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The Role of Dietary Polyphenols in the Management of Inflammatory Bowel

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196 Current Pharmaceutical Biotechnology, 2015, 16, 196-210

The Role of Dietary Polyphenols in the Management of Inflammatory

Bowel Disease

Mohammad H. Farzaei1,2, Roja Rahimi2 and Mohammad Abdollahi3*

1
Faculty of Pharmacy, Kermanshah University of Medical Science, Kermanshah, Iran; 2Department of
Traditional Pharmacy, Faculty of Traditional Medicine, Tehran University of Medical Sciences, Tehran,
Iran; 3Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences
Research Center, Tehran University of Medical Sciences, Tehran, Iran

Abstract: Inflammatory bowel disease (IBD) is an idiopathic chronic, relapsing inflammation of the
bowel which is caused by dysregulation of the mucosal immune system. Polyphenols as the secondary
plant metabolites universally present in vegetables and fruits and are the most abundant antioxidants in the human diet.
There is evidence demonstrating the beneficial health effects of dietary polyphenols. This review criticizes the potential of
commonly used polyphenols including apple polyphenol, bilberry anthocyanin, curcumin, epigallocatechin-3-gallate
(EGCG) and green tea polyphenols, naringenin, olive oil polyphenols, pomegranate polyphenols and ellagic acid, quer-
cetin, as well as resveratrol specifically in IBD with an emphasis on cellular mechanisms and pharmaceutical aspects. Sci-
entific research confirmed that dietary polyphenols possess both protective and therapeutic effects in the management of
IBD mediated via down-regulation of inflammatory cytokines and enzymes, enhancing antioxidant defense, and suppress-
ing inflammatory pathways and their cellular signaling mechanisms. Further preclinical and clinical studies are needed in
order to understand safety, bioavailability and bioefficacy of dietary polyphenols in IBD patients.
Keywords: Inflammatory bowel disease, polyphenols, review.

INTRODUCTION activities. Investigations have demonstrated that dietary

Inflammatory bowel disease (IBD) is a group of immu-
noinflammatory conditions of the gastrointestinal (GI) tract
with two major types of ulcerative colitis (UC) and Crohn’s
disease (CD) and some atypical forms like collagenous coli-
tis and intractable colitis [1]. Prevalence of IBD is 150-250
per 100000 population and the prevalence of hospitalization
due to UC and CD is estimated 50.6 and 50.1 per 100000
population, respectively [2, 3]. Various etiological factors
have been proposed to involve in IBD; the most important
one is immunological dysregulation [4, 5]. Different drug
categories are used for the management of IBD, including
aminosalicylates, corticosteroids, immunomodulators, anti-
biotics, biological drugs, and probiotics [6, 7]. Poor tolerabil-
ity and undesirable efficacy of these drugs have led research-
ers to pay attention to complementary and alternative medi-
cines [8-10].
As a disorder of the GI tract, inflammatory condition in
IBD could be definitely alleviated by nutritional factors.
Polyphenols are the secondary plant metabolites exclusively
present in vegetables and fruits and are known to be benefi-
cial due to their wide range of biological effects including
antioxidant, anti-inflammatory, and immunomodulatory
*Address correspondence to this author at the Department of Toxicology
and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences
Research Center, Tehran University of Medical Sciences, Tehran
1417614411, Iran; Tel/Fax: +98 21 66959104;
E-mails: Mohammad.Abdollahi@UToronto.Ca; Mohammad@TUMS.Ac.Ir
polyphenols possess protective properties against various
chronic diseases, including cardiovascular and degenerative
diseases, diabetes, osteoarthritis, as well as gastrointestinal
diseases. The biological activities of polyphenols vary due to
numerous parameters such as food processing methods, me-
tabolism, absorption, bioavailability, derived compounds and
their bioefficacy [10-15]. Polyphenols consist of a wide vari-
ety of chemical structures based on the presence of polym-
erization and substitutions of the basic skeleton of polyphe-
nols, as well as the degree of oxidation. Flavonoids and non-
flavonoids are two main structural groups of polyphenols
which are characterized by the presence of different numbers
of phenolic rings, along with two or more hydroxyl substitu-
tions. Flavonoids are comprised of two benzene rings linked
by a linear three-carbon chain, which form an oxygenated
heterocycle. Flavonoids are divided into different subclasses,
according to the oxidation state of the central pyran ring,
including flavones, isoflavones, flavonols, flavanones,
flavanols, anthocyanins, and anthocyanidins. In addition,
nonflavonoids consist of phenolic acids, lignans and stil-
benes [10-15].
This review criticizes the potential effects of commonly
used polyphenols from apple, bilberry anthocyanin, curcu-
min, green tea, naringenin, olive oil, pomegranate and ellagic
acid, quercetin, and resveratrol in various in vitro, animal
and human models of IBD.

1873-4316/15 $58.00+.00 © 2015 Bentham Science Publishers

The Role of Dietary Polyphenols in the Management of Inflammatory
METHODS
A comprehensive literature search of the electronic data-
bases including PubMed, Cochrane, Medline, and Scopus
was performed. Data were collected for the years 1985 up to
May 2014. Only published articles were included in the cur-
rent review and unpublished investigations were not consid-
ered. Only English language articles were included. The
search terms were "inflammatory bowel disease", "IBD",
"colitis", "inflammation", "inflammatory", in combination
with "polyphenol", "flavonoid" and "anthocyanin". Results
obtained from primary search were screened by two inde-
pendent investigators. Also, manual searches of reference
lists of retrieved articles was conducted. All retrieved articles
were evaluated to achieve any in vitro, in vivo, or clinical
evidence for the efficacy, bioefficacy and possible mecha-
nisms of polyphenols in the management of IBD. In human
studies, study design, intervention, type of IBD, number of
patients, duration of treatment and efficacy and tolerability
of the polyphenols were also collected.
FINDINGS AND DISCUSSION
Apple Polyphenols
Apple (Malus spp., Rosaceae) represents an important
source of polyphenols. The main structural classes of the
polyphenols are hydroxycinnamic acids, flavan-3-ols (oli-
gomeric pro-cyanidins and catechins), flavonols (quercetin
glycosides), and dihydrochalcones (phloretin glycosides). Of
the abundant apple polyphenols are chlorogenic acid, pro-
cyanidins, and dihydrochalcones [17, 18]. Various investiga-
tions confirmed the therapeutic potential of apple polyphe-
nols for the management of IBD via different molecular
mechanisms (Table 1) [18-115].
Apple polyphenols improve antioxidant enzymes and
prevent lipid peroxidation in cultured human colon endothe-
lial cells. Imbalanced expression of pro-inflammatory
chemokines, cytokines, cell adhesion agents, and enzymes is
involved in various inflammatory diseases including IBD.
The polyphenols can down-regulate the expression of pro-
inflammatory cytokines and enzymes via suppression of in-
terferon-gamma-inducible protein-10 (IP-10), interleukin
(IL)-8-promoter, signal transducer and activator of transcrip-
tion 1 (STAT1), and nuclear factor (NF)-κB dependent sig-
nal transduction in human colonic epithelial cells [18, 19].
Nuclear factor-erythroid 2-related factor-2 (Nrf2), a re-
dox sensitive transcription factor which modulates redox
homeostasis and cellular antioxidant defenses protects cells
from inflammatory stimuli or injuries. Nrf2 regulates cellular
defense versus oxidative damages with translocating into the
nucleus and causing the expression of various cytoprotective
factors. Enhancement of Nrf2 and also a controller of mito-
chondrial biogenesis, peroxisome proliferator-activated re-
ceptor gamma coactivator (PGC-1α), are among therapeutic
mechanisms of apple polyphenols in IBD [18-20].
Apple polyphenols have also demonstrated efficacies in
animal models of colitis [21-24]. They have improved colonic
damage and inflammation by suppressing pro-inflammatory
cytokines and T cell receptor (TCRαβ) cell recruitment via
modulating IP-10, monokine-induced gamma interferon
(MIG), and interferon-inducible T-cell alpha chemoattractant
Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 3 197
(I-TAC). These result in chemoattraction of monocytes,
macrophages, T cells, and dendritic cells, and promotion of
T cell adhesion to endothelial cells in colon of colitic ani-
mals. In addition, D'Argenio et al. [23] reported that poly-
phenols mitigate wounded fibroblast tissue through regulat-
ing the balance between calpain and tissue transglutaminase
which plays a role in colonic damage.
Dietary supplementation of apple polyphenol exhibited
protective and therapeutic potential in animal colitis by sup-
pressing mitogen-activated protein kinases (MAPK), a sig-
naling cascade which regulates translation and transcription
of proteins involved in inflammatory response, and tumor
necrosis factor alpha (TNF-α)-NFκB inflammatory signaling
pathways [22, 24].
Bilberry Anthocyanins
Bilberry (Vaccinium myrtillus L.) is a massive source of
anthocyanins including glucoside, arabinoside, or galactoside
of cyanidin, delphinidin, malvidin, petunidin, and peonidin.
Anti-inflammatory and protective effects against oxidative
stress are dominant biological characteristics frequently re-
ported from bilberry [25-29]. The bilberry anthocyanins act
against oxidative stress via enhancement of heme-oxygenase-1
and glutathione S-transferase-pi enzymes, inhibition of lipid
peroxidation, and intracellular antioxidant action [26]. Op-
eration of anthocyanins in the inflammatory response is carried
out through inhibition of pro-inflammatory mediator expres-
sion such as IL-6, IL-15, and interferon (IFN)-γ, and sup-
pressing NFκB activation and leukocyte infiltration [25, 29].
The anthocyanins ameliorate expression of IBD-associated
cytokines, including TNF-α, IP-10, I-TAC, soluble intracel-
lular adhesion molecule-1 (sICAM-1) and growth regulated
oncogene-alpha (GRO-α) in the inflammatory condition of
human colon epithelial cells [29]. They diminish disease
severity and colonic inflammation and damage via inhibition
of inflammatory cytokines expression in animal colitis [30].
Dietary supplementation of anthocyanins can protect from
ischemia-reperfusion in the intestines, which is an inflamma-
tory condition with intensified reactive oxygen species
(ROS) and DNA damage [27].
Pharmacokinetics and bioavailability properties of antho-
cyanins are unfavorable [28] and the stability of anthocya-
nidins (aglycon forms) are even less than anthocyanins [29].
Various investigations have been performed to improve
bioavailability of these compounds. Jakesevic et al. [27] re-
ported that microflora can improve absorption of anthocyan-
ins via formation of metabolites with higher bioavailability
and lead to enhanced therapeutic action in GI tissue. Fur-
thermore, encapsulation of anthocyanins elevates the amount
of available anthocyanins and inhibits their degradation
within intestine [31].
Cyanidin-3-glucoside, one of the main anthocyanins of
bilberry, markedly decreases inflammatory response by re-
ducing inflammatory cytokines (nitric oxide (NO), TNFα,
prostaglandin (PG)E2 and IL-8) and inhibiting inducible NO
synthase (iNOS) and cyclooxygenase (COX)-2 expressions
via suppressing STAT1, NF of kappa light polypeptide gene
enhancer in B-cells inhibitor alpha (IκBα), and NFκB activa-
tion in intestinal cells and possesses more potent activity
than 5-aminosalicylic acid [32, 33].
198 Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 3 Farzaei et al.

Table 1. Mechanisms of polyphenols in the management of IBD.

