The Potential Role of Phytonutrients Flavonoids Influencing Gut Microbiota in the Prophylaxis and Treatment of Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD), characterized by the chronic inflammation of the gastrointestinal tract, is comprised of two idiopathic chronic intestinal inflammatory diseases. As the incidence of IBD increases, so does the need for safe and effective treatments. Trillions of microorganisms are colonized in the mammalian intestine, coevolve with the host in a symbiotic relationship. Gut microbiota has been reported to be involved in the pathophysiology of IBD. In this regard, phytonutrients flavonoids have received increasing attention for their anti-oxidant and anti-inflammatory activities. In this review, we address recent advances in the interactions among flavonoids, gut microbiota, and IBD. Moreover, their possible potential mechanisms of action in IBD have been discussed. We conclude that there is a complex interaction between flavonoids and gut microbiota. It is expected that flavonoids can change or reshape the gut microbiota to provide important considerations for developing treatments for IBD.

Introduction

In recent years, some studies have investigated complex and chronic diseases, including Inflammatory bowel disease (IBD), and focused on their association with the gut microbiota in the intestines. The incidence of IBD has persistently increased with over 3.5 million affected people and has become a global epidemic disease threatening human health (1, 2). Two major defined forms of IBD include ulcerative colitis (UC) and Crohn's disease (CD), characterized by chronic progressive inflammation, which affects the whole gastrointestinal tract and colon mucosa, respectively, leading to an increased risk of colon cancer. There has been substantial research undertaken on the cause of IBD, such as genetic interaction between the human gut microbiome and mucosal immune system, as well as changes in environmental factors (3). There is an intricate interrelationship between the IBD and gut microbiota. It has been reported that gut microbes consist of about 100 trillion microorganisms. The ratio of the number of gut microbes to human cells is close to 1:1, covering more than 1,100 species known to the human body, and the genes displayed are 100 times that of the human genome (4–6). This implies that the gut microbiota is a key component in the human body, playing important roles in the regulation of intestinal permeability, education of host immune responses, metabolism of dietary nutrients, and host's protection against invading pathogens (7, 8). With the increase in the availability of multi-omics approaches, the gradually-revealed mechanism of interaction between gut microbiota and the host has been thought to be distinct in healthy individuals than the IBD patients. The development of various large-scale microbiome projects, such as metagenomics of human intestinal tract (MetaHIT) (5), human microbiome project (HMP), and integrative human microbiome project (iHMP) (9, 10) reveals that the composition, diversity, and stability of gut microbiota are associated with the normal physiological functions and occurrence of diseases (11). The disorders in intestinal microbiota result in perturbation in the intestinal homeostasis and eventually contribute to the IBD.

Diet is a major contributor in shaping the composition and function of human intestinal microbiota by directly or indirectly affects. The complex interactions between diet and intestinal microbiota determines the beneficial or harmful effects on human health, which may be due to the immunomodulatory effects of the improved microbiota, downstream effects on host gene expression, or changes in the metabolite landscape produced by the microbiota (12). The increasing numbers of epidemiological studies have pointed toward the beneficial effects of phytonutrients to decrease the incidence of chronic diseases, including cardiovascular diseases, neurodegenerative diseases, and cancer (13, 14). Flavonoids are present as secondary metabolites in various fruits and vegetables in their different parts, representing a large representative family of the phytonutrients compounds with anti-oxidants and anti-microbial properties. Flavonoids are supplied as nutrition and food additives in functional dietary supplements because of their beneficial effects on human health (15, 16). Some studies have simultaneously demonstrated the beneficial effects of flavonoids on host energy metabolism by regulating the intestinal microbiota and suggested that the diversity and abundance of the intestinal microbiota are associated with the consumption of flavonoids (17–19). At present, flavonoids are considered to be vital for the treatment of acute or chronic intestinal inflammation through multiple mechanisms, including resistance to oxidative stress, protection of intestinal epithelial barrier, and immunomodulation (20). In this review, we summarized the classification and structural characteristics of phytonutrient flavonoids based on previous studies. We also described the latest advances in our understanding of how flavonoids and gut microbiota act independently or synergistically to influence IBD.

Phytonutrients Flavonoids

Natural compounds isolated from plants hold a large reservoir of important bioactive molecules for drugs' discovery. Phytonutrients, also called nutritive phytochemicals, are secondary metabolites accumulated in the different parts of plants (21, 22). The bioactive compounds have potential to be applied as therapeutic mediators in the treatment of diseases. Despite the fact that most of the phytonutrients are non-essential for humans unlike vitamins or other essential mineral micronutrients, they contribute to a significant protection against chronic diseases (23, 24). In traditional medical practices, the phytonutrients have been widely used not only in dietary supplements but also as therapeutic agents for the enhancement of immunity and prevention of diseases (25). On the basis of their unique properties and various structures, the phytonutrients are classified into phenolic acids, flavonoids, carotenoids, tocochromanols, and curcuminoids (26).

Flavonoids, a large family of phytonutrients, are one of the most biologically important poly-phenolic compounds, which occur ubiquitously in plant-based diets or medicinal plants, and comprise of a large group of unique compounds with oxygen-containing heterocyclic framework. The previous studies on flavonoids were focused on their curative effect because of their natural anti-oxidants, anti-carcinogenic (27, 28), anti-atherogenic (29), anti-ulcer (30), anti-thrombotic (31, 32), anti-inflammatory (33, 34), anti-allergenic (35), anti-coagulant (36, 37), immune modulating (34), anti-microbial (38, 39), vaso-dilatory (40, 41), and analgesic activities, which are summarized in Figure 1 (13, 42–44). The neuro-protective effects of flavonoids have been demonstrated in epidemiological studies to change the trajectories of degenerative diseases and improve the cognitive functions (45–49). Similarly, there are some evidences demonstrating the beneficial effect of flavonoids on cardiovascular and cerebrovascular health, either directly or indirectly by acting on the signaling molecules, biomarkers of oxidative stress, platelet function, and lipid metabolism, etc. (50–54). The anti-microbial properties of flavonoids have been extensively studied. The anti-bacterial mechanisms of flavonoids may include: damaging the structure of the cell membrane, inhibiting the synthesis of proteins, nucleic acids, or cell wall's components, and decreasing the production of energy (55–58). A growing body of evidence suggested flavonoids could inhibit carcinogenesis and the development of tumors by multiple mechanisms, such as showing anti-inflammatory effects (suppressing the expression of lipoxygenase, lipoxygenase, and inducible nitric oxide synthase, etc.) (59, 60). Dietary flavonoids were reported to have good anti-oxidant properties as scavengers of ROS and RNS, which can strongly inhibit the progression of inflammation, including inhibiting the release of inflammatory mediators and regulating inflammation-related signal pathways (NF-κB, AP-1, PPAR, Nrf2, and MAPK, etc.) (61). This review will focus on the beneficial effects of flavonoids on IBD, including protection of the intestinal epithelial cell barrier function, prevention of oxidative stress, and immunomodulatory properties, which will be discussed in detail in the following sections.

Figure 1

The flavonoids are a group of organic compounds with diverse chemical structures, characterized with structural backbone C6–C3–C6 called 2-phenylbenzo-pyran, composed of two benzene rings (A and B) and a oxygen-containing six-membered hetero-cycles. In the presence of the basic skeleton of flavonoids, many types of compounds are formed due to different chemical reactions, including glycosylation, hydroxylation, methoxylation, and prenylation. Flavonoids are classified into several different types, including flavonols, flavones, isoflavones, flavan-3-ols, flavanones, and anthocyanins. These compounds sometimes also occur as glycosides, methylated derivatives, or aglycones (Figure 2) (13, 62, 63).

Figure 2

Flavones consist of a 2-phenyl-benzo-γ-pyrone skeleton, which is comprised of a heterocyclic pyrone ring linked with two phenyl rings. The structure of flavones appears very similar to that of the flavanones, with the major differences in the formation of linear pyran rings depending on the unsaturated C2–C3 bonds. The flavonoids usually occur in conjugated forms as glycosides, and the flavones are generally found with O-glycosides at the C-3 or C-7 position, where the O-glycosidic linkage connects the sugar group with aglycone. On the other hand, the C-glycosides in flavones have received less attention, the C-glycosidic linkage is a key structural component (64, 65). Flavones are most commonly found in herbs such as parsley and celery, but they are also widely distributed in grains such as wheat, rye, barley, oats, sorghum, and millet. The most prevalent compounds of flavones include apigenin, baicalein, and luteolin. Their glycoside form compounds are vitexin, isovitexin, baicalin, luteolin 7-O-glucuronide, respectively. Apigenin is found in many vegetables and herbal spices, including parsley, celery, basil, chamomile, coriander, and oregano. Baicalein is a traditional Chinese herbal flavonoid found in the roots of Scutellaria baicalensis Georgi. Luteolin exists in a variety of plants, and these plants have a higher content of whole-leaf green orchid, pepper, wild chrysanthemum, honeysuckle, and perilla.

Flavonols have typical structural features within the plane of 3-hydroxyflavone base, which are distinguished according to the modifications in their different hydroxyl groups in benzene rings (62). Green tea, red grapes, onions, especially red onions, leafy vegetables, and berries are the main sources of flavonols. The highest content of flavonols has been observed in berries and onions (66). Distinguished from flavones, the flavonols have one hydroxyl group at C-3 position, which increases their instability but makes them prone to have O-glycosidic linkages in the form of O-glycosides. In addition, the flavonols are also found as O-glycosides at C-7 or other positions having hydroxyl moieties (67). The most common flavonols include quercetin, kaempferol, and myricetin, most of which form glycosidic combinations. Consequently, the glycosylation of these compounds result in enhancing their stability (68). Quercetin is widely found in various foods, including apples, black tea, berries, capers, red wine, and onions. Among them, onions have the highest content of quercetin. Kaempferol is widely distributed in different plant genera such as delphinium, camellia, barberry, tangerine peel. Myricetin is widely found in many natural plants including bayberry.

Isoflavones have a unique structure having B-ring at C-3 rather than at C-2, which is different from the flavones. Not only that, the isoflavones also structurally resemble endogenous estrogens and have estrogenic activity by binding estrogen receptor (69). The primary natural source of isoflavones is soybean, containing various types of compounds, which are classified according to aglycones or modification by other functional groups, such as methoxylation and hydroxylation (70). Genistein, daidzein, and glycitein are the main representative compounds of isoflavones, which belong to soy phytoestrogens. Genistein is a kind of phytoestrogens derived from soybeans, mainly found in the rhizomes of the leguminous plant Genistein. Daidzein is mainly found in the root of the legume Pueraria lobata, the whole legume red clover, and the whole alfalfa. Notably, the equol, which is a metabolite of daidzein, is not a natural plant compound but sometimes ranked among the isoflavones (71).

Anthocyanins contain conjugated double bonds that contribute to chromophore. Moreover, the hydroxylation and methylation also determine their color phenotypes and stability with a wide range of structures varying from simple to complex compounds (72). As water-soluble pigments, the anthocyanins are usually present in cell vacuoles of the plant tissues and tend to occur mainly as glycosides. The most common sugars bonded to them are polysaccharide or monosaccharide, including glucose, rutinose, rhamnose, and xylose (73). Anthocyanins are particularly present in red fruits, some cereals, and root vegetables, such as grapes, purple grapes, blackberries, strawberries, and raspberries. The most common identified anthocyanins include cyanidin, malvidin, petunidin, pelargonidin, delphinidin, and peonidin.

Distinguished from flavones, the flavanones have saturated C2–C3 bonds with non-linear structure and higher bioavailability. The common flavanones include naringenin, eriodictyol, hesperetin, and sakutanetin, which can form various glycosides by the glycosylation of glucose and rhamnose. Hesperidin and naringin are the representative glycosides abundant in citrus having beneficial effects on gastrointestinal health (63, 66).

Flavan-3-ols, also called flavanols, have a single hydroxyl group at C-3 position instead of double bond, and lack the carbonyl group at C4 position. Moreover, the structures of these compounds comprise of a wide range of compounds ranging from simple monomers to condensed tannins, including (+)-Catechin, (–)-Epicatechin, (–)-Epicatechin-3-gallate, gallocatechin, epigallocatechin, and epigallocatechin gallate (74).

