Flavonoids, gut microbiota, and host lipid metabolism

Abstract

Flavonoids are widely distributed in nature and have a variety of beneficial biological effects, including antioxidant, anti‐inflammatory, and anti‐obesity effects. All of these are related to gut microbiota, and flavonoids also serve as a bridge between the host and gut microbiota. Flavonoids are commonly used to modify the composition of the gut microbiota by promoting or inhibiting specific microbial species within the gut, as well as modifying their metabolites. In turn, the gut microbiota extensively metabolizes flavonoids. Hence, this reciprocal relationship between flavonoids and the gut microbiota may play a crucial role in maintaining the balance and functionality of the metabolism system. In this review, we mainly highlighted the biological effects of antioxidant, anti‐inflammatory and antiobesity, and discussed the interaction between flavonoids, gut microbiota and lipid metabolism, and elaborated the potential mechanisms on host lipid metabolism.

Abbreviations

ADRB3

3‐adrenergic receptor

AHR

aryl hydrocarbon receptor

Akt

protein kinase B

ALP

alkaline phosphatase

ALT

alanine aminotransferase

AMPK

adenosine monophosphate activated protein kinase

ApoE^−/−

ApoE‐deficient

AST

aspartate aminotransferase

BAs

bile acids

BAT

brown adipose tissue

BSH

bile salt hydrolase

cAMP

cyclic adenosine monophosphate.

CAT

catalase

CCK

cholecystokinin

COX

cyclooxygenase

CREB

cAMP‐response element binding protein

CYP1A1

cytochrome P450, family 1, subfamily A, polypeptide 1

E. coli

Escherichia coli

ERK

extracellular regulated protein kinases

F/B

ratio of Firmicutes to Bacteroidetes

FGF15

fibroblast growth factor 15

FGF19

fibroblast growth factor 19

FXR

nuclear receptor farnesol X receptor

GLP‐1

glucagon‐like peptide‐1

GPR41

G‐protein‐coupled receptors 41

GPR43

G‐protein‐coupled receptors 43

GSH‐Px

glutathione peroxidase

GTF‐1

glucosyltransferase‐1

HO

hydroxyl radicals

HO‐1

heme oxygenase‐1

HSP90

heat‐shock protein90

IL‐18

interleukin‐18

IL‐1β

interleukin‐1β

IL‐6

interleukin‐6

IL‐8

interleukin‐8

iNOS

inducible nitric oxide synthase

JNK

c‐Jun N‐terminal kinase

LBPC

larch bark proanthocyanidins

LDL‐C

low‐density lipoprotein cholesterol

LPS

lipopolysaccharide

LXR

liver X receptor

MDA

malondialdehyde

MRSA

methicillin‐resistant S. aureus

NA

norepinephrine

NAFLD

non‐alcoholic fatty liver disease

NF‐κb

nuclear factor kappa‐light‐chain‐enhancer of activated B cells

NLRP3

NOD‐like receptor family pyrin domain containing 3

NO·

nitric oxide free radicals

NOX4

recombinant nicotinamide adenine dinucleotide phosphate oxidase 4

Nrf2

Nuclear factor erythroid 2‐related factor 2

O2·‐

superoxide anion free radicals

PCOA

principal coordinate analysis

PGC‐1α

peroxisome proliferators‐activated receptor γ coactivator 1 alpha

PI3K

phosphatidylinositol3‐kinase

PPARs

peroxisome proliferator‐activated receptors

PYY

peptide YY

QS

microbial population sensing

RO·

alkoxy radicals

ROO·

alkyl peroxyradicals

ROS

reactive oxygen species

S. aureus

Staphylococcus aureus

SCFAs

short‐chain fatty acids

SOD

superoxide dismutase

SREBPs

sterol regulatory element‐binding proteins

TC

total cholesterol

TG

triglycerides

TGR5

membrane receptor G protein‐coupled bile acid receptor 5

Th17

T helper cell 17

TLR2

Toll‐like receptor 2

TLR4

Toll‐like receptor 4

TLR6

Toll‐like receptor 6

TNF‐α

tumor necrosis factor‐α

UC

ulcerative colitis

UCP1

uncoupling protein 1

WAT

white adipose tissue

XO

xanthine oxidase

1. INTRODUCTION

In recent decades, with the improvement in living standards, most people's dietary structure and habits have undergone significant changes with the high intake of high sugar, high fat and refined processed foods, sedentary work, and lack of exercise. The physiological processes associated with lipid metabolism encompass the dysregulated synthesis and metabolism of fatty acids and cholesterol [1, 2, 3]. Diseases, including, obesity, type 2 diabetes, hyperlipidemia, hyperglycemia, atherosclerosis, nonalcoholic fatty liver disease, asthma, and osteoarthritis arise from disorders in lipid metabolism [4, 5]. More than 2.1 billion adults are estimated to be overweight or obese worldwide; for instance, between 2015 and 2016, the prevalence of obesity in the United States reached nearly 40% (National Health and Nutrition Examination Survey), which was the main health challenge for humans [6, 7]. Disorders of lipid metabolism are accompanied by many abnormal physiological processes, including oxidative stress, chronic inflammation, depression, and microecological destruction. These factors will accelerate the deterioration of the host's metabolic syndrome [8, 9]. Nevertheless, the modulation mechanisms and therapeutic solutions for lipid metabolism are not yet entirely clear; therefore, deeper insight into lipid metabolism modulation methods and their mechanisms is vital to alleviate the risk of incidence and mortality of related diseases.

Flavonoids are a large class of heterocyclic organic compounds produced by natural plant secondary metabolism. It is widely found in fruits, vegetables, and beans in the form of flavonoid glycosides. They play important probiotic effects on antioxidation, antibacterial and anti‐inflammatory, antitumor, immune regulation, and gut health [10, 11]. Following intake, flavonoids are metabolized by gut microbiota and host tissues; in particular, hindgut microbiota are able to improve the bioavailability of flavonoids, but individual differences exist [12]. An increasing number of studies have described the ability of flavonoids to inhibit disorders of lipid metabolism and are associated with the correction of oxidative stress, inflammation, and gut microbiota disorders [13, 14, 15]. In particular, gut microbiota and host health have been extensively studied, but the mechanism by which flavonoids regulate host lipid metabolism through gut microbiota is unclear.

Growing evidence indicates that the gut microbiota contributes to host metabolism and that dysbiosis is closely associated with metabolic disorders that worsen the pathogenesis process [16, 17]. For example, obese individuals usually have a lower relative abundance of Akkermansia muciniphila, Bacteroidetes, and Bifidobacterium, and a higher abundance of Firmicutes, Fusobacteria, and Proteobacteria [18]. ​Several studies have also transplanted the gut microbiota from obese mice into the gut of lean mice, resulting in weight gain and an imbalance in lipid metabolism. Conversely, transplanting the gut microbiota from lean to obese mice produced weight loss and reversed lipid metabolism disorders [19]. More interestingly, germ‐free mice fed a high‐fat diet failed to gain weight [20]. This shows that gut microbiota may play an important role in host lipid metabolism.