Polyphenol Intervention Results References

Apple LPS/IFN-γ induced inflammation in human cell lines ↓TNF-a, ↓IL-1β, ↓MIG, ↓IP-10, ↓COX-2 ↓CYP3A4, and [18]
polyphenol (DLD-1, T84, MonoMac6, Jurkat) treated with apple ↓transcription factors: STAT1 and IRF1; via ↓NFκB,
polyphenols ↓IP-10, ↓IL-8-promoter, and ↓STAT1 reporter gene activity

DSS-induced and oxazolone-induced colitis protected with ↓Mortality rate, ↓weight loss in both models via ↓IL-8 [21]
apple polyphenols

Fe/Asc induced oxidative stress and LPS-induced inflam- ↑Antioxidant enzymes: glutathione reductase and peroxidase, [19]
mation in Caco-2/15 cells treated with apple polyphenols SOD, ↓pro inflammatory cytokines: TNF-α, IL-6, COX-2,
PGE2 and NFκB; via ↑Nrf2 and ↑PGC-1α activity

DSS induced colitis in genetically immunodeficient mice ↓Weight loss, ↓colonic inflammation, ↓colonic shortening, [22]
protected with apple polyphenol (oral or i.p. or as dietary ↓IL-1β, ↓TNF-α, ↓IL-6, ↓IL-17, ↓IL-22, ↓IP-10, ↓I-TAC,
supplementn in drinking water) ↓MIG, ↓IFN-γ, ↓recruitment of TCRαβ cells to the colon;
peritoneal administration had no effect

TNBS-induced colitis in rats treated with apple polyphe- ↓Colonic damage, ↓COX-2, ↓TNF-α, ↓calpain, [23]
nols ↑recovery of wounded fibroblast tissue, ↑transglutaminase

HLA-B27 transgenic rats (spontaneous IBD) treated with ↓Colonic damage, ↓diarrhea, ↓MPO, ↓COX-2, ↓iNOS, [24]
apple polyphenol as dietary supplement ↓cell proliferation; via ↓MAPK and ↓TNF-α-NFκB signaling

Bilberry Cytokine-induced inflammation in human colon epithelial ↓TNF-α, ↓IP-10, ↓I-TAC, ↓sICAM-1, ↓GRO-α [29]
anthocyanins cells (T84) treated with bilberry anthocyanins

DSS-induced acute and chronic colitis in mice treated with ↓Colonic damage, ↓histological scores, ↓disease severity, [30]
bilberry anthocyanins ↓inflammation, ↓cytokine secretion: TNF- α and IFN- γ

Ischemia-reperfusion induced intestinal oxidative stress in ↓LPO with ↓MDA, addition of Lactobacillus plantarum [27]
mice protected with bilberry/ bilberry + Lactobacillus enhanced levels of anthocyanins and phenolic acids in intestinal
plantarum as dietary supplement mucosa

Cytokine-induced inflammation in intestinal cells line ↓Inflammatory mediators: NO, PGE2, IL-8, iNOS and COX-2 [32]
(HT-29) treated with cyanidin-3-glucoside at a much lower concentration than 5-aminosalicylic acid; via
↓activated STAT1 accumulated in the cell nucleus; no effect on
IkB-α or NFκB or p38-MAPK pathway

Curcumin IL-10 gene-deficient mice (chronic colitis) treated with ↓Colonic damage, ↓histology injury scores, ↓weight-to-length [42]
curcumin + carboxymethyl cellulose ratios of colon, ↓MPO, ↓IFN-γ and ↓IL-17

TNBS-induced colitis in rats treated with curcumin ↓Colonic damage, ↓histological scores, ↓MPO, ↓TNF-α, [36]
↓colonic levels of nitrites, ↓COX-2 and iNOS expression; via
↓p38-MAPK activation,

TNBS-induced colitis in rats treated with curcumin (i.p.) ↑Survival,↓weight loss, ↓colonic damage and histological [37]
scores, ↓IL-1, ↓TNF- α, ↓IFN- γ, ↓IL-4, ↑PGJ2, ↑PGE2; via
↑PPAR-γ, ↑15d-PGJ2. Curcumin was more effective than
dexamethasone

DNBS-induced colitis in mice protected and treated with ↓Colonic damage and histopathology, ↓IL-1β, ↓MPO; via [38]
curcumin as dietary supplement ↓NFκB activation and ↓p38-MAPK signaling

TNBS-induced colitis in BALB/c and C57BL/6 mice ↑Survival, ↓ weight loss, ↓colonic damage and histopathology, [39]
protected and treated with curcumin as dietary supplement ↓IL-6, ↓IL-12, ↓TNF- α, ↓IFN- γ, ↓CD 4+ T cell infiltration, via
↓NFκB activation

TNBS-induced colitis in mice protected with curcumin ↓Weight loss, ↓diarrhea, ↓colon weight, ↓colonic damage and [40]
histological scores, ↓MPO, ↓NO, ↓ROS, ↓serine protease,
↓IFN-γ, IL-12 and IL-4 mRNA of colon; via ↓NFκB activity

TNBS-induced colitis in rats protected and treated with ↑Survival, ↓weight loss, ↓colonic damage and histological [41]
curcumin as dietary supplement scores, ↓IL-1β mRNA; via ↓colonic NFκB and IκB activation.
The effect of curcumin was similar to sulphasalazine
The Role of Dietary Polyphenols in the Management of Inflammatory Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 3 199

(Table 1) Contd….

Polyphenol Intervention Results References

EGCG and DSS-induced colitis in mice (ulcerative colitis) and IL-10 ↓Colonic damage and histological scores in both models; [58]
green tea deficient mice with exposure to microbiota (enterocolitis) ↓inflammatory markers (TNF-α, IL-6, and serum amyloid A),
polyphenols treated with grean tea polyphenols or EGCG or slufasa- ↑hepatic and colonic antioxidants (↑GSH, ↓oxidized GSH),
lazine ↓circulatory leptin by EGCG

Rat intestinal epithelial cell line (IEC-6) treated with green ↓NFκB through ↓IKK activation, [51]
tea polyphenols or EGCG ↓phosphorylation of IκBα-GST

IL-10 deficient mice (chronic inflammatory bowel disease) ↓Colonic damage and histological scores via ↓IFN-γ and [53]
received green tea polyphenols as supplement in drinking ↓TNF-α
water

DSS-induced colitis in mice treated with green tea poly- ↓Colonic damage and histological scores, ↓IL-1β, [57]
phenols ↑antioxidant enzymes: SOD and CAT

IFN-γ and IL-4 induced epithelial barrier dysfunction in ↓Epithelial barrier dysfunction and permeability induced by [59]
T84 human colonic epithelial cells treated with EGCG IFN-γ but not by IL-4

Mdr1a(-/-) (multidrug resistance targeted mutation) mouse ↓Colonic damage and histological scores, ↓colon mRNA [55]
model of IBD protected with green tea polyphenols extract transcript and colon protein expression of immune and inflam-
matory response and fibrinogenesis pathways, ↑colon mRNA
transcript and colon protein expression of xenobiotic metabo-
lism, ↑ PPAR-α and STAT1

DSS-induced colitis in mice treated with EGCG in addition ↓Weight loss, ↓colonic damage and histological scores, [56]
with piperine ↓ROS, ↓LPO, ↓MDA production, ↓MPO,
↑antioxidant enzymes: SOD, GPO

DNBS-induced colitis in rats treated with green tea poly- ↓Diarrhea, ↓weight loss, amelioration of colonic architecture, [60]
phenols ↓MPO, ↓TNF-α, ↓nitrotyrosine immunoreactivity,
↓up-regulation of ICAM-1

LPS-induced inflammation in peritoneal macrophages ↓NO production, ↓iNOS gene expression via ↓ NFκB [52]
treated with EGCG

Naringenin Acetic acid-induced ulcerative colitis in rats protected with ↓Colonic injury, ↓histological damage, ↑colonic mucus content, [62]
naringenin ↑antioxidant enzymes: CAT, SOD, Total GSH, non-protein
sulphydryls; ↓MDA, ↓DNA and RNA damage; ↓inflammatory
mediators: TNF-α, IL-1β, IL-6, PGE2, NO

DSS-induced colitis in mice protected with naringenin ↓Colon shortening, ↓colitis severity, ↓histological scores, [64]
↓iNOS, ↓ICAM-1, ↓MCP-1, ↓COX2, ↓TNF-α,
↓IL-6 in colon mucosa via ↓mucosal TLR4 mRNA and protein,
↓phospho-NFκB p65 protein and ↓phospho-IκBα

DDS-induced colitis in mice protected with naringenin as ↓Colon damage and inflammation; ↓DAI, ↓colon shortening, [63]
dietary supplement ↓gene expressions of inflammatory cytokines (IFN-γ, IL-6,
macrophage inflammatory protein-2, and IL-17A); protection of
the intestinal tight junction barrier

Olive oil H2O2 or xanthine oxidase induced oxidative stress in ↓LPO with ↓MDA and ↓paracellular inulin transport, ↓ROS [72]
polyphenols human intestinal epithelium Caco-2 cell line treated with
hydroxytyrosol

DSS induced colitis protected with hydroxytyrosol- en- ↓Clinical signs and ↓histological scores, ↓DAI, ↓mortality, [73]
riched extra virgin olive oil extract as dietary supplement ↓TNF-α, ↓iNOS, ↓COX-2, via ↓p38 and MAPKs

DSS induced colitis protected with polyphenol-enriched ↓DAI, ↓histological scores, ↓MCP-1, ↓TNF-α, ↓iNOS, [69]
extra virgin olive oil extract as dietary supplement ↓COX-2; via ↓IκBα, ↑PPARγ upregulation, ↓p38 and
↓JNK-MAPKs phosphorylation
200 Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 3 Farzaei et al.

(Table 1) Contd….

Polyphenol Intervention Results References

Pomegranate DSS-induced colitis in rats protected with pomegranate ↓Colonic damage, ↓histological scores, ↓inflammatory cells [83]
polyphenols extract or urolithinA as dietary supplement infiltration, ↓PGE2, ↓NO production, ↓iNOS, ↓PGES, im-
and ellagic acid provement of microbiota condition (↑bifidobacteria and lactoba-
cilli, ↓E. coli, enterobacteria and total aerobic bacteria);
↓oxidative stress (ROS and MDA) in plasma and colon mucosa
only by pomegranate; improvement of colonic architecture only
by urolithin A

DSS-induced colitis in rats protected with ellagic acid or ↓Ulceration area, ↓colon shortening, ↓MPO, ↓ROS, ↓MDA [79]
ellagic acid containing microspheres ↓weight loss; microspheres of ellagic acid had higher activity

DSS-induced colitis in mice treated with pomegranate ↓Colonic damage, ↓histological scores, ↓DAI, ↓MPO, [77]
extract or ellagic acid fraction ↓histamine (marker of mast cell degranulation),
↓superoxide anion generation, ↓LPO; pomegranate polyphenols
extract was as effective as sulphasalazine

TNBS-induced colitis in rats protected with ellagic acid ↓Colonic damage, ↓histological scores, ↓neutrophil infiltration, [78]
↑mucus production, ↓iNOS, ↓COX-2, ↓NFκB; via ↓ activation
of p38, JNK and ERK1/2 MAPKs and↓IκB-degradation

TNBS-induced chronic colitis in rats protected and treated ↓Colonic damage, ↓histological scores, ↓MPO, ↓TNF-α, ↓iNOS, [76]
with ellagic acid-enriched pomegranate extract ↓COX-2, via ↓p38- MAPKs phosporylation, ↓IKBα and nuclear
p65 [NFκB] activation

1,2-dimethylhydrazine induced colon carcinogenesis in ↓Cancer tumour markers: 5´-ND, c-GT, CEA, AFP, and CD; [81]
rats treated with ellagic acid ↓pathophysiological markers ALP and LDH; ↓inflammatory
cytokines iNOS, COX-2, TNF-a, IL-6, via ↓NFκB

Quercetin and TNBS-induced colitis in rats treated with rutin (orally) or ↓Colonic damage and inflammation, ↓pathological scores, [89]
its glycozides quercetin (rectally) ↓MPO which was similar to sulphasalazine and 5-ASA

