts composed of 95 % natural materials have mechanical and
physical properties comparable to synthetic phenol–formaldehyde
foams, including fire resistance (Pizzi, 2019; Santiago-Medina et al.,
2018).
The application of CTs in the production of plywood adhesives and
panels demonstrates that tannins help to enhance the adhesion between
the fibres and matrix, achieving the best physical and mechanical
properties of wood-based composites (Hafiz et al., 2020).
The crude extract of purple Euterpe oleracea Mart. (açaí), rich in
proanthocyanidins, proved to be a promising corrosion inhibitor when
tested on AI-SI 1020 carbon steel in corrosive solutions. The formation of
a protective and dark film was observed, probably due to the adsorption
of the inhibitor, protecting the steel from corrosion (Martins et al.,
L.F.M. Melo et al.
2021). Thus, tannate films derived from tannin extracts are formed on
iron and steel surfaces to protect them from atmospheric corrosion
(Byrne et al., 2019).
Tannins may be associated with many other biotechnological ap­
plications, such as organic gels with different porosities, contaminant
removal, thermal insulation, and energy storage. The organic gels may
also be used as plant-based coagulants to treat water surfaces, industrial
effluents, and mineral flotation. Their waste decomposition activity and
metal complexation are also based on their ecological functions, similar
to plant defence against herbivores (Fraga-Corral et al., 2021).
Tannins are associated with wine production, and CTs confer bio­
logical importance to wine through their antioxidative properties. It is
rich in catechin, epicatechin, epicatechin gallate, catechin gallate, and
galocatechin-3-O-gallate (Ma et al., 2018). Anthocyanins are mainly
present in the skin of grapes and are usually present in 3-O-glucosidic
forms (delphinidin, cyanidin, petunidin, peonidin, and malvidin). Fla­
vanols and anthocyanins are the main compounds in dry red wine. They
are responsible for the dry mouth sensation, wine structure, and colour
stability (Li & Duan, 2019), and the type of CT varies according to the
grapevine cultivar and its cultivation (Pinasseau et al., 2017; Zhijing
et al., 2018).
Other clinical applications of tannins include skin wounds because of
their protein complexation properties, and tannic acid hydrogels can be
produced at low-cost (Fraga-Corral et al., 2021; Guo et al., 2018;
Koopmann et al., 2020; Marsh et al., 2020).
Many published works continue to point to a growing and diverse use
of tannins to solve biotechnological challenges at the industrial scale and
improve health of living beings.
2. Nutritional applications
Recently, dietary components have been shown to play an essential
role in preventing and treating chronic diseases (Andreescu et al., 2018;
Sapienza & Issa, 2016). Therefore, nutraceuticals have received atten­
tion in various research fields, opening many paths for exploration, such
as a better understanding of the functional roles of some essential di­
etary molecules, components of foods/superfoods, environmental, and
gene expression; the impact of these different foods/superfoods and
environmental conditions on health and physiology; and the role of
these components in disease prevention or development (Andreescu
et al., 2018; Ikram et al., 2019; McCubrey et al., 2017; Sapienza & Issa,
2016).
Natural products have emerged as an interesting treatment strategy
for some pathologies based on different molecules and biological ac­
tivities. Epigenetic therapy has emerged as a novel field for nutraceut­
icals owing to its potential to prevent cancer by modulating gene
expression (Del Bo’ et al., 2019; Kelly & Issa, 2017; Quero et al., 2020).
In addition to quality nutrition, gut microbiota has received much
attention, as several studies revealed that good nutrition has an impor­
tant role in maintaining homeostasis between the microbiota and its
host by interacting with the immune and nervous systems (Childs et al.,
2019; Kolodziejczyk et al., 2019; Lynch & Pedersen, 2016). Under
healthy conditions, the gut microbiota performs a wide variety of
functions essential to organisms, such as the production of short-chain
fatty acids (SCFAs), which act as local and systemic signals important
for healthy and disease conditions (Tan et al., 2014). The gut microbiota
participates in different metabolic processes, such as sugar, amino acids,
vitamins, polyphenols, xenobiotics, and bile acid metabolisms (Das
et al., 2016; Rowland et al., 2018). The microbiota–host relationship is a
two-way association, wherein the gut microbiota produces and controls
the metabolism of molecules, and, in return, these molecules modulate
the composition of the microbiota (Ramírez-Pérez et al., 2017).
Furthermore, an important communication has been verified in the
microbiota–gut–brain axis, with metabolic products linking the gut and
brain (Cryan et al., 2019). Moreover, an imbalance in the gut microbiota
was shown to disturb the balance in this axis, resulting in altered
6
Food Chemistry 414 (2023) 135645
microbiota composition. Dysbiosis has emerged as a type of pathology in
which pathogens are present in the microbiota and has been associated
with inflammatory, neurodegenerative, and autoimmune diseases;
metabolic disorders; oxidative stress; and ageing (Levy et al., 2017).