The Complex Interaction Between Flavonoids and Gut Microbiota

The ingested flavonoids, such as phytonutrients, indirectly provide energy and key elements in humans with health-promoting effects, where the gut microbiota serves a pivotal role. The gut microbiota comprises of microorganisms residing in the human gastrointestinal tract with the total number of more than 100 trillion cells (75). Its composition varies along the digestive tract and remains plastic according to the lifestyle as well as nutritional status of host throughout the life. The gut microbiota defines the gastrointestinal functional ecology by absorption, digestion, metabolism, and excretion of flavonoids, leading to the regulation of host immune response and behavior with long-term effects (17). Moreover, the changes in the composition of gut microbiota also introduce perturbation to bioavailability and biological effect of flavonoids. Consequently, the flavonoids regulate gut microbiota with varying levels of efficacy, including the stimulation of commensal and beneficial microbiota or the inhibition of the colonization of enteric pathogens (19, 76). It is therefore crucial to decipher the reciprocal correlation between flavonoids and gut microbiota.

Regulation of Gut Microbiota by Flavonoids

Natural flavonoids can regulate the gut microbiota from the aspects of type and amount and ameliorate dysbiosis or maintain intestinal homeostasis, thereby maintaining the host gut health. Besides, the different types of flavonoids exhibit different efficacy in boosting or suppressing the growth of gut microbiota. Recent evidence suggests that the flavonoids from tart cherries substantially increase the specific Bacteroides and Collinsella. Furthermore, an in vivo study showed that gut microbiota composition changed with the consumption of tart cherries (77). In this case, the tart cherries flavonoids, such as cyanidin-glycosylrutinoside and quercetin-rutinoside, showed its prebiotic effects. In other examples, in vitro digestion models, simulating anaerobic human fecal fermentation, showed that Green tea, rich in flavones and flavonols, showed multiple health-beneficial properties by increasing the populations of Lactobacilli spp. and Bifidobacteria spp. (78). The cranberry or its extracts increased the abundance of Akkermansia spp. and inhibited Bacteroides and Bifidobacteria, reducing the intestinal inflammation (79). Three plant flavonoids, including quercetin, catechin, and puerarin, were compared in a study for their regulatory functions on gut microbiota in vitro. Experimental results suggested their different capacities to regulate the abundance of Bifidobacterium spp. Moreover, the aglycones rather than glycosides were shown to influence the growth of certain species. In detail, the quercetin stimulated Firmicutes, Proteobacteria, and Actinobacteria, while puerarin increased Fusobacteria and Proteobacteria, as the consequence of increasing the richness and diversity of microbial communities (80).

Many studies have reported the effects of flavonoids on the gut microbiota. In vitro models proved that the flavonols, such as quercetin, had the following prebiotic actions: increasing the abundance of Bifidobacterium adolescentis; anti-inflammatory activity by producing NO inhibitors in murine macrophage-like RAW264 cells (81); inhibiting gut pathogen Salmonella typhimurium's growth and adhesion to human gut cell line; enhancing the proliferation and adhesion of probiotic Lactobacillus rhamnosus (82). Kaempferol was reported to suppress the vacuolating cytotoxin A and cytotoxin-associated gene A translocation of Helicobacter pylori in the AGS cells model (83). Baicalein showed the similar effects (84). In vivo experiments confirmed that the oral quercetin treatment in high-fat diet (HFD)-fed mice suppressed the abundance of Verrucomicrobia and increased that of Actinobacteria, Cyanobacteria, and Firmicutes, as well as the diversity of microbiota diversity (85–87). Baicalein regulated the composition of gut microbiota via its influence on the abundance of beneficial and pathogenic bacteria (88). The treatment of genistein the abundance among the Prevotella and Akkermansia genera, particularly Prevotella copri and Akkermansia muciniphila (89). Other special in vivo models, such as the APP/PS1 transgenic mice, found that under low vitamin D supplementation, quercetin elevated the diversity of gut microbiota including Facklamia and Aerococcus, improving the cognitive function (90). In female perinatal non-obese diabetic (NOD) mice, the exposure of genistein showed an increase in the level of Enterobacteriales, suggesting a pro-inflammatory response (91). In other experimental settings, the flavanones in Citrus were investigated for their interference with quorum sensing (QS), which showed reduction in the levels of QS signal mediated by acyl homoserine lactone (AHL) with the down-regulation of relative genes, and inhibition of biofilm formation as well as bacterium swimming and swarming motility (92). As for the flavan-3-ols, they changed the gut micro-ecology by affecting the adhesion of Lactobacilli strains to intestinal epithelial cells (93, 94). Anthocyanidin showed anti-bacterial activity by either killing the pathogenic bacteria or inhibiting their growth, such as Bacillus subtilis, Staphylococcus aureus, Enterococcus faecalis, and Pseudomonas aeruginosa (95). The regulation of gut microbiota by flavonoids is systematically summarized in Table 1. Previous studies were focused on the effects of the monomeric component of flavonoids on the specified strain of gut microorganisms. With the advancement in the development of metagenomics, metabolomics, proteomics, and transcriptomics, more research could focus on the in-depth regulatory mechanisms of flavonoids on gut microbiota.

Effect of Gut Microbiota on the Bioaccessibility of Flavonoids

It is well-known that the bioaccessibility of flavonoids in the human gastrointestinal tract is induced by many factors (116), including its structure, hydrolyzing enzymes throughout the gastrointestinal tract, composition of the intestinal microbiota, and transporter proteins in intestinal epithelial cells. The gut microbiota contributes to further modification and transformation of flavonoids for beneficial physiological effects. Due to its specific and vast gene pool, the intestinal microbiota has great potential in exploring the metabolites of flavonoids, and catalyzing important reactions in the intestinal tract. The gut microbiota is thought to be helpful in various metabolic reactions, including biosynthesis, catabolism, conjugation, and modification by containing various types of enzymes (117). During the conversion of flavonoids, the catalysis reaction by gut microbiota includes the following three types; hydrolysis, cleavage, and reduction. These three types are further subdivided into O-de-glycosylation, ester hydrolysis, C-ring cleavage, de-lactonization, de-methylation, de-hydroxylation, and double bond reduction (17).

The most common flavonoids are in the form of glycosides, which require the removal of attached sugars before absorption. Besides carrying glucose, galactose, arabinose, rhamnose, and xylose in the form of rhamnosides or rutinosides also contribute to the structural diversity of flavonoids, such as hesperidin, naringin, narirutin, and neohesperidin. These compounds are needed to be hydrolyzed by enzymes either from gut microbiota or human intestinal enzymes before absorption. Some enzymes can cleave glycosidic linkages present in human cells, except rhamnosidases. It has been reported that some bacteria have β-glucosidase activities in the human intestinal microbiota, which mainly include B. adolescentis, Bifidobacterium longum, Enterococcus faecalis, Bacteroides ovatus, Bacteroides uniformis, Parabacteroides distasonis, and Escherichia coli (118–124), etc. The same is true for rhamnosidase (125–129). Recent advances have reported identifying human intestinal bacterial species and strains related to flavonoid conversion, which could catalyze de-glycosylation reactions, especially O-de-glycosylation (130). For example, 22 strains of Bifidobacterium representative among the eight major species from human origin were found to have the ability of bio-conversion of soy isoflavones (120). Tao et al. characterized and isolated intestinal bacteria from the human feces sample and investigated their ability to convert buddleoside by using UPLC-LTQ/Orbitrap/MS/MS, and found four strains showing more powerful conversion capability (128). After releasing their aglycones, the flavonoids can be metabolized by phase II biotransformation enzymes into glucuronidated, sulfated and methylated products (131), which then require specific transferases, including glucuronyl-transferase, phenol-sulfo-transferase, and acetyl-transferase. The catabolic reactions of flavonoids include the removal of methyl ethers, opening of carbon rings, and breaking of C-C bonds. These catabolic reactions are regulated by the enzymatic activities of anaerobic bacteria, such as Clostridium and Coriobacteriaceae (17). The phenolic rings of flavonoids often contain methoxy groups, and some strains have the ability to O-demethylate, such as Bacterium Bautia sp. MRG-PMF1 and Eubacterium limosum (132–135). Recently, Feng et al. (136) have summarized that some intestinal bacteria could metabolize flavonoids in various metabolites with cleaved rings enzymes, mainly from Enterococcus casseliflavus, Eubacterium ramulus, Clostridium orbiscindens sp. nov. These microbe-derived metabolites were reported to possess multiple bioactivities in different metabolic pathways (136–138). Table 2 lists some main flavonoid-converting enzymes related to the human gut bacteria.

Gut Microbiota and IBD

Inflammatory bowel disease is an autoimmune intestinal disorder, having UC and CD as the most common phenotype, characterized with the intermittent episodes having relapse and clinical remission, potentially causing intestinal injury and dysfunction. The UC is characterized with continuous inflammation, which is limited to the mucosa and extends from the rectum to a variable degree in the colon. The pathological features of UC are micro-abscesses, in which the neutrophils infiltrate into the lamina propria and intestinal crypts. Other histological feature includes the depletion of goblet cells. Unlike UC, the CD is characterized with the segmental and chronic inflammation and sharp demarcation between bowel segments, accompanied by the pathological features of transmural inflammation, granulomatous inflammation, and narrow or penetrating ulcers, involving any site of the gastrointestinal tract (140). The human gastrointestinal tract contains a complex and diverse microbial community, making a strong symbiotic relationship with the host. The gut homeostasis needs the interaction between commensal microbiota and host immune system (141). At present, the gut microbiota is reported to have multiple important functions, including the synthesis of essential vitamins, fermentation and digestion of other nutrients, and protection of the gastrointestinal from colonization by pathobionts. In general, the gut microbiota sustains a relative balance, which can be changed by environmental factors, such as anti-biotic exposure and diet (142–144). The gut microbiota is a key regulator of health and disease, which is, sometimes considered as an essential “organ” that provides nourishment, regulates the epithelial development, and instructs the innate immunity (145). However, it has also been linked to the risk of a variety of diseases, including the metabolic diseases, IBD, colorectal cancer, and allergic diseases (146). The excellent studies (Table 3), recently published by HMP and iHMP launched by NIH, have comprehensively characterized the metabolic changes in the microbiota and host immune responses during the IBD using multi-omics data, including macro-genomics, macro-transcriptomics, and macro-proteomics. All the relevant data is deposited in the Inflammatory Bowel Disease Multi-omics Database (IBDMDB) (3). This showed that the IBD, which is a heterogeneous disease, is caused by the genetic variabilities as well as the complex interactions between intrinsic host factors and environmental factors (147). However, the exact mechanism of pathogenesis of IBD is still remained to be elucidated, and there is no consensus theory according to existing literature. In the following, the complex interactions between IBD and gut microbiota are discussed to serve as primary targets for potential therapeutic strategies (Figure 3).

Figure 3

IBD and Microbial Dysbiosis

Studies have shown that cesarean section, non-breastfeeding, too clean life urbanization and anti-biotic abuse may lead to a lack of exposure to microorganisms in early life, resulting in the loss of adverse regulatory pathways, leading to an overactive immune response to the symbiotic gut microbiota. When the steady-state balance between the host and its microbial content is disrupted, it is called dysbiosis, which is considered to be closely related to IBD in some studies on animal models and humans. This uncontrolled intestinal immune response to the bacterial antigens leads to the activation of leukocytes and epithelial cells, causing the production of numerous cytokines and chemokines, thereby triggering a series of oxidation reactions and inflammatory responses (156). Differences in the compositions of intestinal microbiota exist between IBD patients and healthy people. Similarly, Rehman et al. profiled the bacterial community by analyzing 89 mucosal biopsies samples from German, Lithuanian, and Indian individuals and found that the Faecalibacteria and Papillibacter, which belong to the Clostridium leptum subgroup, served as reliable microbiota-based biomarkers (150). The relative abundances of Firmicutes and Enterobacteriaceae were also found to be correlated with the IBD (157). Recent metagenomic analyses also revealed the effects of the gut microbiota's dysbiosis at the strain level, demonstrating Enterococcus faecalis as an inflammatory genotype from UC patients (149). Moreover, the association between Malassezia and CD has also been demonstrated in the dextran sulfate sodium (DSS) -induced mouse models (158). M. restricta mainly triggers innate inflammation through CARD9 and is recognized by anti-fungal anti-bodies in patients with CD; it will produce strong inflammatory cytokines from innate cells carrying IBD-related CARD9 polymorphisms and aggravate colitis in mice model. Among various chemically induced colitis models, the DSS-induced colitis model is widely used because of its simplicity and many similarities with human UC. The acute, chronic, and recurring models of intestinal inflammation can be achieved by modifying the concentration and frequency of DSS.