TNBS-induced colitis in rats protected with quercitrin ↓NOS and ↓AP in colonic tissue, ↓MDA, [87]
↑electrolyte absorption

TNBS-induced acute and chronic colitis in rats protected Acute phase: ↓diarrhea, ↓colonic damage, ↓MPO, ↓AP, ↑GSH, [92]
and treated with quercitrin ↑fluid absorption in colonic tissue; chronic phase: ↓diarrhea,
↓colonic damage, ↑fluid absorption; no significant effect on
inflammatory cytokines

DSS-induced colitis in rats protected with quercetin or ↓Colonic damage, ↓DAI, ↓MPO, ↓IL-1B, ↓TNF-α, ↓iNOS; via [90]
quercetrin ↓NFκB activity; quercetin had no preventive action

DSS-induced colitis in mice protected and treated with ↓Weight loss; ↓colonic shortening, ↓histopathological score, [91]
quercetin or rutin as dietary supplement ↓IL-1B, ↓IL-6, ↓GM-CSF and ↓COX-2 mRNA; quercetin had
no effect

DSS-induced colitis in rats protected and treated with ↓DAI, ↓histological scores, ↑GSH, ↓MPO, ↓iNOS; via [97]
quercitrin as supplement in drinking water ↓NFκB activation, no effect on LTB4

DSS-induced colitis in mice treated with quercetin + ↓Weight loss, ↓mortality, ↓inflammatory scores, ↓inflammatory [94]
piperine encapsulated into reconstituted oil bodies (i.p.) cytokines: IL-6, IL-23, IL-12; ↑anti-inflammatory mediators:
IL-10 and IL-1Ra; via ↓p38 MAPK phosphorylation

Acetic acid-induced colitis in mice treated with quercetin- ↓Colonic damage, ↓histological alterations, [95]
loaded microcapsule using pectin/casein polymer ↓neutrophil recruitment, ↓edema, via ↓IL-1β and ↓IL-33 and
↑anti-inflammatory cytokine (IL-10)

Acetic acid-induced colitis in mice protected with quer- ↓Damage score and ↓colonic weight/longitude ratio only by [93]
cetin, or chloronaphthoquinone quercetin, or monochlo- chloronaphthoquinone quercetin
ropivaloyl quercetin
The Role of Dietary Polyphenols in the Management of Inflammatory Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 3 201

(Table 1) Contd….

Polyphenol Intervention Results References

Resveratrol and TNBS-induced ulcerative-colitis in rats treated with res- ↓Colonic damage and histological scores, ↓weight loss, [105]
piceatannol veratrol ↓MPO activity via↓ICAM-1 and VCAM-1 levels in the colon
and serum, ↑antioxidant function (↓LPO, ↑GSH)

DSS-induced chronic colitis in mice protected with res-
veratrol as dietary supplement
↓Weight loss, ↓diarrhea and rectal bleeding, ↓colonic damage [102]
and histological scores; via ↓pro-inflammatory cytokines:
TNF-α, IL-1β, PGES-1, COX-2 and iNOS proteins expression;
↑anti-inflammatory cytokines IL-10; through ↓p38 in MAPK
signal pathway

DSS-induced colitis in mice treated with resveratrol ↓Colonic damage and histological scores ↓weight loss, ↓colon [99]
shortening, ↑amyloid A level in serum, ↓TNF-α, ↓IL-6, ↓IL-1β,
↓percentage of CD4+ T cells and macrophages in mesenteric
lymphnodes; via ↑SIRT1, ↓IκB expression and NFκB activation

DSS-induced colitis in mice treated with resveratrol or ↓Colonic damage and histological score, ↓colon shortening, [100]
piceatannol ↓iNOS; via ↓NFκB and ↓phosphorylation of IKK, ERK and
STAT3 by both drugs

DSS-induced colitis in mice treated with piceatannol ↓Clinical signs, ↓histological scores,↓weight loss, ↓colonic [113]
MPO, ↓NO, ↓PGE2, ↓IL-1β, ↓IL-6, ↓TNF-α, ↓MCP-1 and
↓KC-1

Streptavidin-preoxidase (hypoxia) induced necrotizing ↓Colonic damage and ↓weight loss, ↓histological destruction [110]
enterocolitis in newborn rats treated with resveratrol as (vacuolization, necrosis, loss of brush border), ↓ileal tissue
enteral supplement nitrate/nitrite levels and ↓iNOS

TNBS-induced ulcerative-colitis in rats ↓Colonic injury, ↓neutrophil infiltration, ↓ histological damage; [118]
via ↓PGD2 concentration and ↓COX-2 expression, no signifi-
cant effect on PGE2 and COX-1 expression

DSS-induced colitis in mice and Azoxymethane + DSS
induced tumor treated with resveratrol as dietary supple-
ment
↓Colonic injury, ↓inflammation score, ↓percentage of neutro- [109]
phils and ↓CD3+ T cells in the mesenteric lymph nodes and
lamina propiria, ↓iNOS, ↓Cox-2, ↓TNF-α, ↓IFN-γ and p53-
Phospho-Serine 15 (Markers of inflammatory stress); via ↓p53.
In cancer study, ↓tumor incidence and ↓tumor multiplicity

DSS-induced colitis in murine (rodents) treated with ↓Colitis symptoms, ↓diarrhea, ↓DAI, ↓mucosal barrier imbal- [115]
resveratrol-3-O-(6'-O-butanoyl)-β-D-glucopyranoside or ance, ↓intestinal metabolism of resveratrol
resveratrol-3-O-(6'-O-octanoyl)-β-D-glucopyranoside
(prodrugs of resveratrol)

DDS-induced colitis in rats protected with resveratrol in
dietary dose (low dose)
↓Colon tissue damage, modulation of gut microbiota [108]
(↑lactobacilli and bifidobacteria, ↓enterobacteria), improvement
of colonic mucosa architecture, ↓weight loss, suppression of
anemia, ↓ROS, ↓inflammatory mediators: PGE2, COX-2, PGES
and NO levels in colonic mucosa

