Ming Li, Ping Li, Rongxue Tang, Hui Lu*

State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China

Keywords:

Resveratrol

Inflammatory bowel disease

Intestinal barrier

Gut microbiota

Inflammatory signaling pathways

A B S T R A C T

Inflammatory bowel disease (IBD) is a chronic inflammatory lesion of the intestine, mainly manifested by infiltration of intestinal inflammatory cells and imbalance of gut microbiota.Conventional treatments for IBD include antibiotics, immunosuppressive agents, 5-aminosalicylic acid, steroids and surgery, which have high toxic side effects.Resveratrol is a natural polyphenol, and its various derivatives have anti-oxidation and anti-inflammatory properties.In this paper, we comprehensively review the mechanism of resveratrol and its derivates to alleviate IBD by improving intestinal barrier, regulating the unbalanced gut microbiota, and targeting various inflammatory signaling pathways.

1.Introduction

Inflammatory bowel disease (IBD) is a recurrent inflammatory disease with a key feature of uncontrollable intestinal mucosal inflammation [1].It is a rapidly growing global health problem with more than 1.5 million and 2 million IBD patients in North America and Europe, respectively [2].Although the IBD’s exact pathogenesis has not been clearly illuminated so far, it is generally thought that it is affected by many factors that alter gut homeostasis, including genetic factors, immune response, and gut microbiota imbalance [3].The two main forms of IBD are Crohn’s disease (CD) and ulcerative colitis (UC).They vary in pathogenic site and severity.UC generally only affects the rectum and sigmoid colon only, involving the colonic mucosal lamina propria, and generally forms a continuous inflammatory plaque.CD results from abnormal immune response of intestinal epithelial cells to microbial antigens, which can damage the entire intestinal wall and form ulcers [4].

Traditional IBD therapies include 5-aminosalicylic acid (5-ASA),corticosteroids (CS), Janus kinase inhibitors, anti-tumor necrosis factor-alpha (anti-TNF-α), antibodies and surgery.However, their efficacies are limited and harmful to the immune system.For example,5-ASA therapy may lead to the paradoxical worsening of disease,headache and pancreatitis [5].CS treatment’s side effects include osteopenia/osteoporosis and impairment of linear growth [6].Anti-TNF-α therapies for IBD can induce anti-drug antibody formation [7].Novel IBD treatments include regulatory T cell therapy [8], antiinflammatory cytokines therapy [9], stem cell-based therapy [10], and fecal microbiota transplantation (FMT) [11,12].But they have yielded disappointing results.For instance, the anti-inflammatory cytokines therapy showed low efficacy in patients with UC [13].Although the regulatory T cell therapy might be therapeutically effective in UC,further prospective studies are needed to determine its efficacy and safety.The gut microbiota of the human body is highly personalized,it is difficult to develop the accurate personalized medical strategies for patients treating with FMT [14].These IBD treatments are ineffective for certain patients, which cause an increased demand for complementary or alternative medicines, especially herbal therapies.For example,Hericium erinaceusmycelium polysaccharide ameliorates the UC rats by increasing the level of short chain fatty acids (SCFA), modulating the composition of gut microbiota community and suppressing the expression of G-protein-coupled receptor 41 (GPR41) and GPR43 [15].

Resveratrol and its derivatives have anti-oxidation, anti-tumor [16]and anti-inflammatory functions [17], and a wide range of evidence have been reported that resveratrol can improve IBD through reducing mucosal inflammation [18].For example, IBD patients who were treated with resveratrol showed the decreased levels of proinflammatory factor such as TNF-α, nuclear factor kappa-B(NF-κB) p65 [19]and increased expression of superoxide dismutase [20].However, the anti-inflammatory mechanism of resveratrol is still unclear and needs further research.Here, we first summarized the absorption and metabolism of resveratrol.Then we review the mechanism of resveratrol and its derivatives alleviate IBD [21,22]through ameliorating the damaged intestinal barrier, the imbalance of gut microbiota and various inflammation signaling pathways.

