Hui M, Yozhong Hu, Bowei Zhng, Zeping Sho, Eugeni Rour,*, Shuo Wng,*

a Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China

b Centre for Nutrition and Food Sciences, Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, Brisbane, QLD 4072, Australia

Keywords:

Tea polyphenols

Gut microbiota

Metabolic syndrome

Metabolites

Gut organ/tissue axis

A B S T R A C T

The metabolic syndrome (MS) has become one of the main problems in public health.Tea polyphenols (TPs),the main bioactive components of tea, has been claimed to have the potential to regulate metabolism and effectively prevent or mitigate the MS.However, many studies into the effects of TPs on MS have provided conflicting findings and the underlying mechanism has been elusive.The predominant TPs in unfermentedand and fermented tea are catechins and oxidized polyphenols (theaflavins and thearubigins), both of which have low bioavailability and reach the colon where most gut microbes inhabit.Gut microbiota has been demonstrated to be tightly associated with host metabolism.The interactions between TPs and gut microbiota will lead to the alterations of gut microbiota composition and the production of metabolites including short chain fatty acids, bile acids, amino acids and TPs derived metabolites, accordingly exerting their biological effects both locally and systemically.This review highlighted the contribution of metabolites and specific gut bacteria in the process of TPs intervention on the MS and further discuss how TPs impact the MS via gut microbiota from the viewpoint of gut organ/tissue axis.

1.Introduction

The metabolic syndrome (MS) has been defined as the association of central (abdominal) obesity with at least two of the following factors: elevated triglycerides, reduced high-density lipoprotein (HDL)cholesterol, high blood pressure, and increased fasting blood glucose [1].The rapidly increased prevalence of MS, which predisposes individuals to diabetes, cardiovascular and liver diseases, has attracted great attention in many countries.Tea is one of the most widely consumed beverages worldwide.Based on the manufacturing process,tea can be classified as unfermented (green tea), semifermented(oolong tea), fermented (black tea), and post-fermented (dark tea),which are all harvest from the dried leaves ofCamellia sinensis[2].The predominant tea polyphenols (TPs) in unfermented tea are catechins, while in fermented tea, the catechins oxidized into dimers,known as theaflavins (TFs) and polymers known as thearubigins [3].A myriad of cell experiments, animal and human intervention studies have documented the beneficial effects of TPs on reducing inflammation, decreasing blood lipid and increasing insulin sensitivity or glucose tolerance in the MS [4,5].However, the underlying mechanisms are still unclear, limiting the application of TPs in the prevention or treatment of the MS.The systemic bioavailability of TPs is low because of their poor intestinal absorption [6].In contrast,in the gastrointestinal tract (GIT) TPs reach high concentrations with a 70% recovery of the ingested TPs [7].Chen et al.[8]investigated the tissue distribution of TPs administered intravenously and found that the intestine level of major TPs was much higher than those in the liver, lung and kidney.Besides, the highest intestinal level declined slowly with a half-lives (t1/2) of 173 min.Therefore, it’s anticipated that the main effects of TPs will take place in the GIT lumen.

The human gastrointestinal tract is the habitat for trillions of microorganisms encoding over three million genes.This microbiota tightly associated with the host metabolism, immunity and neuronal development plays an important role in maintaining body health[9,10].In particular, there is a strong link between gut microbiota dysbiosis and the development of obesity and the MS [11].The major mechanisms are: 1) disruption of intestinal barrier contributing to the inflammation and insulin resistance [12]; 2) malfunction of the energy homeostasis (and appetite) mechanisms associated with dysregulation of gut hormones [13]; and 3) dietary energy obtained through microbial fermentation [1].