In this review, we highlight the biological effects of flavonoids in terms of antioxidant, antibacterial, and anti‐inflammatory properties and describe the current understanding of how flavonoids affect the gut microbiota, discussing how the interaction between dietary flavonoids and the gut microbiota modulates host lipid metabolism.

2. THE PHYSIOLOGICAL FUNCTIONS OF FLAVONOIDS

Flavonoids are a large subclass of polyphenol compounds and more than 8,000 flavonoid molecules. Their basic structure consists of one heterocyclic pyran ring (C) and two aromatic rings (A and B), forming a 15‐carbon phenylpropane nucleus with a C6 ‐C3 ‐C6 structure [21, 22]. According to the degree of oxidation of the three‐carbon bond (C3), whether C3 is cyclized, the connection position of the benzene ring and substituents, and the form of substituents on C3, it is divided into the following subcategories (Table 1): flavone, flavanone, isoflavone, flavonol, flavanol, flavanonol, chalcone, and anthocyanin.

TABLE 1.

The main basic structures and examples of natural flavonoids.

Flavonoids subclasses	Structure	Examples	Food source
Flavone		Apigenin, luteolin, baicalein, chrysin	Cabbage, wheat sprouts, celery, chamomile, carrot
Flavanone		Hesperetin, naringenin, holy grass, glycyrrhizin	Naringin, naringenin, eriodictyol, hesperidin
Isoflavone		Daidzein, genistein, soy isoflavones, glycitein	Soybean, kudzu, alfalfa, red clover
Flavonol		Quercetin, kaempferol, myricetin	Berries, grapes, tomatoes, onions, kale, broccoli, tea, red wine
Flavanol		Theaflavins, catechins, epicatechins, theafucins	Red wine, grape skin, tea, apricot, apple, cherry, cocoa
Chalcone		Licorice Chalcone, phloridin, aureoflocin	Licorice, grapefruit peel, orange peel, eyesight leaves
Anthocyanin		Anthocyanin, cyanidin, delphinium pigment, anthocyanin	Blueberry, eggplant, cherry, cabbage, elderberry, red onion

Whereas flavonoids are diverse and exhibit a range of biological activities (Table 2), we focused on three biological effects of antioxidant, anti‐inflammatory, and anti‐obesity to understand the flavonoids, and they are closely connected to lipid metabolism. Importantly, the physiological functions of flavonoids are mostly governed by their structures; for example, the more phenolic hydroxyl groups there are, the stronger the antioxidant activity, and biological activity is improved by methylation and hydroxylation modification [23, 24].

TABLE 2.

Physiological effects of flavonoids.

Effect	Example flavonoids	Reference
Antioxidant	Quercetin, xanthohumol, baicalein, catechin, procyanidin	[28, 37, 78]
Antibacterial	Procyanidin, quercetin, baicalein, genistein	[35, 79–81]
Anti‐inflammatory	Xanthohumol, dihydroretrochalcones, quercetin	[82, 83, 84]
Anticancer	Quercetin, procyanidin	[85, 86]
Anti‐depression	Epigallocatechin‐3‐gallate, puerarin, genistein	[87, 88]
Anti‐obesity	Quercetin, cyanidin, myricetin	[54, 73, 76, 89]
Analgesic	Loureirin, cochinchinemin, hesperidin	[90, 91]
Antiviral	Apigenin, luteolin, kaempferol	[92]
Wound healing	Apigenin, baicalein, quercetin	[93, 94, 95]
Hair repair	Luteolin, formononetin, epigallocatechin‐3‐gallate	[96, 97, 98]
Anti‐type 2 diabetes	Hesperetin, quercetin, luteolin	[99, 100]
Anti‐atherosclerosis	Kaempferol, myricetin, cyanidin	[101, 102, 103]

2.1. Antioxidants

Oxygen atoms, as the final electron acceptors of the electron flow system, are constantly involved in redox reactions in aerobic organisms, but when excess reactive oxygen radicals (such as ROO·, RO·, O2·‐, HO·, and NO· are produced beyond their own scavenging capacity, disturbing the normal oxidative balance of the organism, damaging cells or tissues, causing oxidative stress, affecting normal life processes and even endangering life and health) [25]. The normal oxidative balance of the organism can be disturbed, destroying cells or tissues, causing oxidative stress, affecting normal life processes, and even endangering life health. In this case, such as disorders of lipid metabolism, although the endogenous antioxidant system can maintain the formation of free radicals and scavenge some of them to a certain extent, there are still some reactive oxygen radicals that are not scavenged and are continuously accumulated, so dietary antioxidants are needed to reduce the cumulative effect of oxidative damage throughout the life cycle as well as to repair damaged tissues [26].

Flavonoids, as a kind of phenolic compound, contain a large number of phenolic hydroxyl groups in their structure, which are a good class of hydrogen‐donating antioxidants and scavengers of reactive oxygen species and reactive nitrogen species in vivo and in vitro [27]. Due to the structural uniqueness of flavonoids, their capacity to scavenge free radicals is highly unique and changeable. For example, in comparison to the A ring, the hydroxyl groups in the B and C rings contribute substantially to the antioxidant activity of quercetin and glucoside [28]. Among the five flavonoids (wogonin, baicalin, baicalein, catechin, and procyanidin B2), catechin exhibited the greatest 1,1‐diphenyl‐2‐picrylhydrazyl scavenging activity, followed by procyanidin B2, baicalein, baicalin, and wogonin. Catechin had the greatest superoxide scavenging efficacy, followed by baicalein, procyanidin B2, and baicalin. Only baicalein demonstrated a strong ability to scavenge hydroxyl radicals [29]. Similarly, a study showed that quercetin 7‐rhamnoside exhibited strong scavenging effects on 1,1‐diphenyl‐2‐picrylhydrazyl, 2,20‐azinobis‐(3‐ethylbenzthiazolin‐6‐sulfonate), and ferrous reducing antioxidant power free radicals in vitro [30]. Therefore, group modification may be a new strategy to improve the antioxidant properties of some flavonoids.

Metal ions such as iron and copper can generate reactive free radicals during physiological processes, eliciting redox imbalances to facilitate an increase in ROS. Thus, chelation of transition state ions contributes to antioxidant properties [31]. Nevertheless, some studies show that chelating divalent ions has more favorable antioxidant properties than chelating trivalent ions, which may be related to the inhibition of the Fenton reaction [32]. Flavonoid chelation of metal ions is usually related to the location and amount of hydroxyl and carbonyl groups. For example, quercetin can chelate various divalent metal ions, such as Fe, Cu, Al, Co, Cr, and Pb, thereby reducing the production of reactive free radicals [33, 34]. The chelation state is influenced by a variety of conditions, such as the structure of the flavonoid, the pH of the environment in which the reaction takes place, the solvent, and the stoichiometric relationship, making it difficult to achieve optimal chelation of flavonoids with metal ions [32].