2.The absorption and metabolism of resveratrol

Resveratrol (3,4’,5-trihydroxystilbene), also known as ninhydrin,is a bioactive natural polyphenol.It is mainly derived from peanuts,grapes and polygonum cuspidatum.Its poor bioavailability and high metabolic rate in the gut and liver results in low plasma concentration.As summarized in Fig.1, when resveratrol enters the small intestine,resveratrol passes through the enterocyte apical membrane through passive transport or carrier-mediated transport as glycoside.Then it is catalyzed by the cytoplasmic glucosidase (CBG) into the aglycone form of resveratrol (RSV).In addition, the gut microbiota can also produce theβ-glycosidase (BG) that cleaves resveratrol to the RSV in the lumen.Then RSV can cross the apical membrane via passive diffusion and get absorbed in epithelial colorectal adenocarcinoma cells (Caco-2) [23].After entering the intestinal cells, there are two main pathways to metabolize resveratrol, glucuronidation and sulfation [24].

Fig.1 The metabolism of resveratrol in the human body.

Glucuronidation of resveratrol is considered to be the primary reason for its low oral availability.Resveratrol is metabolized into cyclic resveratrol glucuronic acid (resveratrol 3-O-glucoside (R3G)and resveratrol 4’-O-glucoside (R4’G)) under the action of uridine-5’-diphosphate-glucuronosyltransferase (UGT).Sulfation refers to the process of metabolizing resveratrol into resveratrol-3-O-sulfate and resveratrol-3,4’-O-disulfate under the action of sulfotransferase(SULT) [25,26].After being metabolized by intestinal epithelial cells,resveratrol and its derivates are transported to the liver cells, where the glucuronidation and sulfation are further carried out.Resveratrol and its derivates can be transported to the blood vessel or returned to the small intestine again for digestion and absorption, or excreted through the urinary system.

Not only do enzymes in human catalyze the metabolic process of resveratrol, but gut bacteria also have been reported to target the resveratrol metabolism.Two strains of human gut bacteria (Slackia equolifaciensandAdlercreutzia equolifaciens) can convert resveratrol into dihydro-resveratrol, lunularin [27], and 3,4-dihydroxy-transtilbene [28].In addition,Eggerthella lentaATCC 43055 can also metabolize resveratrol into dihydro-resveratrol.Dihydro-resveratrol can be glucuronidated or sulfated in the enterocytes.Interestingly,all three strains belong to the Coriobacteriaceae, indicating that the Coriobacteriaceae can perform a certain degree of biotransformation of the resveratrol.Furthermore, Jung et al.[29]identified that theBacillus cereusNCTR-466 can metabolize resveratrol into piceid and resveratroloside.Fig.2 shows the main derivates of resveratrol.

Fig.2 The derivates of resveratrol metabolized by enzymes of the human and gut microbiota.

3.The mechanism of resveratrol improves IBD

3.1 The brief introduction of the mechanism of the disease

The mechanism of IBD is mainly caused by genetic susceptibility and environmental factors interacting with the gut microbiota.The microorganisms get through a weakened intestinal barrier and activate inappropriate gut immunity in the host [30].The gut microbiota and the intestinal barrier are functional mutually.The imbalance of the gut microbiota leads to the reduction of beneficial metabolites like SCFA, the damage of the function of antimicrobial peptides and mucus in the intestinal barrier.The weakened intestinal barrier can also promote the transmission of microorganisms through the mucosa [31].Furthermore, the immune system can activate various signaling pathways to trigger a series of pro-inflammatory and antiinflammatory cytokines after it is stimulated.In this article, we review the relationship of IBD with the intestinal barrier, gut microbiota,and inflammatory signaling pathways, as well as the mechanism of resveratrol to improve IBD through these three aspects.

3.2 Resveratrol improves the damage of the intestinal barrier

The functional integrity of the intestinal barrier is maintained by intestinal mucus and tight junctions (TJs).The damage of intestinal barrier integrity can stimulate inflammation of intestinal mucosa and increase the translocation of pathogens, which is the primary pathological manifestation of IBD.The intestinal mucus contains mucin with complex and extensiveO-oligosaccharide modifications.The production and processing defects of mucin can lead to the direct contact between the colonic bacteria and the epithelial barrier[32].For example, patients with UC show a significant decrease in goblet cells and a reduction of the synthesis and secretion of mucin 2(MUC2) [33].Studies have shown that oxyresveratrol can stimulate the synthesis of mucin in goblet cells and increase the mRNA and protein level of MUC2 [34].TJ proteins are significantly related to the integrity of the mucosal barrier.Reduction of the TJ proteins causes the leakage of intracavitary antigens through the epithelial barrier.Resveratrol can downregulate the expression of claudin-2 and increase the mRNA level of the heat-shock protein, MUC2 and TJ genes to improve the integrity of intestinal barrier and reverse the expression of pro-inflammatory cytokines [35].Wang et al.[36]reported that resveratrol not only increased the expression of Zonula occludens-1(ZO-1) and the phosphorylation of occludin, but decreased the peroxide-induced oxidative damage and malondialdehyde levels in Caco-2 cells in a dose-dependent manner.The defects of intestinal epithelial barrier were sufficient to cause the development of chronic inflammation [37].Future studies can focus on the prevention of intestinal barrier injury via resveratrol.Besides, the colonization and translocation mechanisms of the conditionally pathogenic bacteria should also be explored.Lastly, whether resveratrol can directly affect the development and formation of epithelial barrier by regulating TJ proteins need further research.