Relevant to this review, the population profile of the gut microbiota has been strongly associated to the diet [9,14].Microbiota can be reshaped by diet intervention, and then potentially influence human health.Besides, the gut microbial metabolism of dietary components also lead to the production of metabolites that are either beneficial or detrimental for host metabolic homeostasis and immunity, such as short chain fatty acids (SCFAs), bile acid (BAs)or branched chain amino acids (BCAAs) [15].Thus, the role of diet in orchestrating the diet–microbiota–health crosstalk render sit a potent manageable target for the treatment of various diseases.In particular, the inclusion of TPs in the diet could interact with the gut microbiota [2,16].On the one hand, TPs modulate the composition and the function of gut microbiota.On the other hand, gut microbiota will degrade TPs to increase their bioavailability and change their activity.The complex metabolites and integration of their effects make it difficult to discern a precise mechanism.Thus, this review mainly concentrates on these metabolites and specific gut bacteria as well as their effects on the MS during TPs intervention.Furthermore,we discuss how TPs impact the MSviagut microbiota from the viewpoint of gut organ/tissue axis.Finally, future research orientation will also be provided.

2.Interaction between TPs and gut microbiota

The absorption of TPs through the intestinal wall is about 2%–20% depending on the structures of the TPs [17].Thus, most TPs will reach the large intestine undigested where they can influence microbial populations.The modulation of gut microbiota by TPs has been shown byin vitrofermentation, animal models and human studies.Sun et al.[18]investigated the effects of green tea, oolong tea and black tea on human intestinal microbiotain vitro.The results indicated these TPs could significantly increaseBifidobacteriumspp.,Lactobacillusspp.,andEnterococcusspp., while suppress the proliferation ofPrevotella,Bacteroides, andClostridium histolyticumgroups.Wang et al.[19]evaluated the changes of gut microbiome across time by long-term TPs intervention in female sprague-dawley rats.The results showed an increase in theBacteroidetesandOscillospirapopulations which have been linked to a lean phenotype in previous human and animal studies.Moreover, the modulatory effect of dark tea, such as Ganpu tea, has been observed to promote the growth of beneficial bacteria,in order to positively alter the composition of the gut microbiota [20].Recently the two-way interaction between epigallocatechin-3-gallate(EGCG) and human gut microbiotain vitrowas investigated.EGCG treatment stimulated the growth of beneficial bacteria, meanwhile, it was degraded into a series of metabolites [21].

While the literature studying the effect of TPs on gut microbiota is abundant using “in vitro” or animal models, research in humans has been limited.One study that assessed changes in the human intestinal microbiota of 10 volunteers drinking green tea instead of water for 10 days.The results concluded that green tea consumption acted as a prebiotic and improved the colon environment by increasing the proportion of theBifidobacteriumspecies [22].Yuan et al.[23]studied the modulatory effect of green tea liquid (GTL) on the intestinal and oral microbiome in healthy volunteers aged between 27 and 50 years.The result showed that GTL consumption could alter both oral and gut microbiome.However, no significant effect of green TPs on gut microbiota of healthy subjects was observed in a 12-week randomized clinical trial [24].The fecal microbiome was also not significantly affected in a randomized, placebo-controlled, doubleblinded trial in which a green tea polyphenols (GTP) supplement was taking for 12 months by healthy postmenopausal women [25].Given that the investigations concerning the modification of gut microbiota by TPs in human intervention trials are rare, additional long-term intervention studies are required to verify the beneficial effects and quantify the optimal dose range of TPs on human health and the relationship with gut microbiota.

On the other hand, TPs that reach the large intestine undigested will be modified by gut microbiota through ring-cleavage, reduction,hydrolysis, decarboxylation, demethylation, and dihydroxylation reactions.Phenylvalericacid (PVAs) and phenylvalerolactones(PVLs) are the main metabolites [26].Previous studies in humans reported that the bioavailability of the TPs flavan-3-ol was 39%.However, the bioavailability increased to 62% when considering the colonic metabolites [27,28].Interestingly, a large variation was observed in TPs bioavailability ranging from 100% in some volunteers to nil in others.This may be attributed to the different gut microbiota profiles between individuals.The metabolites of major TPs by the bioconversion of gut microbiota were well summarized and documented in previous reviews [26,29].In addition to the interindividual variability in the gut microbial community, the physiological status also affects the absorption and metabolism of TPs.Chen and co-workers [30]compared 10 metabolites of catechins in normal rats and obese rats, showing that plasma and fecal concentrations of 4-hydroxyphenylacetic acid were significantly lower in the obese compared to the normal groups.In contrast, the levels of 4-hydroxyphenylpropionic acid in plasma and feces were increased when obese compared to normal individuals.