IBD and Immune Response

The host immune system and indigenous gut microbiota co-evolve with each other, maintaining a rigid balance between tolerance to the symbiotic bacteria and responding to the threat from pathogenic bacteria (159). The balance of T_reg/T_H17 with pro-inflammatory and anti-inflammatory cytokines is essential for efficient host gut homeostasis and is directly affected by the gut microbiota, which has been demonstrated in mouse models (160, 161). Under the transcriptional regulation of retinoic acid-related orphan receptor (ROR)-γt, the T_H17 mediates effector functions, which is a characteristic feature for the production of signature cytokines, including interleukin (IL)-17, IL-21, IL-22, IL-23, and IL-25, which, in turn, induce other pro-inflammatory cytokines and chemokines, promoting tissue inflammation. The T_reg cells are regulated by the transcription factor forkhead box P3 (Foxp3), and can be divided into natural and induced T_reg cells (162). The germ-free mouse models showing the symptoms of intestinal immune deficits demonstrated that the microbiota was required for the development of intestinal immune system (163). The increase in the intestinal T_H17 and T_H2 cells and decrease in the ROR γt Treg cells were reported in the germ-free mice being supplemented with the IBD microbiota (164). Some species in the gut microbiota directly or indirectly participate in the inflammatory processes. Their pathogenetic effect is based on the induction of proinflammatory immune cells, followed by the effector function. A number of studies have identified several specific commensal bacteria with intestinal T_reg-inducing capacity, such as Bacteroides fragilis and Clostridium (163, 165, 166). Interestingly, a study found the commensal bacterium, involved in the pathogenesis of CD, produced the anti-inflammatory proteins, revealing its anti-inflammatory effect by inhibiting the NF-κB pathway in the dinitrobenzene sulfonic acid (DNBS)-induced colitis mouse models (167). On the other hand, a study found that the total mucosa-associated bacteria increased in the UC and CD samples from the normal intestinal epithelium, while the quantity and abundance of Akkermansia muciniphila reduced by many fold (168). Another study found that the human commensal bacterial strain, B. fragilis, had a protective effect in DSS-induced mouse models of experimental colitis (169).

IBD and Barrier Disruption

The alterations in the gut microbiota resulted from the increase in the nitrosative and oxidative stress in the intestinal environment during IBD include the decrease in microbial diversity and the increase in the relative abundance of facultative anaerobe (7). One of the typical symptoms of IBD pathology is the dysfunction of intestinal barrier with increasing intestinal permeability, which results from disruption of tight junction proteins and release of pro-inflammatory mediators, including ROS and RNS (170). As a result, the aberrant mucosal immune response affects the genetically predisposed individuals, causing the pathologic alterations in their intestinal microbiota (171). In healthy people, the normal intestinal microbiota inhabiting the colon mucus is relatively stable, which does not trigger the inflammatory response. This is due to the inner and outer mucus layers of colon, which are consisted of mucins, trefoil peptides, immunoglobulins and other proteins, consequently maintaining the barrier integrity (172). The anti-microbial proteins also play an important role in the prevention of the overgrowth of pathogenic strains (173). The dysregulation of mucosal immune system usually results in the pathogenic immune response to the intestinal commensal microbiota (174). Vrakas et al. collected blood and tissue biopsy samples from the active/inactive UC and CD adult patients, as well as healthy individuals, and determined their composition of gut microbiota using real-time quantitative reverse transcription PCR. The result showed that in comparison with healthy controls, the total bacterial DNA concentration levels were higher in the IBD patients with the increase in Bacteroides spp. and reduction in Clostridium leptum group and Faecalibacterium prausnitzi (148).

Flavonoids and IBD

Inflammatory bowel disease is characterized by the chronic inflammation of gastrointestinal tract. The development of disease course seriously impairs the quality of life of the patients, who then require sustained drug treatments and surgical interventions. Based on these situations, the treatment targets of IBD is the remission of symptoms during the acute flare and lowering the chronic inflammatory state (20). In order to overcome these problems, the effective and safe treatment strategies for the prevention and treatment of IBD are needed. Flavonoids may be one of such potential agents (Table 4). Previous studies have shown the following beneficial effects of flavonoids on the gastrointestinal tract: maintaining the integrity of the intestinal barrier; preventing the intestinal wall from pharmacological insults and food toxins; regulating the gut immune system; shaping the profiles of microbiota; regulating the gut hormonal secretions by enteroendocrine cells (Figure 4) (187).

Figure 4

Flavonoids: Mucosal Integrity and the Function of Intestinal Epithelial Barrier

The mucosal barrier is imperative for the maintenance of intestinal homeostasis. The dysfunction of intestinal barrier is correlated with the etiology of IBD (188). One of the prospective studies about the IBD patients and mucosal healing demonstrated the relationship between impaired intestinal permeability and ongoing bowel symptoms of diarrhea or abdominal pain (189). The in vivo DSS-induced mouse colitis models also demonstrated that the increase in the gut permeability resulted in chronic inflammatory responses (190, 191). The two main factors used for the evaluation of the function of intestinal mucosal barrier include the integrity of mucus layer and the production and assembly of tight junction proteins (192). The mucus layer provides a physicochemical barrier to protect the surface of epithelial cells. The tight junction proteins are the main determinants of intestinal physical barrier. The expression and association of the tight junction proteins and actin cytoskeleton determine the permeability of tight junction proteins, which are dynamically regulated by various intracellular signaling molecules. Studies have reported that flavonoids could enhance the integrity of tight junction proteins, including ZO-2, occludins, and occluding. Quercetin, myricetin, and kaempferol could enhance tight junction protein expression and inhibit PKCδ in human Caco-2 cells (193, 194). In addition, the DSS-induced mouse model has also demonstrated that the supplement of naringenin decreased the disease activity index and expression of inflammatory cytokine (IL-6 and IL-17A) (175). In similar animal models, the sinensetin reversed the colitis-associated increase in the intestinal permeability, promoted the autophagy of epithelial cells, decreased the apoptosis of epithelial cells, and reduced the mucosal claudin-2 (176).

Many studies currently focus on the association of morphological and functional changes in the vascular endothelium with IBD (177, 195–197). The functional and structural changes in vascular endothelium lead to the activation of endothelial cells. These changes cause the expression of a variety of cell-adhesion molecules and chemokines on the endothelia cell surface, including ICAM-1, VCAM-1, and IL-1β, and the enrichment of leukocyte activation following inflammatory responses. As compared to healthy controls, the IBD patients showed an increase in the adhesion of CAM and leukocyte (195). Microvascular expression of CAMs could mediate the recruitment of circulating leukocytes. The quercetin has been reported to reduce the overproduction of TNF-α, IL-1β, interleukin-6, ICAM-1, and VCAM-1 in the cellular model of lipopolysaccharide (LPS)-induced rat intestinal microvascular endothelial cells (196). Using the same in vitro models, investigating the integrity of intestinal endothelial barrier, the naringin effectively ameliorated the disruption of gut-vascular barrier (197). The kaempferol showed similar effects. Moreover, it has a protective effect against the dysfunction of barrier via preventing the activation of NF-κB signaling pathway in the LPS-induced epithelial-endothelial co-culture model (177).

Flavonoids and Immunomodulation

The different activities and properties of flavonoids have important implications in the activation, maturation and signal transduction of cells and the production and secretion of several cytokines in immune cells (198). A recent study showed that the astragalin reduced the level of pro-inflammatory cytokines and their mRNAs, such as TNF-α, IL-6, and IL-1β, and affected the key relative groups abundance of potentially beneficial Ruminococcaceae and potentially harmful Escherichia-Shigella (183). As mentioned previously, the imbalance of the immune system is associated with the pathogenesis of IBD. The adaptive immune system is usually considered as a main contributor to the pathogenesis of IBD, which may arise from an increase in the pro-inflammatory factors driven by TH cells and ineffectual anti-inflammatory T_reg cells (199). For example, using the DSS-induced mouse colitis models, Tao et al. found that the natural icariin inhibited the T_H1/T_H17 responses by suppressing the activation of STAT1 and STAT3, leading to the mitigation of inflammation (200). Abron et al. demonstrated that the genistein skewed the M1 macrophages toward M2 phenotypes, and reduced the systemic cytokine levels in part to attenuate the colitis symptoms (201). The majority of published studies performed using the experimental models of colitis have indicated that the altered immune response was correlated with the increasing release of pro-inflammatory cytokines, including IFN γ, TNFα, IL-6, IL-1β, GM-CSF, and IL-17A (20). With the increase in the mucosal permeability, the Toll-like receptors (TLRs) in endothelial cells of the intestinal epithelium are activated by the LPS exposed on the surface of gram-negative bacteria. In such case, the quercetin was found to prevent activation of inflammatory responses by inhibiting the LPS-induced expression of TLR4 in endothelium, through the MyD88-dependent NF-κB, MAPKs, and STAT pathways (202). In the 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis mouse models, the baicalin exhibited anti-inflammatory effects by inhibiting the activation of TLR4/NF-κB and PI3K/AKT pathways (180, 203). Likewise, the same in vivo models showed the beneficial effect of oral tangeretin, alleviating the disease symptoms in TNBS-induced colitis models. The possible mechanisms of action of tangeretin might be the inhibition of LPS binding to the immune cells, such as dendritic cells, by suppressing the expression of IL-12 and TNF-α as well as the activation of NF-κB (204). The similar results were also observed for astragalin and taxifolin (182, 205).

Flavonoids and Gut Microbiota

The interaction between flavonoids and microbiota offers considerable potential for the maintenance of gastrointestinal and systemic health. The beneficial effects of flavonoids for improving the health are not only attributed to their direct impact on the colon, but also to their alteration of the intestinal microbiota and performance of metabolism, which provide a therapeutic basis for the IBD with dysbiosis (187). Many studies have reported that the commonly observed variations in the IBD samples mainly focused on the reduced diversity of gut microbiota with reduction in the relative abundance of reducing Firmicutes and increasing Proteobacteria (206).

Flavonoids are reported to positively regulate the composition of gut microbiota. Several studies have shown a great therapeutic potential of the quercetin for the IBD patients, suppressing the abnormal expression of proinflammatory cytokines and modifying the gut microbiota by increasing the relative abundance of Bacteroides, Bifidobacterium, Lactobacillus, and Clostridia, while reducing the relative abundance of Fusobacterium and Enterococcus (184, 185). In addition, both the quercetin aglycone alone and in combination with the mono-glycosides exhibited higher Chao1 and Shannon indices and a lower Simpson index to counteract the adverse effect by colitis (207). Furthermore, the flavonoids upregulated the beneficial bacteria and down-regulated the growth of pathogen. Recently, the A. muciniphila showed protective effects against colitis in the DSS-induced colitis mouse models (208), confirming its main biological functions, which included the maintenance of gut barrier function and host metabolism (168, 209). Dietary supplementations with some flavonoids positively regulates this bacterial growth (79, 210, 211). For example, cranberry extract treatment markedly increased the proportion of A. muciniphila, and it was identified that the daily intake of flavonols were at 18.8 mg kg⁻¹ d⁻¹, total anthocyanins were at 6.6 mg kg⁻¹ d⁻¹ (79). The Clostridium difficile infection (CDI) has dramatically increased over the past decade worldwide (212). This bacterium induces aberrant inflammatory immune responses, which causes the breakdown of gastrointestinal barrier in the genetically susceptible individuals, leading to the development of IBD (213). The literature evidence suggests that the flavonoids significantly reduce toxin synthesis, sporulation, and spore outgrowth of C. difficile, while down-regulates the genes critical for pathogenesis (214, 215).