Considering the importance of food in preventing and treating dis­
eases, Iwatani and Yamamoto (2019) proposed some criteria for foods to
be considered functional. They must be available as part of a usual diet,
food in natural and whole form instead of processed to powder or pills
and have a known function in the human body (i.e., impact on the im­
mune system, prevention or recovery of diseases or delay ageing)
(Iwatani & Yamamoto, 2019). Studies have proposed nutritional in­
terventions with therapeutic or preventive potential once these modi­
fications may interfere with the gut–brain axis by modulating the
hypothalamic region, changing appetite, and eating habits (Schröder
et al., 2020; Zawada et al., 2020). In this context, secondary metabolites
are important molecules for prevention and treatment. Polyphenols are
an example of secondary metabolites that may act as ROS reduction and
anti-inflammatory agents and are involved in gut microbiota homeo­
stasis (Koudoufio et al., 2020).
The ingestion of foods containing complex carbohydrates, fibres,
polyunsaturated fatty acids, and bioactive components with ROS
reduction properties (flavonoids, phytosterols, terpenes, and poly­
phenols) has been shown to promote nutritional support and balances
the gut microbiota by increasing the abundance of beneficial bacteria,
such as Bifidobacterium spp. and Lactobacillus lactis. These bacteria have
been associated with decreased levels of inflammatory interleukins (IL-
6, IL-17A, and IL-1β), TNF-α, COX-2, and colon cells and blood vessel
protection. Environmental pH reduction has been verified to inactivate
receptors; consequently, these beneficial bacteria may compete for food
and secrete molecules against the pathogenic bacteria, suppressing their
proliferation in the gut (Serra-Majem et al., 2019).
2.1. Polyphenols
Polyphenols are secondary metabolites present in fruits and vege­
tables. They are considered health promoters due to their ROS reduction
and anti-inflammatory activities. In addition to stabilising the gut
microbiome, these properties help lower the risk of cancer and vascular
diseases (AL-Ishaq et al., 2020; Chang et al., 2019; Durazzo et al., 2019;
Kang et al., 2020). The hydroxyl groups in the chemical structure of
phenols facilitate electron donation, subsequently helping to eliminate
free radicals from the cells. Polyphenols are bioactive molecules that
may also have a protective effect on the functions of intestinal barrier
junctions by increasing transepithelial electrical resistance (TEER)
through the modulation of barrier integrity (Toschi et al., 2022; Ling
et al., 2016). This action may prevent the subsequent translocation of
luminal antigens via the mucosa to the whole body, which may change
intestinal mucosal homeostasis, consequently increasing susceptibility
to systemic and chronic inflammation and changing nutrient absorption
(Murphy & Westmark, 2020; Nakashima et al., 2020).
Different organs metabolise polyphenols; for example, the liver it
undergoes to hydroxylation, which helps their cellular absorption in
glycosylated or conjugated forms (Al-Ishaq et al., 2020). In the gastro­
intestinal tract, polyphenols may accumulate in the large intestine,
where they are metabolised by microbiota (Nie et al., 2019). During
dysbiosis, the imbalance in the microbial composition of the intestine
might affect its functionality and metabolic activities. Furthermore, the
imbalance resulted in associated allergies, inflammatory and chronic
diseases, and obesity. Therefore, polyphenols present in our diet have
the potential to be used as nutraceuticals owing to their direct action on
the gut microbiota and the ability to maintain a good balance between
beneficial (e.g., Lactobacillus sp.) and pathogenic bacteria (Enterococcus
caccae) (Mahajan et al., 2017; Man et al., 2020).
Hydroxytyrosol, quercetin, and resveratrol present in extra-virgin
olive oil, citrus fruits and vegetables, and red grapes, respectively, are
polyphenols with beneficial properties. For example, hydroxytyrosol has
L.F.M. Melo et al.
ROS reduction and anti-inflammatory properties and it has been studied
as a nutraceutical to modify inflammation parameters (TNF-α, IL-1 β, IL-
6, TLR-4, and NK-kB) and fat index in obese individuals with high-fat
diets (Liu et al., 2019; Perrone et al., 2019). Resveratrol is a potent
agent to reduce ROS and anti-inflammatory agent widely used as a nu­
traceutical (Bird et al., 2017) and it exhibits many activities. For
example, they block TLR4 and pro-inflammatory genes, modify epige­
netic markers, and interact with various enzymes involved in gluco­
neogenesis, lipid metabolism, mitochondrial biogenesis, angiogenesis,
and apoptosis (Malaguarnera, 2019). Quercetin is the most widely
evaluated polyphenol because of its anti-carcinogenic, antiviral, anti­
platelet, and anti-inflammatory effects owing to its inhibition of LPS,
NO, PGE2, iNOS, COX-2, TNF-, IL-1, and IL-6 (Endale et al., 2013).