3.Impact of dietary TPs on MS through gut microbiota

TPs improve the MS through gut microbiota in a multi-element and multi-target manner.In addition to trigger changes on gut microbiota, dietary TPs seem to alter metabolites which are the key communicators between the host and gut microbiota [31,32].These metabolites such as SCFAs, BAs and amino acids (AAs) along with the modifications of gut microbiota have the capacity to affect energy metabolism and the development of the MS [15](Fig.1).Moreover, TPs derived-microbial metabolites may also be effective against the MS.

Fig.1 Interactions between TPs and gut microbiota improve the MS in a multi-element and multi-target manner.Intricate reactions occur in the intestine where TPs and gut microbiota interact with each other.Both the changes in the composition of gut microbiota and the metabolites produced following exposure to TPs exert their biological effects locally and systemically, contributing to the improvement of MS.Vertically upward red arrows represent increase or activation effects; vertically downward blue arrows represent decrease or inhibition effects; the protein or organ which solid arrows point to has been reported in the studies about the regulation effects of TPs on the MS.The protein or organ which dotted arrows point to has not been reported in these studies.

3.1 Multifunctional elements during TPs intervention

3.1.1 Remodeling gut microbiota

The signatures of gut microbiota for the MS includes a lower bacterial diversity, a remarkably increased ratio of Firmicutes to Bacteroidetes (F/B) at phylum level, as well as specific changes at the lower taxonomic level, such as an expansion ofProteobacteriaand reduced abundance ofAkkermansia[33].This gut microbiota dysbiosis could be reversed by TPs intervention in varying degrees.The study of the modulatory effect of green tea, oolong tea and black tea on obese mice revealed that tea infusion increased the diversity and quantitative composition of gut microbiota.However, the increased ratio of F/B was not restored [34].In contrast, dietary green tea and black tea polyphenols reduced the F/B ratio in another study [35].Besides, consumption of post-fermented Fuzhuan brick tea (FBT)significantly reduced the ratio of F/B in HF feeding mice [36].The apparent contradictory results might be explained by differences in experiment design including types of tea and ways of administration.The detailed experimental design and main outcomes of the most relevant publications on the matter in recent 5 years have been summarized in Table 1.

Table 1The modulatory effect of TPs on gut microbiota addressing metabolic diseases.

Table 1 (Continued)

Several conundrums need to be considered when investigating TPs activity.One important aspect relates to dosage.The study by Wang et al.[37]suggested that only a 0.2% TPs (but not 0.05% or 0.8%) supplementation resulted in significantly higher levels of lactic acid bacteria and increased diversity.A previous study investigated the correlation between intestinal redox state and gut microbiota after TPs intervention on high-fat diet (HFD) fed mice [38].The results showed that a low dosage of TPs had the lowest intestinal oxidative stress and steady gut microbiota.Another important aspect concerned is the causal relationship between the variation of gut microbiota by TPs and the improvement of MS.One study on fecal transplants observed that changes on gut microbiota mediated the anti-obesity effect of Pu-erh tea extract.In particular, feces from donor mice treated with ripened Pu-erh tea extract significantly ameliorated the MS in recipient mice [39].These studies further demonstrated the importance of gut microbiota in the regulation of MS mediated by TPs.Liu et al.[40]explored the contribution of gut microbiota on the anti-obesity effects of FBT by utilizing the microbiota-depleted mice with nonabsorbable broad-spectrum antibiotics.The result suggested that FBT-induced variation of gut microbiota were the prerequisites for FBT to improve metabolic disorders.Zhu et al.[41]performed the research to determine whether green tea can persistently exert protective effect against obesity by changing the microbiota.The results demonstrated that a 5-week preventive TPs consumption could protect lean mice fed HFD from obese.However, the anti-obesity effect of drinking green tea was abrogated on already obese mice.