The regulation of process enzymes such as COX, XO, GSH‐Px, SOD, and CAT is also an important way in which flavonoids exert their antioxidant properties [22]. Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a master transcriptional regulator of redox homeostasis and influences the expression of downstream antioxidant genes. In a soybean oil‐induced oxidative stress model in broiler chickens, quercetin ameliorated oxidized oil–induced oxidative stress by upregulating the transcription of Nrf2 and its downstream genes, such as CAT, SOD1, GSH‐Px2, HO‐1, and thioredoxin, and decreased plasma MDA levels to restore redox balance [35]. Dong et al. administered a high‐fat diet to ApoE^−/− mice and treated them with alpinetin and found reduced atherosclerotic lesions by increasing nuclear translocation to activate Nfr2, promoting thiol‐dependent glutathione and thioredoxin antioxidant systems in macrophages to reduce ROS production [36]. Similarly, flavonoids have shown positive antioxidant enzyme modulation in other disease models to restore redox reaction homeostasis [30, 37].

The flavonoid mechanism of action is roughly as follows (Figure 1): (1) supplying electrons to neutralize free radicals; (2) chelating minerals to prevent the generation of reactive oxygen species and free radical production; and (3) activating or upregulating antioxidant signaling pathways to increase the activity and levels of antioxidant enzymes.

FIGURE 1.

Antioxidant pathways of flavonoids.

2.2. Anti‐inflammatory

Disorders of lipid metabolism manifest pathologically as chronic inflammation, causing damage to the organism [38]. Many studies have shown that flavonoids can have an anti‐inflammatory effect in many different ways. The anti‐inflammatory activity of flavonoids is structure dependent; for example, flavonoids with a 3‐ or 4‐position hydroxyl substituent on the B ring act as selective lipoxygenase inhibitors, whereas flavonoids with five or more methoxy substituents have a greater inhibitory activity against phosphodiesterase [39].

NF‐κb (nuclear factor kappa‐light‐chain‐enhancer of activated B cells) is important in the inflammatory response because it activates the release of proinflammatory factors such as IL‐6 and TNF‐α. In the Salmonella typhimurium infection RAW264.7‐cell model, Salmonella typhimurium activated the TLR4/AMPK/NF‐κb signaling pathway, increased cellular autophagy, and increased levels of IL‐1β, IL‐6, IL‐8, TNF‐α, and ROS, which were corrected by treatment with baicalein [40]. Cellular autophagy, ROS, and inflammation promote each other. Additionally, baicalin has been shown to relieve mycoplasma fowlis‐induced pneumonia in hens by decreasing NF‐κb‐p65 nuclear translocation mediated by TLR6 [41]. While both Th17 and Treg cells are helper T cells, their roles in controlling inflammation are quite distinct. Th17 cells produce proinflammatory cytokines, whereas Treg cells suppress immune responses. In dextran sodium sulfate‐induced colitis, sanguinarine, a potential aryl hydrocarbon receptor activator, increased CYP1A1 expression, promoted dissociation of the AHR/HSP90 complex and induced AHR nuclear translocation to upregulate CREB and Foxp3 promoter region association and Treg differentiation‐associated mDNMT‐1 expression in CD4+ T cells, restoring the ratio of Th17 to Treg cells and ameliorating colitis [42]. NLRP3 inflammatory vesicles recruit pro‐caspase‐1, modulate caspase‐1 activity and activate caspase‐1. When activated, caspase‐1 cleaves the inactive proinflammatory cytokines pro‐IL‐1β and pro‐IL‐18 to mature body IL‐1β and IL‐18 and mediates apoptosis [43]. Luteolin reduced LPS‐stimulated inflammatory damage in H9c2 cells by downregulating Nlrp3, decreasing TNF‐α, IL‐1, IL‐18, and IL‐6 production, and inhibiting iNOS and NOX4 protein expression [44]. Additionally, flavonoids can help reduce inflammation by controlling gut microbiota and altering the metabolism of gut microbiota [45, 46].

2.3. Antiobesity

Obesity is a prevalent and complicated worldwide metabolic illness syndrome marked by an excessive buildup of fat, and its prevalence is increasing year after year as material living standards rise. Obesity can be brought on by a number of things, especially in excessive consumption of sugar and fat, inactivity, and genetics. Patients with obesity are also commonly found to have abnormal physiological conditions such as insulin resistance, chronic inflammation, and oxidative stress, which raises their risk of developing diseases such as diabetes, hyperlipidemia, hyperglycemia, and chronic low‐grade inflammation [47]. Numerous studies have demonstrated that flavonoids have an anti‐obesity impact with almost no negative effects when compared to pharmaceutical weight loss medications [48, 49]. Additionally, flavonoids are α‐glucosidase inhibitors and insulin sensitizers that reduce insulin resistance and increase the rate of glucose uptake and utilization by cells [50, 51]. Interestingly, flavonoids also positively influence the hypothalamic regulation of food intake and satiety, such as enhancing GLP‐1, CCK, and PYY release [52, 53]. In animal tests, it was discovered that when mice fed a high‐fat diet were continuously supplemented with flavonoids, their fecal fat excretion increased, body weight gain decreased significantly, and fat deposition and fat droplet size in the liver, epididymides, groin, and other tissues decreased [54, 55, 56]. Moreover, flavonoids regulate biochemical indices and hormone levels associated with lipid metabolism. For example, TC, TG, AST, ALT, ALP, LDL‐C, leptin, and the leptin/adiponectin ratio were reduced in mouse serum, and adiponectin and stomach growth hormone‐releasing hormone levels were increased [57, 58]. At the microscopic level, the expression of lipid metabolism‐related genes such as FNTA, PON1, PPARG, ALDH1B1, APOA4, SREBP‐1C, ABCG5, GPAM, ACACA, FAS, CD36, FDFT1, and FASN may be altered by inhibiting key receptors such as PPARs and SREBPs, thereby reducing the accumulation of adipose tissue [54, 59–61].

Continuous adipocyte hypertrophy and an excess of new adipocytes produced by precursor cells are the fundamental causes of obesity, so regulating adipocyte production and hypertrophy is considered a viable tool for preventing and controlling obesity. It was discovered that flavonoids induce apoptosis in precursor adipocytes by activating AMPK signaling, revealing that inhibition of the ERK and JNK pathways induces apoptosis in mature adipocytes [62]. They decrease cellular glucose absorption by activating the Akt and AMPK signaling pathways [63], increase adipocyte mitochondrial number and oxygen consumption rate [64], increase glucose consumption [65], and inhibit adipocyte lipid formation [66]. Flavonoids may limit lipid accumulation in adipocytes by downregulating the mRNA and protein expression of important adipogenic genes, such as EBPA, PPAR, C/EBP, FABP4, AP2, LPL, and ApoB [67, 68, 69].