Various studies have shown that anti-inflammatory activity inhibits
COX-1 and COX-2 enzymes and reduces NF-κB signalling and nuclear
translocation (Bowtell & Kelly, 2019). For example, studies on phenolic
compounds from blueberries have identified different activity levels
through inhibiting inflammatory enzymes (Bowtell & Kelly, 2019).
Paulino et al. (2016) observed that phenolic compounds from Uru­
guayan propolis and grape pomace extracts were able to inhibit COX-1
and COX-2 in a similar manner.
Considering the importance of COX-1 and COX-2 markers, Paulino
et al. (2016) used a docking approach with phenolic data at COX-1 and
COX-2 active sites. The docking protocol was validated using the cele­
coxib position in COX-1 (3KK6 crystal) and COX-2 (3LN1 crystal) as
references. They observed high similarity in both functional amino acid
sequences and evaluated the distances between hydrogen donors and
acceptors for phenols with the ten best SI values for COX-1 and COX-2.
For the selection of a local receptor for COX-1 and COX-2, with crys­
tallographic resolutions in the range of 2–3 Å, two criteria are listed for
the receptor structures of the enzymes: 1) the existence of a co-
crystallised ligand similar in function to the endogenous ligand and 2)
best possible X-ray crystallographic resolution. Therefore, the corre­
sponding crystallographic complexes suggested that phenols are
competitive inhibitors of COX-1 and COX-2.
2.2. Tannins
Tannins are a broad class of biomolecules derived from polyphenolic
compounds with high molecular weights (500–3000 Da) (Pizzi, 2021)
(Fig. 2). These biomolecules are present in the human diet and are found
in tea, coffee, vegetables, and fruits (Caballero et al., 2016). They consist
of a specific group of polyphenols that form inter- and intra-molecular
hydrogen bonds owing to the hydroxyl groups; therefore, these mole­
cules have a unique ability to interact with other molecules and then
precipitate proteins, alkaloids, and carbohydrates. Tannins are not
bioavailable and have been neglected in nutrition science and been
considered as antinutrients for a long time. However, this view has
changed as it has recently been observed that ellagic acid, for example,
may be released from ellagitannins in the gastrointestinal tract, and it
may be metabolized by the gut microbiota to form bioavailable com­
pounds known as urolithins (Djedjibegovic et al., 2020). New studies are
required to understand the importance of these biomolecules for health
maintenance and disease prevention. Other studies have revealed their
antidiabetic, antimicrobial, ROS reduction, and anti-inflammatory
properties (Chung et al., 1998; Petroski & Minich, 2020; Smeriglio
et al., 2014; Soares et al., 2019). These activities may be associated with
inhibition of microbial enzymes, changes in the oxidative phosphory­
lation of ionophore channels in bacterial membranes, and chelation of
metal ions (Guil-Guerrero et al., 2016; Smeriglio et al., 2017).
Tannins are divided into two major groups, namely, hydrolysable
tannins and CTs (Fig. 2). Hydrolysable tannins are hydrolysed by weak
acids (Fraga-Corral et al., 2020) and they remain stable under normal
physiological conditions in the stomach. They are metabolised by the
intestinal microbiota (Ismail et al., 2016; Smeriglio et al., 2017). For
example, ellagic acid is hydrolysed in the small intestine at pH ranging
7
Food Chemistry 414 (2023) 135645
from neutral to alkaline. At present CTs are the most abundant poly­
phenols derived from plants. They are oligomers of flavan-3-ol (catechin
monomers) or flavan-3,4-diol, also known as oligomeric procyanidins.
These compounds are not easily hydrolysed and decompose into acids
under alcoholic conditions, generating red pigments that are absorbed in
the small intestine. Examples of CTs are PCs, with a degree of poly­
merisation ranging from 3 to 11, where the polymers of flavan-3-ols,
considered to be elementary units, are linked by C and C and occa­
sionally C, O, and C. Oxidative condensation occurs between the C4
carbon of the heterocycle and the C6 or C8 carbons (Fig. 4).
Jia et al. (2011) observed that tannins obtained from grape seed
extract promote a decrease in the expression of p38 and c-Jun N-ter­
minal portion (JNK) protein kinase, NF-кB, and MAPK signalling, reduce
the expression of oxidative proteins in B-3 and HLE-B3 cells, and protect
these cells against cataractogenesis. Furthermore, Veras et al. (2021)
verified that tannins might reduce oxidative stress by modulating cata­
lase and superoxide dismutase levels and reducing glutathione levels.