The colonic inflammation stimulates the production of IFN-γ, generating ROS by phagocytic innate immune cells, which causes a series of radicals as their end-products by facultative anaerobes. As a result, the bacterial diversity is decreased. Nevertheless, the beneficial effects of flavonoids for promoting the gut health are due to its anti-oxidant and free radical-scavenging activity (216). Most of the flavonoids assayed have the hallmark features of possessing numerous hydroxyl groups with the ability of amelioration oxidative stress (20, 216). A number of studies have reported that the flavonoids inhibit the expression of iNOS, while reduce the production of NO (20, 217). Moreover, the flavonoids enhance the activities of different enzymes having anti-oxidant properties, such as glutathione, superoxide dismutase and gluthathione peroxidases (218, 219).

Conclusions and Future Perspectives

In this review, the flavonoids have been systematically summarized, providing evidences with a focus on the interactions between flavonoids and gut microbiota and their potential therapeutic effect, including their potential mechanisms of action, on IBD. However, it should be noted that there are still many problems need to be solved. Currently, some aspects of the pathogenesis of IBD are not completely understood. The gut microbiota has been widely recognized as a key factor for the intestinal homeostasis and has correlation with the pathogenesis of IBD (220). The current therapies for IBD are comprised of corticosteroids, immunosuppressants, anti-biotics, and biological agents. However, these therapies are neither curative nor cost-effective. Furthermore, these therapies do not target the microorganisms directly for the cause or contribution to inflammation (221). Thus, to develop more effective strategies for the treatment of IBD still remains a challenge. The flavonoids have received much attention for their biological properties, as well as their anti-oxidant and anti-inflammatory activities have been well-documented. Meanwhile, the flavonoids and their metabolites also affect the intestinal ecology by regulating the microbiota with bacteriostatic or bactericidal effects for the pathogenic and harmful bacteria, and prebiotic effects for the beneficial bacteria (222). On the other hand, due to the low bioavailability of flavonoids, 90% of them persists in the colon. The gut microbiota exhibits a great metabolic capacity of metabolizing the flavonoids via hydrolyzation, de-methylation, de-hydroxylation, and de-carboxylation, resulting in smaller metabolites, which are absorbed across the intestinal mucosa to benefit human health. In summary, flavonoids have tremendous therapeutic potential for the treatment of IBD. However, most flavonoids have poor water solubility, so their clinical application is hindered. Future studies could focus on IBD treatment by targeting gut microbiota and studying flavonoid drug delivery methods, including proteins, peptides, monoclonal anti-bodies, nucleic acids, and living cells, etc. The potential molecular mechanisms or toxicological assessments of flavonoid regulation of intestinal microbiota have not been well-elucidated, nor have their actual efficacy in the treatment of human IBD been proven. Thus, further research should also pay attention to more animal or cellular models and even clinical data to evaluate the safety and efficacy of flavonoid monomer molecules targeting gut microbiota against IBD.

Funding

The present study was supported by grants from National Key Research and Development Project (No. 2019YFA0905600), Science and Technology Program of Tianjin, China (No. 19YFSLQY00110).

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

• 1.

  MolodeckyNASoonISRabiDMGhaliWAFerrisMChernoffGet al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. (2012) 142:46–54. 10.1053/j.gastro.2011.10.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2.

  KaplanGG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. (2015) 12:720–7. 10.1038/nrgastro.2015.150

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3.

  Lloyd-PriceJArzeCAnanthakrishnanANSchirmerMAvila-PachecoJPoonTWet al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature. (2019) 569:655–62. 10.1038/s41586-019-1237-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4.

  LeyREPetersonDAGordonJI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. (2006) 124:837–48. 10.1016/j.cell.2006.02.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 5.

  QinJLiRRaesJArumugamMBurgdorfKSManichanhCet al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. (2010) 464:59–65. 10.1038/nature08821

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6.

  SenderRFuchsSMiloR. Are We really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell. (2016) 164:337–40. 10.1016/j.cell.2016.01.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7.

  SchirmerMGarnerAVlamakisHXavierRJ. Microbial genes and pathways in inflammatory bowel disease. Nat Rev Microbiol. (2019) 17:497–511. 10.1038/s41579-019-0213-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8.

  SinghAKCabralCKumarRGangulyRRanaHKGuptaAet al. Beneficial effects of dietary polyphenols on gut microbiota and strategies to improve delivery efficiency. Nutrients. (2019) 11:2216–37. 10.3390/nu11092216

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 9.

  HuttenhowerCGeversDKnightRAbubuckerSBadgerJHChinwallaATet al. Structure, function and diversity of the healthy human microbiome. Nature. (2012) 486:207–14. 10.1038/nature11234

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10.

  ProctorLMCreasyHHFettweisJMLloyd-PriceJMahurkarAZhouWet al. The integrative human microbiome project. Nature. (2019) 569:641–8. 10.1038/s41586-019-1238-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11.

  LozuponeCAStombaughJIGordonJIJanssonJKKnightR. Diversity, stability and resilience of the human gut microbiota. Nature. (2012) 489:220–30. 10.1038/nature11550

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12.

  ZmoraNSuezJElinavE. You are what you eat: diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol. (2019) 16:35–56. 10.1038/s41575-018-0061-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13.

  Del RioDRodriguez-MateosASpencerJPETognoliniMBorgesGCrozierA. Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid Redox Signal. (2013) 18:1818–92. 10.1089/ars.2012.4581

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14.

  LuM-FXiaoZ-TZhangH-Y. Where do health benefits of flavonoids come from? Insights from flavonoid targets and their evolutionary history. Biochem Biophys Res Commun. (2013) 434:701–4. 10.1016/j.bbrc.2013.04.035

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15.

  CirilloGCurcioMVittorioOIemmaFRestucciaDSpizzirriUGet al. Polyphenol conjugates and human health: a perspective review. Crit Rev Food Sci Nutr. (2016) 56:326–37. 10.1080/10408398.2012.752342

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16.

  CaoHOuJYChenLZhangYBSzkudelskiTDelmasDet al. Dietary polyphenols and type 2 diabetes: human study and clinical trial. Crit Rev Food Sci Nutr. (2019) 59:3371–9. 10.1080/10408398.2018.1492900

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17.

  Carlos EspinJGonzalez-SarriasATomas-BarberanFA. The gut microbiota: a key factor in the therapeutic effects of (poly) phenols. Biochem Pharmacol. (2017) 139:82–93. 10.1016/j.bcp.2017.04.033

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18.

  LooYTHowellKChanMZhangPZNgK. Modulation of the human gut microbiota by phenolics and phenolic fiber-rich foods. Compr Rev Food Sci Food Saf. (2020) 19:1268–98. 10.1111/1541-4337.12563

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19.

  PengMFTabashsumZAndersonMTruongAHouserAKPadillaJet al. Effectiveness of probiotics, prebiotics, and prebiotic-like components in common functional foods. Compr Rev Food Sci Food Saf. (2020) 19:1908–33. 10.1111/1541-4337.12565

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20.

  VezzaTRodriguez-NogalesAAlgieriFUtrillaMPRodriguez-CabezasMEGalvezJ. Flavonoids in inflammatory bowel disease: a review. Nutrients. (2016) 8:211–33. 10.3390/nu8040211

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21.

  Septembre-MalaterreARemizeFPoucheretP. Fruits and vegetables, as a source of nutritional compounds and phytochemicals: changes in bioactive compounds during lactic fermentation. Food Res Int. (2018) 104:86–99. 10.1016/j.foodres.2017.09.031

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22.

  ShabbirMAMehakFKhanZMAhmadWKhanMRZiaSet al. Interplay between ceramides and phytonutrients: new insights in metabolic syndrome. Trends Food Sci Technol. (2021) 111:483–94. 10.1016/j.tifs.2021.03.010

  • CrossRef
  • Google Scholar

• 23.

  MartinCZhangYTonelliCPetroniK. Plants, diet, and health. Annu Rev Plant Biol. (2013) 64:19–46. 10.1146/annurev-arplant-050312-120142

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24.

  MartinC. A role for plant science in underpinning the objective of global nutritional security?Ann Bot. (2018) 122:541–53. 10.1093/aob/mcy118

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25.

  WlodarskaMWillingBPBravoDMFinlayBB. Phytonutrient diet supplementation promotes beneficial Clostridia species and intestinal mucus secretion resulting in protection against enteric infection. Sci Rep. (2015) 5:1–9. 10.1038/srep09253

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 26.

  PuttaSYarlaNSKumarEKLakkappaDBKamalMAScottiLet al. Preventive and therapeutic potentials of anthocyanins in diabetes and associated complications. Curr Med Chem. (2018) 25:5347–71. 10.2174/0929867325666171206101945

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27.

  OgunleyeAAXueFMichelsKB. Green tea consumption and breast cancer risk or recurrence: a meta-analysis. Breast Cancer Res Treat. (2010) 119:477–84. 10.1007/s10549-009-0415-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 28.

  JeongWYJinJSChoYALeeJHParkSJeongSWet al. Determination of polyphenols in three Capsicum annuum L. (bell pepper) varieties using high-performance liquid chromatography-tandem mass spectrometry: their contribution to overall antioxidant and anticancer activity. J Separ Sci. (2011) 34:2967–74. 10.1002/jssc.201100524

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 29.

  MulvihillEEHuffMW. Antiatherogenic properties of flavonoids: implications for cardiovascular health. Can J Cardiol. (2010) 26:17A−21A. 10.1016/s0828-282x(10)71056-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30.

  ZakariaZAHisamEEARofieeMSNorhafizahMSomchitMNTehLKet al. In vivo antiulcer activity of the aqueous extract of Bauhinia purpurea leaf. J Ethnopharmacol. (2011) 137:1047–54. 10.1016/j.jep.2011.07.038

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31.

  HanNGuYYeCCaoYLiuZYinJ. Antithrombotic activity of fractions and components obtained from raspberry leaves (Rubus chingii). Food Chem. (2012) 132:181–5. 10.1016/j.foodchem.2011.10.051

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32.

  TaoW-WDuanJ-AYangN-YTangY-PLiuM-ZQianY-F. Antithrombotic phenolic compounds from Glycyrrhiza uralensis. Fitoterapia. (2012) 83:422–5. 10.1016/j.fitote.2011.12.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33.

  BearaINLesjakMMOrcicDZSiminNDCetojevic-SiminDDBozinBNet al. Comparative analysis of phenolic profile, antioxidant, anti-inflammatory and cytotoxic activity of two closely-related Plantain species: Plantago altissima L. and Plantago lanceolata L. LWT Food Sci Technol. (2012) 47:64–70. 10.1016/j.lwt.2012.01.001

  • CrossRef
  • Google Scholar

• 34.

  ZimmerARLeonardiBMironDSchapovalEde OliveiraJRGosmannG. Antioxidant and anti-inflammatory properties of Capsicum baccatum: from traditional use to scientific approach. J Ethnopharmacol. (2012) 139:228–33. 10.1016/j.jep.2011.11.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35.

  Schmitz-EibergerMABlankeMM. Bioactive components in forced sweet cherry fruit (Prunus avium L), antioxidative capacity and allergenic potential as dependent on cultivation under cover. LWT Food Sci Technol. (2012) 46:388–92. 10.1016/j.lwt.2011.12.015

  • CrossRef
  • Google Scholar

• 36.

  SchuetzKSassMde WithAGraubaumH-JGruenwaldJ. Immune-modulating efficacy of a polyphenol-rich beverage on symptoms associated with the common cold: a double-blind, randomised, placebo-controlled, multi-centric clinical study. Br J Nutr. (2010) 104:1156–64. 10.1017/s0007114510002047

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 37.

  BijakMBobrowskiMBorowieckaMPodsedekAGolanskiJNowakP. Anticoagulant effect of polyphenols-rich extracts from black chokeberry and grape seeds. Fitoterapia. (2011) 82:811–7. 10.1016/j.fitote.2011.04.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38.

  XiaDWuXShiJYangQZhangY. Phenolic compounds from the edible seeds extract of Chinese Mei (Prunus mume Sieb. et Zucc) and their antimicrobial activity. LWT Food Sci Technol. (2011) 44:347–9. 10.1016/j.lwt.2010.05.017

  • CrossRef
  • Google Scholar

• 39.

