Van-Long Truong, Woo-Sik Jeong*

Food and Bio-industry Research Institute, School of Food Science & Biotechnology, College of Agriculture and Life Sciences,

Kyungpook National University, Daegu 41566, Korea

Keywords:

Antioxidant

Anti-inflammation

Epithelial barrier function

In flammatory bowel diseases

Gut microbiota

Tea polyphenols

A B S T R A C T

Polyphenols, including phenolic acids, flavonoids, and procyanidins, are abundant in food and beverage derived from plants.Tea (Camellia sinensis) is particularly rich in polyphenols (e.g., catechins, thea flavins,thearubigins, gallic acid, and flavonols), which are thought to contribute to the health benefits of tea.High intake of tea polyphenols has been described to prevent and/or attenuate a variety of chronic pathological conditions like cardiovascular diseases, neurodegenerative diseases, diabetes, and cancer.This review focuses on established antioxidant and anti-inflammatory properties of tea polyphenols and underlying mechanisms of their involvement in inflammatory bowel diseases (IBD).Tea polyphenols act as efficient antioxidants by inducing an endogenous antioxidant defense system and maintaining intracellular redox homeostasis.Tea polyphenols also regulate signaling pathways such as nuclear factor-κB, activator protein 1, signal transducer and activator of transcriptions, and nuclear factor E2-related factor 2, which are associated with IBD development.Accumulating pieces of evidence have indicated that tea polyphenols enhance epithelial barrier function and improve gut microbial dysbiosis, contributing to the management of inflammatory colitis.Therefore, this study suggests that supplementation of tea polyphenols could prevent inflammatory conditions and improve the outcome of patients with IBD.

1.Introduction

Primary metabolites (e.g., carbohydrates, amino acids, and fatty acids) that are ubiquitously present in animal and plant cells are essential to cell structure and basic metabolism.These compounds are also involved in the synthesis of a wide range of other molecules called secondary metabolites, which are accumulated at low concentrations and vary among different species.In plants,secondary metabolites have roles in ecological interactions and protection from environmental stressors (e.g., ultraviolet radiation,herbivores, chemical toxins, and fungal and bacterial infections) [1].Polyphenols belong to one of the most important groups of secondary plant metabolites abundantly found in a variety of fruits, vegetables,tea, essential oils, and their derived foods and beverages.The term phenolic indicates compounds possessing an aromatic bearing one hydroxyl group, while polyphenols have one or more aromatic rings carrying more than one hydroxyl group.Polyphenols can be classified into several subgroups according to structural features.However,these agents can be divided in general into three major subgroups(phenolic acids, flavonoids, and nonflavonoids).Phenolic acids are the derivatives of benzoic and cinnamic acids with one or more hydroxyl groups at the benzene ring.Flavonoids, sharing a common C6–C3–C6 skeleton structure, possess two benzene rings (A and B rings) interconnected by an oxygenated three carbons heterocycle (C ring).Flavonoids are classified into 6 subclasses, including flavones,flavonols, flavanols, flavanones, isoflavones, and procyanidins [2].Accumulating pieces of evidence strongly support that dietary polyphenols exhibit human health benefits as well as diseasepreventive effects [3,4].

Tea (Camellia sinensis), preferably made from young leaves and leaf bubs, has been consumed in China for thousands of years and is currently the second most widely consumed beverage after water.Tea can be categorized in general into three main types (green,oolong, and black teas), which differ in production methods and chemical compositions [5,6].Tea leaves are rich in polyphenols,mainly phenolic acids and hydrolysable tannins, flavan-3-ols and their oligomers, flavonols and their glycosides, theaflavins, and thearubigins [7].The majority of tea polyphenols are the monomeric flavan-3-ols, also known as catechins, which account for about 30%of the dry weight of tea leaves [5,8,9].The common catechins present in the natural products of tea include (?)-epicatechin (EC, 6.4% of the total catechin content), (?)-epicatechin-3-gallate (ECG, 13.6%),(?)-epigallocatechin (EGC, 19%), and (?)-epigallocatechin-3-gallate(EGCG, 59%).Catechin and gallocatechin (GC) are found in tea leaves ofC.sinensisat small concentrations [10-12].EGCG is the major chemical compound in the fresh bud and the first two leaves ofC.sinensisaccounting for approximately 10% of dry weight,followed by ECG (2.8%), EGC (1.7%), and EC (0.8%) [7].However,polyphenol content in tea leaves, especially with the catechin component, can be changed by the fermentation and heating processes during the tea manufacturing process.