They also verified potential anti-inflammatory activity by reducing the
expressions of TNF-α, IL-1α, IL-6, and IL-10. Due to their anti-
inflammatory activity, tannins have been used for gastroprotection to
regulate inflammation. Hence, tannins can be used as a functional food
(nutraceuticals) to prevent and treat various diseases (Veras et al.,
2021). Another example is oligopin, a metabolite composed of proan­
thocyanidin oligomers, including flavan-3-ol units. These oligomers
interfered with tau protein misfolding in vitro. Tau protein is a patho­
logical feature of AD. Therefore, oligopin may be a potential new ther­
apeutic target for AD treatment (Ono et al., 2020). Moreover, ellagic
acid in the gastrointestinal tract may be metabolised by the intestinal
microbiota to generate a bioactive compound known as urolithin, which
modulates oxidative stress and may have anti-inflammatory, anti­
proliferative, and anti-ageing properties (Djedjibegovic et al., 2020;
Kawabata et al., 2019). These activities have been associated with
reduced pro-inflammatory cytokine expression, inhibiting cell prolifer­
ation by topoisomerases I and II, and apoptosis induction through NF-κB
inhibition (Al-Ishaq et al., 2020). Moreover, emblicanin, a tannin ob­
tained from Emblica officinalis, may attenuate cognitive impairment by
modulating neuronal death via inhibiting NF-κB in the brain (Husain
et al., 2018). Other studies have shown that proanthocyanidins might
reduce oxidative stress by inhibiting lipid peroxidation and decreasing
iNOS and COX-2 expression, consequently reducing the inflammatory
process, decreasing the risk of cardiovascular diseases, diabetes, asthma,
neuropathology, obesity, and cancer (Rauf et al., 2019; Rodríguez-Pérez
& Aznar, 2020).
3. Conclusions
Tannins are a relevant chemical group obtained from many natural
sources, mainly plants. Polyphenol derivatives are condensed and
hydrolysable tannins, the two main categories of tannins found in the
bark, leaves, fruit, fruit peel, seeds, buds, and stems.
This review shows that polyphenol and tannin structures are versa­
tile, with many biological and biotechnological functions, as they
interact with other molecules, such as proteins and carbohydrates. These
interactions were associated with the structures of the hydroxyl and
aromatic rings (Fig. 5). Depending on the type of tannin used, applica­
tions can vary. In health, polyphenols and tannins have great potential
for use as nutraceuticals to prevent or treat some diseases. Polyphenols
can help decrease the risk of cardiovascular and Alzheimer’s disease,
delay cellular ageing, and maintain intestinal microbiota homeostasis.
There are studies on their functions as molecules with pharmacological
activity potentials, such as ROS reducing agent, anti-inflammatory,
antifungal, antimicrobial, antiviral, anthelmintic, antimutagenic, and
anticancer activities.
With respect to biotechnological and industrial applications, tannin
usage in tanneries for the treatment and preservation of leather is widely
known. They have the advantage of being inactivated by biodegradation
L.F.M. Melo et al. Food Chemistry 414 (2023) 135645

Fig. 4. Condensed tannins. Schematic representation of procyanidins A and B, which differ in the type of connections they make with each other. This figure was
drawn using ACD/ChemSketch software (Freeware) 2020.2.1.

Fig. 5. Tannins and different action mechanisms in cells. Schematic chemical structure representation of hydrolysable and condensed tannins and in the centre with
tannin name and fruit figures the different action mechanisms that this bioactive molecule may be associated with. T-shaped arrows correspond to inhibition, and
upward arrows correspond to upregulation.

from wastewater before elimination. Moreover, biotechnology uses Declaration of Competing Interest
them as adhesives for wood and for the protection and improvement of
wood properties, water treatment, anti-corrosion of metals, and pro­ The authors declare that they have no known competing financial
duction of bio-based foams and substrates for 3D printing. However, interests or personal relationships that could have appeared to influence
more studies are required to explore tannin properties, solve problems, the work reported in this paper.
and meet industrial needs. This review shows the characteristics and
activities of tannins and promotes exploration of other naturally abun­
dant bioactive compounds.

8
L.F.M. Melo et al.
Data availability
It is a review, it was used the articles available on pubmed
Acknowledgements
Funding: The authors wish to thank PROPESQ/UFRN, Coordenação
de Aperfeiçoamento Pessoal de Nível Superior-CAPES, Conselho
Nacional de Desenvolvimento Científico e Tecnológico-CNPq for finan­
cial support. LFMM and APS received a scholarship from CAPES, and
HAOL received a fellowship from CNPq.
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