  SilvaJCRodriguesSFeasXEstevinhoLM. Antimicrobial activity, phenolic profile and role in the inflammation of propolis. Food Chem Toxicol. (2012) 50:1790–5. 10.1016/j.fct.2012.02.097

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40.

  JiXWWuBZhouZQKangDGLeeHSChoKWet al. Mechanisms of vasodilatory effects of total flavonoids from Euphorbia humifusa in rat aorta. Faseb J. (2017) 31:619−28. 10.1096/fasebj.31.1_supplement.835.13

  • CrossRef
  • Google Scholar

• 41.

  WanYYuYPanXMoXGongWLiuXet al. Inhibition on acid-sensing ion channels and analgesic activities of flavonoids isolated from dragon's blood resin. Phytother Res. (2019) 33:718–27. 10.1002/ptr.6262

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42.

  Rodriguez-MateosAVauzourDKruegerCGShanmuganayagamDReedJCalaniLet al. Bioavailability, bioactivity and impact on health of dietary flavonoids and related compounds: an update. Arch Toxicol. (2014) 88:1803–53. 10.1007/s00204-014-1330-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43.

  FarhadiFKhamenehBIranshahiMIranshahyM. Antibacterial activity of flavonoids and their structure-activity relationship: an update review. Phytother Res. (2019) 33:13–40. 10.1002/ptr.6208

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44.

  GowdVKarimNShishirMRIXieLChenW. Dietary polyphenols to combat the metabolic diseases via altering gut microbiota. Trends Food Sci Technol. (2019) 93:81–93. 10.1016/j.tifs.2019.09.005

  • CrossRef
  • Google Scholar

• 45.

  RendeiroCSpencerJPEVauzourDButlerLTEllisJAWilliamsCM. The impact of flavonoids on spatial memory in rodents: from behaviour to underlying hippocampal mechanisms. Genes Nutr. (2009) 4:251–70. 10.1007/s12263-009-0137-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46.

  Kesse-GuyotEFezeuLAndreevaVATouvierMScalbertAHercbergSet al. Total and specific polyphenol intakes in midlife are associated with cognitive function measured 13 years later. J Nutr. (2012) 142:76–83. 10.3945/jn.111.144428

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47.

  NeshatdoustSSaundersCCastleSMVauzourDWilliamsCButlerLet al. High-flavonoid intake induces cognitive improvements linked to changes in serum brain-derived neurotrophic factor: two randomised, controlled trials. Nutr Health Aging. (2016) 4:81–93. 10.3233/nha-1615

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48.

  KoebeTWitteAVSchnelleATeskyVAPantelJSchuchardtJ-Pet al. Impact of resveratrol on glucose control, hippocampal structure and connectivity, and memory performance in patients with mild cognitive impairment. Front Neurosci. (2017) 11:105. 10.3389/fnins.2017.00105

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49.

  HollandTMAgarwalPWangYLeurgansSEBennettDABoothSLet al. Dietary flavonols and risk of Alzheimer dementia. Neurology. (2020) 94:e1749–56. 10.1212/wnl.0000000000008981

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50.

  HooperLKayCAbdelhamidAKroonPACohnJSRimmEBet al. Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: a systematic review and meta-analysis of randomized trials. Amer J Clin Nutr. (2012) 95:740–51. 10.3945/ajcn.111.023457

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51.

  PetersonJJDwyerJTJacquesPFMcCulloughML. Associations between flavonoids and cardiovascular disease incidence or mortality in European and US populations. Nutr Rev. (2012) 70:491–508. 10.1111/j.1753-4887.2012.00508.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52.

  RiedKSullivanTRFaklerPFrankORStocksNP. Effect of cocoa on blood pressure. Cochrane Database Syst Rev. (2012) 8:CD008893. 10.1002/14651858.CD008893.pub2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53.

  WangXOuyangYYLiuJZhaoG. Flavonoid intake and risk of CVD: a systematic review and meta-analysis of prospective cohort studies. Br J Nutr. (2014) 111:1–11. 10.1017/s000711451300278x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54.

  Di LorenzoACurtiVTenoreGCNabaviSMDagliaM. Effects of tea and coffee consumption on cardiovascular diseases and relative risk factors: an update. Curr Pharm Des. (2017) 23:2474–87. 10.2174/1381612823666170215145855

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55.

  DzoyemJPHamamotoHNgameniBNgadjuiBTSekimizuK. Antimicrobial action mechanism of flavonoids from Dorstenia species. Drug Discov Ther. (2013) 7:66–72. 10.5582/ddt.2013.v7.2.66

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56.

  SuriyanarayananBShanmugamKSanthoshRS. Synthetic quercetin inhibits mycobacterial growth possibly by interacting with DNA gyrase. Rom Biotechnol Lett. (2013) 18:8587–93.

  • Google Scholar

• 57.

  RoyRTiwariMDonelliGTiwariV. Strategies for combating bacterial biofilms: a focus on anti-biofilm agents and their mechanisms of action. Virulence. (2018) 9:522–54. 10.1080/21505594.2017.1313372

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58.

  GorniakIBartoszewskiRKroliczewskiJ. Comprehensive review of antimicrobial activities of plant flavonoids. Phytochem Rev. (2019) 18:241–72. 10.1007/s11101-018-9591-z

  • CrossRef
  • Google Scholar

• 59.

  LeeKWBodeAMDongZ. Molecular targets of phytochemicals for cancer prevention. Nat Rev Cancer. (2011) 11:211–8. 10.1038/nrc3017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60.

  AlbiniATosettiFLiVWNoonanDMLiWW. Cancer prevention by targeting angiogenesis. Nat Rev Clin Oncol. (2012) 9:498–509. 10.1038/nrclinonc.2012.120

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61.

  ChenLTengHJiaZBattinoMMironAYuZet al. Intracellular signaling pathways of inflammation modulated by dietary flavonoids: the most recent evidence. Crit Rev Food Sci Nutr. (2018) 58:2908–24. 10.1080/10408398.2017.1345853

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62.

  OzdalTSelaDAXiaoJBoyaciogluDChenFCapanogluE. The reciprocal interactions between polyphenols and gut microbiota and effects on bioaccessibility. Nutrients. (2016) 8:78. 10.3390/nu8020078

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63.

  ZhaoCYWangFLianYHXiaoHZhengJK. Biosynthesis of citrus flavonoids and their health effects. Crit Rev Food Sci Nutr. (2020) 60:566–83. 10.1080/10408398.2018.1544885

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64.

  XiaoJCapanogluEJassbiARMironA. Advance on the flavonoid C-glycosides and health benefits. Crit Rev Food Sci Nutr. (2016) 56:S29–45. 10.1080/10408398.2015.1067595

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65.

  XiaoJ. Dietary flavonoid aglycones and their glycosides: which show better biological significance?Crit Rev Food Sci Nutr. (2017) 57:1874–905. 10.1080/10408398.2015.1032400

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66.

  StevensYVan RymenantEGrootaertCVan CampJPossemiersSMascleeAet al. The intestinal fate of citrus flavanones and their effects on gastrointestinal health. Nutrients. (2019) 11:1464. 10.3390/nu11071464

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67.

  CaoHChenXJassbiARXiaoJ. Microbial biotransformation of bioactive flavonoids. Biotechnol Adv. (2015) 33:214–23. 10.1016/j.biotechadv.2014.10.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68.

  PlazaMPozzoTLiuJAraKZGTurnerCKarlssonEN. Substituent effects on in vitro antioxidizing properties, stability, and solubility in flavonoids. J Agric Food Chem. (2014) 62:3321–33. 10.1021/jf405570u

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69.

  ParkHJinU-HOrrAAEchegaraySPDavidsonLAAllredCDet al. Isoflavones as Ah receptor agonists in colon-derived cell lines: structure-activity relationships. Chem Res Toxicol. (2019) 32:2353–64. 10.1021/acs.chemrestox.9b00352

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70.

  JungYSRhaC-SBaikM-YBaekN-IKimD-O. A brief history and spectroscopic analysis of soy isoflavones. Food Sci Biotechnol. (2020). 29:1605–17. 10.1007/s10068-020-00815-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71.

  KrizovaLDadakovaKKasparovskaJKasparovskyT. Isoflavones. Molecules. (2019) 24:1076. 10.3390/molecules24061076

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72.

  Rodriguez-AmayaDB. Update on natural food pigments - a mini-review on carotenoids, anthocyanins, and betalains. Food Res Int. (2019) 124:200–5. 10.1016/j.foodres.2018.05.028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73.

  FangJ. Bioavailability of anthocyanins. Drug Metab Rev. (2014) 46:508–20. 10.3109/03602532.2014.978080

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74.

  PinentMBlayMSerranoJArdevolA. Effects of flavanols on the enteroendocrine system: repercussions on food intake. Crit Rev Food Sci Nutr. (2017) 57:326–34. 10.1080/10408398.2013.871221

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75.

  MocoSMartinF-PJRezziS. Metabolomics view on gut microbiome modulation by polyphenol-rich foods. J Proteome Res. (2012) 11:4781–90. 10.1021/pr300581s

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76.

  ValdesLCuervoASalazarNRuas-MadiedoPGueimondeMGonzalezS. The relationship between phenolic compounds from diet and microbiota: impact on human health. Food Funct. (2015) 6:2424–39. 10.1039/c5fo00322a

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77.

  Mayta-ApazaACPottgenEDe BodtJPappNMarasiniDHowardLet al. Impact of tart cherries polyphenols on the human gut microbiota and phenolic metabolites in vitro and in vivo. J Nutr Biochem. (2018) 59:160–72. 10.1016/j.jnutbio.2018.04.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78.

  RhaC-SSeongHJungYSJangDKwakJ-GKimD-Oet al. Stability and fermentability of green tea flavonols in in-vitro-simulated gastrointestinal digestion and human fecal fermentation. Int J Mol Sci. (2019) 20:5890. 10.3390/ijms20235890

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79.

  AnheFFRoyDPilonGDudonneSMatamorosSVarinTVet al. A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut. (2015) 64:872–83. 10.1136/gutjnl-2014-307142

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80.

  HuangJCChenLXueBLiuQYOuSYWangYet al. Different flavonoids can shape unique gut microbiota profile in vitro. J Food Sci. (2016) 81:H2273–9. 10.1111/1750-3841.13411

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81.

  KawabataKSugiyamaYSakanoTOhigashiH. Flavonols enhanced production of anti-inflammatory substance(s) by Bifidobacterium adolescentis: prebiotic actions of galangin, quercetin, and fisetin. Biofactors. (2013) 39:422–9. 10.1002/biof.1081

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82.

  ParkarSGStevensonDESkinnerMA. The potential influence of fruit polyphenols on colonic microflora and human gut health. Int J Food Microbiol. (2008) 124:295–8. 10.1016/j.ijfoodmicro.2008.03.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83.

  YeonMJLeeMHKimDHYangJYWooHJKwonHJet al. Anti-inflammatory effects of Kaempferol on Helicobacter pylori-induced inflammation. Biosci Biotechnol Biochem. (2019) 83:166–73. 10.1080/09168451.2018.1528140

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84.

  ChenM-ESuC-HYangJ-SLuC-CHouY-CWuJ-Bet al. Baicalin, Baicalein, and Lactobacillus rhamnosus JB3 alleviated Helicobacter pylori infections in vitro and in vivo. J Food Sci. (2018) 83:3118–25. 10.1111/1750-3841.14372

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85.

  EteberriaUAriasNBoqueNMacarullaMTPortilloMPMartinezJAet al. Reshaping faecal gut microbiota composition by the intake of trans-resveratrol and quercetin in high-fat sucrose diet-fed rats. J Nutr Biochem. (2015) 26:651–60. 10.1016/j.jnutbio.2015.01.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86.

  NieJZhangLZhaoGDuX. Quercetin reduces atherosclerotic lesions by altering the gut microbiota and reducing atherogenic lipid metabolites. J Appl Microbiol. (2019) 127:1824–34. 10.1111/jam.14441

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87.