LPS induced inflammation in human intestinal Caco-2 and ↓iNOS mRNA and protein expression dose-dependently, [104]
SW480 cells treated with resveratrol ↓NO production; via ↓TLR4 expression, ↓phosphorylation of IκB
15d-PGJ2: 15-deoxy-D 12, 14-prostaglandin J2; 5-ASA: 5-aminosalicylic acid; 5´-ND: 5´-nucleotidase; AFP: alphafetoprotein; AP: alkaline phosphatase; CAT: catalase; CD: cathep-
sin-D; CEA: carcinoembryonic antigen; c-GT: gamma glutamyl transpeptidase; COX-2: cyclooxygenase-2; DNBS: dinitrobenzene sulphonic acid; DSS: dextran sodium sulfate;
EGCG: epigallocatechin-3-gallate; EC: epicatechin; ECG: epicatechin-3-gallate EGC: epigallocatechin; ERK: extracellular signal-regulated kinase; GM-CSF: granulocyte macro-
phage colony-stimulating factor; GPO: glutathione peroxidase; GRO-α: growth regulated oncogene-alpha; GSH: glutathione; GST: glutathione S-transferase; IBD: inflammatory
bowel disease; ICAM-1: intercellular adhesion molecule 1; IκB: inhibitory κB; IKK: IκB kinase; IL: interleukin; INF: interferon; iNOS: inducible NO synthase; IP-10:Interferon-
inducible protein-10; IRF1:INF regular factor 1; I-TAC: Interferon-inducible T-cell alpha chemoattractant; JNK: c-Jun N-terminal kinase; KC: keratinocyte chemoattractant; LDH:
lactate dehydrogenase; LPO: lipid peroxidation; LPS: lipopolysaccharide; MAPK: mitogen-activated protein kinases; MCP-1: monocyte chemoattractant protein-1; Mdr1a(-/-):
multidrug resistance targeted mutation mouse model of IBD; MDA: malondialdehyde; MIF: macrophage-migration inhibitory factor; MIG: monokine induced by gamma interferon;
MPO: myeloperoxidase; NFκB: nuclear factor-κB; NO: nitric oxide; Nrf2: nuclear factor-erythroid 2-related factor-2; PGC-1α: peroxisome proliferator-activated receptor gamma
coactivator-1 alpha; PGD2: prostaglandin D2; PGES: prostaglandin E synthase; PPAR: Peroxisome proliferator-activated receptor; ROS: reactive oxygen species; sICAM-1: soluble
ICAM-1; SOD: superoxide dismutase; SIRT1: silent mating type information regulation-1; STAT: signal transducer and activator of transcription; TLR4:Toll-like receptor 4; TNBS:
trinitrobenzene sulfonic acid; TNF: tumor necrosis factor; VCAM-1: vascular cell adhesion molecule-1.
202 Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 3
Biedermann et al. [34] reported that administration of a
standardized anthocyanin-rich bilberry formulation for pa-
tients with UC resulted in improvement of disease symptoms
in terms of remission rate with no serious adverse effects.
Curcumin
Curcumin (diferuloylmethane), is a diarylheptanoid
which consists of aromatic ring joined by two α,β-
unsaturated carbonyl groups. Curcumin is the major com-
pound of turmeric the spice derived from the plant Curcuma
longa that is responsible for its vibrant yellow color. Curcu-
min is a potent anti-inflammatory and antioxidant molecule
[35, 37, 43]. Anti-inflammatory action of curcumin is due to
its high capacity to interact with various molecular targets
involved in the inflammatory pathway. Curcumin modulates
the inflammatory response via inhibiting the expression of
pro-inflammatory cytokines, including IL-1, TNF-α, IFN-γ,
IL-4, and IL-1β [36-40]. It has been proven that suppressing
the activation of NFκB via inhibition of IκB phosphorylation
and P38-MAPK signaling activation is the main anti-
inflammatory mechanisms of curcumin in IBD [36-42].
Peroxisome proliferator-activated receptor (PPAR)-γ is a
transcription factor which can suppress NFκB and mitigate
colitis. The 15-deoxy-D 12, 14-prostaglandin J2 (15d-PGJ2)
as end-product metabolite of PGD2 is an endogenous agonist
of PPARγ which acts as its ligand through PPARγ signaling
or as an independent pathway modulating NFκB activation.
Curcumin elevates the level of PPARγ and 15d-PGJ2 in in-
testinal tissue of animals with colitis [37, 44].
Beneficial effects of curcumin in colitis have been inves-
tigated in various animal models (Table 1). In addition, con-
sumption of curcumin as a dietary supplement demonstrated
both protective and healing activity in animal colitis similar
to the standard drug sulphasalazine via inhibition of pro-
inflammatory cytokine expression, leukocyte infiltration, and
suppression of nuclear factors and MAPK inflammatory sig-
naling pathways [38, 39, 41].
Two clinical trials evaluated the efficacy of curcumin in
IBD patients. In one, curcumin showed improvement in both
CD and UC patients regarding significant decrease in the
inflammatory indicators and disease activity index (DAI).
Sigmoidoscopy and biopsy assessment confirmed the thera-
peutic effect of curcumin [45]. Another study on UC patients
in the maintenance phase showed significant decrease in
relapse rate in those received curcumin with 5-aminosalisylates
comparing to those received 5-aminosalisylates alone [46].
Curcumin has a rapid plasma conjugation and clearance,
leading to reduction of its therapeutic function. Complexa-
tion of curcumin with particular substances may increase its
bioavailability. Piperine is one of those molecules that en-
hance serum bioavailability of curcumin, through inhibition
of curcumin intestinal metabolism. Also complexation of
curcumin with phosphatidylcholine resulted in the enhance-
ment of its bioavailability via promoting the lipophilic mem-
branes transmission [47, 48].
EGCG and Green Tea Polyphenols
Tea (Camellia sinensis) an evergreen shrub has been con-
sumed for about 4000 years and is the most common bever-
Farzaei et al.
age after water [49]. Polyphenols of green tea encompass
various phenolic compounds such as epigallocatechin-3-
gallate (EGCG), epigallocatechin (EGC), epicatechin-3-
gallate (ECG), and epicatechin (EC). EGCG, the predomi-
nant green tea polyphenol (about 40% of tea polyphenols), is
a type of catechin and is the ester of gallic acid and EGC.
EGCG possesses anti- inflammatory and antioxidant capa-
bilities. Various studies consider the EGCG as the major
antioxidant and anti-inflammatory agent of tea phenolic
compounds [50, 51]. The ameliorative action of EGCG and
green tea extract on the models of UC and enterocolitis are
well described (Table 1). Most of the investigations are
based on its ability to suppress the production of key
inflammatory mediators (e.g., TNF-α, INF-γ, NO, iNOS, and
IL-1β) via inhibition of NFκB activation [51-54].
Blocking transcripts and proteins associated with im-
mune and inflammatory response and fibrinogenesis path-
ways, and inducing those associated with xenobiotic metabo-
lism pathways by PPAR-α and STAT1 are other mechanisms
involved in anti-colitis activity of green tea polyphenols [55].
Oxidative stress and ROS generation play an obvious
role in initiation and exacerbation of IBD pathogenesis. In
addition to anti-inflammatory activity, green tea polyphenols
diminish the oxidative stress condition and scavenge free
radicals and enhance antioxidant enzymes in inflamed GI
tissue [56-58].
Green tea polyphenols have been evaluated in various
animal models of IBD presenting positive effects on clinical
conditions, colonic damage and histological scores in all the
experimental models [53, 55- 60].
One human study evaluated the efficacy of EGCG on
refractory patients to conventional UC therapy and showed
improvement in response and remission rate indicating a
beneficial effect of EGCG [61]. Administration of EGCG
and green tea polyphenols in both animals and human
showed that these phenolic agents were well tolerated and
completely safe and only trivial side effect in patients was
detected [56, 58, 61]. Brückner et al. [56] showed an en-
hanced bioavailability of EGCG when administrated to coli-
tis animals by the addition of piperine which inhibits its me-
tabolism within the intestinal lumen.
Naringenin
Naringenin (4',5,7-Trihydroxyflavanone), one of the most
abundant flavonoids present in citrus, grapefruits, cherries,
and tomatoes, is a flavanone. Naringenin is potentially effec-
tive in the prevention and treatment of IBD [62-64]. It at-
tenuates clinical signs (DAI), colonic damage and inflamma-
tory condition in animal models of colitis. Anti-inflammatory
activity is the main mechanism of naringenin by which
modulates colitis [63, 64].
Naringenin suppresses mRNA and protein expression of
Toll-like receptor 4 (TLR4) which activates signaling pro-
teins, including the adaptor proteins myeloid differentiation
primary response gene 88 (MyD88) involved in NFκB acti-
vation, resulted in subsequent stimulation of NFκB signaling
genes, e.g. TNF-α, IL-1, IL-6, IL-8, IL-15, iNOS, and ICAM-1
[64, 65]. In addition, naringenin suppresses NFκB signaling
cascade through inhibiting phospho-NFκB p65 protein,
The Role of Dietary Polyphenols in the Management of Inflammatory
NFκB luciferase reporter, and phospho-IκBα’s protein and
gene expressions [64].
Another mechanism of naringenin in attenuating colitis
backs to its antioxidant and cytoprotective properties. It ap-
parently elevates antioxidant capacity and enzymes and
hence potentates intestinal and mucosal barrier and DNA
protection against oxidative damages [62, 63, 66]. Azuma
et al. [63] reported that dietary supplementation of narin-
genin acts as a preventive factor against moderate and severe
colitis in animal models.
Clinical administration of naringenin is restricted due to
its deficient solubility and bioavailability because of the hy-
drophobic structure. Complexation with hydroxypropyl-β-
cyclodextrin has improved the solubility, transmission within
the gut epithelium and plasma concentration of naringenin
with no toxicological event in animal models [67].
Olive Oil Polyphenols
Olive (olea uropaea, oleaceae) oil is the major fat com-
ponent of the Mediterranean diet. A large amount of poly-
phenolic compounds is absorbed following ingestion of olive
oil [68]. Sánchez-Fidalgo et al. [69] showed that dietary
olive oil polyphenols significantly reduce DAI, histological
scores, and pro-inflammatory cytokines via suppression of
IκBα and c-Jun N-terminal kinase (JNK)-MAPKs signaling
pathway activation in animal models of colitis.
One of the characteristics of olive oil phenolic com-
pounds is hydroxytyrosol which is present in olive oils in the
free or conjugated form. Hydroxytyrosol is both hydrosoluble
and liposoluble and significantly absorbed from intestine
[70, 71]. This polyphenol mitigates oxidative stress in the
human intestinal cell with alleviating lipid peroxidation and
antioxidant activity [72]. Its supplementation in animal diet
has had protective activity against colitis via inhibiting in-
flammatory enzymes and p38-MAPKs cellular signaling [73].
Pomegranate Polyphenols and Ellagic Acid
Pomegranate (Punica granatum L., Punicaceae) is a fruit
that is native to Persia, but grows in all over the world [74].
Polyphenolic compounds are the main constituents of this
fruit, with confirmed antioxidant and anti-inflammatory
properties [75].
Rosillo et al. [76] reported that ellagic acid-enriched
pomegranate extract exhibits protective and therapeutic function
via suppressing leukocyte infiltration and pro-inflammatory
cytokines and enzymes production mediated via blocking
p38-MAPK cellular signaling, nuclear p65 translocation, and
IKBα activation. Mast cell stabilizing is another anti-colitis
mechanism of these polyphenols. The efficacy of ellagic
acid-enriched pomegranate extract in animal models of coli-
tis is similar to sulphasalazine [77].
Ellagic acid or benzoaric acid is a benzopyran which is
the main in vivo hydrolysis product of pomegranate poly-
phenols. Ellagic acid demonstrated protective effect on ani-
mal models of colitis by inhibiting inflammatory enzymes
(iNOS, COX-2) via suppression of JNK, extracellular signal-
regulated kinase (ERK)-MAPK, and nucleus factors (IκB
and NFκB) signaling pathways [78]. Though, ellagic acid
Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 3 203
possesses significant therapeutic effect in colitis, deficient
bioavailability restricts its clinical approach. Ogawa et al.
[79] demonstrated that microspheres of ellagic acid enhance
its bioavailability and improve therapeutic advantages.
Ellagic acid also exhibits a chemopreventive effect on
colon carcinogenesis through inhibition of NFκB. The NFκB
dimers (p65 and p50) have been known as promoters of tu-
morigenesis and a stimulator of chemokines gene expression
and growth factors which result in colorectal cancer [80, 81].
Colonic microbiota metabolizes ellagitannins as the most
active pomegranate phenolics to urolithins that are absorbed
and reach many organs [82]. Larrosa et al. [83] reported that
dietary supplementation of urolithin-A alleviates colonic
damage, inhibits inflammatory cells infiltration and pro-
inflammatory cytokines production and mitigates inflamma-
tory response. Also, González-Sarrías et al. [84] showed that
urolithins suppress the cellular inflammatory signaling,
MAPK, in vitro.
Dietary supplementation of pomegranate extract and its
active metabolite, urolithin-A, modulate microflora of the
colon via increasing bifidobacteria and lactobacilli, and de-
creasing E. coli, enterobacteria and total aerobic bacteria. It
has been proven that the type and amounts of intestinal mi-
crobiota play a crucial role in IBD. Bifidobacterium and Lac-
tobacillus as probiotics improve various pathological pa-
rameters such as pro-inflammatory cytokines, epithelial re-
pair, and oxidative damage in animal models of colitis [85].
They also prevent colonization and invasive activity of en-
terobacteria e.g. E. coli. In addition, Bifidobacteria enhances
the absorption and bioavailability of pomegranate polyphe-
nols and improves its therapeutic effects on chronic inflam-
mation [86].
Larrosa et al. [83] reported that the supplementation of
urolithin-A exhibited higher activity than pomegranate ex-
tract in ameliorating inflammation, however, only dietary
pomegranate extract has anti-oxidative stress potential in
animal colitis.
Quercetin
Quercetin (2-(3,4-dihydroxyphenyl) -3,5,7-trihydroxy-
4H-chromen-4-one), a flavone present in various plants, is
naturally found as a glycoside form of 3-rhamnosylquercetin
(quercitrin) or 3-O-rhamnosyl-glucosyl-quercetin (rutin) [87-
91]. Quercetin is one of the most potent scavengers of free
radicals (e.g. superoxide, hydroxyl and nitrogen radicals)
[88]. The glycosides have deficient absorption in the small
intestine and microflora of colon metabolizes them in the
local active aglycone form of quercetin [87, 89]. Various
studies have investigated therapeutic benefits of quercetin
and its derivatives on the models of intestinal inflammatory
conditions (Table 1). Despite the strong antioxidant and anti-
inflammatory potential of quercetin, its oral administration
or dietary supplementation has no advantage in the treatment
of animal models of IBD [90, 91]. Nevertheless, rectal ad-
ministration of quercetin as well as rutin (orally) was as effi-
cacious as sulphasalazine (orally) and 5-aminosalicylic acid
(rectally) in the management of colitis [89]. In addition,
quercitrin exhibited reliable protective and therapeutic activ-
ity in animal colitis, due to the intestinal release of quercetin
204 Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 3 Farzaei et al.

by microflora enzyme, rhamnosidase, which prepares ab- Resveratrol

sorbable amounts of quercetin [87, 90, 92]. Furthermore,
chloronaphthoquinone quercetin improved colonic damage
in animal colitis [93].
Various studies have attempted to increase the efficacy of
quercetin in IBD by preparation of more absorbable dosage
forms such as complexation with piperine or microcapsula-
tion [94, 95].
Quercetin and its derivatives have demonstrated protec-
tive and therapeutic effects on IBD via various biological
mechanisms; they suppress the production of pro-inflammatory
cytokines, enhance anti-inflammatory cytokines e.g. IL-10
and IL-1Ra, inhibit inflammatory enzymes e.g. COX-2 and
iNOS and leukocytes infiltration via blocking p38-MAPK
cellular signaling pathway and NFκB activation. They also
improve antioxidant capacity (Table 1). Quercetin also regu-
lates the function of transporter-mediated transport of N-
acetyl 5-aminosalicylic acid and its co-administration has de-
creased therapeutic dose of sulfasalazine or 5-aminosalicylic
acid [96].
Dietary supplementation of querceitrin or rutin has exhib-
ited protective and therapeutic potential in animal models of
colitis via suppressing NF signaling pathway, inflammatory
enzymes and granulocyte macrophage colony-stimulating
factor (GM-CSF) expression, an important mediator for
inflammatory reactions which stimulates the release of ara-
chidonic acid metabolites and increased generation of ROS
[91, 97].
Resveratrol (3,4',5-Stilbenetriol), a polyphenolic com-
pound from stilbenoid subgroup and a natural phytoalexin, is
isolated from grape skin, berries and peanuts [98]. Positive
function of resveratrol due to free radical scavenging, modu-
lating the key enzymes of cell life, and anti-inflammatory
properties resulted in the consideration of this molecule as
one of the most promising natural agents in the prevention
and treatment of IBD [99-106].
The ability of resveratrol to diminish leukocytes infiltra-
tion is mediated by suppression of their adhesion to endothe-
lial cells, through down-regulating the expression of ICAM-
1 and vascular cell adhesion molecule (VCAM)-1. Such anti-
inflammatory mechanism of resveratrol causes similar effi-
cacy of resveratrol to sulfasalazine in animal models of coli-
tis [107-109].
Various animal studies elucidate the beneficial action of
resveratrol as a dietary supplement in IBD (Table 1). Thirty-
day administration of a diet enriched resveratrol as the pro-
tective regime in mice, which followed by induction of coli-
tis resulted in the survival of all animals while standard diet
group showed 40% mortality. The protective potential is due
to the suppression of pro-inflammatory cytokines and in-
flammatory enzymes proteins expression. Resveratrol has
shown modulatory activity on inflammatory pathways via
down-regulation of MAPK signal pathway [102]. Such pro-
tective function with resveratrol diet was also reported by
Larrosa et al. [110]. Its dietary supplementation improves