Brown adipose tissue (BAT) and beige adipose tissue in animals produce nonshivering thermogenesis by activating uncoupling protein 1 (UCP1) on the inner mitochondrial membrane, which consumes energy substances such as glucose and fatty acids in the body [70]. Thus, promoting BAT production and WAT browning and increasing its activity are considered promising for intervention in obesity and other metabolic diseases. Flavonoids were observed to increase the expression of CETED1, HOXC9, PGC1, PRDM16, and UCP1 and white adipose tissue (WAT) marker genes via a SIRT1‐ or 3AR‐dependent pathway, triggered WAT browning to form beige adipose tissue, increased BAT development, and decreased the amount of WAT. Enhance the weight of brown adipose tissue and beige adipose tissue [65, 71–73]. BAT and beige fat exerted their thermogenic action primarily through the release of norepinephrine from sympathetic nerve terminals. Flavonoid supplementation elevated NA levels and boosted the gene and protein expression of the ADRB3, enhancing NA binding to ADRB3 and upregulating the expression of downstream associated genes [74, 75]. Mitochondria are thermogenic organelles. Flavonoids can activate mitochondrial biogenesis, increase the number of mitochondria in BAT cells, enhance mitochondrial structure and function in BAT cells, upregulate mitochondrial inner membrane UCP1 expression, promote nonshivering thermogenesis, and increase the consumption of energy substances such as glucose and fat [76, 77].

3. THE INTERACTION OF FLAVONOIDS WITH THE GUT MICROBIOTA

Recent research has established that flavonoids and gut microbiota interact and encourage one another. On the one hand, flavonoids influence the composition and relative abundance of the gut microbiota by promoting or inhibiting certain microbes, hence modifying their metabolites. On the other hand, gut microbiota convert and degrade flavonoids via their own enzyme systems, releasing additional active compounds to improve biological effects [104, 105].

3.1. Flavonoids are metabolized by gut microbiota

Flavonoids, the most abundant type of secondary metabolites found in plants, are found in food as glycosides, glucosyl, rutinosyl, neohesperidinyl, and rhamnolipidyl [106]. Low bioavailability is often associated with low bioactivity. A study showed that antibiotic‐treated mice had less metabolism of quercetin, kaempferol, lignan, apigenin and naringenin, the concentrations of p‐hydroxyphenylacetic acid, protocatechuic acid, p‐hydroxybenzoic acid, vanillic acid, hydrocaffeic acid, coumaric acid and 3‐(4‐hydroxyphenyl) propionic acid were lower in serum [107]. These results indicated that the gut microbiota play an important role in flavonoid metabolism.

The flavonoids that enter the hindgut undergo anaerobic fermentation by gut microbiota, where they undergo dehydroxylation, decarboxylation, demethylation, and glycoside hydrolysis, resulting in the release of more easily absorbed free aglycones and the formation of new metabolites, thereby enhancing the biological activity of flavonoids [108]. Glycosylated flavonoids can operate as the sole carbon source for hindgut microbes, which first digest the glycosidic fraction, thus eliminating the O‐glycosylation of flavonoids [109]. The metabolism of naringenin is accompanied by demethylation, C‐ring cleavage, and dehydroxylation, with the A‐ring metabolized to m‐benzotrienol and the B‐ring metabolized to 3‐(4′‐hydroxyphenyl)‐propionic acid, as well as the production of sageol [110]. m‐Benzotriol can be further metabolized into acetic acid, propionic acid, and caseic acid, and 3‐(4′‐hydroxyphenyl)‐propionic acid is metabolized into small molecules such as p‐coumaric acid, 3‐phenylpropionic acid, and 4′‐hydroxybenzoic acid, which are thus absorbed by the colon and converted into maleic acid through the portal vein into the liver [111]. Isoflavones are also not well absorbed in the animal intestine but show excellent clinical effectiveness, so it is likely to be related to the metabolites they are converted to, such as estramol. In particular, bacterial strains of Eggerthellaceae, a well‐known family of bacteria in the gut microbiota, are capable of converting isoflavones into equol [112]. Wang et al. fermented soybean flavonoids anaerobically in rat feces and observed their conversion to dihydrosoybean sapogenins, S‐equol and O‐desmethylangolensin [113].

Bacterial enzymes such as lactase rhizosphingoside hydrolase, β‐glucuronidase, β‐glucosidase, and α‐rhamnosidase have been reported as possible key enzyme families for the microbial metabolism of flavonoids, and the main microorganisms of the normal animal intestine contain these enzymes, such as Lactobacillidae, Trichophyceae, and Enterococcaceae [12, 111]. For example, Casseliflavus and Eubacterium ramulus ferment isoquercitrin [114]. Likewise, microbial metabolites of some flavonoids exhibit greater biological activity than the originals, such as hippuric acid, homovanillic acid, and 5‐phenylvaleric acid, which are all metabolites of epicatechin, and the metabolites more effectively enhance glucose‐stimulated insulin secretion in β‐cells [115]. In summary, although the metabolic pathways of certain flavonoids vary, available evidence shows that gut microorganisms are essential for flavonoid biotransformation, mostly in terms of improving flavonoid structure and bioavailability.

3.2. Flavonoids alter gut microbiota

The gut microbiota is a large and complicated microbial community composed of bacteria, fungi, viruses, and archaea in the intestine of animals, which is closely related to the metabolism, immunity and other vital life activities of animals. It has been discovered that supplementation with flavonoids is helpful to the dynamic changes in the composition structure, microbial abundance, and microbial metabolites of the animal gut microbiota (Table 3). Notably, in this part, we are equally interested in how flavonoids exert bacteriostatic effects on microorganisms.

TABLE 3.

Flavonoids alter gut microbiota.