  PorrasDNistalEMartinez-FlorezSLuis OlcozJJoverRJorqueraFet al. Functional interactions between gut microbiota transplantation, quercetin, and high-fat diet determine non-alcoholic fatty liver disease development in germ-free mice. Mol Nutr Food Res. (2019). 63:e1800930. 10.1002/mnfr.201800930

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88.

  ZhangBWSunWLYuNSunJYuXXLiXet al. Anti-diabetic effect of baicalein is associated with the modulation of gut microbiota in streptozotocin and high-fat-diet induced diabetic rats. J Funct Foods. (2018) 46:256–67. 10.1016/j.jff.2018.04.070

  • CrossRef
  • Google Scholar

• 89.

  LopezPSanchezMPerez-CruzCVelazquez-VillegasLASyedaTAguilar-LopezMet al. Long-term genistein consumption modifies gut microbiota, improving glucose metabolism, metabolic endotoxemia, and cognitive function in mice fed a high-fat diet. Mol Nutr Food Res. (2018) 62:e1800313. 10.1002/mnfr.201800313

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90.

  LvMYangSCaiLQinL-qLiB-yWanZ. Effects of quercetin intervention on cognition function in APP/PS1 mice was affected by vitamin D status. Mol Nutr Food Res. (2018) 62 :e1800621. 10.1002/mnfr.201800621

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91.

  HuangGXuJCaiDChenS-YNagyTGuoTL. Exacerbation of type 1 diabetes in perinatally genistein exposed female non-obese diabetic (NOD) mouse is associated with alterations of gut microbiota and immune homeostasis. Toxicol Sci. (2018) 165:291–301. 10.1093/toxsci/kfy162

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92.

  TruchadoPGimenez-BastidaJ-ALarrosaMCastro-IbanezICarlos EspinJTomas-BarberanFAet al. Inhibition of quorum sensing (QS) in Yersinia enterocolitica by an orange extract rich in glycosylated flavanones. J Agric Food Chem. (2012) 60:8885–94. 10.1021/jf301365a

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93.

  BustosIGarcia-CayuelaTHernandez-LedesmaBPelaezCRequenaTCarmen Martinez-CuestaM. Effect of flavan-3-ols on the adhesion of potential probiotic Lactobacilli to intestinal cells. J Agric Food Chem. (2012) 60:9082–8. 10.1021/jf301133g

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94.

  CuevaCSanchez-PatanFMonagasMWaltonGEGibsonGRMartin-AlvarezPJet al. In vitro fermentation of grape seed flavan-3-ol fractions by human faecal microbiota: changes in microbial groups and phenolic metabolites. FEMS Microbiol Ecol. (2013) 83:792–805. 10.1111/1574-6941.12037

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95.

  CardonaFAndres-LacuevaCTulipaniSTinahonesFJIsabel Queipo-OrtunoM. Benefits of polyphenols on gut microbiota and implications in human health. J Nutr Biochem. (2013) 24:1415–22. 10.1016/j.jnutbio.2013.05.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96.

  OuyangJSunFFengWSunYQiuXXiongLet al. Quercetin is an effective inhibitor of quorum sensing, biofilm formation and virulence factors in Pseudomonas aeruginosa. J Appl Microbiol. (2016) 120:966–74. 10.1111/jam.13073

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97.

  LeeJHParkJHChoHSJooSWChoMHLeeJ. Anti-biofilm activities of quercetin and tannic acid against Staphylococcus aureus. Biofouling. (2013) 29:491–9. 10.1080/08927014.2013.788692

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98.

  AaL-xFeiFQiQSunR-bGuS-hDiZ-zet al. Rebalancing of the gut flora and microbial metabolism is responsible for the anti-arthritis effect of kaempferol. Acta Pharmacol Sin. (2020) 41:73–81. 10.1038/s41401-019-0279-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99.

  WuTZangXHeMPanSXuX. Structure-activity relationship of flavonoids on their anti-Escherichia coli activity and inhibition of DNA gyrase. J Agric Food Chem. (2013) 61:8185–90. 10.1021/jf402222v

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100.

  TaheriYSuleriaHARMartinsNSytarOBeyatliAYeskaliyevaBet al. Myricetin bioactive effects: moving from preclinical evidence to potential clinical applications. BMC Complement Med Ther. (2020) 20:14. 10.1186/s12906-020-03033-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101.

  SilvaLNDa HoraGCASoaresTABojerMSIngmerHMacedoAJet al. Myricetin protects Galleria mellonella against Staphylococcus aureus infection and inhibits multiple virulence factors. Sci Rep. (2017) 7:16. 10.1038/s41598-017-02712-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102.

  WangMFirrmanJLiuLYamK. A Review on flavonoid apigenin: dietary intake, ADME, antimicrobial effects, and interactions with human gut microbiota. Biomed Res Int. (2019) 2019:1–19. 10.1155/2019/7010467

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103.

  WangMQFirrmanJZhangLQArango-ArgotyGTomasulaPLiuLSet al. Apigenin impacts the growth of the gut microbiota and alters the gene expression of Enterococcus. Molecules. (2017) 22:22. 10.3390/molecules22081292

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104.

  GaoLLiJZhouYHuangXQinXDuG. Effects of baicalein on cortical proinflammatory cytokines and the intestinal microbiome in senescence accelerated mouse prone 8. ACS Chem Neurosci. (2018) 9:1714–24. 10.1021/acschemneuro.8b00074

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105.

  AndradeNMarquesCAndradeSSilvaCRodriguesIGuardaoLet al. Effect of chrysin on changes in intestinal environment and microbiome induced by fructose-feeding in rats. Food Funct. (2019) 10:4566–76. 10.1039/c9fo01142k

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106.

  PaulBRoystonKJLiYStollMLSkibolaCFWilsonLSet al. Impact of genistein on the gut microbiome of humanized mice and its role in breast tumor inhibition. PLoS ONE. (2017) 12 :e0189756. 10.1371/journal.pone.0189756

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107.

  ReygaertWC. The antimicrobial possibilities of green tea. Front Microbiol. (2014) 5:434. 10.3389/fmicb.2014.00434

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108.

  RezaMAHossainMALeeS-JKimJ-CParkS-C. In vitro prebiotic effects and quantitative analysis of Bulnesia sarmienti extract. J Food Drug Anal. (2016) 24:822–30. 10.1016/j.jfda.2016.03.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109.

  LiLSomersetS. Associations between flavonoid intakes and gut microbiota in a group of adults with cystic fibrosis. Nutrients. (2018) 10:1264. 10.3390/nu10091264

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110.

  FirrmanJLiuLArgotyGAZhangLTomasulaPWangMet al. Analysis of temporal changes in growth and gene expression for commensal gut microbes in response to the polyphenol naringenin. Microbiol Insights. (2018) 11:1–12. 10.1177/1178636118775100

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111.

  VikramAJayaprakashaGKJesudhasanPRPillaiSDPatilBS. Suppression of bacterial cell-cell signalling, biofilm formation and type III secretion system by citrus flavonoids. J Appl Microbiol. (2010) 109:515–27. 10.1111/j.1365-2672.2010.04677.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112.

  HeXWOuyangPYuanZWYinZQFuHLLinJCet al. Eriodictyol protects against Staphylococcus aureus-induced lung cell injury by inhibiting alpha-hemolysin expression. World J Microbiol Biotechnol. (2018) 34:7. 10.1007/s11274-018-2446-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113.

  LiuFWangTTYTangQXueCLiRWWuVCH. Malvidin 3-glucoside modulated gut microbial dysbiosis and global metabolome disrupted in a murine colitis model induced by dextran sulfate sodium. Mol Nutr Food Res. (2019) 63:e1900455. 10.1002/mnfr.201900455

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114.

  HidalgoMOruna-ConchaMJKolidaSWaltonGEKallithrakaSSpencerJPEet al. Metabolism of anthocyanins by human gut microflora and their influence on gut bacterial growth. J Agric Food Chem. (2012) 60:3882–90. 10.1021/jf3002153

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115.

  ChenGWangGZhuCJiangXSunJTianLet al. Effects of cyanidin-3-O-glucoside on 3-chloro-1,2-propanediol induced intestinal microbiota dysbiosis in rats. Food Chem Toxicol. (2019) 133:110767. 10.1016/j.fct.2019.110767

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116.

  GonzalesGBSmaggheGGrootaertCZottiMRaesKVan CampJ. Flavonoid interactions during digestion, absorption, distribution and metabolism: a sequential structure-activity/property relationship-based approach in the study of bioavailability and bioactivity. Drug Metab Rev. (2015) 47:175–90. 10.3109/03602532.2014.1003649

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117.

  LucaSVMacoveiIBujorAMironASkalicka-WozniakKAprotosoaieACet al. Bioactivity of dietary polyphenols: the role of metabolites. Crit Rev Food Sci Nutr. (2020) 60:626–59. 10.1080/10408398.2018.1546669

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118.

  MarottiIBonettiABiavatiBCatizonePDinelliG. Biotransformation of common bean (Phaseolus vulgaris L.) flavonoid glycosides by Bifidobacterium species from human intestinal origin. J Agric Food Chem. (2007) 55:3913–9. 10.1021/jf062997g

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119.

  AvilaMHidalgoMSanchez-MorenoCPelaezCRequenaTde Pascual-TeresaS. Bioconversion of anthocyanin glycosides by Bifidobacteria and Lactobacillus. Food Research International. (2009) 42:1453–61. 10.1016/j.foodres.2009.07.026

  • CrossRef
  • Google Scholar

• 120.

  RaimondiSRoncagliaLDe LuciaMAmarettiALeonardiAPagnoniUMet al. Bioconversion of soy isoflavones daidzin and daidzein by Bifidobacterium strains. Appl Microbiol Biotechnol. (2009) 81:943–50. 10.1007/s00253-008-1719-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121.

  YounSYParkMSJiGE. Identification of the β-glucosidase gene from Bifidobacterium animalis subsp lactis and its expression in B. bifidum BGN4. J Microbiol Biotechnol. (2012) 22:1714–23. 10.4014/jmb.1208.08028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122.

  MichlmayrHKneifelW. β-Glucosidase activities of lactic acid bacteria: mechanisms, impact on fermented food and human health. FEMS Microbiol Lett. (2014) 352:1–10. 10.1111/1574-6968.12348

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123.

  DelgadoSGuadamuroLBelen FlorezAVazquezLMayoB. Fermentation of commercial soy beverages with Lactobacilli and Bifidobacteria strains featuring high beta-glucosidase activity. Innov Food Sci Emerg Technol. (2019) 51:148–55. 10.1016/j.ifset.2018.03.018

  • CrossRef
  • Google Scholar

• 124.

  GayaPPeirotenALandeteJM. Expression of a beta-glucosidase in bacteria with biotechnological interest confers them the ability to deglycosylate lignans and flavonoids in vegetal foods. Appl Microbiol Biotechnol. (2020) 4903–13. 10.1007/s00253-020-10588-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125.

  YangJQianDWJiangSShangEXGuoJMDuanJA. Identification of rutin deglycosylated metabolites produced by human intestinal bacteria using UPLC-Q-TOF/MS. J Chromatogr B Anal Technol Biomed Life Sci. (2012) 898:95–100. 10.1016/j.jchromb.2012.04.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126.

  AmarettiARaimondiSLeonardiAQuartieriARossiM. Hydrolysis of the rutinose-conjugates flavonoids rutin and hesperidin by the gut microbiota and Bifidobacteria. Nutrients. (2015) 7:2788–800. 10.3390/nu7042788

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127.

  ShinNRMoonJSShinSYLiLLeeYBKimTJet al. Isolation and characterization of human intestinal Enterococcus avium EFEL009 converting rutin to quercetin. Lett Appl Microbiol. (2016) 62:68–74. 10.1111/lam.12512

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128.

  TaoJ-hDuanJ-aJiangSQianY-yQianD-w. Biotransformation and metabolic profile of buddleoside with human intestinal microflora by ultrahigh-performance liquid chromatography coupled to hybrid linear ion trap/orbitrap mass spectrometer. J Chromatogr B Anal Technol Biomed Life Sci. (2016) 1025:7–15. 10.1016/j.jchromb.2016.04.055

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129.