Polyphenols as dietary
supplementation

↑ Tissue and systemic levels of

polyphenols and its metabolites

× × ×

TLR4 IKK PPARαγ MAPK Nrf2

×
NFκB

× ×
I-TAC, MCP, TNF-α, iNOS, ICAM, ROS, NOO- SOD, GSH,
KC, etc COX-2, etc VCAM, etc CAT, etc

Inflammation Oxidative stress

Fig. (1). Cellular mechanisms of dietary polyphenols as protective or therapeutic agents in IBD; TLR4: Toll-like receptor 4; IKK: IκB
kinase; PPAR: Peroxisome proliferator-activated receptor; MAPK: mitogen-activated protein kinases; Nrf2: nuclear factor-erythroid 2-
related factor-2; NFκB: nuclear factor-κB; I-TAC: Interferon-inducible T-cell alpha chemoattractant; MCP-1: monocyte chemoattractant
protein; KC: keratinocyte chemoattractant; TNF-α: tumor necrosis factor alpha; iNOS: inducible nitric oxide synthase; COX-2: cyclooxy-
genase-2; ICAM: intercellular adhesion molecule; VCAM: vascular cell adhesion molecule; ROS: reactive oxygen species; NOO-:nitrogen
radical; SOD: superoxide dismutase; GSH: glutathione; CAT: catalase.
The Role of Dietary Polyphenols in the Management of Inflammatory Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 3 205

gut microbiota, protects the colonic mucosa, and diminishes
ROS and systemic inflammatory markers [110]. In addition,
Cui et al. reported healing effect of dietary resveratrol in
animal colitis [111].
Enteral resveratrol supplementation in newborn rats with
necrotizing enterocolitis, the leading cause of GI-related
mortality in premature infants, resulted in the improvement
of necrosis and inflammation via diminishing free nitrogen
radicals and iNOS enzyme activity [112].
Silent mating type information regulation (sirtuin or
SIRT) plays a key role in genetic control of aging and en-
hancement the longevity. Up-regulation of this nuclear factor
by resveratrol resulted in the prevention and improvement of
chronic inflammations such as IBD [99].
Chronic colitis elevates colon cancer risk apparently. It
was reported that resveratrol decreases the incidence and
multiplicity of colitis associated tumors [111]. It is approved
that STAT3 is strongly phosphorylated in patients with CD
and UC. Moreover, hyperactivation of STAT3 stimulates
tumor progression in gastric and colorectal cancers [113,
114]. The suppression of STAT3 phosphorylation is the
other mechanism of resveratrol in the treatment of IBD and
subsequent colon cancer [100].
The hydroxylated analog of resveratrol, piceatannol,
which is a stilbene present in grapes, demonstrated therapeu-
tic beneficial in animal models of IBD through anti-
inflammatory and antioxidant properties. Piceatannol inhibits
inflammatory mediators and pro-inflammatory cytokines
through suppression of NF signaling pathway involving IKK
and ERK phosphorylation. It reduces the chemokines, mono-
cyte chemoattractant protein (MCP)-1 and keratinocyte
chemoattractant (KC) which gather immune cells to local
tissue of inflammation. It also diminishes STAT3 activation
leading to suppression of inflammatory-induced gastric and
colorectal cancers [105, 115].
It was demonstrated that resveratrol prodrugs enhance
delivery of resveratrol to the colon and increase its efficacy
in the management of colitis symptoms [116].
CONCLUSION AND FUTURE DIRECTIONS
A large body of evidence supports the beneficial health
properties of dietary polyphenols. Polyphenols as nonessen-
tial dietary components presumably play a crucial role in
improving chronic, relapsing inflammation and oxidative
reactions [14, 15, 117]. Dietary polyphenols possess both
protective and therapeutic effects in the management of IBD
possibly mediated via down-regulation of inflammatory cy-
tokines and enzymes, enhancing antioxidant defense, and
suppressing inflammatory pathway and their cellular signal-
ing mechanism. Figure 1 illustrates the possible cellular
mechanisms of dietary polyphenols as protective or thera-
peutic agents in IBD. It must be noted that (Fig. 1) is based
on the mechanisms exhibited in the literature with various
dietary polyphenols, and not all of these mechanisms imply
to each dietary polyphenol.
Literature evidences show that dietary polyphenols can
modulate inflammatory response and improve gut microbiota
[83, 85]. The metabolic activity of gut microbiota increases the
generation of bioactive compounds from dietary polyphenols
and these metabolites mutually improve the composition and
metabolic activity of the gut microbiota. Figure 2 illustrates
the mutual influence of polyphenols or their metabolites and
intestinal microflora in the development of IBD.

Polyphenols as dietary
supplementation

↑Polyphenol metabolite in
intestinal lumen

Improving intestinal
microbiota
↑Lactobacilli, ↑Enterobacteria,
bifidobacteria, E. coli, etc
etc

Suppressing
inflammatory reactions

Fig. (2). Mutual influence of polyphenols or their metabolites and intestinal microflora in the development of IBD.
206 Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 3 Farzaei et al.

Table 2. Clinical trials on the efficacy of polyphenols in the management of IBD.

No. of Treatment
Polyphenol Intervention Study design IBD type Results References
patients duration

↑Remission of patients (63.4%),

↑response of patients (90.9%), ↓total
Mayo score (p<0.001), ↓fecal calpro-
Standardized antho- tectin levels (p=0.049), ↓endoscopic
Bilberry
cyanin-rich bilberry Open label pilot UC 13 9 weeks Mayo score, ↓histologic Riley index; [34]
anthocyanins
preparation ↑calprotectin levels and disease
activity after cessation of bilberry
intake; no serious adverse events
were observed

↓Relapse of disease during the six-

month study (4.7% in curcumin
1g Curcumin twice daily
Randomized, compared to 20.5% in placebo),
plus sulfasalazine or
multicenter, ↓clinical activity index (p=:0.038),
mesalamine (n=43);
Curcumin double-blind, UC 82 Six months ↓endoscopic index (p=0.001); ↓UC- [46]
placebo group received
placebo- con- associated morbidity. Curcumin plus
sulfasalazine or mesala-
trolled standard therapy was more effective
mine (n=39)
in maintaining remission than pla-
cebo plus standard UC treatment

UC patients: 550 mg
twice daily (first month)
550 mg three times daily
(second month) with ↓CDAI in CD patients,
conventional drugs ↓inflammatory indicators: ESR and
CD patient: 360 mg three CD (n=5) and CRP, ↓sedimentation rates
Curcumin Open label pilot 10 60 days [45]
times daily (first month) UC (n=5) ↓concomitant drug therapy; im-
and four times daily provement in sigmoidoscopy and
(second month) with biopsy test in both disease
conventional drugs
control group: placebo
with conventional drug

↓UCDAI (6.5±1.9 in comparison

Treatment group re-
Double-blinded, with 7.3±1.7 in control group)
ceived EGCG 400 mg or
EGCG placebo- UC 20 56 days ↑response rate (66.7%) (P = 0.03), [61]
800 mg daily/control
controlled pilot ↑remission rate (53.3%) (P = 0.10);
received placebo
trivial side effect was observed
CD: crohn's disease; CDAI: Crohn's Disease Activity Index; CRP: C-reactive protein; DAI: disease activity index; ESR: erythrocyte sedimentation rate, UC: ulcerative colitis.