Flavonoids	Animal models	Effect on gut microbiota	Reference
Quercetin	Arbor Acre broilers	Pseudomonas aeruginosaxiang↓, Salmonella enterica serotype Typhimurium↓, Staphylococcus aureus↓, Escherichia coli↓, Lactobacillus↑, Bifidobacterium↑.	[35, 80]
Flavanol‐Enriched Cocoa Powder	5‐mo‐old male pigs	Lactobacillus↑, Bifidobacterium↑.	[148]
Procyanidins	Bama mini‐pigs	Firmicutes↑, Coprococcus↑, Spirochetes↓.	[149]
Baicalin	UC rats	Firmicutes↑, Butyricimonas spp.↑, Roseburia spp.↑, Subdoligranulum spp.↑, Eubacteriu spp.↑, Proteobacteria↓, Actinomycetes↓; butyrate↑.	[46]
Kaempferol	UC rats	Prevotellaceae↑, Ruminococcaceae↑, Proteobacteria↓.	[45]
Puerarin	Depressed mice	Firmicutes↑, Bacillales↑, Lactobacillus↑, Proteobacteria↓, Flexispira↓, Desulfovibrio↓.	[87]
Puerarin	UC rats	Proteobacteria↓, Ruminococcus↓, Ruminococcaceae↓; acetate↑, propionate↑, butyrate↑.	[150]
Puerarin	Ovariectomized rats as osteoporosis model	Bacteroidia↑, Clostridia↓, Bacteroidales↑, Peptococcaceae↑, Lachnospiraceae↓, Melainabacteria↓, Prevotellaceae↑, Desulfovibrionaceae↓; acetate↑, butyrate acids↑.	[151]
Myricetin	NAFLD rats induced by high‐fat diets	Actinobacteria↑, Allobaculum↑, Brachybacterium↑, Allobaculum spp.↑, Lachnospiraceae↑, B. paraconglomeratum↑, Nocardiaceae↑, Tyzzerella 4 spp↑, Turicibacter spp.↑, Lactobacillus intestinalis↑, Lactobacillus spp↑.	[135]
Isoflavone	Postmenopausal women	Lachnospiraceae↑, Pseudoflavonifractor↑, Slackia↑, Dorea↑.	[152]
Catechin	High‐fat diets rats	lithocholic acids↓, hyodeoxycholic acids↓.	[153]
Theabrownin	High‐fat diets rats	Lactobacillus↓, Bacillus↓, Streptococcus↓, Lactococcus↓, ileal conjugated bile acids↑.	[154]
Citrus polymethoxyflavones	Metabolic syndrome induced by high‐fat diets	Bacteroides ovatus↑, B. thetaiotaomicron↑, B. vulgatus↑, B. dorei↑, B. caccae↑, B. stercoris↑, B. uniformis↑, Firmicutes Paraprevotella↓, Firmicutes Streptococcus↓, B. fragilis↓, B. finegoldii↓, B. coprophilus↓.	[155]
Quercetin	Atherosclerosis induced by high cholesterol diets	Phascolarctobacterium↑, Anaerovibrio↑.	[156]

3.2.1. How flavonoids inhibit microorganisms

The attachment of bacteria to the mucosal surface of the organism, such as by physical adsorption, is the first step in the initiation of their relationship with the organism, and the pathogenic process can only continue to develop when the bacteria are in contact with certain specific structures of the organism's cells for a certain period of time. Yu et al. reported that sorghum procyanidin tetramers, by binding to a site in the catalytic region of Streptococcus mutans GTF‐1/CAT protein (GTF‐1, also known as water‐insoluble glucan synthase, is a control enzyme for bacterial synthesis of adhesion site material glucan and is essential for the expression of virulence factors in Streptococcus mutans), alter the GTF‐1/CAT secondary structure in the ratio of α‐helix, β‐sheet, and random helix, thus affecting the normal function of GTF‐1 and hindering the adhesion of Streptococcus mutans [116]. As a bacterial surface appendage, pili play a critical function in host cell adhesion and biofilm development, which increases bacterial attachment to the host and aids pathogen colonization. Furthermore, it can promote pathogen resistance to host defensive mechanisms and medications. Vasudevan et al. discovered that type A anthocyanin trimers can suppress the expression of pili adhesion‐related genes (such as focA, papG, fimA, and fimH), reduce biofilm formation by approximately 70% and have synergistic effects with furantoin [117]. The surface hydrophobicity of bacteria is also closely related to the bacterial adhesion process, and appropriate surface hydrophobicity is the basis for the formation of bacterial organisms, which can promote the adhesion and agglutination of pathogens [118]. Flavonoids such as quercetin and myricetin have been shown to drastically reduce the hydrophobicity of urine‐derived Escherichia coli (E. coli) and limit the formation of biofilms, hence preventing bacteria from attaching to the host [119]. The effect of flavonoids on bacterial adherence could be a result of the structure's particular groups. For instance, A‐type procyanidins include at least double interflavanyl linkages, and the addition of nitro to the A ring of procyanidins can boost their antibacterial and biofilm‐preventive effects [120]. Additionally, the presence of a methyl group at position 6 in the A ring of flavonoids inhibits the formation of biofilms, whereas the presence of methyl groups at positions 6 and 8 stimulates the production of biofilms [121].

Quorum sensing (QS), an intercellular communication process used by bacteria to regulate population behavior, regulates critical invasive processes such as bacterial biofilm formation and virulence factor release and is a key collaborator in chronic infections, with interruption of QS considered one of the most effective ways to control various virulence factors [122]. It was found that flavonoids have inhibitory effects on the expression of major regulatory target genes of microbial QS; for example, baicalin downregulates the expression of LASI, LASR, RHLI, and RHLR in Pseudomonas aeruginosa and agrA, RNAIII, sarA, and ica in Staphylococcus aureus (S. aureu)s, thus reducing the secretion of signaling molecules (e.g., N‐acylhomoserine lactones, furanylboronic acid diesters) that impede the progression of QS and reducing the release of virulence factors such as enterotoxin A, α‐hemolysin released by S. aureus, and pyocyanin, protease, elastase and rhamnolipids released by Pseudomonas aeruginosa. Moreover, the formation of biofilms was inhibited, and existing biofilms were disrupted. A significant reduction in biofilms was observed by electron microscopy; biofilm clumps were dispersed, and the extracellular polysaccharide matrix was significantly reduced [123, 124]. Microbial motility is also an important influence on QS and is critical for QS colonization, virulence expression and biofilm formation. Flavonoids such as quercetin, baicalin, and catechin have all been reported to inhibit bacterial swimming and cluster motility and partially exhibit dose dependence [125, 126, 127].

As the structural basis for ensuring the stability of the intracellular environment and normal cellular metabolism, the structural integrity of cell membranes is related to the normal life activities of the bacterium. Therefore, modulating the cell membrane structure is also one of the important targets of capturing microorganisms. Wang et al. treated E. coli with quercetin and observed the ultrastructure of the bacterium by transmission electron microscopy and found separation of the cytoplasmic membrane from the cell wall, cell wall lysis, inhomogeneous density of the inner cell membrane, leakage and polarization of the cytoplasmic contents as well as cell deformation and cell cavitation in E. coli, indicating that quercetin caused a break in the ring of the cell wall and cell membrane of the bacterium and its structural integrity was lost, resulting in significant increases in alkaline phosphatase and β‐galactosidase activities and soluble protein concentrations were observed outside the cell (only exposed to the cell wall and cell membrane permeability increased) [80]. Kusuda et al. also reported that polymeric proanthocyanidins can cause damage to the cell membrane of methicillin‐resistant S. aureus (MRSA), decrease its membrane structural stability and tolerance to hypo‐ and hyperosmotic environments, and inhibit ‐lactamase activity, thereby significantly lowering the minimum inhibitory concentration of ‐lactam antibiotics against MRSA [128].

Normal genetic material replication, protein synthesis, and food metabolism are required for optimal microbial life activities, and disruption to any of these processes would impair normal growth and reproduction. Li et al. treated S. aureus with LBPC and discovered changes in the total protein content and protein production of S. aureus, a decrease in the activity of essential energy metabolizing enzymes (succinate dehydrogenase, malate dehydrogenase, and adenosine triphosphatase ATPase), and LBPC binding to small grooves in the DNA double helix to form complexes that affected genetic material and protein expression systems [129]. Lin et al. discovered using transcriptome technology that when E. coli was treated with flavonoids from agastache leaves, the signal pathway and transcription level closely related to the nucleotide metabolic pathway, energy metabolic pathway, and carbohydrate metabolic pathway were significantly reduced, while the number of SNPs in E. coli increased significantly (indicating an increased probability of nucleotide mutation) [130]. Additionally, studies have shown that flavonoids reduce microorganism total RNA and DNA synthesis, as well as protein synthesis [131], which may be related to the inhibition of enzymes involved in DNA synthesis (such as DNA gyrase and ATP synthase) [132].