  Pereira-CaroGFernandez-QuirosBLudwigIAPradasICrozierAManuel Moreno-RojasJ. Catabolism of citrus flavanones by the probiotics Bifidobacterium longum and Lactobacillus rhamnosus. Eur J Nutr. (2018) 57:231–42. 10.1007/s00394-016-1312-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130.

  BrauneABlautM. Bacterial species involved in the conversion of dietary flavonoids in the human gut. Gut Microbes. (2016) 7:216–34. 10.1080/19490976.2016.1158395

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131.

  del Carmen Villegas-AguilarMFernandez-OchoaAde la Luz Cadiz-GurreaMPimentel-MoralSLozano-SanchezJArraez-RomanDet al. Pleiotropic biological effects of dietary phenolic compounds and their metabolites on energy metabolism, inflammation and aging. Molecules. (2020) 25:1–27. 10.3390/molecules25030596

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132.

  PossemiersSHeyerickARobbensVDe KeukeleireDVerstraeteW. Activation of proestrogens from hops (Humulus lupulus L.) by intestinal microbiota; Conversion of isoxanthohumol into 8-prenylnaringenin. J Agric Food Chem. (2005) 53:6281–8. 10.1021/jf0509714

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133.

  KimMKimNHanJ. Metabolism of Kaempferia parviflora polymethoxyflavones by human intestinal bacterium Bautia sp MRG-PMF1. J Agric Food Chem. (2014) 62:12377–83. 10.1021/jf504074n

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134.

  BurapanSKimMHanJ. Curcuminoid demethylation as an alternative metabolism by human intestinal microbiota. J Agric Food Chem. (2017) 65:3306–11. 10.1021/acs.jafc.7b00943

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135.

  BurapanSKimMHanJ. Demethylation of polymethoxyflavones by human gut bacterium, Blautia sp MRG-PMF1. J Agric Food Chem. (2017) 65:1620–9. 10.1021/acs.jafc.7b00408

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136.

  FengXCLiYOppongMBQiuF. Insights into the intestinal bacterial metabolism of flavonoids and the bioactivities of their microbe-derived ring cleavage metabolites. Drug Metab Rev. (2018) 50:343–56. 10.1080/03602532.2018.1485691

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137.

  BrauneABlautM. Deglycosylation of puerarin and other aromatic C-glucosides by a newly isolated human intestinal bacterium. Environ Microbiol. (2011) 13:482–94. 10.1111/j.1462-2920.2010.02352.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138.

  KutscheraMEngstWBlautMBrauneA. Isolation of catechin-converting human intestinal bacteria. J Appl Microbiol. (2011) 111:165–75. 10.1111/j.1365-2672.2011.05025.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139.

  SchoeferLMohanRSchwiertzABrauneABlautM. Anaerobic degradation of flavonoids by Clostridium orbiscindens. Appl Environ Microbiol. (2003) 69:5849–54. 10.1128/aem.69.10.5849-5854.2003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 140.

  CarusoRLoBCNunezG. Host-microbiota interactions in inflammatory bowel disease. Nat Rev Immunol. (2020) 20:411–26. 10.1038/s41577-019-0268-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141.

  Vilela de OliveiraGLLeiteAZHiguchiBSGonzagaMIMarianoVS. Intestinal dysbiosis and probiotic applications in autoimmune diseases. Immunology. (2017) 152:1–12. 10.1111/imm.12765

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142.

  DoreJBlottiereH. The influence of diet on the gut microbiota and its consequences for health. Curr Opin Biotechnol. (2015) 32:195–9. 10.1016/j.copbio.2015.01.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143.

  BokulichNAChungJBattagliaTHendersonNJayMLiHet al. Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci Transl Med. (2016) 8:1–14. 10.1126/scitranslmed.aad7121

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144.

  SonnenburgJLBackhedF. Diet-microbiota interactions as moderators of human metabolism. Nature. (2016) 535:56–64. 10.1038/nature18846

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145.

  EckburgPBBikEMBernsteinCNPurdomEDethlefsenLSargentMet al. Diversity of the human intestinal microbial flora. Science. (2005) 308:1635–8. 10.1126/science.1110591

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146.

  MarchesiJRAdamsDHFavaFHermesGDAHirschfieldGMHoldGet al. The gut microbiota and host health: a new clinical frontier. Gut. (2016) 65:330–9. 10.1136/gutjnl-2015-309990

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147.

  MentellaMCScaldaferriFPizzoferratoMGasbarriniAMiggianoGAD. Nutrition, IBD and gut microbiota: a review. Nutrients. (2020) 12:1–20. 10.3390/nu12040944

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148.

  VrakasSMountzourisKCMichalopoulosGKaramanolisGPapatheodoridisGTzathasCet al. Intestinal bacteria composition and translocation of bacteria in inflammatory bowel disease. PLoS ONE. (2017) 12:e170034. 10.1371/journal.pone.0170034

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149.

  SeishimaJIidaNKitamuraKYutaniMWangZYSekiAet al. Gut-derived Enterococcus faecium from ulcerative colitis patients promotes colitis in a genetically susceptible mouse host. Genome Biol. (2019) 20:1–18. 10.1186/s13059-019-1879-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150.

  RehmanARauschPWangJSkiecevicieneJKiudelisGBhagaliaKet al. Geographical patterns of the standing and active human gut microbiome in health and IBD. Gut. (2016) 65:238–48. 10.1136/gutjnl-2014-308341

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151.

  KnightsDSilverbergMSWeersmaRKGeversDDijkstraGHuangHLet al. Complex host genetics influence the microbiome in inflammatory bowel disease. Genome Med. (2014) 6:11. 10.1186/s13073-014-0107-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152.

  MorganXCKabakchievBWaldronLTylerADTickleTLMilgromRet al. Associations between host gene expression, the mucosal microbiome, and clinical outcome in the pelvic pouch of patients with inflammatory bowel disease. Genome Biol. (2015) 16:67. 10.1186/s13059-015-0637-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153.

  LlewellynSRBrittonGJContijochEJVennaroOHMorthaAColombelJFet al. Interactions between diet and the intestinal microbiota alter intestinal permeability and colitis severity in Mice. Gastroenterology. (2018) 154:1037–46. 10.1053/j.gastro.2017.11.030

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154.

  WishartDSFeunangYDMarcuAGuoACLiangKVazquez-FresnoRet al. HMDB 4.0: the human metabolome database for 2018. Nucleic Acids Res. (2018) 46:D608–17. 10.1093/nar/gkx1089

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155.

  ChenLCollijVJaegerMvan den MunckhofICLVich VilaAKurilshikovAet al. Gut microbial co-abundance networks show specificity in inflammatory bowel disease and obesity. Nat Commun. (2020) 11:1–12. 10.1038/s41467-020-17840-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156.

  BiasiFAstegianoMMainaMLeonarduzziGPoliG. Polyphenol supplementation as a complementary medicinal approach to treating inflammatory bowel disease. Curr Med Chem. (2011) 18:4851–65. 10.2174/092986711797535263

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157.

  MorganXCTickleTLSokolHGeversDDevaneyKLWardDVet al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. (2012) 13:1–18. 10.1186/gb-2012-13-9-r79

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 158.

  LimonJJTangJLiDLWolfAJMichelsenKSFunariVet al. Malassezia is associated with Crohn's disease and exacerbates colitis in mouse models. Cell Host and Microbe. (2019) 25:377–88. 10.1016/j.chom.2019.01.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159.

  WlodarskaMKosticADXavierRJ. An integrative view of microbiome-host interactions in inflammatory bowel diseases. Cell Host Microbe. (2015) 17:577–91. 10.1016/j.chom.2015.04.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160.

  NiJWuGDAlbenbergLTomovVT. Gut microbiota and IBD: causation or correlation?Nat Rev Gastroenterol Hepatol. (2017) 14:573–84. 10.1038/nrgastro.2017.88

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161.

  KhanIUllahNZhaLJBaiYRKhanAZhaoTet al. Alteration of gut microbiota in inflammatory bowel disease (IBD): cause or consequence? IBD treatment targeting the gut microbiome. Pathogens. (2019) 8:1–28. 10.3390/pathogens8030126

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162.

  LuoANLeachSTBarresRHessonLBGrimmMCSimarD. The microbiota and epigenetic regulation of T helper 17/regulatory T cells: in search of a balanced immune system. Front Immunol. (2017) 8:417. 10.3389/fimmu.2017.00417

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 163.

  GriggJBSonnenbergGF. Host-microbiota interactions shape local and systemic inflammatory diseases. J Immunol. (2017) 198:564–71. 10.4049/jimmunol.1601621

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164.

  BrittonGJContijochEJMognoIVennaroOHLlewellynSRNgRet al. Microbiotas from humans with inflammatory bowel disease alter the balance of Gut Th17 and ROR gamma T(+) regulatory T cells and exacerbate colitis in mice. Immunity. (2019) 50:212–24. 10.1016/j.immuni.2018.12.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165.

  AtarashiKTanoueTShimaTImaokaAKuwaharaTMomoseYet al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. (2011) 331:337–41. 10.1126/science.1198469

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 166.

  RoundJLLeeSMLiJTranGJabriBChatilaTAet al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. (2011) 332:974–7. 10.1126/science.1206095

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 167.

  QuevrainEMaubertMAMichonCChainFMarquantRTailhadesJet al. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn's disease. Gut. (2016) 65:415–25. 10.1136/gutjnl-2014-307649

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168.

  PngCWLindenSKGilshenanKSZoetendalEGMcSweeneyCSSlyLIet al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Amer J Gastroenterol. (2010) 105:2420–8. 10.1038/ajg.2010.281

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169.

  LeeYKMehrabianPBoyajianSWuW-LSelichaJVonderfechtSet al. The protective role of bacteroides fragilis in murine model of colitis-associated colorectal cancer. Msphere. (2018) 3:e00587-18. 10.1128/mSphere.00587-18

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170.

  MouraFAde AndradeKQdos SantosJCFAraujoORPGoulartMOF. Antioxidant therapy for treatment of inflammatory bowel disease: does it work?Redox Biol. (2015) 6:617–39. 10.1016/j.redox.2015.10.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171.

  LaneERZismanTLSuskindDL. The microbiota in inflammatory bowel disease: current and therapeutic insights. J Inflamm Res. (2017) 10:63–73. 10.2147/jir.S116088

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172.

  JohanssonMEVLarssonJMHHanssonGC. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. Proc Natl Acad Sci USA. (2011) 108:4659–65. 10.1073/pnas.1006451107

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 173.

  JandhyalaSMTalukdarRSubramanyamCVuyyuruHSasikalaMReddyDN. Role of the normal gut microbiota. World J Gastroenterol. (2015) 21:8787–803. 10.3748/wjg.v21.i29.8787

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174.

  KosticADXavierRJGeversD. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. (2014) 146:1489–99. 10.1053/j.gastro.2014.02.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175.

  AzumaTShigeshiroMKodamaMTanabeSSuzukiT. Supplemental naringenin prevents intestinal barrier defects and inflammation in colitic mice. J Nutr. (2013) 143:827–34. 10.3945/jn.113.174508

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176.

  XiongYJDengZBLiuJNQiuJJGuoLFengPPet al. Enhancement of epithelial cell autophagy induced by sinensetin alleviates epithelial barrier dysfunction in colitis. Pharmacol Res. (2019) 148:10. 10.1016/j.phrs.2019.104461

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 177.

  BianYDongYSunJSunMHouQLaiYet al. Protective effect of kaempferol on lps-induced inflammation and barrier dysfunction in a coculture model of intestinal epithelial cells and intestinal microvascular endothelial cells. J Agric Food Chem. (2020) 68:160–7. 10.1021/acs.jafc.9b06294

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178.

  ChenSZhaoHChengNCaoW. Rape bee pollen alleviates dextran sulfate sodium (DSS)-induced colitis by neutralizing IL-1β and regulating the gut microbiota in mice. Food Res Int. (2019) 122:241–51. 10.1016/j.foodres.2019.04.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 179.

  ParkMYJiGESungMK. Dietary kaempferol suppresses inflammation of dextran sulfate sodium-induced colitis in mice. Dig Dis Sci. (2012) 57:355–63. 10.1007/s10620-011-1883-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180.