This review calls attention to a group of dietary antioxi- CONFLICT OF INTEREST

dants/polyphenols, whose role in human nutrition deems
The authors confirm that this article content has no con-
crucial. The current article reveals that more in vitro, phar-
flict of interest.
maceutical and preclinical investigations are necessary to
understand the metabolism, absorption, efficacy, and cellular
ACKNOWLEDGEMENTS
mechanisms of dietary polyphenols. More well-designed
human clinical trials are compulsory to evaluate the activity This invited paper is the outcome of an in-house finan-
of dietary polyphenols as promising protective and therapeu- cially non-supported study. This review is partly supported
tic nutrients in terms of bioavailability, bioefficacy, and by National Elites Foundation of Iran.
safety researches. Dietary polyphenols can be also consid-
ered as adjuvant therapy with conventional drugs to improve REFERENCES
their efficacy and bioavailability in the treatment of IBD.
[1] Rahimi, R.; Nikfar, S.; Abdollahi, M. Induction of clinical response
Advanced clinical and pharmacological studies are recom- and remission of inflammatory bowel disease by use of herbal
mended in order to obtain more conclusive results about the medicines: A meta-analysis. World J. Gastroenterol., 2013, 19(34),
role of dietary polyphenols for the management of IBD. 5738-5749.
The Role of Dietary Polyphenols in the Management of Inflammatory
[2] Halpin, S.J.; Ford, A.C. Prevalence of symptoms meeting criteria
for irritable bowel syndrome in inflammatory bowel disease: Sys-
tematic review and meta-analysis. Am. J. Gastroenterol., 2012,
107, 1474-1482.
[3] Button, L.A.; Roberts, S.E.; Goldacre, M.J.; Akbari, A.; Rodgers,
S.E.; Williams, J.G. Hospitalized prevalence and 5-year mortality
for IBD: record linkage study. World J. Gastroenterol., 2010, 16,
431-438.
[4] Zenlea, T.; Peppercorn, M.A. Immunosuppressive therapies for
inflammatory bowel disease. World J. Gastroenterol., 2014,
20(12), 3146-3152.
[5] Esmaily, H.; Sanei, Y.; Asadi-Shahmirzadi, A.; Mozaffari, S.;
Baeeri, M.; Abdollahi, M. Induction of inflammatory bowel disease
through activation of immune system against enteric bacteria. J.
Gastroenterol. Hepatol. Res., 2014, 3(2), 977-984.
[6] Rahimi, R.; Nikfar, S.; Abdollahi, M. Comparison of the efficacy
and tolerability of herbal medicines with 5-aminosalisylates in in-
flammatory bowel disease: A meta-analysis of placebo controlled
clinical trials involving 812 patients. Int. J. Pharmacol., 2013, 9,
227-244.
[7] Mozaffari, S.; Nikfar, S.; Abdolghaffari, A.H.; Abdollahi, M. New
biologic therapeutics for ulcerative colitis and Crohn's disease. Ex-
pert. Opin. Biol. Ther., 2014, in press.
[8] Rahimi, R.; Mozaffari, S.; Abdollahi, M. On the use of herbal
medicines in management of inflammatory bowel diseases: A sys-
tematic review of animal and human studies. Dig. Dis. Sci., 2009,
54(3), 471-480.
[9] Rahimi, R.; Baghaei, A.; Baeeri, M.; Amin, G.; Shams-Ardekani,
M.R.; Khanavi, M.; Abdollahi, M. Promising effect of Magliasa, a
traditional Iranian formula, on experimental colitis on the basis of
biochemical and cellular findings. World J. Gastroenterol., 2013,
19, 1901-1911.
[10] Tsao, R. Chemistry and biochemistry of dietary polyphenols. Nu-
trients, 2010, 2, 1231-1246.
[11] Farzaei, M.H.; Khanavi, M.; Moghaddam, G.; Dolatshahi, F.; Ra-
himi, R.; Shams-Ardekani, M.R.; Amin, G.; Hajimahmoodi, M.
Standardization of Tragopogon graminifolius DC. extracts based
on phenolic compounds and antioxidant activity. J. Chem., 2014,
2014, Article ID 425965.
[12] Daglia, M. Polyphenols as antimicrobial agents. Curr. Opin. Bio-
technol., 2012, 23(2), 174-181.
[13] Farzaei, M.H.; Abbasabadi, Z.; Rahimi, R.; Farzaei, F. Parsley: A
review of ethnopharmacology, phytochemistry and biological ac-
tivities. J. Tradit. Chin. Med., 2013, 33, 815-826.
[14] Kawaguchi, K.; Matsumoto, T.; Kumazawa, Y. Effects of antioxi-
dant polyphenols on TNF-alpha-related diseases. Curr. Top. Med.
Chem., 2011, 11(14), 1767-1779.
[15] Cardona, F.; Andrés-Lacueva, C.; Tulipani, S.; Tinahones, F.J.;
Queipo-Ortuño, M.I. Benefits of polyphenols on gut microbiota
and implications in human health. J. Nutr. Biochem., 2013, 24(8),
1415-1422.
[16] Farzaei, M.H.; Ghasemi-Niri, S.F.; Abdolghafari, A.H.; Baeeri, M.;
Khanavi, M.; Navaei-Nigjeh, M.; Abdollahi, M.; Rahimi, R. Bio-
chemical and histopathological evidence on the beneficial effects of
Tragopogon graminifolius in TNBS-induced colitis. Pharm. Biol.
2014, In press.
[17] Vrhovsek, U.; Rigo, A.; Tonon, D.; Mattivi, F. Quantitation of
polyphenols in different apple varieties. J. Agric. Food Chem.,
2004, 52, 6532 -6538.
[18] Jung, M.; Triebel, S.; Anke, T.; Richling, E.; Erkel, G. Influence of
apple polyphenols on inflammatory gene expression. Mol. Nutr.
Food Res., 2009, 53, 1263-1280.
[19] Denis, M.C.; Furtos, A.; Dudonné, S.; Montoudis, A.; Garofalo, C.;
Desjardins, Y.; Delvin, E.; Levy, E. Apple peel polyphenols and
their beneficial actions on oxidative stress and inflammation. PLoS
One, 2013, 8(1), e53725.
[20] Niture, S.K.; Kaspar, J.W.; Shen, J.; Jaiswal, A.K. Nrf2 signaling
and cell survival. Toxicol. Appl. Pharmacol., 2010, 244, 37-42.
[21] Yoshioka, Y.; Akiyama, H.; Nakano, M.; Shoji, T.; Kanda, T.;
Ohtake, Y.; Takita, T.; Matsuda, R.; Maitani, T. Orally adminis-
tered apple pro-cyanidins protect against experimental
inflammatory bowel disease in mice. Int. Immunopharmacol., 2008,
8, 1802-1807.
[22] Skyberg, J.; Robison, A.; Golden, S.; Rollins, M.F.; Callis, G.;
Huarte, E.; Kochetkova, I.; Jutila, M.A.; Pascual, D.W. Apple
polyphenols require T cells to ameliorate dextran sulfate sodium-
Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 3 207
induced colitis and dampen proinflammatory cytokine expression.
J. Leukoc Biol., 2011, 90(6), 1043-1054.
[23] D'Argenio, G.; Mazzone, G.; Tuccillo, C.; Ribecco, M.T.; Graziani,
G.; Gravina, A.G.; Caserta, S.; Guido, S.; Fogliano, V.; Caporaso,
N.; Romano, M. Apple polyphenols extract (APE) improves colon
damage in a rat model of colitis. Dig. Liver. Dis., 2012, 44(7), 555-
562.
[24] Castagnini, C.; Luceri, C.; Toti, S.; Bigagli, E.; Caderni, G.; Femia,
A.P.; Giovannelli, L.; Lodovici, M.; Pitozzi, V.; Salvadori, M.;
Messerini, L.; Martin, R.; Zoetendal, E.G.; Gaj, S.; Eijssen, L.;
Evelo, C.T.; Renard, C.M.; Baron, A.; Dolara, P. Reduction of
colonic inflammation in HLA-B27 transgenic rats by feeding Marie
Ménard apples, rich in polyphenols. Br. J. Nutr., 2009, 102(11),
1620-1628.
[25] Karlsen, A.; Paur, I.; Bøhn, S.K.; Sakhi, A.K.; Borge, G.I.; Serafini,
M.; Erlund, I.; Laake, P.; Tonstad, B.S.; Blomhoff, R. Bilberry
juice modulates plasma concentration of NFκB related
inflammatory markers in subjects at increased risk of CVD. Eur. J.
Nutr., 2010, 49, 345-355.
[26] Milbury, P.E.; Graf, B.; Curran-Celentano, J.M.; Blumberg, J.B.
Bilberry (Vaccinium myrtillus) anthocyanins modulate heme oxy-
genase-1 and glutathione s-transferase-pi expression in ARPE-19
Cells. Invest. Ophthalmol. Vis. Sci., 2007, 48(5), 2343-2349.
[27] Jakesevic, M.; Aaby, K.; Borge, G.A.; Jeppsson, B.; Ahrné, S.;
Molin, G. Antioxidative protection of dietary bilberry, chokeberry
and Lactobacillus plantarum HEAL19 in mice subjected to intesti-
nal oxidative stress by ischemia-reperfusion. BMC Complement.
Altern. Med., 2011, 11, 8.
[28] Bornsek, S.M.; Ziberna, L.; Polak, T.; Vanzo, A.; Ulrih, N.P.;
Abram, V.; Tramer, F.; Passamonti, S. Bilberry and blueberry an-
thocyanins act as powerful intracellular antioxidants in mammalian
cells. Food Chem., 2012, 134(4), 1878-1884.
[29] Triebel, S.; Trieu, H.L.; Richling, E. Modulation of inflammatory
gene expression by a bilberry (Vaccinium myrtillus L.) extract and
single anthocyanins considering their limited stability under cell
culture conditions. J. Agric. Food. Chem., 2012, 60(36), 8902-8910
[30] Piberger, H.; Oehme, A.; Hofmann, C.; Dreiseitel, A.; Sand, P.G.;
Obermeier, F.; Schoelmerich, J.; Schreier, P.; Krammer, G.; Ro-
gler, G. Bilberries and their anthocyanins ameliorate experimental
colitis. Mol. Nutr. Food Res., 2011, 55(11), 1724-1729.
[31] Oidtmann, J.; Schantz, M.; Mäder, K.; Baum, M.; Berg, S.; Betz,
M.; Kulozik, U.; Leick, S.; Rehage, H.; Schwarz, K.; Richling, E.
Preparation and comparative release characteristics of three antho-
cyanin encapsulation systems. J. Agric. Food Chem., 2012, 60(3),
844-851.
[32] Serra, D.; Paixão, J.; Nunes, C.; Dinis, T.C.; Almeida, L.M. Cya-
nidin-3-glucoside suppresses cytokine-induced inflammatory re-
sponse in human intestinal cells: Comparison with 5-aminosalicylic
acid. PLoS One, 2013, 8(9), e73001.
[33] Zhang, Y.; Lian, F.; Zhu, Y.;, Xia, M.; Wang, Q.; Ling, W.; Wang,
X. Cyanidin-3-O-β-glucoside inhibits LPS-induced expression of
inflammatory mediators through decreasing IκBα phosphorylation
in THP-1 cells. Inflamm. Res., 2010, 59(9), 723-730.
[34] Biedermann, L.; Mwinyi, J.; Scharl, M.; Frei, P.; Zeitz, J.; Kullak-
Ublick, G.A.; Vavricka, S.R.; Fried, M.; Weber, A.; Humpf, H.U.;
Peschke, S.; Jetter, A.; Krammer, G.; Rogler, G. Bilberry ingestion
improves disease activity in mild to moderate ulcerative colitis - an
open pilot study. J. Crohns Colitis, 2013, 7(4), 271-279.
[35] Jurenka, J.S. Anti-inflammatory properties of curcumin, a major
constituent of curcuma longa: a review of preclinical and clinical
research. Altern. Med. Rev., 2009, 14(2), 141-153.
[36] Camacho-Barquero, L.; Villegas, I.; Sánchez-Calvo, J.M.; Talero,
E,; Sánchez-Fidalgo, S,; Motilva, V.; de la Lastra, C.A. Curcumin,
a Curcuma longa constituent, acts on MAPK p38 pathway modulat-
ing COX-2 and iNOS expression in chronic experimental colitis.
Int. Immunopharmacol., 2007, 7, 333-342.
[37] Zhang, M.; Deng, C.; Zheng, J.; Xia, J.; Sheng, D. Curcumin inhib-
its trinitrobenzene sulphonic acid-induced colitis in rats by activa-
tion of peroxisome proliferator-activated receptor gamma. Int. Im-
munopharmacol., 2006, 6(8), 1233-1242.
[38] Salh, B.; Assi, K.; Templeman, V.; Parhar, K.; Owen, D.; Gómez-
Muñoz, A.; Jacobson, K. Curcumin attenuates DNB-induced mur-
ine colitis. Am. J. Physiol. Gastrointest. Liver Physiol., 2003,
285(1), G235-43.
[39] Sugimoto, K.; Hanai, H.; Tozawa, K.; Aoshi, T.; Uchijima, M.;
Nagata, T.; Koide, Y. Curcumin prevents and ameliorates trinitro-
208 Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 3
benzene sulfonic acid-induced colitis in mice. Gastroenterology,
2002, 123(6), 1912-1922.
[40] Ukil, A.; Maity, S.; Karmakar, S.; Datta, N.; Vedasiromoni, J.R.;
Das, P.K. Curcumin, the major component of food flavour tur-
meric, reduces mucosal injury in trinitrobenzene sulphonic acid in-
duced colitis. Br. J. Pharmacol., 2003, 139(2), 209-218.
[41] Jian, Y.T.; Mai, G.F.; Wang, J.D.; Zhang, Y.L.; Luo, R.C.; Fang,
Y.X. Preventive and therapeutic effects of NFkappaB inhibitor cur-
cumin in rats colitis induced by trinitrobenzene sulfonic acid.
World J. Gastroenterol., 2005, 11(12), 1747-1752.
[42] Ung, V.Y.L.; Foshaug, R.R.; MacFarlane, S.M.; Churchill, T.A.;
Doyle, J.S.G.; Sydora, B.C.; Fedorak, R.N. Oral administration of
curcumin emulsified in carboxymethyl cellulose has a potent anti-
inflammatory effect in the IL-10 gene-deficient mouse model of
IBD. Dig. Dis. Sci., 2010, 55, 1272-1277.
[43] Nabavi, S.F.; Daglia, M.; Moghaddam, A.H.; Habtemariam, S.;
Nabavi, S. M. Curcumin and liver disease: from chemistry to medi-
cine. Compr. Rev. Food. Sci. F., 2014, 13(1), 62-77.
[44] Straus, D.S.; Glass, C.K. Cyclopentenone prostaglandins: new
insights on biological activities and cellular targets. Med. Res. Rev.,
2001, 21(3), 185-210.
[45] Holt, P.R.; Katz, S.; Kirshof, F. R. Curcumin therapy in inflamma-
tory bowel disease: a pilot study. Dig. Dis. Sci., 2005, 50, 2191-
2193.
[46] Hanai, H.; Iida, T.; Takeucbi, K.; Watanabe, F.; Maruyama, Y.;
Andoh, A.; Tsujikawa, T.; Fujiyama, Y.; Mitsuyama, K.; Sata, M.;
Yamada, M.; Iwaoka, Y.; Kanke, K.; Hiraishi, H.; Hirayama, K.;
Arai, H.; Yoshii, S.; Uchijima, M.; Nagata, T.; Koide, Y. Curcumin
maintenance therapy for ulcerative colitis: randomized, multicenter,
double-blind, placebo- controlled trial. Clin. Gastroenterol. Hepa-
tol., 2006, 4(12), 1502-1506.
[47] Shoba, G.; Joy, D.; Joseph, T.; Majeed, M.; Rajendran, R.; Srini-
vas, P.S. Influence of piperine on the pharmacokinetics of curcu-
min in animals and human volunteers. Planta Med., 1998, 64(4),
353-356.
[48] Marczylo, T.H.; Verschoyle, R.D.; Cooke, D.N.; Morazzoni, P.;
Steward, W.P.; Gescher, A.J. Comparison of systemic availability
of curcumin with that of cutcumin formulated with phosphatidyl-
choline. Cancer Chemother. Pharmacol., 2007, 60(2), 171-177.
[49] Sharma, V. K.; Bhattacharya, A.; Kumar, A.; Sharma, H.K. Health
benefits of tea consumption. Trop. J. Pharm. Res., 2007, 6, 785-
792.
[50] Nabavi, S.M.; Daglia, M.; Moghaddam, A.H.; Nabavi, S.F.; Curti,
V. Tea consumption and risk of ischemic stroke: A brief review of
the literature. Curr. Pharm. Biotechnol., 2014, in press.
[51] Yang, F. The green tea polyphenol (-)-epigallocatechin-3-
gallateblocks nuclear factor-κB activation by inhibiting IκB kinase
activity in the intestinal epithelial cell line IEC-6. Mol. Pharmacol.,
2001, 60, 528-533.
[52] Lin, Y.L.; Lin, J.K. (-)-Epigallocatechin-3-gallate blocks the induc-
tion of nitric oxide synthase by down-regulating lipopolysaccha-
ride-induced activity of transcription factor nuclear factor-kB. Mol.
Pharmacol., 1997, 52, 465-472.
[53] Varilek, G.W.; Yang, F.a., Lee, E.Y.; deVilliers, W.J.S.; Zhong J.;
Oz, H.S.; Westberry, K.F.; McClain, C.J. Green tea polyphenol ex-
tract attenuates inflammation in interleukin-2-deficient mice, a
model of autoimmunity. J. Nutr., 2001, 131, 2034-2039.
[54] May, M.J.; Ghosh, S. Signal transduction through NF-kB. Immu-
nology, 1998, 19, 80-88.
[55] Barnett, M.P.; Cooney, J,M.; Dommels, Y.E.; Nones, K.; Brewster,
D.T.; Park, Z.; Butts, C.A.; Mc Nabb W.C.; Laing W.A.; Roy, N.C.
Modulation of colonic inflammation in Mdr1a(-/-) mice by green
tea polyphenols and their effects on the colon transcriptome and
proteome. J. Nutr. Biochem., 2013, 24(10), 1678-1690.
[56] Brückner, M.; Westphal, S.; Domschke, W.; Kucharzik,. ALüger-
ing, T. Green tea polyphenol epigallocatechin-3-gallate shows
therapeutic antioxidative effects in a murine model of colitis J.
Crohns Colitis, 2012, 6(2), 226-235
[57] Kim, M.; Murakami, A.; Miyamoto, S.;Tanaka, T.; Ohigashi, H.
The modifying effects of green tea polyphenols on acute colitis and
inflammation-associated colon carcinogenesis in male ICR mice.
Bio. Factors, 2010, 36(1), 43-51.
[58] Oz, H.S.; Chen, T.; de Villiers, W.J. Green tea polyphenols and
sulfasalazine have parallel anti-inflammatory properties in colitis
models. Front. Immunol., 2013, 5(4), 132.
Farzaei et al.
[59] Watson, J.L.; Ansari, S.; Cameron, H.; Wang, A.; Akhtar, M.
McKay, D.M. Green tea polyphenol (-)-epigallocatechingallate
blocks epithelial barrier dysfunction provoked by IFN-but not by
IL-4. Am. J. Physiol. Gastrointest. Liver Physiol., 2004, 287, G954-
G961.
[60] Mazzon, E.; Muià, C.; Paola, R.D.; Genovese, T.; Menegazzi, M.;
De Sarro, A.; Suzuki, H.; Cuzzocrea, S. Green tea polyphenol ex-
tract attenuates colon injury induced by experimental colitis. Free
Radic. Res., 2005, 39(9), 1017-1025.
[61] Dryden, G.W.; Lam, A.; Beatty, K.; Qazzaz, H.H.; McClain, C.J. A
pilot study to evaluate the safety and efficacy of an oral dose of (-)-
epigallocatechin-3-gallate-rich polyphenon E in patients with mild
to moderate ulcerative colitis. Inflamm. Bowel. Dis., 2013, 19(9),
1904-1912.
[62] Al-Rejaie, S.S,; Abuohashish, H.M.; Al-Enazi, M.M.; Al-Assaf,
A.H.; Parmar, M.Y.; Ahmed, M.M. Protective effect of naringenin
on acetic acid-induced ulcerative colitis in rats. World J. Gastroen-
terol., 2013, 19(34), 5633-5644
[63] Azuma, T.; Shigeshiro, M.; Kodama, M.; Tanabe, S.; Suzuki, T.
Supplemental naringenin prevents intestinal barrier defects and in-
flammation in colitic mice. J. Nutr., 2013, 143(6), 827-834.
[64] Dou, W.; Zhang, J.; Sun, A.; Zhang, E.; Ding, L.; Mukherjee, S.;
Wei, X.; Chou, G.; Wang, Z,T.; Mani, S. Protective effect of narin-
genin against experimental colitis via suppression of Toll-like re-
ceptor 4/NFκB signalling. Br. J. Nutr., 2013, 110(4), 599-608.
[65] Andersen, V.; Christensen, J.; Ernst, A.; Jacobsen, B.A.; Tjønne-
land, A.; Krarup, H.B.; Vogel, U. Polymorphisms in NFκB, PXR,
LXR, PPARγ and risk of inflammatory bowel disease. World J.
Gastroenterol., 2011, 17(2), 197-206.
[66] Oršolić, N.; Gajski, G.; Garaj-Vrhovac, V.; Dikić, D.; Prskalo,
Z.Š.; Sirovina D. DNA-protective effects of quercetin or naringenin
in alloxan-induced diabetic mice. Eur. J. Pharmacol., 2011, 656,
110-118.
[67] Shulman, M.; Cohen, M.; Soto-Gutierrez, A.; Yagi, H.; Wang, H.;
Goldwasser, J.; Lee-Parsons, C.W.; Benny-Ratsaby, O.; Yarmush,
M.L.; Nahmias, Y. Enhancement of naringenin bioavailability by
complexation with hydroxypropoyl-β-cyclodextrin. PLoS One,
2011, 6(4), e18033.
[68] Vissiers, M.N.; Zock, P.L.; Roodenburg, A.J.; Leenen, R.; Katan,
M.B. Olive oil phenols are absorbed in humans. J. Nutr., 2002,
132, 409-417.
[69] Sánchez-Fidalgo, S.; Cárdeno, A.; Sánchez-Hidalgo, M.; Aparicio-
Soto, M.; de la Lastra, C.A. Dietary extra virgin olive oil polyphe-
nols supplementation modulates DSS-induced chronic colitis in
mice. J. Nutr. Biochem., 2013, 24(7), 1401-13.
[70] Manna, C.; Galletti, P.; Maisto, G.; Cucciolla, V.; D’Angelo, S.;
Zappia, V. Transport mechanism and metabolism of olive oil hy-
droxytyrosol in Caco-2 cells. FEBS Lett., 2000, 470, 341-344.
[71] Tsimidou, M.; Papadopoulos, G.; Boskou, D. Phenolic compounds
and stability of virgin olive oil-Part I. Food. Chem., 1992, 45(2),
141-144.
[72] Manna, C.; Galletti, P.; Cucciolla, V.; Moltedo, O.; Leone, A.;
Zappia, V. The protective effect of the olive oil polyphenol (3,4-
dihydroxyphenyl)-ethanol counteracts reactive oxygen metabolite-
induced cytotoxicity in Caco-2 cells. J. Nutr., 1997, 127, 286-292.
[73] Sánchez-Fidalgo, S.; Sánchez de Ibargüen, L., Cárdeno, A.; Alar-
cón de la Lastra, C. Influence of extra virgin olive oil diet enriched
with hydroxytyrosol in a chronic DSS colitis model. Eur. J. Nutr.,
2012, 51(4), 497-506.
[74] Seeram, N.P,; Adams, L.S.; Henning, S.M.; Niu, Y.; Zhang, Y.;
Nair, M.G.; Heber, D. In vitro antiproliferative, apoptotic, and anti-
oxidant activities of punicalagin, ellagic acid and a total pomegran-
ate tannin extract are enhanced in combination with other polyphe-
nols as found in pomegranate juice. J. Nutr. Biochem., 2005, 16(6),
369-370.
[75] Lansky, E.P.; Newman, R.A.; Punica granatum (pomegranate) and
its potential for prevention and treatment of inflammation and can-
cer. J. Ethnopharmacol., 2007, 109, 177-206.
[76] Rosillo, M.A.; Sánchez-Hidalgo, M.; Cárdeno, A.; Aparicio-Soto,
M.; Sánchez-Fidalgo, S.; Villegas, I.; de la Lastra CA. Dietary sup-
plementation of an ellagic acid-enriched pomegranate extract at-
tenuates chronic colonic inflammation in rats. Pharmacol. Res.,
2012, 66(3), 235-242.
[77] Singh, K.; Jaggi, A.S.; Singh, N. Exploring the ameliorative poten-
tial of Punica granatum in dextran sulfate sodium induced ulcera-
tive colitis in mice. Phytother. Res., 2009, 23(11), 1565-1574.
The Role of Dietary Polyphenols in the Management of Inflammatory
[78] Rosillo, M.A.; Sanchez-Hidalgo, M.; Cardeno, A.; Alarcon De La
Lastra, C. Protective effect of ellagic acid, a natural polyphenolic
compound, in a murine model of Crohn's disease. Biochem. Phar-
macol., 2011, 82(7), 737-745.
[79] Ogawa, Y.; Kanatsu, K.; Iino, T.; Kato, S.; Jeong, Y.I.; Shibata, N.
Takada, K.; Takeuchi, K. Protection against dextran sulfate so-
dium-induced colitis by microspheres of ellagic acid in rats. Life
Sci., 2002, 71(7), 827-39.
[80] Surh, Y.J.; Chun, K.S.; Cha, H.H.; Han, S.S.; Keum, Y.S.; Park,
K.K.; Lee, S.S. Molecular mechanisms underlying chemopreven-
tive activities of anti-inflammatory phytochemicals: Down-
regulation of COX-2 and iNOS through suppression of NF-kappa B
activation. Mutat. Res., 2001, 481, 243-68.
[81] Umesalma, S.; Sudhandiran, G. Differential inhibitory effects of
the polyphenol ellagic acid on inflammatory mediators NFκB,
iNOS, COX-2, TNF-a, and IL-6 in 1,2-dimethylhydrazine-induced
rat colon carcinogenesis. Basic Clin. Pharmacol. Toxicol., 2010,
107(2), 650-655.
[82] Cerdá, B.; Periago, P.; Espín, J.C.; Tomás-Barberán, F.A. Identifi-
cation of urolithin a as a metabolite produced by human colon mi-
croflora from ellagic acid and related compounds. J. Agric. Food
Chem., 2005, 53, 5571-6.
[83] Larrosa, M.; González-Sarrías, A.; Yáñez-Gascón, M.J.; Selma,
M.V.; Azorín-Ortuño, M.; Toti, S.; Tomás-Barberán, F.; Dolara, P.;
Espín, J.C. Anti-inflammatory properties of a pomegranate extract
and its metabolite urolithin-A in a colitis rat model and the effect of
colon inflammation on phenolic metabolism. J. Nutr. Biochem.,
2010, 21(8), 717-725.
[84] González-Sarrías, A.; Espín, J.C.; Tomás-Barberán, F.A.; García-
Conesa, M.T. Gene expression, cell cycle arrest and MAPK signal-
ling regulation in Caco-2 cells exposed to acid ellagic and its me-
tabolites, urolithins. Mol .Nutr. Food Res., 2009, 53, 686-98.
[85] Fooks, L.J.; Gibson, G.R. Probiotics as modulators of the gut flora.
Br. J. Nutr., 2002, 88, S39-S49.
[86] Neyrinck, A.M.; Van Hée, V.F.; Bindels, L.B.; De Backer, F.;
Cani, P.D.; Delzenne, N.M. Polyphenol-rich extract of pomegran-
ate peel alleviates tissue inflammation and hypercholesterolaemia
in high-fat diet-induced obese mice: potential implication of the gut
microbiota. Br. J. Nutr., 2013, 109(5), 802-809.
[87] Sánchez de Medina, F.; Vera, B.; Galvez, J.; Zarzuelo, A. Efect of
quercitrin on the early stages of hapten induced colonic inflamma-
tion in the rat. Life Sci., 2002, 70, 3097-3108.
[88] Butkovic, V.; Klasinc, L.; Bors, W. Kinetic study of flavonoid
reactions with stable radicals. J. Agric. Food. Chem., 2004, 52,
2816-2820.
[89] Kim, H.; Kong, H.; Choi, B.; Yang, Y.; Kim, Y.; Lim, M.J.; Neck-
ers, L.; Jung, Y. Metabolic and pharmacological properties of rutin,
a dietary quercetin glycoside, for treatment of inflammatory bowel
disease. Pharm. Res., 2005, 22(9), 1499-1509.
[90] Comalada, M.; Camuesco, D.; Sierra, S.; Ballester, I.; Xaus, J.;
Gálvez , J.; Zarzuelo, A. In vivo quercitrin anti-inflammatory effect
involves release of quercetin, which inhibits inflammation through
down-regulation of the NF-kappa B pathway. Eur. J. Immunol.,
2005, 35(2), 584-592.
[91] Kwon, K.H.; Murakami, A.; Tanaka, T.; Ohigashi, H. Dietary rutin,
but not its aglycone quercetin, ameliorates dextran sulfate sodium-
induced experimental colitis in mice: Attenuation of pro-
inflammatory gene expression. Biochem. Pharmacol., 2005, 69(3),
395-406.
[92] Sánchez de Medina, F.; Galvez, J.; Romero, J.A.; Zarzuelo, A.
Effect of quercitrin on acute and chronic experimental colitis in the
rat. J. Pharmacol. Exp. Ther., 1996, 278(2), 771-779.
[93] Sotnikova, R.; Nosalova, V.; Navarova, J. Efficacy of quercetin
derivatives in prevention of ulcerative colitis in rats. Interdiscip.
Toxicol., 2013, 6(1), 9-12.
[94] Cavalcanti, E.; Vadrucci, E.; Delvecchio, F.R,; Addabbo, F.; Bet-
tini,S.; Liou, R.; Monsurrò, V.; Huang, A.Y.; Pizarro, T.T.;
Santino, A.; Chieppa, M. Administration of reconstituted polyphe-
nol oil bodies efficiently suppresses dendritic cell inflammatory
pathways and acute intestinal inflammation. PLoS One, 2014, 9(2),
e88898.
[95] Guazelli, C.F.; Fattori, V.; Colombo, B.B.; Georgetti, S.R.;
Vicentini, F.T.; Casagrande, R.; Baracat, M.M.; Verri, W.A. Jr.
Quercetin-loaded microcapsules ameliorate experimental colitis in
mice by anti-inflammatory and antioxidant mechanisms. J. Nat.
Prod., 2013, 76(2), 200-208.
Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 3 209
[96] Kamishikiryo, J.; Matsumura, R.; Takamori, T.; Sugihara, N. Effect
of quercetin on the transport of N-acetyl 5-aminosalicylic acid. J.
Pharm. Pharmacol., 2013, 65(7), 1037-1043.
[97] Camuesco, D.; Comalada, M.; Rodriguez-Cabezas, M.E.; Nieto,
A.; Lorente, M.D.; Concha, A.; Zarzuelo, A.; Gálvez, J. The intes-
tinal anti inflammatory effect of quercitrin is associated with an in-
hibition in iNOS expression. Br. J. Pharmacol., 2004, 143(7), 908-
918.
[98] Yadav, M.; Jain, S.; Bhardwaj, A.; Nagpal, R.; Puniya, M.; Tomar,
R.; Singh, V.; Parkash, O.; Prasad, G.B.; Marotta, F.; Yadav, H.
Biological and medicinal properties of grapes and their bioactive
constituents: An update. J. Med. Food., 2009, 12(3), 473-484.
[99] Singh, U.P.; Singh, N.P.; Singh, B.; Hofseth, L.J.; Price, R.L.;
Nagarkatti, M.; Nagarkatti, P.S. Resveratrol (trans-3,5,4′-
trihydroxystilbene) induces silent mating type information regula-
tion-1 and down-regulates nuclear transcription factor-kB activa-
tion to abrogate dextran sulfate sodium-induced colitis. J. Pharma-
col. Exp. Ther., 2010, 332(3), 829-839.
[100] Youn, J.; Lee, J.S.; Na, H.K.; Kundu, J.K.; Surh, Y.J. Resveratrol
and piceatannol inhibit iNOS expression and NF-kB activation in
dextran sulfate sodium-induced mouse colitis. Nutr. Cancer, 2009,
61(6), 847-854.
[101] Feng, Y.H.; Zhou, W.L.; Wu, Q.L.; Li, X.Y.; Zhao, W.M.; Zou,
J.P. Low dose resveratrol enhanced immune response of mice.
Acta. Pharmacol. Sin., 2002, 23(10), 893-897.
[102] Sánchez-Fidalgo, S.; Cárdeno, A.; Villegas, I.; Talero, E.; de la
Lastra, C.A. Dietary supplementation of resveratrol attenuates
chronic colonic inflammation in mice. Eur. J. Pharmacol., 2010,
633(1-3), 78-84.
[103] Yao, J.; Wang, J.Y.; Liu, L.; Li, Y.X.; Xun, A.Y.; Zeng, W.S.; Jia,
C.H.; Wei, X.X.; Feng, J.L.; Zhao, L.; Wang, L.S. Anti-oxidant ef-
fects of resveratrol on mice with DSS- induced ulcerative colitis.
Arch. Med. Res., 2010, 41(4), 288-294.
[104] Panaro, M.A.; Carofiglio V.; Acquafredda A.; Cavallo P.; Cianci-
ulli A. Anti-inflammatory effects of resveratrol occur via inhibition
of lipopolysaccharide-induced NFκB activation in Caco-2 and
SW480 human colon cancer cells. Br. J. Nutr., 2012, 108(9), 1623-
1632.
[105] Kim, Y.H. Piceatannol, a stilbene present in grapes, attenuates
dextran sulfate sodium-induced colitis. Int. Immunopharmacol.,
2008, 8, 1695-1702.
[106] Renaud, J.; Martinoli, M.G. Resveratrol as a protective molecule
for neuroinflammation: A review of mechanisms. Curr. Pharm.
Biotechnol., 2014, in press.
[107] Abdallah, D.M.; Ismael, N.R. Resveratrol abrogates adhesion
molecules and protects against TNBS-induced ulcerative colitis in
rats. Can. J. Physiol. Pharmacol., 2011, 89, 811-818.
[108] Park, H.J.; Jeong, S.K.; Kim, S.R.; Bae, S.K.; Kim, W.S.; Jin, S.D.;
Koo, T.H.; Jang, H.O.; Yun, I.; Kim, K.W.; Bae, M.K. Resveratrol
inhibits Porphyromonas gingivalis lipopoly-saccharide-induced
endothelial adhesion molecule expression by suppressing NF-
kappaB activation. Arch. Pharm. Res., 2009, 32(4), 583-591.
[109] Deng, Y.H.; Alex, D.; Huang, H.Q.; Wang, N.; Yu, N.; Wang,
Y.T.; Leung, G.P.; Lee, S.M. Inhibition of TNF-alpha-mediated
endothelial cell- monocyte cell adhesion and adhesion molecules
expression by the resveratrol derivative, trans-3,5,4’-
trimethoxystilbene. Phytother. Res., 2010, 25(3), 451-457.
[110] Larrosa, M.; Yañéz-Gascón, M.J.; Selma, M.V.; González-Sarrías,
A.; Toti S.; Cerón, J.J.; Tomás-Barberán, F.; Dolara, P.; Espín, J.C.
Effect of a low dose of dietary resveratrol on colon microbiota, in-
flammation and tissue damage in a DSS-induced colitis rat model.
J. Agric. Food Chem., 2009, 57(6), 2211-20.
[111] Cui, X.; Jin, Y.; Hofseth, AB.; Pena, E.; Habiger, J.; Chumanevich,
A.; Poudyal, D.; Nagarkatti, M.; Nagarkatti, P.S.; Singh, U.P.; Hof-
seth, L.J. Resveratrol suppresses colitis and colon cancer associated
with colitis. Cancer Prev. Res., 2010, 3(4), 549-559.
[112] Ergün, O.; Ergün G.; Öktem G.; Selvi N.; Doğan H.; unçyürek
M.T.; Saydam G.; Erdener, A. Enteral resveratrol supplementation
attenuates intestinal epithelial inducible nitric oxide synthase activ-
ity and mucosal damage in experimental necrotizing enterocolitis.
J. Pediatr. Surg., 2007, 42, 1687-1694.
[113] Mudter, J.; Weigmann, B.; Bartsch, B.; Kiesslich, R.; Strand, D.;
Galle, P.R.; Lehr, H.A.; Schmidt, J.; Neurath, M.F. Activation pat-
tern of signal transducers and activators of transcription (STAT)
factors in inflammatory bowel diseases. Am. J. Gastroenterol.,
2005, 100(1), 64-72.
 210 Current Pharmaceutical Biotechnology, 2015, Vol. 16, No. 3
[114] Takaki, K.; Mitsuyama, K.; Tsuruta, O.; Toyonaga, A.; Sata, M.
Attenuation of experimental colonic injury by thiazolidinedione
agents. Inflamm. Res., 2006, 55, 10-15.
[115] Ovesná, Z.; Kozics, K.; Bader, Y.; Saiko, P.; Handle, N.; Erker, T,;
Szekeres, T. Antioxidant activity of resveratrol, piceatannol and
3,3',4,4',5,5'-hexahydroxy-trans-stilbene in three leukemia cell
lines. Oncol. Rep., 2006, 16(3), 617-24.
[116] Larrosa, M.; Tomé-Carneiro, J.; Yáñez-Gascón, M.J.; Alcántara,
D.; Selma, M.V.; Beltrán, D.; García-Conesa, M.T.; Urbán, C.; Lu-
cas, R.; Tomás-Barberán, F.; Morales, J.C.; Espín, J.C. Preventive
oral treatment with resveratrol pro-prodrugs drastically reduce
Received: April 25, 2014 Revised: August 20, 2014 Accepted: November 10, 2014
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Farzaei et al.
colon inflammation in rodents. J. Med. Chem., 2010, 53(20), 7365-
76.
[117] Bahramsoltani, R.; Farzaei, M.H,; Rahimi, R. Medicinal plants and
their natural components as future drugs for the treatment of burn
wounds: an integrative review. Arch. Dermatol. Res., 2014, DOI:
10.1007/s00403-014-1474-6.
[118] Martín, A.R.; Villegas, I.; La Casa, C.; de la Lastra, C.A. Resvera-
trol, a polyphenol found in grapes, suppresses oxidative damage
and stimulates apoptosis during early colonic inflammation in rats.
Biochem. Pharmacol., 2004, 67(7), 1399-1410.