Briefly, flavonoids inhibit microorganisms primarily by blocking population sensing, disrupting biofilm formation, impeding adhesion, reducing the release of virulence factors, enhancing cell membrane permeability, and inhibiting genetic material replication and protein synthesis and nutrient metabolism.

3.2.2. Remodeling/restoring gut microbiota

Unfortunately, the balance of the gut microbiota can be readily disrupted by diets high sugar and fat, enteropathy, and stress [16, 18].+ Remodeling gut microbiota to promote health by regulating dietary flavonoids is a frontier of food nutrition research. Emerging evidence suggests that flavonoids possess the potential to reshape or restore the balance of the gut microbiota, thus contributing to the regulation of host immunity, metabolism, and inflammation [13, 45].

Long‐term or short‐term high‐fat diets have been shown to alter microbiota structure and diversity, such as a higher F/B, a higher abundance of bile acid‐resistant and pathogenic bacteria, and a lower abundance of probiotics (Bifidobacterium, Lactobacillus, Akkermansia muciniphila, etc.), resulting in gut microbiota dysbiosis. Altering gut permeability increases blood endotoxin levels, activates the inflammatory response, and further exacerbates complications resulting from high‐fat diets [133, 134]. Sun et al. supplemented rats on a high‐fat diet for 12 weeks with myricetin and found that myricetin significantly increased the Shannon index and decreased the ratio of Firmicutes to Bacteroidetes (F/B) and LPS levels, and principal coordinate analysis also showed that myricetin significantly corrected the changes in gut microbiota caused by the high‐fat diet [135]. Similarly, supplementation with other flavonoids in other high‐fat diet trials has been observed to reshape gut microbiota, increase probiotic abundance and reduce pathogenic bacterial abundance [136, 137]. Ulcerative colitis (UC) is a clinically common chronic nonspecific inflammatory bowel disease. Qu et al. observed that kaempferol reshaped the gut microbiota structure, decreased F/B and increased the level of beneficial bacteria such as Prevotellaceae and Rhinococcus. Additionally, the transplantation of fecal microbiota from kaempferol‐treated mice into DSS‐induced mice resulted in decreased levels of serum IL‐1β, IL‐6, TNF‐α, and LPS, increased colon length, decreased DAI score, and alleviation of pathological features. These findings provide confirmation that kaempferol attenuated inflammation through the regulation of gut microbiota [45]. Similar results were observed in UC mice supplemented with baicalin by Zhu et al., baicalin effectively reduced the abundance of the F/B and endotoxin‐producing Proteobacteria, thereby reversing the dysbiosis in the gut microbiota induced by UC. Additionally, baicalin significantly increased the fecal butyrate content, which exhibited a strong positive correlation with the abundance of Butyricimonas spp., Roseburia spp., Subdoligranulum spp., and Eubacteriu spp. [46].

The remodeling/restoring of the gut microbiota by flavonoids may be attributed to an increase in intestinal probiotics [138]. Several studies have demonstrated that flavonoids serve as a source of nutrients for probiotics, providing both energy and nutrients to promote their growth and reproduction [11, 139]. For instance, Feng et al. conducted in vitro fermentation experiments and observed that lotus leaf brass stimulated the growth of Actinobacteria and Firmicutes in colonic contents, inhibited the growth of Proteobacteria, and triggered the production of fermentation gases and short‐chain fatty acids (SCFAs) [140]. The intestinal environment plays a critical role in the proliferation of probiotics as well. Intestinal microorganisms can metabolize flavonoids to produce short‐chain fatty acids, such as propionic acid and butyric acid [139, 141]. These acids help maintain the acid‐base balance in the intestines, regulate intestinal pH, inhibit the proliferation of harmful bacteria, and create an intestinal environment that is more conducive to the growth of probiotics [142]. Moreover, short‐chain fatty acids not only act as a carbon source for probiotics like Lactobacillus and Bifidobacterium, but also provide energy and nutritional support to intestinal epithelial cells [143]. This, in turn, helps maintain the integrity and barrier function of the intestinal mucosa and further promotes the colonization of probiotics [11, 143]. Yan et al. found that flavonoids from green seaweed significantly increased the relative abundance of Lachnospiraceae, Odoribacter, and Alisties members in an animal model of type 2 diabetes [144]. Notably, Lachnospiraceae and Alisties belong to the core genus of the gut and are among the most abundant bacteria producing SCFAs [143]. In addition, mulberry leaf flavonoids increased Akkermansia levels and Bacteroidetes/Firmicutes ratio in animal models of obesity fed with high‐fat diet [145]. In the animal model of high‐fat diet induced obesity and insulin resistance, nobiletin increased the relative abundance ratio of Bacteroidetes to Firmicutes, and decreased the relative abundance of Oscillibacter [146]. Recent studies have shown that the increase in the relative abundance of Oscillibacter may lead to inflammatory response, obesity and insulin resistance, and the increase in the relative abundance of Oscillibacter is closely related to excessive intestinal permeability [138, 147]. Previous studies have demonstrated that flavonoids have the capability to alter the composition of the gut microbiota. However, the current literature on flavonoid remodeling of the gut microbiota has mainly focused on phenotypic changes, while the mechanisms of remodeling have rarely been reported and should be emphasized to better understand the gut microbiota remodeling process.

4. INTERACTION BETWEEN FLAVONOIDS AND GUT MICROBIOTA TO MODULATE LIPID METABOLISM

The interaction between flavonoids and gut microbiota to modify lipid metabolism is complex, and the exact mechanism of interaction is still unclear (Figure 2). In general, on the one hand, flavonoids are metabolized by gut microbiota to produce secondary metabolites such as phenolic acids, which are absorbed through the gut, activating relevant pathways and directly participating in the modulation of lipid metabolism; on the other hand, some flavonoids, together with their secondary metabolites, act on the gut microbiota to indirectly improve lipid metabolism by modulating relevant pathways through the gut microbiota and its metabolites.

FIGURE 2.

The pathway of the interaction between flavonoids and gut microbiota on lipid metabolism. After flavonoids are ingested by the body, some of them enter the blood directly, and some of them are decomposed by microorganisms in the gut to produce secondary metabolites, while flavonoids and their secondary metabolites affect the gut microbiota and change the microbial metabolites, both of which are absorbed by the body into the blood and reach the liver, brain, fat, and other tissues to improve host lipid metabolism.