3.1.2 Specific bacteria

Extracts from tea water was summarized to have the effect to decrease the relative abundance of family Desulfovibrionaceae,which are Gram-negative and sulphate-reducing with the effect to produce lipopolysaccharide (LPS) and induce inflammation [42].Gao et al.[43]found thatAkkermansia muciniphilaandFaecalibacterium prausnitziiwere the key gut bacteria mediating the Pu-erh tea treatment that resulted in improvements of the MS.In addition, the effects ofA.muciniphilaandF.prausnitziion the MS were confirmed by administration to the mice fed on HFD.TheA.muciniphilahas been identified as a specialized mucus degrading bacterium that possesses the strong capacity to anchor colonocytes [44].Mucin degradation byA.muciniphilacould in turn reinforce the gut barrier by stimulating the production of mucus and thickening the mucus layer.More importantly, several studies demonstrated thatA.muciniphilaadministration decreased the gut permeability and improved metabolic parameters in obesity and diabetes [45,46].F.prausnitzii, a butyrate-producing bacteria, facilitates the modulation of intestinal immune system and have been reported to decrease adipose tissue inflammation in high-fat fed mice [47].Recently, key bacterial phylotypes responding to the TPs treatment were clustered into 11 coabundance groups (CAGs) and it was revealed that one of these CAGs was associated with the decrease in blood glucose [48].Thus, overall,there seems to be evidence for a promotion of beneficial bacteria and the inhibition of harmful bacteria related to dietary TPs.

Noteworthy, different species in the same bacterial family or genus may respond differently to TPs.Some uncultured/unidentified operational taxonomic units (OUTs) defined by clustering at 97% sequence similarity were also affected by TPs.Therefore, the benefits of TPs on the modulation of gut microbiota cannot be attributed only to the known genera/family.Furthermore, the function of the altered microbiota should be characterized for a deep understanding of the underlying mechanism on metabolic regulation.The gut contents in the GTP-treated rats were analyzedviametabolomics analysis by Zhou et al.[49].The results indicated that the gut-microbiota dependent metabolism changes, accompanied with the variation of gut-microbiome, may contribute to the health benefits of green tea consumption.Through a combination of 16S rRNA Illumina sequencing and meta-proteomic analyses, Xia et al.[50]reported that feeding of raw Pu-erh tea stimulated the growth ofA.muciniphilaby increasing the expression level of certain key enzymes.Zhou et al.[51]performed 16S rRNA, metagenomics and metabolomics analysis to summarize a systematic mechanism on how GTPs enhance gutmicrobiota dependent energy conversion in a rat model.The results clearly showed that GTPs enhance the efficiency of systematic energy conversion by modifying tricarboxylic acid (TCA) cycle and urea cycle of gut-microbiota, which further induces the reduction of glucose, triglycerides and total cholesterol in blood.The metabolic modulation is accomplished by enriching some beneficial strains.Multiomics analysis including metagenomics, metatranscriptomics,metabolomics, and metaproteomics techniques is well believed to be a powerful research tool to identify relevant interactions between certain strains of host-microbiome after TPs intervention.Importantly,the latter and most other studies reporting effects of altered gut microbiota by TPs were confined to the correlative analysis or deduced from previous conclusions but not cause-relationship can be concluded.Thus, the causality and explicit mechanisms still need in-depth exploration.The function of the species/strains highly correlated with metabolic improvement should be validatedin vivoafter being identified.