Green tea contains significantly higher amounts of polyphenols compared with oolong or black tea because the processing of tea leaves following harvest is carried out by different methods.For green tea, fresh tea leaves are quickly heated, either in a pan or with hot steaming, and dried to inactivate polyphenol oxidase and native micro flora, which catalyze the aerobic oxidation of tea catechins.This process prevents the oxidation of catechins, maintains the polyphenols in their monomeric forms, and prolongs the shelf life of tea.Moreover, during the black tea fermentation process, auto-oxidation and/or enzymatic oxidation by polyphenol oxidase convert catechins into dimeric thea flavins (3%–5% of black tea solid extract) as well as polymeric thearubigins (about 20% of the total solids of black tea),which are responsible for the characteristic color and taste of black tea [7,13].ECG and EGCG are regarded to be major catechins present in black tea [14,15].Oolong tea, a semifermented product, possesses a mixture of monomeric catechins and high-molecular-weight thea flavins compared with green tea having only monomeric flavan-3-ols [16].Moreover, all 3 types of tea contain EC, ECG, EGC, and EGCG, in which EGCG is the most predominant catechin constituent in the leaves of green, oolong, and black teas [17,18].On the other hand, procyanidins or condensed tannins, oligomers and polymers of flavan-3-ols units are found and identified in fresh tea leaves ofC.sinensisand oolong tea.However, highly polymerized flavan-3-ols are not stable and get easily oxidized during processing.Thus, they are less detected in fully fermented or black tea [7].

Tea also contains small amounts of flavonols, mainly myricetin,quercetin, kaempferol, and their glycosides.The content of flavonols and their glycosides is about 0.01–2.00 mg/g of the dry weight of tea leaves.Flavonols are structurally more stable than flavan-3-ols and less affected by processing.Thus, these flavonol compounds become important polyphenol components because flavan-3-ols can be oxidized or degraded during the fermentation process of the tea leaves.Consequently, the flavonol content present in green tea is equivalent to that in black tea [7,19].In addition, many phenolic acids and their hydrolysable tannins (e.g., gallic, chlorogenic, caffeic,quinic, galloylquninic, and caffeoylquinic acids) are found in tea leaves or tea beverages [20].

2.Biological implications of tea polyphenols

Inflammation is a part of the defense mechanism of the host against harmful stimuli (e.g., pathogens, damaged cells, and irritants).However, the failure to maintain immune homeostasis leads to chronic inflammation that causes tissue damage [21].In addition,systemic or chronic inflammation is associated with the initiation and progression of various diseases such as inflammatory bowel diseases (IBD), rheumatoid arthritis, psoriasis, and cancer.Along with the inflammatory stimuli, reactive oxygen/nitrogen species(ROS/RNS) also trigger an inflammatory response by modifying redox-sensitive signaling pathways in the inflammatory or immune cells.Consequently, chronic inflammation results in ROS/RNS overproduction that overwhelms cellular antioxidant defense systems.Thus, persistent inflammation coupled with oxidative/nitrosative stress can cause progressive damages and aggravate pathological conditions [22,23].

Recent studies demonstrated that polyphenols possess antioxidant and anti-inflammatory properties, which bring about health benefits and contribute to managing inflammation-related diseases [24].Furthermore, polyphenolic compounds are absorbed, metabolized,and delivered to different tissues or organs where various effects are exerted.The unabsorbed polyphenols can interact with receptors on the enterocytes and immune cell surfaces and thus inhibit proinflammatory signaling.The unabsorbed polyphenols can be metabolized by the gut microbiota.Both unabsorbed polyphenols and their metabolites may exert positive effects for local inflammation or act as prebiotics to promote the growth of beneficial microbes,leading to enhanced gut health [3,25].Dietary tea polyphenols have been demonstrated to reduce inflammation by directly acting as antioxidant, inducing cytoprotective systems, and inhibiting proinflammatory signaling transduction [8,26,27].A better understanding of the antioxidant and anti-inflammatory roles of tea polyphenols is important to develop effective dietary interventions for inflammatory disease prevention strategies.This review provides recent pieces of evidence for the roles of tea polyphenols in the prevention and treatment of IBD with a special focus on their antioxidant and antiinflammatory properties as well as underlying molecular mechanisms(Fig.1).

3.IBD pathophysiology

IBD has gradually become more common worldwide with the rise of its incidence and prevalence in Asia countries.IBD,composed of Crohn’s and ulcerative colitis, is a multifactorial disorder characterized by diarrhea, rectal bleeding and abdominal pain.In addition, IBD is a chronic-remitting inflammation of the gastrointestinal tract that requires long-term treatment and thus profoundly affects the quality of life.Consequently, IBD is closely associated with colorectal cancer.Moreover, anti-inflammatory medications effectively reduce the risk of inflammation-associated colorectal cancer [28].

The IBD pathogenesis is believed to be the result of a wide range of risk factors (e.g.immune dysregulation, genetic predisposition,abnormal gut microbiota, and other environmental factors), although the etiology of IBD remains unknown.The increased adoption of unhealthy lifestyles (e.g.smoking, lack of exercise, overweight and obesity, red and processed meat consumption, excessive alcohol consumption, and pollution) also contributes to IBD development [29,30].

Dysregulation of the innate and adaptive immune system is closely associated with the abnormal response of the intestinal inflammation in IBD patients.The immunity system acts as a host defense mechanism against pathogens and is mediated by diverse types of immune and non-immune cells.Loss of immune tolerance results in the overproduction of proinflammatory mediators and cytokines(e.g., inducible nitric oxide synthase (iNOS), cyclooxygenase 2(COX-2), interleukine (IL)-1β and tumor necrosis (TNF)-α) through the activation of several inflammation-related signaling pathways.These factors disturb the homeostasis of the gastrointestinal tract as a consequence of intestinal inflammation, disruption of epithelial barrier integrity and imbalance of gut microbiota [31].

Oxidative/nitrosative stress is also associated with inflammation,thus promoting the progression of metabolic and chronic diseases.The inflammatory response is mediated by the interaction of proteins involved in signal transduction and gene expression.In addition to proinflammatory mediators, cytokines, and pathogenassociated molecular patterns (e.g.endotoxin), ROS/RNS regulates the synthesis of proinflammatory factors through the activation of mitogen-activated protein kinases and transcription factors such as nuclear factor-kappa B (NF-κB) and activator protein 1 (AP-1),signal transducer and activator of transcriptions (STATs), and nuclear factor E2-related factor 2 (Nrf2), which regulate the expression of a wide range of genes (including genes trigger inflammation and genes manage inflammatory response).During oxidative/nitrosative stress, ROS/RNS stimulates the release of damageassociated molecular patterns, which trigger signaling receptors, such as toll-like receptors (TLRs) in immune cells [32].Simultaneously,NF-κB-, AP-1-, and STATs-mediated target genes such as iNOS, COX-2, and NADPH oxidase lead to enhanced ROS/RNS formation [33].In addition, increased ROS level is believed to be an essential event for nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain containing 3 (NLRP3)inflammasome activation, a regulatory node of oxidative stress and inflammation [34,35].The inflammasome activation further leads to the maturation and excretion of IL-1β that in turn activates TLR1-mediated inflammatory signaling.TLRs, conserved components of the immune system, can be activated by inflammatory cytokines or pathogen-associated molecules, leading to the stimulation of various inflammation-associated intracellular signaling pathways,like NF-κB.The induction of a series of pathways finally results in the expression of pro-inflammatory factors, including iNOS,COX-2, IL-1β, IL-6, and TNF-α, which cause local or systemic inflammation.Oxidative/nitrosative stress is also one of the most crucial factors contributing to the IBD pathophysiology via several mechanisms.Increased levels of ROS/RNS cause oxidative damage to the gastrointestinal muscosa, resulting in increased pathogen invasion and inflammatory response exaggaration.Furthermore,oxidative/nitrosative stress is also associated with changes in the gut microbial community [31].

The intestinal epithelial layer plays dual functionality, which absorbs essential nutrients and prevents invasion of harmful contents.Moreover, the mucus layer covering the entire intestinal epithelium acts as the first line of physical barrier against intestinal bacteria and toxicants.The mucus layer is the residence of the goblet cells,enterocytes, and Paneth cells, which produce mucin and antimicrobial peptides.However, the defective epithelial barrier is often observed in IBD patients, leading to increased intestinal permeability and reduce release of antibacterial molecules [36].

Recent studies have shown pieces of evidence favoring the association between gut microbiota alterations and IBD.The composition of intestinal flora is affected by various factors,especially diet and exercise.Altered gut microbiota downregulates the expression of tight junction proteins and decreases gut barrier integrity, followed by augmented penetration of microbes and/or microbe molecular patterns, and consequently causes overactivated innate and adaptive immunities and inflammation.In addition,proinflammatory and pro-oxidant profiles generated during inflammatory conditions of the gastrointestinal tract also cause alterations in gut microbiota, contributing to adverse diseases outcomes [37].

4.Tea polyphenols and IBD

Tea polyphenols have been reported to exert antioxidant and anti-inflammatory properties that contribute to IBD management.Tea polyphenols diminish oxidative/nitrosative stress, inflammation,and cell injury through differential regulation of gene expression while enhancing cytoprotective defense.The beneficial effects of tea polyphenols on IBD are reviewed in the following subsections (Table 1).

Table 1Representative studies on therapeutic effects of tea polyphenols in models of IBD.

Table 1 (Continued)

4.1 Effect of tea polyphenols on inflammatory response in IBD

In flammation plays an essential role in host defense mechanisms against pathogen invasion, injured cells, or other environmental hazards.However, uncontrolled and/or chronic inflammation can provoke the development of a wide range of diseases, including IBD.In the IBD initial stage, innate immune cells consist of phagocytic cells (e.g.macrophages, dendritic cells, and intestinal epithelial cells),which cause a nonspecific and rapid inflammatory response against intestinal pathogens.In addition, these cells also enhance the secretion of cytokines and chemokines that trigger the adaptive immune system including T and B cell-mediated responses.Activation of the adaptive immune system, particularly T cells, can differentiate into various effector T cells such as T-helper (Th)1, Th2, and Th17.The aggressive behavior of activated T cell subsets results in the overproduction of proinflammatory cytokines and chemokines (e.g.interferon-γ and TNF-α by Th1 cells; IL-4, IL-5, IL-13, and IL-23 by Th2 cells; IL-6, IL-17, and IL-22 by Th17 cells), which result in the onset of chronic intestinal inflammation.Regulatory T cells (Tregs)are a subset of T cells that are crucial for maintaining immune homeostasis through the release of anti-inflammatory as well as tissues repair cytokines, IL-10 and transforming growth factor beta(TGF-β).Increased levels of T-helper cells and decreased level of Tregs are observed in IBD [31,38,39].

Several mouse models for IBD have shown that the administration of tea polyphenols is an effective strategy for preventing and/or treating intestinal inflammation and injury.Acute and chronic colitis can be induced by intrarectal administration of dinitrobenzene sulfonic acid (DNBS) and trinitrobenzene sulfonic acid (TNBS), or by the addition of dextran sulfate sodium (DSS) in drinking water,or by target gene manipulations that cause defects in the epithelial integrity, innate immunity or adaptive immunity [1,40].However, tea polyphenols reduce mortality rates, disease activity indices (e.g., body weight loss, diarrhea, and bloody stools), and colonic inflammation(e.g., myeloperoxidase activity, neutrophil in filtration, and cytokines and chemokines production) in the DSS- or TNBS-induced colitis models [41-43,44], and the IL-2 deficient [45], IL-10 deficient [43]or multidrug-resistance transporter 1a (Mdr1a) deficient [46]spontaneous colitis models.The oral administration of 6 types of tea extracts, including green, white, yellow, oolong, black, and dark teas(0.05% (m/V) extract solutions), for 14 days ameliorated DSS-induced colon injury, colon inflammation, pro-oxidant enzyme activity and suppressed DSS-induced NF-κB activation as well as the production of proinflammatory cytokines [47].Green tea polyphenol, as well as an individual catechin EGCG, attenuated the severity of colitis equivalent to sulfasalazine, a positive control, by using the ulcerative colitis model (DSS-induced mouse colitis) and mimicking Crohn’s diseases (IL-10-deficient mice).In this study, green tea polyphenols and EGCG markedly reduced inflammatory markers (e.g.IL-6, TNF-α,and serum amyoid A (SAA)) but significantly restored antioxidant status in colitic animals [43].The green tea polyphenol extract was found to attenuate DNBS-induced colonic and extracolonic signs of diseases, colon macropathology and micropathology, and inflammation [48].Mice pre-fed 0.2% and 1% black tea extract in diet experienced less aggressive body weight loss and colon shortening than the DSS-treated mice.Moreover, the blockade of NF-κB and apoptosis could contribute to attenuating acute colon inflammation and injury [49].In another study, dietary supplementation of green tea polyphenols attenuated colonic inflammation in theMdr1a?/?spontaneous colitis model.Consequently, transcriptome and proteome analyses showed that green tea polyphenols exerted anti-inflammatory property and inhibition of the innate immune response through suppression of STAT1 or NF-κB (via TLR2 and CD14) pathways,or activation of peroxisome proliferator-activated receptor (PPAR)αand PPARγ-related pathways.Furthermore, green tea polyphenols also upregulated the gene expression of phase-II detoxifying and antioxidant enzymes possibly through inducing transcription factors such as Nrf2, retinoid X receptor, or PPARα.The dietary intake of green tea polyphenol reduced the expression of genes involved in the fibrinogenesis pathway possibly by blocking the AP1 transcription factor [46].In the fecal microbiota transplantation study, the fecal microbiota from the green tea extract- and dark tea extract-treated donor mice attenuated colitis-related symptoms (e.g.body weight loss and colonic inflammation) and inhibited the TLR4/MyD88/NF-κB pathway.Additionally, fecal microbiota transplantation also inhibited DSS-induced NLRP3 inflammasome activation as evident from reduced levels of NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain(ASC), and caspase-1 [50].Furthermore, EGCG treatment regulates the balance of splenic Treg/Th17 ration, increases plasma levels of IL-10 and TGF-β1, and decreases colonic hypoxia-inducible factor 1α(HIF-1α) and STAT3 expression in the ulcerative colitis model [51].A clinical trial showed that administration of Polyphenon E (200 mg or 400 mg of total EGCG) twice daily for 56 days had therapeutic benefits for patients with mild to moderate ulcerative colitis and less side effects [52].

The activation of the cytoprotective system probably contributes to the therapeutic benefit of tea polyphenols in colitis in addition to the inhibition of NF-κB, AP1, and STAT transcription factors and leucocyte and T-cell infiltration.The induction of HO-1,which decreases oxidative stress and increases the formation of the antioxidant bilirubin as well as carbon monoxide, may also blunt IBD injury.The treatment of green tea polyphenol extract was found to upregulate the expression of HO-1 in the colons of DNBS-induced mice [48].Oral administration of EGCG had beneficial effects on acetic acid-induced colitis potentially via its antioxidant activity by decreasing levels of NO and lipid peroxidation as well as increasing superoxide dismutase and concurrently its antiinflammatory activity by inhibiting NF-κB activation as well as cytokine production [53].Dietary feeding of an EGCG derivative,peracetylated (?)-epigallocatechin-3-gallate, to mice-reinforced Nrf2/HO-1 pathway via post-translation (phosphorylation) and epigenetic(acetylation) modulations thereby suppresses DSS-induced NF-κB activation and colon inflammation [54].Another study indicated that in addition to anti-inflammatory property, antioxidant nature of gallic acid contributed to its therapeutic effects on colitis.Gallic acid was found to normalize colonic redox status and upregulate the expression of Nrf2 and its target, including UDP-glucuronosyltransferase (UDPGT) and NQO1, in DSS-induced colitis [55].Overall, tea polyphenols attenuate colon injury by blocking the expression of inflammatory proteins and inducing cytoprotective ones through the positive regulation of the signaling pathways (Fig.2).

Fig.2 Tea polyphenols inhibit colon inflammation by downregulating inflammatory genes and upregulating phase-II antioxidant/detoxifying genes.

4.2 Tea polyphenols and gut microbiota

The gastrointestinal tract is typically colonized with microbiota,which interacts with the host immune system to achieve a homeostasis of intestinal health.The microbial community contributes to producing short-chain fatty acids (SCFAs), providing energy, synthesizing specific vitamins, fermenting the indigestible polysaccharides, protecting intestinal mucosa, and suppressing pathologic microorganisms.Accumulating studies in recent years accentuated the role of gut microbiota and their metabolites in the host physiological processes (e.g.immune, metabolic, and nutritional homeostasis) [30].The failure to maintain homeostasis between the host and gut microbes may result in spontaneous colitis and increased sensitivity to colitis although intestinal inflammation may cause shifts in the intestinal micro flora [56].

The imbalance of the gut microbial community, referred to as gut dysbiosis, has been reported in IBD patients and contributes to the enhanced IBD development and colorectal cancer.Characteristic compositional alterations observed in patients with IBD include a decrease in bacterial diversity, with the expansion of pathogenic bacteria groups (such as Proteobacteria,Fusobacteriumspecies,andRuminococcus gnavus) combined with decreases in beneficial groups (such asFirmicutes,Bifidobacteriumspecies, and theFaecalibacteriumandRoseburiagenera), causing alteration of the metagenome and production of metabolites, namely SCFAs [57].Moreover, the beneficial effects of tea polyphenols on colitis may at least in part be mediated by improving gut dysbiosis.

Several studies have indicated that tea polyphenols possess the inhibitory ability to putative aggressive bacteria and prebioticslike effects to enhance the growth of protective bacteria, thereby improving gut dysbiosis [58].The administration of green tea extract in a mouse model of colitis prevented DSS-induced reduction in gut microbiota diversity as evident from ACE and Shannon indices and alteration in microbial composition [47].The abundance ofOscillibacterwas significantly elevated in DSS-induced colitis mice but was significantly decreased by treatment with six types of tea extracts, including green, white, yellow, oolong, black, and dark tea extracts.Moreover, green, black, and dark tea extracts were also found to reduce the abundance ofBacteroidesandBrachyspirain colitis mice.Bacteroidesare associated with gut inflammation and enriched in several animal models and patients with IBD [59],while theBrachyspiragenera are potential enteric pathogens that may cause colitis diarrhea and/or dysentery in animals [60].Mucispirillum,mucus-dwelling pathobionts, could attenuate intestinal barrier integrity by degrading host-derived mucin [61].Therefore, the reduction inMucispirillum, by the green and dark tea extracts may contribute to protective effect against DSS-induced loss of epithelial barrier function.Mucispirillumhas been reported to bloom during intestinal inflammation due to its adaption to the microoxic conditions and the high-redox environment of the mucus layer [62].Consequently,deficient neutrophil recruitment and NADPH oxidase activity in mutant mice promote the accumulation and intestinal invasion ofMucispirillum, and the outgrowth of specific pathobionts can trigger intestinal inflammation [63].Moreover,Helicobacter, which importantly contribute to the development of IBD and gastric diseases,was inhibited by green and dark tea extracts in colitis mice [47].The promoting effects of tea polyphenols on the growth of beneficial bacteria through their prebiotics-like activity were observed in colitis mice along with the inhibition of pathogenic bacteria.Oral administration of dark tea extract increased theBifidobacteriumlevel in DSS-induced colitis.Bifidobacteriumis believed to be probiotics, which enhance host health by positively modulating the immune system, reducing inflammation, and inhibiting pathogen growth.Furthermore, clinical trials suggested thatBifidobacteriumsupplementation may be a promising therapy for IBD treatment [64].In addition, SCFAs-producing bacteria such asFaecalibaculum,Odoribacter, Ruminococcaceae, and Lachnospiraceae, which exert health benefits and anti-inflammatory properties, were restored in colitis mice treated with different types of tea extracts.Consistently,the treatment of tea extracts also significantly improved fecal levels of SCFAs (e.g., acetic, propionic, and butyric acids) in colitis mice [47].SCFAs, the main products of gut micro flora, play important roles in maintaining colonic health as well as mitigating colitis via inhibiting signaling pathways (e.g.NF-κB)-mediated inflammation, providing energy for intestinal epithelial cells and upregulating expression of tight junction proteins, resulting in enhanced epithelial barrier integrity [59,65].Moreover, theaflavin and theaflavin-3'-gallate positively correlated withFaecalibaculumwhile thea flavin-3-gallate negatively correlated withOscillibacter, suggesting that polyphenolic components in teas, especially in black tea, exhibited potentially regulatory effects on gut microbiota dysbiosis [47].

Fecal microbial transplantation has been attracting much interest in recent years for IBD treatment.A study indicated that fecal microbiota from the green and dark tea extract-treated donor mice exhibited protective effects against DSS-induced colitis in mice by modulating microbiota composition.Fecal microbial transplantation from the green tea extract-treated donor group significantly restored the abundance ofAkkermansiaand reduced levels of potentially harmful bacteria such asB.uniformis,Desulfovibrio,Lachnoclostridium, andA.finegoldiiin colitis mice.Fecal microbial transplantation from the dark tea extract-treated donor group significantly increased abundances ofBifidobacterium,Ileibacterium,I.valens, andAllobaculumand normalized levels ofBacteroides,Lachnoclostridium, andA.finegoldiiin the DSS-induced mouse model of colitis.This study suggested that green and dark tea extracts modulated gut microbiome and thereby prevent DSS-induced microbiota dysbiosis in colitis mice [50].

The causality of gut microbiota and IBD remains unknown although several studies reported on the effects of tea administration on gut microbiota.In addition, a few studies have been conducted to evaluate the role of tea polyphenols as well as their compounds in improving gut microbial dysbiosis in colitis.Therefore, further studies, especially clinical trials, are required.

4.3 Effect of tea polyphenols on intestinal barrier integrity

The intestinal epithelial barrier that constituents a single-cell layer separating host components from the external environment plays an essential role in assisting host homeostasis.Gut barrier integrity is maintained by the tight junction proteins (e.g.claudins, Zona occludin-1(ZO-1), and occludins) that are important for epithelial barrier functions.Consequently, previous studies indicated the downregulated levels of the tight junction protein in IBD conditions resulting in increased gut permeability to bacteria, microbial components, and noxious metabolites leading to systemic inflammatory responses [66-68].Therefore, preventing gut permeability by enhancing barrier functions also importantly contributes to IBD management in addition to suppressing inflammation.

Several studies have reported that tea polyphenols may exert beneficial effects on IBD by improving epithelial barrier integrity.A study showed that oral administration of tea polyphenols to mice preserved ileal mucosal barrier and increased the expression of tight junction proteins ZO-1, claudin-1 and occludin, which were destroyed by theSalmonella typhimuriuminfection [69].Moreover,EC prevented TNFα-triggered Caco-2 monolayer permeabilization by the restoration and redistribution of ZO-1, implying that dietary EC may be a potential strategy to mitigate IBD progression [70].Similarly, several polyphenols, including EGCG, were found to exert a protective effect against indomethacin-induced epithelial barrier damage in Caco-2 monolayer through upregulating ZO-1 and occludin expressions [71].Another study indicated that EGCG completely prevented IFN-γ andStaphylococcusenterotoxin B-caused intestinal T84 barrier dysfunction but did not alleviate the barrier disruption evoked by IL-4 or enteropathogenicEscherichia coli[72,73].The pretreatment of black tea theaflavins also significantly induced the expression of AMP-activated protein kinase-mediated tight junction proteins (e.g.ZO-1, claudin-1 and occludin) and thus enhanced the intestinal barrier function in Caco-2 cell monolayer [74].Polyphenolsrich extracts from green, black, yellow, oolong, white, and dark teas inhibited DSS-induced decrease of ZO-1 and occludin, contributing to mitigating intestinal mucosal damage and barrier dysfunction as well as colitis induced by DSS [47].Fecal microbiota from the green tea extract and dark tea extract-treated donor mice recovered colonic barrier integrity in colitis mice by restoring the levels of tight junction protein ZO-1 and mucin 2 [50].

5.Conclusions

The consumption of tea polyphenols is believed to have health benefits for the prevention and/or treatment of chronic diseases.Tea polyphenols exert antioxidant and anti-inflammatory properties that importantly contribute to IBD mitigation.Current studies show that tea polyphenols are powerful antioxidants against free radicals and oxidants.Moreover, such antioxidant potential of tea polyphenols is also observedin vivostudies and several clinical trials.In addition, tea polyphenols also exert anti-inflammatory properties by regulating cellular signaling transductions (e.g., Nrf2, NF-κB,AP-1, and STATs).Along with the antioxidant and anti-inflammatory activities, enhanced epithelial barrier function as well as improved gut microbiota dysbiosis by tea polyphenols also contributes to IBD management.However, high doses of tea polyphenols may cause adverse effects.Therefore, future research on tea polyphenols should focus on finding the proper formulation of tea polyphenolsrich functional foods or nutraceuticals that prevent chronic diseases,especially IBD.

Declaration of competing interest

All authors declare no conflicts of interest.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No.NRF-2020R1F1A1073595 and 2021R1A2C2006745).