4.1. Flavonoid secondary metabolites modulate lipid metabolism

The gut microbiota plays an important role in the metabolism of flavonoids, promoting not only flavonoid absorption but also some flavonoid metabolites, which exhibit enhanced effects [157]. Equol is a microbial metabolite of isoflavones that plays an important role in the modulation of lipid metabolism by isoflavones. Estramol activates Nrf2, alleviates endoplasmic reticulum stress, downregulates hepatic FAS expression, improves the plasma lipid profile and reduces fat accumulation, but there are sex differences [158, 159].

Hidalgo et al. fermented malvidin‐3‐glucoside, a mixture of anthocyanins, with human hindgut microorganisms and discovered that malvidin‐3‐glucoside was metabolized to syringic acid, and the anthocyanin mixture was metabolized to produce gallic acid, syringic acid, and p‐coumaric acid, all of which could positively modulate lipid metabolism [109, 160, 161]. Gallic acid can improve glucose transport in adipose tissue by partially activating PPARγ and PI3K/p‐Akt signaling while enhancing β‐oxidation, glycolysis and ketogenesis to control adipogenesis [161, 162, 163]. p‐coumaric acid increases nonshivering thermogenesis, upregulates carnitine palmitoyltransferase 1 expression, decreases lipogenic enzyme activity, increases fecal lipid excretion and reduces fat deposition and adipocyte size [164, 165]. Ham et al. observed that syringic acid reduced lipogenesis (CIDEA, PPARγ, SREBP‐1C, SREBP‐2, HMGCR, FASN) and inflammation (TLR4, MyD88, NF‐κB, TNF‐α, IL‐6)‐related genes, upregulated fatty acid oxidation (PPARα, ACSL, CPT1, CPT2)‐related genes, and increased fatty acid oxidase activity, thereby reducing fat deposition and weight gain due to high‐fat diets [160].

This is an intriguing line of research to contribute to the understanding of flavonoid metabolism. Unfortunately, due to the complexity of flavonoid species and gut microbiota, studies on the metabolism of flavonoids by gut microbiota are mainly in vitro only, and few systematic and complete studies have been carried out. Therefore, there is a desire to combine multiomics approaches to investigate the microbial metabolites of flavonoids in animals to better understand the interactions between flavonoids and gut microbes, as well as to identify the active ingredients in which flavonoids function and suggest more clinical treatment strategies.

4.2. Modulation of lipid metabolism by the gut microbiota and its metabolites

4.2.1. Probiotics

Recently, the regulation of host lipid metabolism by probiotics has become an attractive emerging direction. Probiotics and their microbial metabolites serve as substrates for some gut microorganisms and promote their proliferation. Hidalgo et al. observed that anthocyanins enhanced the growth of Bifidobacterium spp. and Lactobacillus−Enterococcus spp. [109]. Other studies have observed that quercetin, proanthocyanidin and epicatechin promote the growth of Akkermansia muciniphila [166, 167, 168]. To date, a number of microorganisms have also been characterized as having a positive role in lipid metabolism, such as Bifidobacterium, Lactobacillus, and Akkermansia muciniphila [169, 170, 171].

These probiotics can regulate lipid metabolism through a variety of pathways. Similar to the next‐generation probiotic Akkermansia muciniphila, which colonizes the gut mucus layer, which can improve the gut barrier, reduce food intake, increase fecal fat excretion, and improve blood lipid parameters, it induces the secretion of systemic GLP‐1 and UCP1 expression in BAT, inhibiting BAT whitening and the inflammatory response, reducing adipocyte size and infiltration, simultaneously activating PPAR‐α and PPAR‐γ to promote fatty acid oxidation, downregulating the mRNA expression of lipid synthesis‐related genes, and upregulating the mRNA expression of lipid transport‐related genes, to improve host lipid metabolism [172, 173, 174, 175, 176]. Furthermore, Lukovac et al. observed that the Akkermansia muciniphila metabolite propionate regulated the expression of FIAF, GPR43, HDACs, and PPAR‐γ, which are vital regulators of lipolysis and satiety [177]. Interestingly, several studies have shown that the extracellular vesicles, membrane proteins, and pasteurized forms of Akkermansia muciniphila exhibit better lipid metabolism modulating activity [173, 174, 178].

Imperfectly, numerous intestinal probiotics remain unidentified or isolated due to technical limitations and the unique growth requirements of certain microorganisms. Functional verification is predominantly confined to in vitro experiments or animal models, and limited clinical research findings have been acquired.

4.2.2. Gut microbiota metabolites

The gut microbiota is thought to be a massive metabolic organ, and its metabolites, such as SCFAs, BAs, tryptophan and its derivatives, are vital signaling molecules for the host to sustain health. Acetic acid, propionic acid, butyric acid, valeric acid, and other short‐chain fatty acids are metabolites of gut microorganisms such as Rumenococcus, Bauerella, Faecoccus, Salmonella, and insoluble carbohydrates such as dietary fiber in the gut [179]. The total SCFA content of the intestinal chyme was 30% lower in the rat UC model than in healthy mice, and the butyric acid amount was halved. However, after puerarin supplementation, the acetic acid, propionic acid, and butyric acid levels in the chyme were dramatically increased, as was the overall SCFA content. The content is 391.80 mol/g, which is approximately 80% greater than that of the UC model. SCFAs provide energy to epithelial cells and suppress associated pathogenic bacteria, thus promoting intestinal homeostasis and UC repair [150]. Additionally, Li et al. observed that puerarin increased fecal and serum levels of acetate, butyric acid, valeric acid and total SCFA in a rat model of osteoporosis [151]. SCFA levels vary as a result of flavonoids affecting the composition and abundance of bacteria involved in SCFA production [135, 152]. Primary BAs can also be metabolized into free BAs and secondary BAs in the gut by some bacteria involving BSH and 7α‐ dehydroxylase, respectively [180]. According to Han et al., supplementation with catechins, quercetin, and rutin can decrease the amount of secondary BAs found in mouse feces, including neutral sterols, lithocholic acid, and hyodeoxycholic acid [153]. Theabrownin is an oxidized polymer of catechins that decreases the relative abundance and activity of bile salt hydrolase‐producing microorganisms such as Lactobacillus, Bacillus, Streptococcus, and Lactococcus, as well as the hydrolysis of glycine‐ and taurine‐bound BAs, thereby increasing ileum combined BA levels [154]. Additionally, the gut microbiota controls the synthesis, transportation, and metabolism of certain amino acids. Citrus polymethoxyflavonoid extracts have the potential to reshape the gut microbiota of metabolic syndrome model mice fed a high‐fat diet. Thus, valine, leucine, iso leucine, and phenylalanine levels in serum and feces are increased [155]. Quercetin reduces atherosclerosis in mice produced by a high cholesterol diet by modulating tryptophan metabolism [156].

SCFAs

SCFAs, the fermentation products of nondigestible carbohydrates, which are a key class of metabolic signaling molecules, are also altered in individuals with disorders of lipid metabolism, usually with lower levels of acetic, propionic and butyric acids [16]. There is an inextricable relationship between SCFAs and lipid metabolism. Our previous study discovered that supplementation of acetic acid to mice on a high‐fat diet upregulated PPARγ and LXR expression in subcutaneous adipose tissue, promoted lipolysis, reduced adipocyte size and fat mass, and decreased weight gain [19].