3.1.3 SCFAs

SCFAs (i.e.acetate, butyrate, and propionate) are produced through the fermentation of indigested dietary fibers, and to a lesser extent of proteins and peptides by anaerobic gut bacteria, such asAlistipes,Rikenella,BlautiaandAllobaculum[52].There is a large body of evidence showing that the key role of SCFAs in regulating intestinal barrier, energy homeostasis, insulin sensitivity and glucose and lipid metabolism is mediatedviathe activation of G proteincoupled receptors (GPCRs) or the inhibition of histone deacetylases(HDACs).The SCFAs induced GPR41/43 on the enteroendocrine cells will promote the secretion of the gut hormone peptide YY(PYY) and glucagon-like peptide-1 (GLP-1), which associated with the reduced energy intake and the promoted insulin secretion.The inhibition of SCFAs on HDACs will attenuate inflammatory response through deactivating pro inflammatory transcription factor (NF-κB)[33,52].Besides, SCFAs could also enhance energy metabolism and intestinal barrier through AMP-activated protein kinase (AMPK)activation [53,54].Thus, dietary interventions inducing the increase of SCFAs may serve as a potent therapeutic strategy to prevent metabolic diseases.Anin vitrofermentation experiment suggested that polyphenols from green tea, oolong tea and black tea could increase the concentrations of SCFAs [18].It has been reported that green tea and black tea had inhibitory potential againstα-amylase andα-glucosidase, which may result in a higher level of unabsorbed carbohydrate in the large intestine, providing the substrate for SCFAs generation [55,56].Ding et al.[57]discovered that the anti-diabetic activity of the dark tea is likely correlated with the increasing level of SCFAs and SCFAs-producing bacteria in diabetic rats.Black tea could increase multiple SCFAs producers and butyric acid levels in healthy SD rats [58].Henning et al.[35]also observed that the consumption of black tea polyphenols was associated with a significant increase in concentration of the cecum SCFAs.The authors hypothesized that this increase in SCFAs contributed to the increased hepatic AMPK phosphorylation and weight loss.Conversely, cecum SCFAs were not significantly changed in mice fed GTP, which is consistent with the results published by others in rats [49].The inconclusive results may be a result of the complex drivers of SCFAs generation determined by a combination of carbohydrate digestive enzyme inhibition and subsequent reactions of undigested carbohydrates with gut microbiota as proposed by others [53,59].In this regard, fermented tea (black,oolong, and dark) are more efficient than non-fermented (green) teas in carbohydrate inhibition.

3.1.4 BAs

BAs are the metabolic end products of hepatic cholesterol.Primary BAs are synthesized in the liverviacholesterol hydroxylase enzymes,then flow into intestine through bile duct and enzymatically modified by gut microbiota to yield secondary BAs.The main bacterial genera with the capability to produce secondary BAs includeBacteroides,Clostridium,Lactobacillus,BifidobacteriumandListeriain BAs deconjugation,Bacteroides,Eubacterium,Clostridium,Escherichia,Eggerthella,Eubacterium,PeptostreptococcusandRuminococcusin oxidation and epimerization,ClostridiumandEubacteriumindihydroxylation [60].BAs could regulate host metabolic pathways and inflammation responsesviaG protein-coupled BAs receptor 1(TGR5) and farnesoid X-activated receptor (FXR) [61].BAs activation of FXR in different organs may have paradoxical effects on the metabolic regulation, resulting in the fat accumulation and inflammation in the liver, lipid storage in white adipose tissue,but insulin secretion inβ-pancreatic cells [61].The intestinalrestricted FXR activation leads to the amelioration of obesity [62].Conversely, BAs binding to TGR5 influences GLP-1 secretion in the intestinal L-cells, promotes insulin sensitivity, and increases energy expenditure in muscle and brown adipose tissue [61].Huang et al.[63]investigated the mechanisms of EGCG on BAs homeostasis and lipid metabolism and found that EGCG decreased intestinal BAs levels leading to lower BAs reabsorption, which further decreased the absorption of lipids.Sheng et al.[64]indicated that EGCG may activate hepatic FXR, while deactivating intestinal FXR which may have beneficial effects on obesity.In addition, the activation of Tgr5 by EGCG increased serum PYY level and GLP-1 release, which may help to improve insulin sensitivity.Ushiroda et al.[65]demonstrated that EGCG activated FXR to suppress liver disease by reducing the population of taurine-conjugated cholic acid,β-muricholic acid and deoxycholic acid in HFD fed mice.The increased abundance ofAkkermansiaand/orParabacteroideswere likely involved in promoting the taurine deconjugation reaction.Recently, Huang et al.[66]investigated the mechanisms behind the cholesterol- and lipid-lowering effects of Pu-erh tea and concluded that the combination of decreased ileal FXR-FGF15 and increased hepatic FXR-SHP signaling by BAs reduced the cholesterol level in serum.The study showed a detailed mechanistic explanation between theabrownin, the major active component of Pu-erh tea, changes in the gut microbiota,FXR signaling and BAs synthesis.

3.1.5 AAs

Gut bacteria can synthesize 9 essential AAs required for mammalian growth [67].Among them, aromatic amino acids(AAAs) and BCAAs have been shown to be positively associated with obesity and type 2 diabetes [68,69].The bacteria responsible for the protein digestion are within theBacillus-Lactobacillus-Streptococcusgroups andProteobacteriain the human small intestine, while belonging to theClostridiaandPeptostreptococciin the large intestine.Besides, gut microbial also play an important role in the catabolism, utilization andde novobiosynthesis of AAs [70].Growing evidence suggests that BCAAs induce insulin resistance mediated by the hyperactivation of mTOR signaling [71].However, some microbial AAs metabolites have positive effects on host metabolism.For instance, several indole derivatives of tryptophan modulate intestinal integrity and the mucosal immune responseviathe aryl hydrocarbon receptor (AhR)/interleukin (IL)-22 axis [72].Zhang et al.[25]collected and analyzed the fecal and urine samples from postmenopausal female subjects taking a GTP supplement or placebo for 12 months.The results revealed that GTP influenced the microbial production of AAAs metabolites.Besides, Pu-erh tea extract could also modulate the AAs metabolism (phenylalanine and tryptophan metabolism) in chronic alcohol-exposed mice.However, the role of BCAAs/AAAs in the anti-obesity effects of TPs remains unclear.

3.1.6 TPs derived-microbial metabolites

Currently, increasing attention has been paid to the biological activities of microbial metabolites of TPs.The production of these metabolites has been reported to be associated withClostridiaandActinobacteria[29,73].There is evidence suggesting that they have antioxidant, anti-proliferative and anti-inflammatory abilities,though the majority experiments conductedin vitro[74].Phenyl-γvalerolactones and their conjugated forms (sulphated) were studied regardingin vitroimpact on brown adipocyte tissue (BAT), the thermogenesis function of which facilitates metabolic health [75].The result showed that PVLs protected brown adipocytes from oxidative stress, indicating that the colonic metabolites of TPs may play a role in the regulation of MS [76].More studies are needed to validate these effectsin vivo.

Reactive carbonyl species (RCS) produced from oxidation of carbohydrates, lipids, and AAs are considered as one of the causing factors to the development of many chronic diseases such as different cancers, MS and aging related diseases.Zhang et al.[77]determined that EGCG and its aminated metabolites could scavenge RCS in the gut effectively.Furthermore, their results demonstrated that gut microbiota facilitate the elimination of these toxic RCS by EGCG possibly through promoting its oxidation and amination.

In short, the understanding of the bioactivity of TPs’metabolites is still far from completed.Factors such as lack of authentic standards and inter-individual differences make the research very challenging.Advanced detection techniques combined with high-throughput sequencing techniques may help to unravel the underlying relationship.Further elaboration about the specific bacterial strains and enzymes in the bioconversion process and the role of these metabolites in the health benefits of TPs are needed.These findings will lead to developments of new therapeutic bacterial natural products.

3.2 Potential targets during TPs intervention

3.2.1 Intestinal barrier

Low-grade inflammation in MS termed ‘metabolic inflammation’could promote disease progression.Some nutrients, especially excess dietary lipids, emerge as causative factors of metabolic inflammation.Adipose tissue and liver were once considered as major sources of inflammatory mediators [78].Recently, the gastrointestinal tract has been shown to be the origin of relevant inflammatory processes following the disruption of the intestinal barrier, which consist of physical (tight junctions), immunological(intestinal innate and adaptive immune system), and microbiological barriers [78,79].TPs may ameliorate MS by maintaining intestinal barrier.Gao et al.[43]demonstrated that TPs administration could recover the expression levels of tight junction proteins including occludin, and ZO-1 to maintain the intestinal physical barrier and alleviate endotoxemiain HFD fed mice.Li et al.[80]revealed that the consumption of GTP strengthened intestinal immunity in canines with a HFD.Particularly, a double-blind, randomized, placebo-controlled crossover trial has been conducted to evaluate the potential benefits of green tea extract (GTE) on intestinal barrier function in MS and healthy adults.This ground-breaking clinical trial demonstrated that GTE mitigate metabolic inflammation in persons with MS by improving gut barrier function, contributing to establish evidencebased dietary recommendations for the GTE supplement [81].Noteworthily, different intestinal barrier components could function alone or cooperate interactively to achieve gut health.The maintaining of intestinal barrier may not be the consequence of single but comprehensive regulation of TPs on the mechanical barrier,immunological barrier and microbiological barrier.

3.2.2 Gut-brain axis

Gut communicates with the brain directly or indirectly through the vagus nerve neurotransmitters, the immune system, the endocrine system, and microbial metabolites, forming the gut-brain axis, which have effects on host metabolism and central regulation of appetite[82,83].EGCG was found to possess protective effects against cognitive impairment triggered in the brain by a high-fat and highfructose diet [84].However, the results of whether TPs can cross the blood-brain barrier were inconsistent.Based on the gut microbiota modulation effect of TPs, the influence of TPs-affected microbial metabolites on gut-brain axis, as well as their implication on the MS may be investigated in the future to shed new light on the underlying metabolic modulation mechanism.Circadian rhythms affected by environmental factors such as light, feeding time, food type, exercise and temperature are established by the host to synchronize with environment, which manipulate the expressions of genes essential to human physiological homeostasis and health.Disorganized circadian rhythms have been suggested to cause various chronic diseases, such as obesity, diabetes, and neurodegenerative diseases [82].Recent researches have revealed that the gut microbiota also have their own diurnal rhythmicity in the composition and function.In particular,host circadian rhythms and circadian rhythms of gut microbiota could interact with each other [85].TPs have been reported to alleviate metabolic disordersviathe mechanism associated with the core circadian clock geneBmal1[86].A more recent study found that oolong TPs significantly restored the disrupted diurnal oscillation of gut microbiota and the transcription of circadian clock genes in mice induced by constant dark treatment [87].More investigations are needed to elucidate the role of the interaction between TPs and gut microbiota in host circadian rhythms, and the overall contributions to MS from the perspective of the gut-brain axis.

3.2.3 Gut-liver/adipose axis

The liver is one of the major targets for alleviation of MS due to its important role in the regulation of glucose and lipid metabolism.The changes in the gut microbiota, FXR signaling and BAs synthesis in the modulation of hypercholesterolemia by TPs have been summarized in section 3.1.4.

In addition, lipopolysaccharides (LPS) derived from Gramnegative bacterial membranes exhibits the potential to cause inflammation by activating Toll-like receptor (TLR) 4 in various tissues and organs after transportation into the blood circulation through intestinal epithelial cells.For instance, excess LPS could stimulate hepatic stellate cells and Kupffer cells (KCs) to induce steatohepatitis [79].Liu et al.[88]studied the preventive effect of raw bowl tea polyphenol on nonalcoholic fatty liver disease in mice.The results showed that the tea intervention could reduce the relative abundance of LPS-producing bacteria and maintain intestinal function.The study by Dey et al.[89]suggested that GTE protected against nonalcoholic steatohepatitis (NASH) partially by alleviating endotoxin-TLR4-NFκB inflammation along the gut-liver axis.

Adipose tissue is a major site responsible for the storage of excess energy, and the trigger of adipose tissue inflammation is a hallmark of obesity [90].Dey et al.[91]tested whether dietary GTE has the effect to prevent obesity-associated inflammation at adipose tissue.The data suggested that regulation of the gut-adipose axis through limitation of LPS translocation and consequent adipose inflammation contributed to the anti-obesity effects of GTE.

Collectively, it’s difficult to decipher exact regulation mechanisms of TPs on the MS.The specific gut bacteria, metabolites and major target organs involved in the TPs intervention on the MS may largely depend on the types of tea, interpersonal unique microbiota signatures and host physiology.Hence, more efforts should be made to shed light on the intricate relationship between different TPs and gut microbiota,furthermore, dosage and timing of TPs administration should be taken into consideration, which may be favorable for the development of personalized nutrition and functional food.

4.Conclusion and future perspectives

Polyphenols are natural products that have emerged as a promising alternative therapy for metabolic disorders.Compared with some available drugs with undesirable side effects and poor outcome,one advantage of plant derived polyphenols is that they are more moderate and friendly.Among them, TPs are widely recognized to have metabolic regulation effects as evidenced by animal experiments and human intervention studies.However, the underlying mechanisms need to be further explored for a better understanding and utilization of the beneficial effects of tea.For example, the “AMPK hypothesis”suggesting that the activation of AMPK in different organs is a possible mechanism for TPs proposed by previous studies to influence energy metabolism and alleviate MS needs to be further assessed.Regulation of the rhythmic expression of the circadian clock genes in the liver and fat was a novel mechanism recently reported for TPs to ameliorate MS [92,93].Nonetheless, TPs have low bioavailability and most of them stay in the large intestine where a large amount of gut microbiota inhabits.Thus, it can be hypothesized that the improved function of metabolism associated internal organs and tissues, including liver, adipose tissue, skeletal muscle and pancreas may rely on TPs’ modulation on gut microbiota.The interactions between TPs and gut microbiota reveal that TPs may improve the MS in a multi-element and multi-target manner.

Several important issues need to be modeled in future researches.Furthermore, future studies can develop towards 3 research orientations.Firstly, the causal relationship between the alteration of gut microbiota and beneficial effects brought by TPs should be proved.The composition and function changes of gut microbiota may be the result rather than the reason for the improvement of metabolic diseases by TPs.Germ-free, antibiotic-treatment mice or the fecal microbiota transplantation technique can be used to resolve this problem.Secondly, multi-omics including metagenomic, metabonomic,proteomic and transcriptome can be applied to identify the potential elements associated with the underlying mechanism ranging from the key strain, the key metabolite to the target gene/protein.Moreover, the definite effects of these important elements should be verified.Lastly, the role of gut microbiota in the beneficial effects of TPs should be testified in the human intervention studies, promoting the transformation of some findings into clinical trials.

Declaration of competing interest

The authors declare no conflict of interest.

Acknowledgements

This work was financially supported by National Key R&D Program of China (No.2017YFC1600402), National Natural Science Foundation of China (No.31772095), and the Fundamental Research Funds for the Central Universities, Nankai University (No.63191426).