3.3 Resveratrol regulates the imbalance of the gut microbiota in IBD

The pathogenesis of IBD is currently unclear, but studies in recent years have shown a strong link to the imbalance of gut microbiota[38].The analysis of 633 cases of IBD found that the mechanism of the increased risk of IBD is partly achieved by the action of the commensal microbiota in the intestine, confirming that the symbiotic gut microbiota mediates the process of susceptibility genes to induce IBD [39].The relationship between gut microbiota and IBD can be broadly classified as follows: 1) Gut microbiota imbalance leads to an increase in the number of conditional pathogenic bacteria with the ability to adhere to intestinal epithelial cells, which reduce the diversity of gut microbiota and induce inflammatory response [40].2) After the gut microbiota is destroyed, the production of related metabolites of gut microbiota (such as SCFA) would also be affected,which correlates with IBD’s pathogenesis.3) The increased number of sulfate-reducing bacteria in IBD-prone patients will cause the production of hydrogen sulfate and other toxic substances, which can damage the intestinal epithelial cells and induce mucosal inflammation.For example,Ruminococcus gnavusa, a common bacteria in IBD patients, produce glucomannan polysaccharide that activates dendritic cells to release TNF-α through toll-like 4 receptors(TLR4) [41].Escherichia Coli,Yersinia[42]andClostridium difficile[43]are the key microbiota leading to IBD.The relative abundance ofYersiniaandC.difficileare significantly greater in CD patients than in the healthy individuals.TheClostridiumcluster genus can influence the enzymatic process of dietary fiber being metabolized into SCFAs, which affect the differentiation and amplification of the regulatory T (Treg) cell [44,45].CD patients showed a significant decrease in the abundance ofFusobacterium prausnizziandC.clustersIV, XIVa, which lead to the decrease of SCFAs [46].The abundance ofDesulfovibriowas highly increased in IBD patients which is related to the damage of the intestinal mucosa [47].

The interactions between resveratrol and gut microbiota are bidirectional and reciprocal.Resveratrol and its metabolites can directly inhibit the growth of some opportunistic pathogenic bacteria, weaken the expression of the virulence factors, reduce the formation of biofilm, and affect the sensitivity of bacteria to various conventional antibiotics.Larrosa et al.[48]indicated that feeding the colitis mice with resveratrol could increase the relative abundance ofLactobacillusandBifidobacterium, and inhibit the reproduction of harmful bacteria such asE.coli.This effect significantly improved the imbalance of gut microbiota in colitis mice.Selma et al.[49]reported that glucuronide derivatives of resveratrol (such as resveratrol-3-O-(6’-O-butanoyl)-β-D-glucopyranoside (BUT) and resveratrol-3-O-(6’-O-octanoyl)-β-D-glucopyranoside (OCT)) inhibited the adhesion ofListeria monocytogenes,Salmonella typhimuriumandE.colito colon cells, and had a potential role in preventing foodborne infection and improving gut homeostasis.In addition, resveratrol and its derivatives can regulate some bacteria ofClostridiumand promote the metabolism of dietary fiber into SCFA.Resveratrol, in collaboration with curcumin, upregulated the relative abundance ofClostridiumand level of SCFA in the colitis model caused byC.difficileinfection [50].Table 1 summarizes the regulation of resveratrol and its derivates on gut microbiota associated with IBD.Resveratrol also participates in regulating gut microbiota in combination with drugs.For example,resveratrol enhance the activity of colistin in antagonizing the resistant strains and reduce the relative abundance ofgram-negative bacteria [51].

Table 1Regulation of resveratrol and its derivates on IBD-related microorganisms.

The antimicrobial mechanism of resveratrol may be related to the following reasons: the decrease of host ligand adhesion, inhibition of biofilm formation and neutralization of bacterial toxins.As a result,it can reduce the expression of pro-inflammatory cytokine and proinflammatory responses [52-54], increase the level of SCFA [55-57],and play a role in immune regulation [58,59].However, the antimicrobial efficacy of resveratrol in the body remains largely unexplored, and the low bioavailability of resveratrol also limits the route of administration.The problem of resistance of gut microbiota to antibiotics may be solved by the synergistic action between resveratrol and its derivates.Resveratrol and its derivates also can be used in combination with antibiotics to enhance their efficacy,which can decrease the dose of antibiotics and the adverse reactions to antibiotics.The synergistic effect of resveratrol and probiotics may also be a potential targeted therapy for IBD.

3.4 Resveratrol targets various signaling pathways to alleviate IBD

Resveratrol regulates the function of immune cells by a variety of signaling pathways, which reduce the production of pro-inflammatory factors and improve IBD.Fig.3 represents that resveratrol participates in various signaling pathways to exert immunomodulatory effects [59].

Fig.3 Resveratrol regulates the potentially relevant signaling pathways of IBD (adapted and modified from [59]).

3.4.1 TLR 2/4 mediated signaling pathway

TLRs are a class of receptors widely present in macrophages and neutrophils [60].There are two types of TLR signaling pathways:myeloid differentiation protein 88 (MyD88)-dependent and toll/IL-1 domain-containing adaptor inducing interferon β-dependent (TRIF) [61].MyD88 signal transduction is usually associated with NF-κB and mitogen-activated protein kinase (MAPK) signaling pathway.TLR4 activates IL-1R-associated kinase (IRAK) through adaptor MyD88, followed by activation of TNF receptor-associated factor 6 (TRAF-6), which activates NF-κB and MAPK signaling pathway successively to regulate signal transmission.Panaro et al.[62]had shown that resveratrol reduced the expression of the LPS receptor TLR-4, inhibited the inhibitor of NF-κB (IκB) degradation and NF-κB activation to regulate expression of inducible nitric oxide synthase(iNOS), IL-6.Wang et al.[63]reported that resveratrol inhibited the TLR4 signaling pathway and decreased the TLR4 protein by downregulating the mRNA levels ofMyD88and TNF receptorassociated factor 6 (TRAF6), and further inhibit the signaling cascade of NF-κB and MAPK, which can reduce pro-inflammatory mediators and increase anti-inflammatory factors.

3.4.1.1 NF-κB signaling pathway

NF-κB is identified as one of the key regulatory factors in immunological environment.NF-κB becomes a complex and inactive form in unstimulated cells with inhibitors [64].After the stimulation,the MyD88-dependent TLR signaling activates the IRAK family,which in turn activates the E3 ubiquitin ligase activity of TRAF6 to cause the self-ubiquitination of TRAF and activation of transforming growth factor-β-activated kinase 1 (TAK1).Then the activation of IκB kinase (IKK) by TAK1 causes the phosphorylation of IκB protein,which leads to continuous ubiquitination and NF-κB activation [65].Resveratrol can block phosphorylation and subsequent degradation of IκB by altering activation of IKK and preventing the binding of nuclear translocation to DNA [66].Capiralla et al.[67]showed that resveratrol inhibited the activation of NF-κB through interfering with IKK activation and IκB phosphorylation.Resveratrol can also reduce the activation of NF-κB through blocking with TLR4 oligomerization and act on inflammation through inhibiting TLR4/NF-κB/STAT signaling cascade.Jin et al.[68]also reported piceatannol suppressed the activator of transcription-3 and phosphorylation of extracellular signal regulated kinases (ERK) to inhibit NF-κB pathway, which improved DSS-induced colitis in mouse.Similarly, resveratrol suppressed the expression of inflammatory factors and activation of NF-κB in patients with active UC [69].

3.4.1.2 MAPKs pathway

MAPKs contain a series of serine/threonine kinases (ERK,Jun N-terminal kinase (JNK), p38MAPK).They act as stressactivated protein kinases for various extracellular signals [70].After phospholipases C (PLC) is activated, its derivates can lead to the activation of phosphoinositide-3-kinase (PI3-k) and protein kinase C(PKC), which cause the activation of MAPK.The phosphorylation transcription factors produced by activated MAPK can enter the nucleus and regulate the transcription of the related genes[59].Resveratrol can inhibit the oxidative stress, reduce the cell apoptosis and production of inflammatory factors by suppressing the phosphorylation of p38MAPK.It has been reported that resveratrol reduced the inflammatory cell infiltrate in the colon, expression of cyclooxygenase (COX)-2, prostaglandin E synthase and iNOS in colonic mucosa via downregulating the p-38 MAPK pathway, which attenuated colonic inflammation induced by DSS [71].Similarly,piceatannol reduced the production of inflammatory mediators by reducing histone deacetylase 4 (HDAC4) and HDAC5 protein expression or inhibiting the p38-MAPK signaling pathway [72].

3.4.2 Arachidonic acid dependent pathway

Arachidonic acid is released from the phospholipid membrane under the cleavage of phospholipase A2 (PLA2).Then various enzymes such as COX and lipoxygenase (LOX) can metabolize it to prostaglandin (PGs), thrombin A2 (TXA2), hydroperoxy eicosaenoic acid (HpETE), leukotriene (LTs), etc.[73].These derivatives are lipid mediators involved in the inflammatory process.One of the mechanisms by which resveratrol regulates the immune response is directly inhibited these pro-inflammatory enzymes.Radwan et al.[74]has reported that resveratrol reduced the levels of IL-1β, arachidonic acid, the oxidized glutathione/reduced glutathione (GSSG/GSH)ratio by inhibiting the arachidonic acid pathway.Resveratrol also exerts protective effects in acute colitis by reducing the production of prostaglandin D2 (PGD2) and the overexpression of COX-2 [75].

3.4.3 Cluster of differentiation antigen 14 (CD14),complement receptor 3 (CR3) mediated signal transduction pathways

CD14, a 55-kDa glycosylphosphatidylinositol-chain protein that present on phagocytic leukocytes surfaces, is a symbol for macrophage differentiation [76].CR3 is a dimeric integrin composed of two transmembrane proteins (CD11b/CD18).LPS binding protein can transfer LPS to CD14 and then activate cells through co-factors.LPS stimulates human neutrophils to cause the association of CR3 and CD14, which then activates the PLC-mediated MAPK or NF-κB signaling pathway to regulate the expression of inflammatory factors [77].It has been reported that resveratrol can downregulate the level of HDAC and COX by inhibiting the NF-κB, phosphoinositide-3-kinase(PI3K)/Akt pathways, resulting in the increased expression of SCFA and improvement of DSS-induced colitis [78].Resveratrol suppresses the expression of CD14, MMP-2 and MMP-9 and upregulates endocytosis, which inhibit the NF-κB signaling pathway and decrease the level of proinflammatory factors [79].

In conclusion, the signal transduction pathways involved in the improvement of IBD by resveratrol and its metabolites are mainly as follows: TLR2/4→IRAK→TRAF6→NF-κB/MAPKs, CD14/CR3→PLC→NF-κB/MAPKs, arachidonic acid.Table 2 summarizes the regulation of resveratrol and its metabolites on IBD.

Table 2The regulation of resveratrol and its derivates on IBD.

3.4.4 Dectin-1-mediated signal pathway and other mechanisms associated with gut inflammation

Dectin-1, the first pattern recognition receptors outside the TLR family, has been found to induce its intracellular signaling [86].Dectin-1 regulates intracellular signal transduction by binding to its ligand and provides a docking site for a spleen tyrosine kinase (Syk)and responding to NF-κB signaling pathway.Dectin-1 can also lead to a Syk independent pathway through serine-threonine kinase RAF-1,which has been shown to integrate with the Syk pathway at NF-κB levels [87].It has been reported that resveratrol suppressed the upregulation of mRNAs ofDectin-1to alleviate the NF-κB signaling pathways, which can exert an anti-inflammatory effect [88].Future studies can focus on IBD-related gut bacteria that can be inhibited by Dectin-1, which in turn controls the differentiation of Treg cells and regulates the homeostasis of intestinal immunity.In addition,we should have an in-depth understanding of the interaction between Dectin-1 and the TLR pathway, which may be useful for improving the current IBD treatment.

Epigenetic modification (including DNA methylation, histone modification, microRNA expression) is defined as the changes of gene structure that do not involve changes in the DNA sequence [89].A series of studies have shown that resveratrol is a potent activator of sirtuins (SIRT1) and a range of kinases.It can regulate NF-κB and its downstream genes, such asCOX-2andiNOS[90].Piceatannol can activate the expression of SIRT1, SIRT3 and upregulate the protein level of NAD(P)H: quinone oxidoreductase to reduce the proinflammatory factor [91].Lunularin, a microbial metabolite of resveratrol, increased the expression of SIRT1 and inhibited some proinflammatory enzymes [92].Resveratrol also acts on DNA methyltransferase, which can reduce oxidative stress and inflammation.Maugeri et al.[93]had shown that resveratrol improved the function of DNA methyltransferase and SIRT1, restored the change of line-1 methylation in cells under oxidative and inflammatory conditions.Recent studies have shown that miR-214 is related to the drive feedback loop of intestinal inflammation.Epithelial miR-214 can significantly promote the activation of NF-κB and the mucosal inflammation process.Targeted inhibition of miR-214 could block the feedback loop and improve experimental colitis [94].Li et al.[95]had reported that 10 μmol/L or 50 μmol/L resveratrol reduced the expression of mi-21, decreased the IkB phosphorylation and NF-κB activity to reduce the production of some inflammatory factors.Furthermore, resveratrol can restore the slight decrease in the expression of miR-let7a (miR-let7a can alleviate the phosphorylation of LPS-induced kinase 1)in LPS-stimulated cells, which in turn promote the expression of IL-10 and BDNF and inhibit various inflammatory factors(TNF-α, IL-6, IL-4, etc.) [96].

4.Conclusion

Resveratrol can be metabolized into microbial metabolites with the action of gut microbiota, which always have a higher bioactivity than resveratrol.A series of cellular and animal experiments have shown that resveratrol and its derivates can generally increase gut microbiota’s diversity and reduce the bacterial translocation.It can promote the growth of beneficial bacteria such asClostridiumandBifidobacterium.Furthermore,resveratrol and its derivates can regulate a variety of signaling pathways (such as NF-κB) to decrease pro-inflammatory factors and infiltration of moderate granulocytes.The interactions between resveratrol, gut microbiota and inflammation signaling pathways can contribute to the alleviation of IBD.

In recent years, FMT has gradually become a research hotspot in the treatment of IBD.There is a common hypothesis that FMT can modulate the dysbiosis of IBD patients, so as to restore the imbalance of gut microbial homeostasis.The similarity between FMT and resveratrol treatment on gut microbiota of IBD is that they can restore gut microbiota imbalance, increase bacterial diversity and production of short-chain fatty acids to improve dysbiosis of IBD.In addition,they both can avoid the drug resistance caused by the long-term use of antibiotics in IBD patients.For the FMT treatment, it can manipulate microbial diversity (including not only bacteria, but also viruses,fungi, and archaea).But it is difficult to develop accurate personalized medical strategies [97].Also, FMT is associated with greater risk and and it is difficult to determine the source of risk [98].In contrast,resveratrol, as a Chinese herbal medicine ingredient, has a relatively wide range of sources and has less toxic and side effects than FMT,it may provide the best raw materials for beneficial symbiotic (or transplanted) microbes (such asLactobacilli,Bifidobacteria), which can have a significant effect on gut microbiota composition in the short term.

Resveratrol and its metabolites are potential therapeutic agents for IBD.However, its oral availability is low and its stability is limited due to the rapid absorption and extensive metabolism in the liver, which weakens its therapeutic effect on IBD.Thus,future research on resveratrol should focus on the following topics: 1) Improve the biological activity and bioavailability of resveratrol and its metabolites, and determine the synergistic and antagonistic effects between resveratrol and its metabolites through mechanistic studies; 2) Although several strains have been found to be bioactive in the conversion of resveratrol, more mechanistic studies should be encouraged to detect gut microbiota that can metabolize resveratrol and enzymes that can catalyze the biological conversion of resveratrol; 3) The integration of resveratrol, gut microbiota, and gut microbiota metabolites (such as SCFA) is necessary to help us systematically understand the mechanism of action of resveratrol.

Conflict of Interest

No conflicts of interest are declared for any of the authors.

Acknowledgements

This study was financial supported by the key research and development of general projects of Jiangxi province(20192BBF60026).