For energy intake, acetic acid, propionic acid and butyric acid bind to GPR41 and GPR43 to promote the secretion of GLP‐1 and PYY from intestinal L cells, modulate host insulin release and appetite, reduce food intake and increase glucose consumption [181, 182]. Regarding lipid synthesis and catabolism, SCFA‐dependent activation of PPARγ, especially butyrate, promotes fatty acid β‐oxidation and white fat browning, reduces adipocyte size, increases the number of small adipocytes and enhances insulin sensitivity, while PPARγ activation increases SREBP expression and promotes cholesterol and lipid excretion [183, 184]. Notably, sometimes PPARγ also promotes adipocyte differentiation and increases lipid synthesis and lipid droplet aggregation [185, 186]. Other studies have also shown that acetic acid promotes leptin secretion from adipocytes, suppresses appetite, reduces energy intake, increases energy expenditure and inhibits fat synthesis. It also induces lipid oxidation in enterocytes by upregulating the AMPK/PGC‐1α/PPARα pathway after acetate uptake by enterocytes [187, 188, 189]. In addition, SCFAs are also involved in the control of inflammation, like butyrate inhibit Gram‐negative bacteria, reduce LPS production, activate NF‐κb, and inhibit TLR2/4 [190, 191].

Emerging research shows that flavonoids restore host SCFA levels by increasing the number of SCFA‐producing microorganisms and by acting as metabolic substrates. Several studies have demonstrated that supplementation with baicalin can increase the levels of SCFA‐producing microorganisms, such as Aeromonas butyricus, Rhus spp., Alcaligenes subtilis, Eubacterium spp., Heterobacterium spp., and Bifidobacterium spp., thereby restoring acetate, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid levels [46, 192]. Akkermansia muciniphila generates propionate, and flavonoids such as quercetin and proanthocyanidins can also promote its growth and increase its density [166–168, 177].

Bile acids

In addition to being involved in the digestion and absorption of lipids such as triglycerides, BAs are also important signaling molecules regulated in glucolipid and energy metabolism [16]. It was shown that BAs mainly regulate glucose and lipid metabolism through FXR and TGR5 to modulate glycolipid metabolism [193]. BAs are natural ligands for FXR and TGR5 in the gut, but different forms of BAs have different activating abilities, such as free BAs over bound BAs and secondary BAs over primary BAs. Notably, the structural transformation of BAs in the gut is strongly based on the microbial enzyme system [194].

Secondary BAs activate FXR, which on the one hand induces FGF19 expression and secretion in the gut, downregulates BA synthesis, increases BA excretion and reduces fat digestion and absorption. On the other hand, it activates PPARγ and PPARα, which promote fatty acid oxidation, reduce TG synthesis and regulate adipocyte differentiation [195]. Additionally, FXR induces the production of FGF15, which excretes more than 60% of absorbed cholesterol into the intestinal lumen via ATP‐binding cassette transporter protein G5 and ATP‐binding cassette transporter protein G8. More interestingly, FXR inhibition also has a positive role in lipid metabolism [196]. Wang et al. found that 3 weeks of hesperidin supplementation reduced the abundance of BSH‐producing and 7α‐dehydroxylase microorganisms such as Bacteroides, Bifidobacterium, and Clostridium in ApoE^−/− female mice on high‐fat diets, which subsequently reduced the hydrolysis of bound BAs and inhibited the FXR/FGF15 pathway to upregulate CYP7A1 to promote the conversion of cholesterol to bile acids, thereby reducing body TG levels and improving atherosclerosis [197]. As the only known endogenous ligand for TGR5, BAs activate TGR5 and initiate cAMP and its downstream related signaling pathways to induce glucagonogenic gene expression and promote GLP‐1 secretion in intestinal L cells, which improves insulin resistance and appetite for food [198]. He et al. supplemented mice on a high‐fat diet with pure total flavonoids for 12 weeks and showed that pure total flavonoids significantly increased the abundance of Bacteroidaceae and Christensenellaceae, increased the content of secondary BAs, activated FXR and TGR5, reduced serum TG levels, and improved non‐alcoholic steatohepatitis in mice [199].

Growing evidence shows that flavonoids are linked to lipid metabolism not only by modulating the synthesis and excretion of BAs but also by improving secondary BA production through the modulation of microorganisms [197, 200]. However, few studies have been conducted to compare the ability of different flavonoids to interact with gut microbiota to modulate bile acids to the extent that we do not know which flavonoids are more appropriate and more promising for clinical studies.

5. CONCLUDING REMARKS AND FUTURE PERSPECTIVES

Increasing evidence indicates that flavonoids play a part in lipid metabolism regulation by decreasing appetite and energy intake, decreasing fat absorption, inhibiting fat cell differentiation, promoting fat cell apoptosis, increasing lipolysis, promoting WAT browning and non‐shivering thermogenesis, and restructuring the microbiota imbalance caused by metabolic disorders. Although the interaction between gut microbiota and flavonoids provides a novel dimension to understand the mechanisms of flavonoids regulating host lipid metabolism, flavonoids are complex in structure, and animal and clinical experiments mostly focus on plant polyphenols. Nevertheless, numerous questions and research directions for future research persist. These include: determining which flavonoid composition is more promising for clinical applications and exploring the interactions among different flavonoid components; identifying the configuration with greater biological potency, the most effective modification of the radical group, and whether modifications in the modified radical group undergo metabolic changes affecting potency; investigating if the biological potency of flavonoids is influenced by diet and lifestyle, and developing strategies to mitigate these lifestyle differences. The clinical application of flavonoids still has some way to go, and there is a need for increased clinical research and the application of modern technology to explore the mechanisms by which flavonoids interact with the body organs to better understand the regulatory targets.

6. LITERATURE COLLECTION METHODS

A comprehensive search was conducted across the PubMed and Google Scholar databases to retrieve relevant literature. The primary search criteria encompassed various keywords such as “flavonoids,” “flavonoid metabolism,” “quercetin,” “baicalin,” “gut microbiota,” “microbial metabolites,” “lipid metabolism,” “obesity,” “antioxidant,” “antibacterial,” and “anti‐obesity.” The retrieved search results underwent evaluation to ascertain their compliance with the predefined inclusion criteria.

AUTHOR CONTRIBUTIONS

Miao Zhou: Writing‐Original draft preparation, revision, and investigation. Jie Ma and Jie Yin: Revision. Wenjie Tang: Conceptualization. Siting Xia and Meng Kang: Investigation. Yulong Yin: Validation. All authors contributed to the article and approved the submitted version.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

Zhou M, Ma J, Kang M, et al. Flavonoids, gut microbiota, and host lipid metabolism. Eng Life Sci. 2024;24:e2300065. 10.1002/elsc.202300065

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated during the current study.