  ZhuLShenHGuPQLiuYJZhangLChengJF. Baicalin alleviates TNBS-induced colitis by inhibiting PI3K/AKT pathway activation. Exp Ther Med. (2020) 20:581–90. 10.3892/etm.2020.8718

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 181.

  XuJLiuJYueGSunMLiJXiuXet al. Therapeutic effect of the natural compounds baicalein and baicalin on autoimmune diseases. Mol Med Rep. (2018) 18:1149–54. 10.3892/mmr.2018.9054

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182.

  HanYMKohJKimJHLeeJImJPKimJS. Astragalin inhibits nuclear factor-κB signaling in human colonic epithelial cells and attenuates experimental colitis in mice. Gut Liver. (2020) 15:100–8. 10.5009/gnl19268

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183.

  PengLGaoXNieLXieJDaiTShiCet al. Astragalin attenuates dextran sulfate sodium (DSS)-induced acute experimental colitis by alleviating gut microbiota dysbiosis and inhibiting NF-κB activation in mice. Front Immunol. (2020) 11:2058. 10.3389/fimmu.2020.02058

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184.

  LinRPiaoMSongY. Dietary quercetin increases colonic microbial diversity and attenuates colitis severity in Citrobacter rodentium-infected mice. Front Microbiol. (2019) 10:1092. 10.3389/fmicb.2019.01092

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 185.

  JuSGeYLiPTianXWangHZhengXet al. Dietary quercetin ameliorates experimental colitis in mouse by remodeling the function of colonic macrophages via a heme oxygenase-1-dependent pathway. Cell Cycle. (2018) 17:53–63. 10.1080/15384101.2017.1387701

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186.

  YuJGuoHXieJLuoJLiYLiuLet al. The alternate consumption of quercetin and alliin in the traditional asian diet reshaped microbiota and altered gene expression of colonic epithelial cells in rats. J Food Sci. (2019) 84:678–86. 10.1111/1750-3841.14473

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187.

  OteizaPIFragaCGMillsDATaftDH. Flavonoids and the gastrointestinal tract: local and systemic effects. Mol Aspects Med. (2018) 61:41–9. 10.1016/j.mam.2018.01.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188.

  MartiniEKrugSMSiegmundBNeurathMFBeckerC. Mend your fences the epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease. Cell Mol Gastroenterol Hepatol. (2017) 4:33–46. 10.1016/j.jcmgh.2017.03.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 189.

  ChangJLeongRWWasingerVCIpMYangMPhanTG. Impaired intestinal permeability contributes to ongoing bowel symptoms in patients with inflammatory bowel disease and mucosal healing. Gastroenterology. (2017) 153:723–31. 10.1053/j.gastro.2017.05.056

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 190.

  IwayaHMaetaKHaraHIshizukaS. Mucosal permeability is an intrinsic factor in susceptibility to dextran sulfate sodium-induced colitis in rats. Exp Biol Med. (2012) 237:451–60. 10.1258/ebm.2011.011269

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191.

  NighotPAl-SadiRRawatMGuoSHWattersonDMMaT. Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis. Amer Jo Physiol Gastrointest Liver Physiol. (2015) 309:G988–97. 10.1152/ajpgi.00256.2015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 192.

  LiSYWuBNFuWYReddivariL. The anti-inflammatory effects of dietary anthocyanins against ulcerative colitis. Int J Mol Sci. (2019) 20:18. 10.3390/ijms20102588

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 193.

  SuzukiTHaraH. Quercetin enhances intestinal barrier function through the assembly of zonnula occludens-2, occludin, and claudin-1 and the expression of claudin-4 in Caco-2 cells. J Nutr. (2009) 139:965–74. 10.3945/jn.108.100867

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 194.

  SuzukiTTanabeSHaraH. Kaempferol enhances intestinal barrier function through the cytoskeletal association and expression of tight junction proteins in Caco-2 cells. J Nutr. (2011) 141:87–94. 10.3945/jn.110.125633

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195.

  CiborDDomagala-RodackaRRodackiTJurczyszynAMachTOwczarekD. Endothelial dysfunction in inflammatory bowel diseases: pathogenesis, assessment and implications. World J Gastroenterol. (2016) 22:1067–77. 10.3748/wjg.v22.i3.1067

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 196.

  BianYLiuPZhongJHuYFanYZhuangSet al. Kaempferol inhibits multiple pathways involved in the secretion of inflammatory mediators from LPS-induced rat intestinal microvascular endothelial cells. Mol Med Rep. (2019) 19:1958–64. 10.3892/mmr.2018.9777

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197.

  LiuPBianYFFanYSZhongJLiuZJ. Protective effect of naringin on in vitro gut-vascular barrier disruption of intestinal microvascular endothelial cells induced by TNF-α. J Agric Food Chem. (2020) 68:168–75. 10.1021/acs.jafc.9b06347

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198.

  MalekiSJCrespoJFCabanillasB. Anti-inflammatory effects of flavonoids. Food Chem. (2019) 299:11. 10.1016/j.foodchem.2019.125124

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 199.

  WallaceKLZhengLBKanazawaYShihDQ. Immunopathology of inflammatory bowel disease. World J Gastroenterol. (2014) 20:6–21. 10.3748/wjg.v20.i1.6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 200.

  TaoFFQianCGuoWJLuoQXuQSunY. Inhibition of Th1/Th17 responses via suppression of STAT1 and STAT3 activation contributes to the amelioration of murine experimental colitis by a natural flavonoid glucoside icariin. Biochem Pharmacol. (2013) 85:798–807. 10.1016/j.bcp.2012.12.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201.

  AbronJDSinghNPPriceRLNagarkattiMNagarkattiPSSinghUP. Genistein induces macrophage polarization and systemic cytokine to ameliorate experimental colitis. PLoS ONE. (2018) 13:e0199631. 10.1371/journal.pone.0199631

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 202.

  YoshidaT. Concise commentary: quercetin flavonoid of the month or IBD therapy?Dig Dis Sci. (2018) 63:3305–6. 10.1007/s10620-018-5269-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 203.

  CuiLFengLZhangZHJiaXB. The anti-inflammation effect of baicalin on experimental colitis through inhibiting TLR4/NF-κB pathway activation. Int Immunopharmacol. (2014) 23:294–303. 10.1016/j.intimp.2014.09.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 204.

  EunSHWooJTKimDH. Tangeretin inhibits IL-12 expression and NF-κB activation in dendritic cells and attenuates colitis in mice. Planta Med. (2017) 83:527–33. 10.1055/s-0042-119074

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 205.

  ManigandanKManimaranDJayarajRLElangovanNDhivyaVKaphleA. Taxifolin curbs NF-κB-mediated Wnt/β-catenin signaling via up-regulating Nrf2 pathway in experimental colon carcinogenesis. Biochimie. (2015) 119:103–12. 10.1016/j.biochi.2015.10.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 206.

  WillingBPDicksvedJHalfvarsonJAnderssonAFLucioMZhengZet al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology. (2010) 139:1844.e1–54.e1. 10.1053/j.gastro.2010.08.049

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 207.

  HongZPiaoM. Effect of quercetin monoglycosides on oxidative stress and gut microbiota diversity in mice with dextran sodium sulphate-induced colitis. Biomed Res Int. (2018) 2018:8343052. 10.1155/2018/8343052

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208.

  BianXYWuWRYangLYLvLXWangQLiYTet al. Administration of Akkermansia muciniphila ameliorates dextran sulfate sodium-induced ulcerative colitis in mice. Front Microbiol. (2019) 10:2259. 10.3389/fmicb.2019.02259

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209.

  EverardABelzerCGeurtsLOuwerkerkJPDruartCBindelsLBet al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA. (2013) 110:9066–71. 10.1073/pnas.1219451110

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210.

  RoopchandDECarmodyRNKuhnPMoskalKRojas-SilvaPTurnbaughPJet al. Dietary polyphenols promote growth of the gut bacterium Akkermansia muciniphila and attenuate high-fat diet-induced metabolic syndrome. Diabetes. (2015) 64:2847–58. 10.2337/db14-1916

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 211.

  ZhangLCarmodyRNKalariyaHMDuranRMMoskalKPoulevAet al. Grape proanthocyanidin-induced intestinal bloom of Akkermansia muciniphila is dependent on its baseline abundance and precedes activation of host genes related to metabolic health. J Nutr Biochem. (2018) 56:142–51. 10.1016/j.jnutbio.2018.02.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 212.

  AnanthakrishnanAN. Clostridium difficile infection: epidemiology, risk factors and management. Nat Rev Gastroenterol Hepatol. (2011) 8:17–26. 10.1038/nrgastro.2010.190

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 213.

  HudsonLEAndersonSECorbettAHLambTJ. Gleaning insights from fecal microbiota transplantation and probiotic studies for the rational design of combination microbial therapies. Clin Microbiol Rev. (2017) 30:191–231. 10.1128/cmr.00049-16

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 214.

  WuXAlamMZFengLTsutsumiLSSunDHurdleJG. Prospects for flavonoid and related phytochemicals as nature-inspired treatments for Clostridium difficile infection. J Appl Microbiol. (2014) 116:23–31. 10.1111/jam.12344

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 215.

  PellisseryAJVinayamohanPGVenkitanarayananK. In vitro antivirulence activity of baicalin against Clostridioides difficile. J Med Microbiol. (2020) 69:631–9. 10.1099/jmm.0.001179

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 216.

  González-QuilenCRodríguez-GallegoEBeltrán-DebónRPinentMArdévolABlayMTet al. Health-promoting properties of proanthocyanidins for intestinal dysfunction. Nutrients. (2020) 12:130. 10.3390/nu12010130

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 217.

  SalaritabarADarvishiBHadjiakhoondiFManayiASuredaANabaviSFet al. Therapeutic potential of flavonoids in inflammatory bowel disease: a comprehensive review. World J Gastroenterol. (2017) 23:5097–114. 10.3748/wjg.v23.i28.5097

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 218.

  BruecknerMWestphalSDomschkeWKucharzikTLuegeringA. Green tea polyphenol epigallocatechin-3-gallate shows therapeutic antioxidative effects in a murine model of colitis. J Crohns Colitis. (2012) 6:226–35. 10.1016/j.crohns.2011.08.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 219.

  Al-RejaieSSAbuohashishHMAl-EnaziMMAl-AssafAHParmarMYAhmedMM. Protective effect of naringenin on acetic acid-induced ulcerative colitis in rats. World J Gastroenterol. (2013) 19:5633–44. 10.3748/wjg.v19.i34.5633

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 220.

  AnanthakrishnanANBernsteinCNIliopoulosDMacphersonANeurathMFAliRARet al. Environmental triggers in IBD: a review of progress and evidence. Nat Rev Gastroenterol Hepatol. (2018) 15:39–49. 10.1038/nrgastro.2017.136

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 221.

  RibeiroDProencaCRochaSLimaJCarvalhoFFernandesEet al. Immunomodulatory effects of flavonoids in the prophylaxis and treatment of inflammatory bowel diseases: a comprehensive review. Curr Med Chem. (2018) 25:3374–412. 10.2174/0929867325666180214121734

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 222.

  EtxeberriaUFernandez-QuintelaAMilagroFIAguirreLAlfredo MartinezJPortilloMP. Impact of polyphenols and polyphenol-rich dietary sources on gut microbiota composition. J Agric Food Chem. (2013) 61:9517–33. 10.1021/jf402506c

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 223.

  GeeJMDuPontMSDayAJPlumbGWWilliamsonGJohnsonIT. Intestinal transport of quercetin glycosides in rats involves both deglycosylation and interaction with the hexose transport pathway. J Nutr. (2000) 130:2765–71. 10.1093/jn/130.11.2765

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 224.

  DayAJCanadaFJDiazJCKroonPAMcLauchlanRFauldsCBet al. Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase. FEBS Lett. (2000) 468:166–70. 10.1016/s0014-5793(00)01211-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 225.

  WilliamsonGKayCDCrozierA. The bioavailability, transport, and bioactivity of dietary flavonoids: a review from a historical perspective. Compr Rev Food Sci Food Saf. (2018) 17:1054–112. 10.1111/1541-4337.12351

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 226.

  WilliamsonGCliffordMN. Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenols. Biochem Pharmacol. (2017) 139:24–39. 10.1016/j.bcp.2017.03.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar