Next Article in Journal
Predictive Value of Repeated Jump Testing on Nomination Status in Professional and under 19 Soccer Players
Previous Article in Journal
eHealth: A Survey of Architectures, Developments in mHealth, Security Concerns and Solutions
Previous Article in Special Issue
Changes in the Gut Microbiome and Pathologies in Pregnancy
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Gut Microbiome: The Interplay of an “Invisible Organ” with Herbal Medicine and Its Derived Compounds in Chronic Metabolic Disorders

1
Department of Diagnostics, College of Korean Medicine, Dongguk University, Dongguk-Ro 32, Goyang 10326, Korea
2
Institute of Bioscience & Integrative Medicine, Daejeon University, 75, Daedeok-daero 176, Seo-gu, Daejeon 35235, Korea
*
Author to whom correspondence should be addressed.
Int. J. Environ. Res. Public Health 2022, 19(20), 13076; https://doi.org/10.3390/ijerph192013076
Submission received: 19 August 2022 / Revised: 29 September 2022 / Accepted: 9 October 2022 / Published: 11 October 2022
(This article belongs to the Special Issue The Gut Microbiota and Human Health)

Abstract

:
Resembling a concealed “organ” in a holobiont, trillions of gut microbes play complex roles in the maintenance of homeostasis, including participating in drug metabolism. The conventional opinion is that most of any drug is metabolized by the host and that individual differences are principally due to host genetic factors. However, current evidence indicates that only about 60% of the individual differences in drug metabolism are attributable to host genetics. Although most common chemical drugs regulate the gut microbiota, the gut microbiota is also known to be involved in drug metabolism, like the host. Interestingly, many traditional herbal medicines and derived compounds are biotransformed by gut microbiota, manipulating the compounds’ effects. Accordingly, the gut microbiota and its specified metabolic pathways can be deemed a promising target for promoting drug efficacy and safety. However, the evidence regarding causality and the corresponding mechanisms concerning gut microbiota and drug metabolism remains insufficient, especially regarding drugs used to treat metabolic disorders. Therefore, the present review aims to comprehensively summarize the bidirectional roles of gut microbiota in the effects of herbal medicine in metabolic diseases to provide vital clues for guiding the clinical application of precision medicine and personalized drug development.

1. Introduction

Since our host origins, trillions of microbes have coexisted and coevolved with humans in the gastrointestinal tract [1]. In an innovative concept, the host and its commensal microbiomes are considered a “supraorganism” [2]. Because various microorganisms can be difficult to culture and because of the limitations of the technology for differentiation, investigations of the gut microbiota (GM) had progressed very slowly in the past [3]. However, recently, with the development of OMICs approaches, many scientists and physicians have established that ten times the cell number and one hundred times the genes exist in the GM compared to the human host itself [4,5]. Moreover, some researchers also estimated that the difference in the number of human cells and GM is not significant [6]. Although the numbers of commensal gut bacteria and their genes are debated by scholars [6], in recent decades, huge numbers of gut commensal bacteria with a tremendous number of genes have been proved to play a critical role in host metabolism, including drug metabolism [7]. Therefore, the studies concerning the relationship between GM-produced drug metabolites and host metabolism dysfunction are noteworthy.
In modern society, metabolic disorders (MetD) are common diseases often referred to as a new pandemic [8], with increasing prevalence [9]. MetD are heterogeneous diseases that occur when the normal metabolic process is disrupted due to abnormal chemical reactions [10]. These abnormal chemical reactions can lead to the maldistribution of macronutrients such as protein, fat, and carbohydrates [11]. Thus, at the physical level, weight loss or gain (in terms of the body mass index) is the primary sign of MetD; at the physiological level, high blood pressure is the primary sign of MetD; and, at the biochemical level, high triglyceride and high carbohydrate levels in the blood are the primary indicators of MetD [12,13,14,15]. These increase the risks of hyperlipidemia, hyperglycemia, and hypertension, resulting in obesity, diabetes, and cardiovascular diseases [16].
For the treatment of MetD, both synthetic and traditional medicines (herbal drugs/formulations) can be considered [17,18,19]. Each kind of medical system has its unique way of maintaining health. Generally, Western medicines are primarily metabolized in the liver via cytochrome P450 enzymes and impact host physiology [20,21]. In the past, it has been supposed that a single drug is appropriate for a single symptom for any individual. However, we still do not fully understand how a drug is metabolized in a particular individual for a particular disease.
Decades earlier, it had already been established that every individual has a unique composition of intestinal bacteria, which can be recognized as commensal, opportunistic, and pathogenic [22]. The GM composition fluctuates due to multifactorial host conditions such as age, genetics, diet, drugs, and various environmental factors [23]. Many scientific findings have already revealed that the GM can directly contribute to MetD by increasing gut permeability and systemic low-grade inflammation [24]. Moreover, it is widely assumed that the host GM has a secondary impact on MetD by modulating the efficacy or availability of drugs taken by the host.
To the best of our knowledge, drug metabolism comprises a sequence of complex processes regulated by host genetics, the GM composition, and environmental factors [25,26,27]. Current evidence indicates that only about 60% of the individual differences in drug metabolism are attributable to host genetics [28]. The GM fundamentally modulates drug metabolism through various enzymes, such as reductases, hydrolases, transferases, and lyases [29]. One ex vivo experiment showed that at least one GM species from 76 human gut commensal bacteria chemically modified approximately two-thirds of common clinical drugs [30]. Moreover, even a single species of the GM can metabolize 11 to 95 kinds of clinical drugs obtained from DrugBank (https://go.drugbank.com, accessed on 4 January 2018). Similarly, many herbal medicines and their derived compounds are biotransformed by GM, manipulating the drugs’ effects and safety [31].
Consequently, we present a comprehensive overview of advances regarding the GM and herbal medicines’ metabolism in MetD and the challenges at the frontiers of this rapidly accelerating field. The current review aims to summarize the outcomes of drug metabolism by the GM in metabolic diseases, which will help researchers to decide their directions of study. Meanwhile, it will provide a vital reference guiding the clinical application of precision medicine and personalized therapy for metabolic disorders. Ultimately, we hope the present overview can contribute to ameliorating the public health issue by widening the understanding of GM and their metabolism of natural drugs.
In the current study, the literature was searched through two well-known databases of biomedical literature, PubMed (www.ncbi.nlm.nih.gov/pubmed, accessed on 8 January 2022) and Google scholar (scholar.google.com), with the combinations of the following keywords: “herb”, “plant”, “herbal medicine”, “herbal drug”, “gut microbiota”, “gut microbiome”, “bioconversion”, “fermentation”, “metabolic diseases”, “metabolic syndrome”, “obesity”, “diabetes”, “NAFLD”, “NASH”, “fatty liver” and “hyperlipidemia”, whereas without time limitation. Eventually, the papers were selected by whether they contain microbial metabolites derived from herbal medicine and their natural compounds and relate to various metabolic diseases.

2. The GM’s Interplay with Herbal Medicine, Altering Drugs’ Efficacy in Metabolic Disorders

Many studies have reported that the GM influences herbal drugs’ efficacy during microbial metabolism by changing pharmacokinetic processes [32]. As typical herbal-origin compounds, glycosides consist of one/several sugar(s) combined with an aglycone [33]. These phytochemicals are secondary plant metabolites and can be present along with phenols, alcohols, flavonoids, saponins, and anthraquinone [34]. However, the herb-derived glycosides are usually inactive due to their conjugated sugar moiety [35]; therefore, they are classified as prodrugs [36]. Nonactivated glycosides can be degraded/metabolized by the GM by their enzymes, producing bioactive aglycones [37]. In the process of microbial transformation, the properties of herbal medicine (HM) compounds have been shown to be greatly changed by general modifications into smaller, less polar, and more lipophilic molecules [38]. The above processes derived from the GM consist of many enzymatic reactions, such as the hydrolysis, oxidation, reduction, and esterification of the functional groups of compounds [39]. The GM-specific bioconversion processes of herbal compounds are highly differentiated into several stages and have distinct structural preferences in functional groups conducted cooperatively or independently [38].
The efficacy of herbal compounds can be modulated by changing their oral bioavailability [40]. In some cases, smaller molecules produced by digestion exhibit stronger efficacy than their parent molecules [31]. The GM also regulates the toxicity of HMs by metabolizing toxic substances [31]. The alteration of herbal toxicity by GM metabolism remains unclear and requires further investigation. Hence, we summarize how the GM modulates the efficacy of HMs used in the treatment of metabolic disorders. To readily comprehend the overview, we organized microbial metabolites of herb-derived compounds produced by gut microbiota in Table 1; we also arranged the impact of microbial metabolism on drug efficacy against metabolic diseases in Table 2. Meanwhile, the molecular and pharmacological properties of major compounds and their metabolites from herbs were listed in Table 3.

2.1. Gut Microbial Metabolism Produces Ginsenosides from Ginseng Radix, Exerting Bioactivity

The ginsenosides are a group of steroidal glycosides and triterpenes derived from ginseng that have pharmacological activity against diabetes, obesity, and other MetD [69]. The GM biotransformation process on ginseng saponins and its influence on host health have been extensively studied [70]. Previous findings revealed that the therapeutic potential of ginseng saponins largely depends on their bioconversion by the host GM, which can result in varying bioavailability, membrane permeability, and stability in the gastrointestinal tract [71]. The biological conversion of ginsenosides has been investigated in various studies, including ex vivo studies (anaerobic incubation with human fecal supernatants), in vivo studies (germ-free or antibiotic-treated animals, and gnotobiotic animals), and clinical trials. The 20(S)-protopanaxadiol-type ginsenosides (Rb1, Rb2, Rb3, Rc, and Rd) are mainly transformed into compound K, and Rh2 and 20(S)-protopanaxatriol-type ginsenosides (Re, Rg1, and Rg2) can also be converted into Rh1 and protopanaxatriol [70,72]. GM species, such as Fusobacterium, Eubacterium, and Bifidobacterium spp., predominantly biotransform the ginsenosides through β-glucosidase [41,42,44,45,46,47,70,73,74,75,76]. Among these bacterial metabolites, compound K, which is a hydrophobic and absorbable compound [73], has the most potent activity against numerous diseases, including various metabolic disorders [46].

2.2. Gut Microbial Metabolism Produces Active Compounds from Puerariae

Puerariae Radix, enriched with isoflavone glucosidases, has a long history of use in east Asia, possessing therapeutic effects on obesity, dyslipidemia, and insulin signaling [77,78]. The typical compounds in Puerariae Radix include puerarin, daidzin, and daidzein [79]. Daidzin and puerarin are metabolized into daidzein and, further, into equol, which is promising for estrogenic activities [80]. It was demonstrated that daidzein shows higher intestinal absorbability than daidzin in the Caco-2 cell model, implying the importance of bacterial hydrolysis in absorption [81]. Another in vitro study revealed that daidzin and puerarin were transformed into daidzein by human fecal bacteria, such as Eubacterium A-44, and the metabolite daidzein displayed effectively increased estrogenic activity [51]. Other flavonoids are found in Pueraria flos, including kakkalide and tectoridin, which also have estrogenic effects similar to those of equol [50]. In this case, kakkalide and tectoridin are mainly metabolized into irisolidone and tectorigenin by the human and rat gut bacterium Bifidobacterium K-110 via β-D-xylosidase, and they exert stronger activity than their corresponding precursors [50,52].

2.3. Gut Microbial Metabolism of Compounds from Coptidis Rhizoma Improves Their Absorption Rate

Flavone glycosides and berberine are the main active compounds from Coptis Chinensis, which exerts notable effects on type 2 diabetes (T2DM) and T2DM-related complications, including hyperlipidemia, heart disease, and retinopathy [82]. Although it is an essential compound from Coptidis rhizoma with many properties, berberine has extremely low bioavailability (<1%) [83], and its absorption is largely attributed to the activity of GM [84]. Berberine can be metabolized by the GM into dihydroberberine, berberrubine, demethyleneberberine, jatrorrhizine, and oxyberberine [85]. The biotransformation of berberine into the reduced form, dihydroberberine, is achieved by Enterobacter cloacae and Enterococcus faecalis by nitroreductase, improving its absorption rate [86]. Once absorbed, dihydroberberine is reverted to berberine in the host’s intestinal epithelial tissue and dispersed to organs, where it exerts its pharmacological activities [55]. Another metabolite, oxyberberine, is metabolized by the intestinal microbiota, showing greater effects than berberine [53].

2.4. Gut Microbial Bioconversion of Compounds from Scutellaria Radix Improves Their Absorption Rate

The root of Scutellaria baicalensis and its major compound, baicalin, have been used to treat metabolic diseases, including obesity, hyperlipidemia, metabolic syndrome, and diabetes [87]. Baicalin is hydrolyzed into its aglycone, baicalein, by β-glucuronidase from E. coli [57] and is thereby easily absorbed in the intestine [88]. Absorbed baicalein can be reconjugated into baicalin by UDP-glucuronosyltransferase in the host’s liver and intestine and exert beneficial activities [56,84]. An in vivo study using a bile-duct-ligated rat model suggested that baicalin is converted to baicalein by the GM generating β-glucuronidase, and that the absorption of baicalein is preferable to that of baicalin in the gastrointestinal tract [89]. Wogonin is another key component of Scutellaria baicalensis. As an aglycone derived from wogonoside, it has a beneficial effect on glucose and lipid metabolism [90]. A rat study demonstrated the fundamental role of the GM in the absorption of compounds from Scutellaria baicalensis, in which antibiotic pretreatment inhibited the absorption of wogonoside and baicalin and its metabolites [91]. Intestinal bacteria of the Lactobacillus spp. and their glucuronidase enzymes are reported to be involved in these enzymatic reactions [58,59], which also increases the bioavailability of compounds.
Table 2. Gut microbial metabolites derived from herbal compounds and their Impact on metabolic diseases.
Table 2. Gut microbial metabolites derived from herbal compounds and their Impact on metabolic diseases.
Herb NameMicrobial MetabolitesTreatment of DiseasesStudy Design
(In Vitro/In Vivo/Clinical Study)
Impact of Drug EfficacyRef.
Ginseng RadixCompound KDiabetesIn vivo
(SD rats)
In vitro
(Caco-2 cell permeability)
Increased absorption[73]
Compound K
Ginsenoside Rh1
NAFLDIn vivo
(HFD-fed SD rats)
In vitro
(HSC-T6 cell)
Increased activity[92]
Compound KDiabetesIn vivo
(STZ and HFD-fed ICR mice)
Increased activity[93]
Puerariae Radix
and
Puerariae Flos
Irisolidone
Tectorigenin
Estrogenic effectIn vitro
(human fecal incubation, MCF-7 cells)
Increased activity
(c-fos and pS2 gene)
[50]
DaidzeinNot indicatedIn vitro
(Caco-2 permeability)
In vivo
(hydrolyzation by rat microvilli)
Increased absorption[81]
DaidzeinEstrogenic effectIn vitro
(human fecal incubation,
MCF-7 cells)
Increased activity[51]
EquolNAFLDIn vivo
(HFD-fed mice)
Increased activity
Changed bioactivity
[94]
Coptidis RhizomaOxyberberineColitisIn vivo
(DSS-induced colitis Balb/C mice)
Increased activity[53]
DihydroberberineDiabetesIn vivo
(KK-Ay mice)
Increased absorption[55]
BerberrubineHypercholesterolemiaClinical study
(n = 12, moderate hypercholesterolemia)
Increased activity[95]
Scutellaria RadixBaicaleinNot intendedIn vivo
(antibiotic-treated SD rats)
Increased absorption[96]
BaicaleinNot intendedIn vivo
(germ-free Wistar rats)
Increased absorption[56]
BaicaleinNot intendedIn vivo
(bile-duct-ligated Wistar rats
Increased absorption[89]
WogoninNot intendedIn vivo
(antibiotic-treated SD rats)
Increased absorption[91]
Curcumae RadixTetrahydrocurcuminDiabetesIn vivo
(STZ-induced diabetic rats)
Increased activity[97]
TetrahydrocurcuminLipid accumulationIn vitro
(THP-1 cells)
Decreased activity[98]
Mori folium,
Bupleurum Radix,
Houttuyniae Herba
QuercetinPlatelet activityIn vitroIncreased activity[65]
QuercetinInsulin resistanceIn vitro
(TNF-α-treated C2C12 cells)
Increased activity[99]
Glycyrrhizae
Radix
Glycyrrhetic acidNot indicatedIn vivo
(SD rats, Wistar germ-free rats)
Increased bioavailability[100]
18β-Glycyrrhetinic acidObesityIn vitro
(3T3-L1)
In vivo
(HFD-fed C57/BL6 mice)
Not indicated[101]
18β-Glycyrrhetinic acidNASHIn vivo
(MCD; C57/BL6 mice)
Increased bioactivity[90]
SD, Sprague Dawley; STZ, streptozotocin; HFD, high-fat diet; HSC, hepatic stellate cell; NAFLD, non-alcoholic fatty liver disease; DSS, dextran sulfate sodium; TNF, tumor necrosis factor; NASH, non-alcoholic steatohepatitis; MCD, methionine- and choline-deficient diet.

2.5. Gut Microbial Metabolism of Curcumin from Curcumae Radix Increases Its Bioavailability

Curcumae Radix contains curcumin, a phenolic pigment insoluble in water, which shows pharmacological activities against metabolic diseases, including obesity, diabetes, and hepatic steatosis [102,103]. As a polyphenol, curcumin has low bioavailability as demonstrated by its in vivo pharmacokinetic data [104]. The main reasons for the low bioavailability of curcumin are its poor absorption, instability, rapid metabolism, and rapid excretion [105]. However, curcumin can be metabolized by the human gut bacteria Blautia sp. MRG-PMF1 into demethylcurcumin and bisdemethylcurcumin [62]. Additionally, an in vitro fermentation study reported that three bacteria, including Escherichia fergusonii and Escherichia coli DH10B, metabolized curcumin via two-step reduction into dihydrocurcumin as an intermediate, followed by tetrahydrocurcumin and ferulic acid as final products [60]. The debate over any difference in biological activity between the parent compound (curcumin) and its major metabolite (tetrahydrocurcumin) is ongoing; however, it seems that they possess differential activity with distinct target molecules [104].

2.6. Gut Microbial Bioconversion of Quercitrin from Several Herbs into Quercetin Increases Its Bioavailability

Quercetin and its glycoside form, quercitrin (quercetin 3-rhamnoside), are the most common flavonoids found in nature [106]. These compounds are distributed in some common traditional medicinal herbs and foods, like Mori folium, Bupleurum Radix, and Houttuyniae Herba [65,107,108]. Like other flavonoids, quercetin glycosides are not bioavailable due to their structures [84]; however, intestinal microbiota including Bacillus subtilis and Fusobacterium K-60 can metabolize quercitrin to produce quercetin through dioxygenase or α-L-rhamnosidase [63,109]. Among the aglycones, quercetin possesses ubiquitous effects of hypoglycemic, hypolipidemic, and hypotensive and anti-obesity with multifaceted mechanisms [110]. Meanwhile, the low bioavailability of quercitrin also affects its delivery into farther regions of the intestine, where it can be decomposed to quercetin, the active aglycone [111].

2.7. Glycyrrhizin from Glycyrrhizae Radix Requires Bacterial Transformation to Be Absorbed in the Intestine

Glycyrrhizin is a triterpenoid saponin derived from Glycyrrhizae Radix (licorice) that is used for its various clinical indications, including nonalcoholic fatty liver disease, gastric disorders, and metabolic disorders [112,113]. Extracted licorice contains glycyrrhizin and its aglycone, glycyrrhetic acid, as bioactive compounds. An in vivo study showed that the administration route of glycyrrhizin is critical for its bioavailability; that bioavailability under oral administration was approximately 1% due to its poor absorption in the intestine [114]. The bioconversion of glycyrrhizin to an active form, 18β-glycyrrhetinic acid or glycyrrhetic acid, occurs in the presence of β-D-glucuronidase from Eubacterium, Ruminococcus, and other species of the intestinal microbiota [115].
Table 3. The molecular and pharmacological properties of major compounds and their metabolites from herbs, described in the main text.
Table 3. The molecular and pharmacological properties of major compounds and their metabolites from herbs, described in the main text.
Herbal MedicineRaw CompoundProperties of Raw CompoundProperties of MetaboliteMetabolite
Ginseng RadixGinsenoside Rb1PubChem CIDGinsenoside Rd
Ijerph 19 13076 i001989827911679800Ijerph 19 13076 i002
Molecular Weight
1109.3963.30
Bioavailability Score
0.170.17
GI Absorption
LowLow
Lipinski’s Criteria
No (3 violations)
MW > 500, NorO > 10, NHorOH > 5
No (3 violations)
MW > 500, NorO > 10, NHorOH > 5
Ginsenoside RcPubChem CIDCompound K
Ijerph 19 13076 i003128558895481990Ijerph 19 13076 i004
Molecular Weight
1079.3653.8
Bioavailability Score
0.170.55
GI Absorption
LowHigh
Lipinski’s Criteria
No (3 violations)
MW > 500, NorO > 10, NHorOH > 5
Yes (1 violation)
MW > 500
Puerariae Radix
and
Puerariae Flos
DaidzinPubChem CIDDaidzein
Ijerph 19 13076 i0051079715281708Ijerph 19 13076 i006
Molecular Weight
416.41254.24
Bioavailability Score
0.550.55
GI Absorption
LowHigh
Lipinski’s Criteria
Yes (0 violations)Yes (0 violations)
Coptidis RhizomaBerberinePubChem CIDOxyberberine
Ijerph 19 13076 i007235311066Ijerph 19 13076 i008
Molecular Weight
336.4351.4
Bioavailability Score
0.550.55
GI Absorption
HighHigh
Lipinski’s Criteria
Yes (0 violations)Yes (0 violations)
Scutellaria RadixBaicalinPubChem CIDBaicalein
Ijerph 19 13076 i009649825281605Ijerph 19 13076 i010
Molecular Weight
446.4270.24
Bioavailability Score
0.110.55
GI Absorption
LowHigh
Lipinski’s Criteria
No (2 violations)
NorO > 10, NHorOH > 5
Yes (0 violations)
Curcumae RadixCurcuminPubChem CIDDihydrocurcumin
Ijerph 19 13076 i01196951610429233Ijerph 19 13076 i012
Molecular Weight
368.4370.4
Bioavailability Score
0.550.55
GI Absorption
HighHigh
Lipinski’s Criteria
Yes (0 violations)Yes (0 violations)
Mori folium/
Bupleurum Radix/Houttuyniae Herba
QuercitrinPubChem CIDQuercetin
Ijerph 19 13076 i01352804595280343Ijerph 19 13076 i014
Molecular Weight
448.4302.23
Bioavailability Score
0.170.55
GI Absorption
LowHigh
Lipinski’s Criteria
No (2 violations)
NorO > 10, NHorOH > 5
Yes (0 violations)
Glycyrrhizae
Radix
Glycyrrhizin
(Glycyrrhizic Acid)
PubChem CID18-β-Glycyrrhetinic Acid
(Glycyrrhetic Acid)
Ijerph 19 13076 i0151498210114Ijerph 19 13076 i016
Molecular Weight
822.9470.7
Bioavailability Score
0.110.85
GI Absorption
LowHigh
Lipinski’s Criteria
No (3 violations)
MW > 500, NorO > 10, NHorOH > 5
Yes (1 violation)
MLOGP > 4.15
Data were obtained from the PubChem (https://pubchem.ncbi.nlm.nih.gov/, accessed on 7 August 2022) and SwissADME (http://www.swissadme.ch/, accessed on 7 August 2022) online databases.

3. Current Status and Future Perspectives

Understanding the variability of the GM and host digestion of drugs is necessary for precision medicine [40]. As presented herein, natural drugs are metabolized by the host GM through complex mechanisms. Based on these findings, some studies have started to interpret the differential efficacies of herbal drugs between individuals, using the different gut microbial compositions.
For instance, a study comparing two groups of Korean subjects with distinct capabilities for metabolizing compound K showed a marked difference in the compositions of their GM, which explained the inconsistency in the drug potency of Panax ginseng between individuals [116]. Another case is the Rhei Radix medicine used in postoperative patients; these patients are frequently administered antibiotics, which prevents the prodrug from being properly metabolized by the GM, and purgative efficacy was not observed in many cases [117]. Another consideration is the fact that the diversity of the GM varied across ethnicities, which could also influence the efficacy of natural drugs [118].
As mentioned above, a series of evidence indicated the undeniable impacts of individual GM on personal health for clinicians. Therefore, it is necessary to establish integrated databases containing herbal compounds and gut microbial metabolites according to the representative types of human microbial communities. However, current studies describing the impacts of microbial conversions of natural drugs on their efficacies are relatively scarce among the studies on drugs and are fragmented by their scope. For instance, most articles focus on the microbial conversion process itself, not exploring the differences in efficacy between the metabolites and parent compounds. Other researchers have only focused on the outcomes of microbial bioconversion, without exploring the bacteria or enzymes involved. Therefore, an integrated natural compound library should cover intact natural components, microbial metabolites, enzymes involved in the process, and predicted consequences for the oral bioavailability or bioactivities, to enable a better understanding and prediction of the impacts of natural products or herbal medicinal treatments on certain diseases. On the other hand, this also requires a metagenomic database of GM in various populations. Fortunately, the outcome of 845 intestinal microbial metagenome data analyses in three Asian countries was recently published (Korea, Japan, and India) [119].
However, the herbal drug–microbiota interaction is reciprocal, not unilateral. As many studies have revealed, herbs exert profound effects on the GM community, sometimes via bactericidal or prebiotic effects. Berberine has been reported to modulate the GM in rats with obesity induced by a high-fat diet [120], and this compound is known to exert antibiotic effects, especially on Gram-negative bacteria. In addition, the antidiabetic effects of baicalein are associated with modulation of the GM [121], and baicalein is also known to restrict the growth of harmful bacterial strains. On the contrary, herbal polysaccharides and glycosides usually possess prebiotic effects, providing carbohydrates as nutrients [40]. As a result, it has been demonstrated that modulation of the GM to ameliorate metabolic disturbances may now be a feasible strategy [122]. Therefore, the Impact of herbal drugs/prescriptions on the commensal gut bacterial community should also be considered, to optimize the use of natural drugs.
Only a small proportion of the interactions between natural drugs and GM have been elucidated, considering the huge contribution of bacterial metabolism in digestion [123,124]. A recent study suggested a novel solution: adopting machine learning to predict drugs’ metabolism by GM [125]. Although the model used in the study predicted the depletion of drugs by gut microbial metabolism and did not suggest any consequent metabolites, it is worth exploring the possibilities of computational analysis in this field. So far, it is still challenging to fully clarify how gut microbial metabolism benefits treating metabolic disease, even with the enhanced bioavailability of drugs. Herein, the selected publications revealed an increasing tendency in the recent decade; however, only 2% of human studies reflected the status of severe deficiency regarding herb–drug metabolism and gut microbiota, especially in metabolic dysfunction (Figure S1). Thus, the scientific evidence is still inadequate, especially from human trials. We anticipate that the complex interaction between GM and herbal medicines and the aftermath of microbial metabolism will be investigated clearly through more and more animal and clinical studies.

4. Conclusion

Overall, the present review explored the roles of the GM in the metabolism of herbal compounds to provide a vital reference for guiding clinical applications and further research. This review also provides valuable clues to assist in the application of clinical drugs in precision medicine and should contribute to personalized drug development for metabolic diseases. For policymakers, good pharmacovigilance needs to consider the host commensal microbiota to guarantee public medication safety and effectiveness, especially for herbal medicine.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/ijerph192013076/s1. Figure S1: general information of selected papers in the present review.

Author Contributions

Conceptualization, J.-H.W.; methodology, J.-H.W. and D.-W.L.; formal analysis, J.-H.W. and D.-W.L.; investigation, D.-W.L.; data curation, D.-W.L.; writing—original draft preparation, D.-W.L.; writing—review and editing, J.-H.W.; visualization, D.-W.L.; supervision, J.-H.W.; project administration, J.-H.W.; funding acquisition, J.-H.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Research Foundation of Korea (NRF), grant number 2020R1F1A1074155.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Davenport, E.R.; Sanders, J.G.; Song, S.J.; Amato, K.R.; Clark, A.G.; Knight, R. The human microbiome in evolution. BMC Biol. 2017, 15, 127. [Google Scholar] [CrossRef]
  2. Dominguez-Bello, M.G.; Godoy-Vitorino, F.; Knight, R.; Blaser, M.J. Role of the microbiome in human development. Gut 2019, 68, 1108–1114. [Google Scholar] [CrossRef] [Green Version]
  3. Farré-Maduell, E.; Casals-Pascual, C. The origins of gut microbiome research in Europe: From Escherich to Nissle. Hum. Microbiome J. 2019, 14, 100065. [Google Scholar] [CrossRef]
  4. Satoor, S.N.; Patil, D.P.; Kristensen, H.D.; Joglekar, M.V.; Shouche, Y.; Hardikar, A.A. Manipulation and assessment of gut microbiome for metabolic studies. Methods Mol. Biol. 2014, 1194, 449–469. [Google Scholar] [CrossRef] [PubMed]
  5. Zhu, B.; Wang, X.; Li, L. Human gut microbiome: The second genome of human body. Protein Cell 2010, 1, 718–725. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Sender, R.; Fuchs, S.; Milo, R. Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLoS Biol. 2016, 14, e1002533. [Google Scholar] [CrossRef] [Green Version]
  7. D’Argenio, V.; Salvatore, F. The role of the gut microbiome in the healthy adult status. Clin. Chim. Acta 2015, 451, 97–102. [Google Scholar] [CrossRef] [Green Version]
  8. Dzherieva, I.; Volkova, N.; Panfilova, N. Depressive disorders in males with metabolic syndrome. J. Biomed. Clin. Res. 2011, 4, 46–49. [Google Scholar]
  9. Im, H.J.; Ahn, Y.C.; Wang, J.H.; Lee, M.M.; Son, C.G. Systematic review on the prevalence of nonalcoholic fatty liver disease in South Korea. Clin. Res. Hepatol. Gastroenterol. 2021, 45, 101526. [Google Scholar] [CrossRef]
  10. Karalliedde, J.; Gnudi, L. Diabetes mellitus, a complex and heterogeneous disease, and the role of insulin resistance as a determinant of diabetic kidney disease. Nephrol. Dial. Transplant. 2014, 31, 206–213. [Google Scholar] [CrossRef]
  11. Lê, K.-A.; Bortolotti, M. Role of dietary carbohydrates and macronutrients in the pathogenesis of nonalcoholic fatty liver disease. Curr. Opin. Clin. Nutr. Metab. Care 2008, 11, 477–482. [Google Scholar] [CrossRef] [PubMed]
  12. Phelan, S.; Wadden, T.; Berkowitz, R.; Sarwer, D.; Womble, L.; Cato, R.; Rothman, R. Impact of weight loss on the metabolic syndrome. Int. J. Obes. 2007, 31, 1442–1448. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Alley, D.E.; Chang, V.W. Metabolic syndrome and weight gain in adulthood. J. Gerontol. Ser. A Biomed. Sci. Med. Sci. 2010, 65, 111–117. [Google Scholar] [CrossRef] [Green Version]
  14. Franklin, S.S.; Barboza, M.G.; Pio, J.R.; Wong, N.D. Blood pressure categories, hypertensive subtypes, and the metabolic syndrome. J. Hypertens. 2006, 24, 2009–2016. [Google Scholar] [CrossRef] [PubMed]
  15. Di Daniele, N.J.N. Association of Dietary Patterns with Metabolic Syndrome; Multidisciplinary Digital Publishing Institute: Basel, Switzerland, 2020; Volume 12, p. 2840. [Google Scholar]
  16. Halpern, A.; Mancini, M.C.; Magalhães, M.E.C.; Fisberg, M.; Radominski, R.; Bertolami, M.C.; Bertolami, A.; de Melo, M.E.; Zanella, M.T.; Queiroz, M.S.J.D.; et al. Metabolic syndrome, dyslipidemia, hypertension and type 2 diabetes in youth: From diagnosis to treatment. Diabetol. Metab. Syndr. 2010, 2, 1–20. [Google Scholar] [CrossRef] [Green Version]
  17. Finsterer, J.; Frank, M. Repurposed drugs in metabolic disorders. Curr. Top. Med. Chem. 2013, 13, 2386–2394. [Google Scholar] [CrossRef]
  18. Scotti, L.; Monteiro, A.F.M.; de Oliveira Viana, J.; Mendonça Junior, F.J.B.; Ishiki, H.M.; Tchouboun, E.N.; Santos, R.; Scotti, M.T. Multi-Target Drugs Against Metabolic Disorders. Endocr. Metab. Immune Disord. Drug Targets 2019, 19, 402–418. [Google Scholar] [CrossRef]
  19. Jang, S.; Jang, B.-H.; Ko, Y.; Sasaki, Y.; Park, J.-S.; Hwang, E.-H.; Song, Y.-K.; Shin, Y.-C.; Ko, S.-G. Herbal Medicines for Treating Metabolic Syndrome: A Systematic Review of Randomized Controlled Trials. Evid. Based Complement. Altern. Med. 2016, 2016, 5936402. [Google Scholar] [CrossRef] [Green Version]
  20. Almazroo, O.A.; Miah, M.K.; Venkataramanan, R. Drug Metabolism in the Liver. Clin. Liver Dis. 2017, 21, 1–20. [Google Scholar] [CrossRef]
  21. Zhao, M.; Ma, J.; Li, M.; Zhang, Y.; Jiang, B.; Zhao, X.; Huai, C.; Shen, L.; Zhang, N.; He, L.; et al. Cytochrome P450 Enzymes and Drug Metabolism in Humans. Int. J. Mol. Sci. 2021, 22, 12808. [Google Scholar] [CrossRef]
  22. Rath, S.; Rud, T.; Karch, A.; Pieper, D.H.; Vital, M. Pathogenic functions of host microbiota. Microbiome 2018, 6, 174. [Google Scholar] [CrossRef] [Green Version]
  23. Qin, Y.; Havulinna, A.S.; Liu, Y.; Jousilahti, P.; Ritchie, S.C.; Tokolyi, A.; Sanders, J.G.; Valsta, L.; Brożyńska, M.; Zhu, Q. Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort. Nat. Genet. 2022, 54, 134–142. [Google Scholar] [CrossRef]
  24. Kang, C.; Wang, B.; Kaliannan, K.; Wang, X.; Lang, H.; Hui, S.; Huang, L.; Zhang, Y.; Zhou, M.; Chen, M. Gut microbiota mediates the protective effects of dietary capsaicin against chronic low-grade inflammation and associated obesity induced by high-fat diet. MBio 2017, 8, e00470-17. [Google Scholar] [CrossRef] [Green Version]
  25. Daly, A.K. Genetic polymorphisms affecting drug metabolism: Recent advances and clinical aspects. Adv. Pharm. 2012, 63, 137–167. [Google Scholar] [CrossRef]
  26. Noh, K.; Kang, Y.R.; Nepal, M.R.; Shakya, R.; Kang, M.J.; Kang, W.; Lee, S.; Jeong, H.G.; Jeong, T.C. Impact of gut microbiota on drug metabolism: An update for safe and effective use of drugs. Arch. Pharm. Res. 2017, 40, 1345–1355. [Google Scholar] [CrossRef]
  27. Zgheib, N.K.; Branch, R.A. Drug metabolism and liver disease: A drug-gene-environment interaction. Drug Metab. Rev. 2017, 49, 35–55. [Google Scholar] [CrossRef]
  28. Belle, D.J.; Singh, H. Genetic factors in drug metabolism. Am. Fam. Physician 2008, 77, 1553–1560. [Google Scholar]
  29. Pant, A.; Maiti, T.K.; Mahajan, D.; Das, B. Human Gut Microbiota and Drug Metabolism. Microb. Ecol. 2022, 1–15. [Google Scholar] [CrossRef]
  30. Zimmermann, M.; Zimmermann-Kogadeeva, M.; Wegmann, R.; Goodman, A.L. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature 2019, 570, 462–467. [Google Scholar] [CrossRef]
  31. An, X.; Bao, Q.; Di, S.; Zhao, Y.; Zhao, S.; Zhang, H.; Lian, F.; Tong, X. The interaction between the gut Microbiota and herbal medicines. Biomed. Pharmacother. 2019, 118, 109252. [Google Scholar] [CrossRef]
  32. Koppel, N.; Maini Rekdal, V.; Balskus, E.P. Chemical transformation of xenobiotics by the human gut microbiota. Science 2017, 356, eaag2770. [Google Scholar] [CrossRef]
  33. Hollman, A. Plants and cardiac glycosides. Br. Heart J. 1985, 54, 258–261. [Google Scholar] [CrossRef]
  34. Leisegang, K. Herbal pharmacognosy: An introduction. In Herbal Medicine in Andrology; Elsevier: Amsterdam, The Netherlands, 2021; pp. 17–26. [Google Scholar]
  35. Hollman, P.C.; Bijsman, M.N.; Van Gameren, Y.; Cnossen, E.P.; De Vries, J.H.; Katan, M.B. The sugar moiety is a major determinant of the absorption of dietary flavonoid glycosides in man. Free Radic. Res. 1999, 31, 569–573. [Google Scholar] [CrossRef]
  36. Bhattacharya, A. High-Temperature Stress and Metabolism of Secondary Metabolites in Plants. In Effect of High Temperature on Crop Productivity and Metabolism of Macro Molecules; Elsevier: London, UK, 2019; pp. 391–484. [Google Scholar]
  37. Kumar, S.; Pandey, A.K. Chemistry and biological activities of flavonoids: An overview. Sci. World J. 2013, 2013, 162750. [Google Scholar] [CrossRef] [Green Version]
  38. Xu, J.; Chen, H.B.; Li, S.L. Understanding the Molecular Mechanisms of the Interplay Between Herbal Medicines and Gut Microbiota. Med. Res. Rev. 2017, 37, 1140–1185. [Google Scholar] [CrossRef] [PubMed]
  39. Wilson, I.D.; Nicholson, J.K. Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl. Res. 2017, 179, 204–222. [Google Scholar] [CrossRef] [Green Version]
  40. Feng, W.; Liu, J.; Ao, H.; Yue, S.; Peng, C. Targeting gut microbiota for precision medicine: Focusing on the efficacy and toxicity of drugs. Theranostics 2020, 10, 11278–11301. [Google Scholar] [CrossRef]
  41. Shi, Z.Y.; Zeng, J.Z.; Wong, A.S.T. Chemical Structures and Pharmacological Profiles of Ginseng Saponins. Molecules 2019, 24, 2443. [Google Scholar] [CrossRef] [Green Version]
  42. Kim, D.H. Gut microbiota-mediated pharmacokinetics of ginseng saponins. J. Ginseng Res. 2018, 42, 255–263. [Google Scholar] [CrossRef]
  43. Kim, H.; Lee, J.H.; Kim, J.E.; Kim, Y.S.; Ryu, C.H.; Lee, H.J.; Kim, H.M.; Jeon, H.; Won, H.J.; Lee, J.Y.; et al. Micro-/nano-sized delivery systems of ginsenosides for improved systemic bioavailability. J. Ginseng Res. 2018, 42, 361–369. [Google Scholar] [CrossRef]
  44. Kim, H.-K. Pharmacokinetics of ginsenoside Rb1 and its metabolite compound K after oral administration of Korean Red Ginseng extract. J. Ginseng Res. 2013, 37, 451. [Google Scholar] [CrossRef] [Green Version]
  45. Paek, I.B.; Moon, Y.; Kim, J.; Ji, H.Y.; Kim, S.A.; Sohn, D.H.; Kim, J.B.; Lee, H.S. Pharmacokinetics of a ginseng saponin metabolite compound K in rats. Biopharm. Drug Dispos. 2006, 27, 39–45. [Google Scholar] [CrossRef]
  46. Jung, I.H.; Lee, J.H.; Hyun, Y.J.; Kim, D.H. Metabolism of ginsenoside Rb1 by human intestinal microflora and cloning of its metabolizing beta-D-glucosidase from Bifidobacterium longum H-1. Biol. Pharm. Bull. 2012, 35, 573–581. [Google Scholar] [CrossRef] [Green Version]
  47. Park, S.Y.; Bae, E.A.; Sung, J.H.; Lee, S.K.; Kim, D.H. Purification and characterization of ginsenoside Rb1-metabolizing beta-glucosidase from Fusobacterium K-60, a human intestinal anaerobic bacterium. Biosci. Biotechnol. Biochem. 2001, 65, 1163–1169. [Google Scholar] [CrossRef]
  48. Quan, L.H.; Min, J.W.; Yang, D.U.; Kim, Y.J.; Yang, D.C. Enzymatic biotransformation of ginsenoside Rb1 to 20(S)-Rg3 by recombinant beta-glucosidase from Microbacterium esteraromaticum. Appl. Microbiol. Biotechnol. 2012, 94, 377–384. [Google Scholar] [CrossRef]
  49. Akao, T.; Kida, H.; Kanaoka, M.; Hattori, M.; Kobashi, K. Drug metabolism: Intestinal bacterial hydrolysis is required for the appearance of compound K in rat plasma after oral administration of ginsenoside Rb1 from Panax ginseng. J. Pharm. Pharmacol. 1998, 50, 1155–1160. [Google Scholar] [CrossRef]
  50. Qian, T.; Cai, Z.; Wong, R.N.; Mak, N.K.; Jiang, Z.H. In vivo rat metabolism and pharmacokinetic studies of ginsenoside Rg3. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2005, 816, 223–232. [Google Scholar] [CrossRef]
  51. Bae, E.-A.; Choo, M.-K.; Park, E.-K.; Park, S.-Y.; Shin, H.-Y.; Kim, D.-H. Metabolism of ginsenoside Rc by human intestinal bacteria and its related antiallergic activity. Biol. Pharm. Bull. 2002, 25, 743–747. [Google Scholar] [CrossRef] [Green Version]
  52. Tawab, M.A.; Bahr, U.; Karas, M.; Wurglics, M.; Schubert-Zsilavecz, M. Degradation of ginsenosides in humans after oral administration. Drug Metab. Dispos. 2003, 31, 1065–1071. [Google Scholar] [CrossRef] [Green Version]
  53. Hasegawa, H. Anticarcinogenesis in mice by ginseng-hydrolyzing colonic bacteria. Microb. Ecol. Health Dis. 2000, 12, 85–91. [Google Scholar]
  54. Hasegawa, H.; Sung, J.H.; Benno, Y. Role of human intestinal Prevotella oris in hydrolyzing ginseng saponins. Planta Med. 1997, 63, 436–440. [Google Scholar] [CrossRef] [PubMed]
  55. Prasain, J.K.; Peng, N.; Rajbhandari, R.; Wyss, J.M. The Chinese Pueraria root extract (Pueraria lobata) ameliorates impaired glucose and lipid metabolism in obese mice. Phytomedicine 2012, 20, 17–23. [Google Scholar] [CrossRef] [Green Version]
  56. Jung, H.W.; Kang, A.N.; Kang, S.Y.; Park, Y.K.; Song, M.Y. The Root Extract of Pueraria lobata and Its Main Compound, Puerarin, Prevent Obesity by Increasing the Energy Metabolism in Skeletal Muscle. Nutrients 2017, 9, 33. [Google Scholar] [CrossRef]
  57. Zhang, Z.; Lam, T.N.; Zuo, Z. Radix Puerariae: An overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J. Clin. Pharmacol. 2013, 53, 787–811. [Google Scholar] [CrossRef] [PubMed]
  58. Jin, J.S.; Nishihata, T.; Kakiuchi, N.; Hattori, M. Biotransformation of C-glucosylisoflavone puerarin to estrogenic (3S)-equol in co-culture of two human intestinal bacteria. Biol. Pharm. Bull. 2008, 31, 1621–1625. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Zhang, L.; Pan Siu, A.K.; Lin, G.; Zuo, Z. Intestinal absorbability of three Radix Puerariae isoflavones including daidzein, daidzin and puerarin. Chin. Med. 2011, 6, 41. [Google Scholar] [CrossRef] [Green Version]
  60. Park, E.K.; Shin, J.; Bae, E.A.; Lee, Y.C.; Kim, D.H. Intestinal bacteria activate estrogenic effect of main constituents puerarin and daidzin of Pueraria thunbergiana. Biol. Pharm. Bull. 2006, 29, 2432–2435. [Google Scholar] [CrossRef] [Green Version]
  61. Shin, J.E.; Bae, E.A.; Lee, Y.C.; Ma, J.Y.; Kim, D.H. Estrogenic effect of main components kakkalide and tectoridin of Puerariae Flos and their metabolites. Biol. Pharm. Bull. 2006, 29, 1202–1206. [Google Scholar] [CrossRef] [Green Version]
  62. Zhang, G.; Gong, T.; Kano, Y.; Yuan, D. Screening for in vitro metabolites of kakkalide and irisolidone in human and rat intestinal bacteria by ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2014, 947–948, 117–124. [Google Scholar] [CrossRef] [PubMed]
  63. Ran, Q.; Wang, J.; Wang, L.; Zeng, H.-R.; Yang, X.-B.; Huang, Q.-W. Rhizoma coptidis as a Potential Treatment Agent for Type 2 Diabetes Mellitus and the Underlying Mechanisms: A Review. Front. Pharmacol. 2019, 10, 805. [Google Scholar] [CrossRef]
  64. Feng, X.; Wang, K.; Cao, S.; Ding, L.; Qiu, F. Pharmacokinetics and Excretion of Berberine and Its Nine Metabolites in Rats. Front. Pharmacol. 2020, 11, 594852. [Google Scholar] [CrossRef]
  65. Dey, P. Gut microbiota in phytopharmacology: A comprehensive overview of concepts, reciprocal interactions, biotransformations and mode of actions. Pharmacol. Res. 2019, 147, 104367. [Google Scholar] [CrossRef]
  66. Cheng, H.; Liu, J.; Tan, Y.; Feng, W.; Peng, C. Interactions between gut microbiota and berberine, a necessary procedure to understand the mechanisms of berberine. J. Pharm. Anal. 2021, 12, 541–555. [Google Scholar] [CrossRef]
  67. Zheng, Y.; Gou, X.; Zhang, L.; Gao, H.; Wei, Y.; Yu, X.; Pang, B.; Tian, J.; Tong, X.; Li, M. Interactions Between Gut Microbiota, Host, and Herbal Medicines: A Review of New Insights Into the Pathogenesis and Treatment of Type 2 Diabetes. Front. Cell. Infect. Microbiol. 2020, 10, 360. [Google Scholar] [CrossRef]
  68. Feng, R.; Shou, J.-W.; Zhao, Z.-X.; He, C.-Y.; Ma, C.; Huang, M.; Fu, J.; Tan, X.-S.; Li, X.-Y.; Wen, B.-Y. Transforming berberine into its intestine-absorbable form by the gut microbiota. Sci. Rep. 2015, 5, 1–15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Li, C.; Ai, G.; Wang, Y.; Lu, Q.; Luo, C.; Tan, L.; Lin, G.; Liu, Y.; Li, Y.; Zeng, H.; et al. Oxyberberine, a novel gut microbiota-mediated metabolite of berberine, possesses superior anti-colitis effect: Impact on intestinal epithelial barrier, gut microbiota profile and TLR4-MyD88-NF-kappaB pathway. Pharm. Res. 2020, 152, 104603. [Google Scholar] [CrossRef]
  70. Baradaran Rahimi, V.; Askari, V.R.; Hosseinzadeh, H. Promising influences of Scutellaria baicalensis and its two active constituents, baicalin, and baicalein, against metabolic syndrome: A review. Phytother. Res. 2021, 35, 3558–3574. [Google Scholar] [CrossRef]
  71. Kim, D.-H.; Jang, I.-S.; Lee, H.-K.; Jung, E.-A.; Lee, K.-Y. Metabolism of glycyrrhizin and baicalin by human intestinal bacteria. Arch. Pharmacal Res. 1996, 19, 292–296. [Google Scholar] [CrossRef]
  72. Noh, K.; Kang, Y.; Nepal, M.R.; Jeong, K.S.; Oh, D.G.; Kang, M.J.; Lee, S.; Kang, W.; Jeong, H.G.; Jeong, T.C. Role of Intestinal Microbiota in Baicalin-Induced Drug Interaction and Its Pharmacokinetics. Molecules 2016, 21, 337. [Google Scholar] [CrossRef] [Green Version]
  73. Akao, T.; Kawabata, K.; Yanagisawa, E.; Ishihara, K.; Mizuhara, Y.; Wakui, Y.; Sakashita, Y.; Kobashi, K. Balicalin, the predominant flavone glucuronide of scutellariae radix, is absorbed from the rat gastrointestinal tract as the aglycone and restored to its original form. J. Pharm. Pharmacol. 2000, 52, 1563–1568. [Google Scholar] [CrossRef]
  74. Taiming, L.; Xuehua, J. Investigation of the absorption mechanisms of baicalin and baicalein in rats. J. Pharm. Sci. 2006, 95, 1326–1333. [Google Scholar] [CrossRef]
  75. Bak, E.J.; Kim, J.; Choi, Y.H.; Kim, J.H.; Lee, D.E.; Woo, G.H.; Cha, J.H.; Yoo, Y.J. Wogonin ameliorates hyperglycemia and dyslipidemia via PPARalpha activation in db/db mice. Clin. Nutr. 2014, 33, 156–163. [Google Scholar] [CrossRef] [PubMed]
  76. Xing, S.; Wang, M.; Peng, Y.; Li, X. Effects of Intestinal Microecology on Metabolism and Pharmacokinetics of Oral Wogonoside and Baicalin. Nat. Prod. Commun. 2017, 12, 509–514. [Google Scholar] [CrossRef]
  77. Ku, S.; Zheng, H.; Park, M.S.; Ji, G.E. Optimization of β-glucuronidase activity from Lactobacillus delbrueckii Rh2 and and its use for biotransformation of baicalin and wogonoside. J. Korean Soc. Appl. Biol. Chem. 2011, 54, 275–280. [Google Scholar] [CrossRef]
  78. Kim, H.S.; Kim, J.Y.; Park, M.S.; Zheng, H.; Ji, G.E. Cloning and expression of beta-glucuronidase from Lactobacillus brevis in E. coli and application in the bioconversion of baicalin and wogonoside. J. Microbiol. Biotechnol. 2009, 19, 1650–1655. [Google Scholar] [CrossRef] [Green Version]
  79. Shao, W.; Yu, Z.; Chiang, Y.; Yang, Y.; Chai, T.; Foltz, W.; Lu, H.; Fantus, I.G.; Jin, T. Curcumin prevents high fat diet induced insulin resistance and obesity via attenuating lipogenesis in liver and inflammatory pathway in adipocytes. PLoS ONE 2012, 7, e28784. [Google Scholar] [CrossRef]
  80. Feng, D.; Zou, J.; Su, D.; Mai, H.; Zhang, S.; Li, P.; Zheng, X. Curcumin prevents high-fat diet-induced hepatic steatosis in ApoE(-/-) mice by improving intestinal barrier function and reducing endotoxin and liver TLR4/NF-kappaB inflammation. Nutr. Metab. 2019, 16, 79. [Google Scholar] [CrossRef]
  81. Aggarwal, B.B.; Deb, L.; Prasad, S. Curcumin differs from tetrahydrocurcumin for molecular targets, signaling pathways and cellular responses. Molecules 2014, 20, 185–205. [Google Scholar] [CrossRef] [Green Version]
  82. Lopresti, A.L. The Problem of Curcumin and Its Bioavailability: Could Its Gastrointestinal Influence Contribute to Its Overall Health-Enhancing Effects? Adv. Nutr. 2018, 9, 41–50. [Google Scholar] [CrossRef] [Green Version]
  83. Burapan, S.; Kim, M.; Han, J. Curcuminoid demethylation as an alternative metabolism by human intestinal microbiota. J. Agric. Food Chem. 2017, 65, 3305–3310. [Google Scholar] [CrossRef]
  84. Tan, S.; Rupasinghe, T.W.; Tull, D.L.; Boughton, B.; Oliver, C.; McSweeny, C.; Gras, S.L.; Augustin, M.A. Degradation of curcuminoids by in vitro pure culture fermentation. J. Agric. Food Chem. 2014, 62, 11005–11015. [Google Scholar] [CrossRef]
  85. Dai, X.; Ding, Y.; Zhang, Z.; Cai, X.; Li, Y. Quercetin and quercitrin protect against cytokineinduced injuries in RINm5F beta-cells via the mitochondrial pathway and NF-kappaB signaling. Int. J. Mol. Med. 2013, 31, 265–271. [Google Scholar] [CrossRef] [Green Version]
  86. Babaei, F.; Mirzababaei, M.; Nassiri-Asl, M. Quercetin in Food: Possible Mechanisms of Its Effect on Memory. J. Food Sci. 2018, 83, 2280–2287. [Google Scholar] [CrossRef]
  87. Kim, D.H.; Kim, S.Y.; Park, S.Y.; Han, M.J. Metabolism of quercitrin by human intestinal bacteria and its relation to some biological activities. Biol. Pharm. Bull. 1999, 22, 749–751. [Google Scholar] [CrossRef] [PubMed]
  88. Enkhmaa, B.; Shiwaku, K.; Katsube, T.; Kitajima, K.; Anuurad, E.; Yamasaki, M.; Yamane, Y. Mulberry (Morus alba L.) leaves and their major flavonol quercetin 3-(6-malonylglucoside) attenuate atherosclerotic lesion development in LDL receptor-deficient mice. J. Nutr. 2005, 135, 729–734. [Google Scholar] [CrossRef] [Green Version]
  89. Hirooka, K.; Fujita, Y. Excess production of Bacillus subtilis quercetin 2,3-dioxygenase affects cell viability in the presence of quercetin. Biosci. Biotechnol. Biochem. 2010, 74, 1030–1038. [Google Scholar] [CrossRef]
  90. PARK, S.-Y.; KIM, J.-H.; KIM, D.-H. Purification and characterization of quercitrin-hydrolyzing α-L-rhamnosidase from Fusobacterium K-60, a human intestinal bacterium. J. Microbiol. Biotechnol. 2005, 15, 519–524. [Google Scholar]
  91. Hosseini, A.; Razavi, B.M.; Banach, M.; Hosseinzadeh, H. Quercetin and metabolic syndrome: A review. Phytother. Res. 2021, 35, 5352–5364. [Google Scholar] [CrossRef]
  92. Comalada, M.; Camuesco, D.; Sierra, S.; Ballester, I.; Xaus, J.; Galvez, J.; Zarzuelo, A. In vivo quercitrin anti-inflammatory effect involves release of quercetin, which inhibits inflammation through down-regulation of the NF-kappaB pathway. Eur. J. Immunol. 2005, 35, 584–592. [Google Scholar] [CrossRef] [PubMed]
  93. Graebin, C.S. The pharmacological activities of glycyrrhizinic acid (“glycyrrhizin”) and glycyrrhetinic acid. Sweeteners 2018, 245. [Google Scholar]
  94. Kwon, Y.J.; Son, D.H.; Chung, T.H.; Lee, Y.J. A Review of the Pharmacological Efficacy and Safety of Licorice Root from Corroborative Clinical Trial Findings. J. Med. Food 2020, 23, 12–20. [Google Scholar] [CrossRef] [PubMed]
  95. Yamamura, Y.; Santa, T.; Kotaki, H.; Uchino, K.; Sawada, Y.; Iga, T. Administration-route dependency of absorption of glycyrrhizin in rats: Intraperitoneal administration dramatically enhanced bioavailability. Biol. Pharm. Bull. 1995, 18, 337–341. [Google Scholar] [CrossRef] [Green Version]
  96. Akao, T. Differences in the metabolism of glycyrrhizin, glycyrrhetic acid and glycyrrhetic acid monoglucuronide by human intestinal flora. Biol. Pharm. Bull. 2000, 23, 1418–1423. [Google Scholar] [CrossRef] [Green Version]
  97. Shin, H.Y.; Lee, J.H.; Lee, J.Y.; Han, Y.O.; Han, M.J.; Kim, D.H. Purification and characterization of ginsenoside Ra-hydrolyzing beta-D-xylosidase from Bifidobacterium breve K-110, a human intestinal anaerobic bacterium. Biol. Pharm. Bull. 2003, 26, 1170–1173. [Google Scholar] [CrossRef] [Green Version]
  98. Nakamura, K.; Zhu, S.; Komatsu, K.; Hattori, M.; Iwashima, M. Deglycosylation of the Isoflavone C-Glucoside Puerarin by a Combination of Two Recombinant Bacterial Enzymes and 3-Oxo-Glucose. Appl. Env. Microbiol. 2020, 86, e00607-20. [Google Scholar] [CrossRef]
  99. Matthies, A.; Blaut, M.; Braune, A. Isolation of a human intestinal bacterium capable of daidzein and genistein conversion. Appl. Environ. Microbiol. 2009, 75, 1740–1744. [Google Scholar] [CrossRef] [Green Version]
  100. Tan, X.S.; Ma, J.Y.; Feng, R.; Ma, C.; Chen, W.J.; Sun, Y.P.; Fu, J.; Huang, M.; He, C.Y.; Shou, J.W.; et al. Tissue distribution of berberine and its metabolites after oral administration in rats. PLoS ONE 2013, 8, e77969. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  101. Hassaninasab, A.; Hashimoto, Y.; Tomita-Yokotani, K.; Kobayashi, M. Discovery of the curcumin metabolic pathway involving a unique enzyme in an intestinal microorganism. Proc. Natl. Acad. Sci. USA 2011, 108, 6615–6620. [Google Scholar] [CrossRef] [Green Version]
  102. Akao, T. Purification and characterization of glycyrrhetic acid mono-glucuronide beta-D-glucuronidase in Eubacterium sp. GLH. Biol. Pharm. Bull. 1999, 22, 80–82. [Google Scholar] [CrossRef] [Green Version]
  103. Yim, J.S.; Kim, Y.S.; Moon, S.K.; Cho, K.H.; Bae, H.S.; Kim, J.J.; Park, E.K.; Kim, D.H. Metabolic activities of ginsenoside Rb1, baicalin, glycyrrhizin and geniposide to their bioactive compounds by human intestinal microflora. Biol. Pharm. Bull. 2004, 27, 1580–1583. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Akao, T. Influence of various bile acids on the metabolism of glycyrrhizin and glycyrrhetic acid by Ruminococcus sp. PO1-3 of human intestinal bacteria. Biol. Pharm. Bull. 1999, 22, 787–793. [Google Scholar] [CrossRef] [Green Version]
  105. Chen, X.J.; Liu, W.J.; Wen, M.L.; Liang, H.; Wu, S.M.; Zhu, Y.Z.; Zhao, J.Y.; Dong, X.Q.; Li, M.G.; Bian, L.; et al. Ameliorative effects of Compound K and ginsenoside Rh1 on nonalcoholic fatty liver disease in rats. Sci. Rep. 2017, 7, 41144. [Google Scholar] [CrossRef] [Green Version]
  106. Li, W.; Zhang, M.; Gu, J.; Meng, Z.J.; Zhao, L.C.; Zheng, Y.N.; Chen, L.; Yang, G.L. Hypoglycemic effect of protopanaxadiol-type ginsenosides and compound K on Type 2 diabetes mice induced by high-fat diet combining with streptozotocin via suppression of hepatic gluconeogenesis. Fitoterapia 2012, 83, 192–198. [Google Scholar] [CrossRef]
  107. Kim, M.H.; Park, J.S.; Jung, J.W.; Byun, K.W.; Kang, K.S.; Lee, Y.S. Daidzein supplementation prevents nonalcoholic fatty liver disease through alternation of hepatic gene expression profiles and adipocyte metabolism. Int. J. Obes. 2011, 35, 1019–1030. [Google Scholar] [CrossRef] [Green Version]
  108. Spinozzi, S.; Colliva, C.; Camborata, C.; Roberti, M.; Ianni, C.; Neri, F.; Calvarese, C.; Lisotti, A.; Mazzella, G.; Roda, A. Berberine and its metabolites: Relationship between physicochemical properties and plasma levels after administration to human subjects. J. Nat. Prod. 2014, 77, 766–772. [Google Scholar] [CrossRef]
  109. Kang, M.J.; Ko, G.S.; Oh, D.G.; Kim, J.S.; Noh, K.; Kang, W.; Yoon, W.K.; Kim, H.C.; Jeong, H.G.; Jeong, T.C. Role of metabolism by intestinal microbiota in pharmacokinetics of oral baicalin. Arch. Pharm. Res. 2014, 37, 371–378. [Google Scholar] [CrossRef] [PubMed]
  110. Murugan, P.; Pari, L. Influence of tetrahydrocurcumin on erythrocyte membrane bound enzymes and antioxidant status in experimental type 2 diabetic rats. J. Ethnopharmacol. 2007, 113, 479–486. [Google Scholar] [CrossRef]
  111. Nakagawa, K.; Zingg, J.M.; Kim, S.H.; Thomas, M.J.; Dolnikowski, G.G.; Azzi, A.; Miyazawa, T.; Meydani, M. Differential cellular uptake and metabolism of curcuminoids in monocytes/macrophages: Regulatory effects on lipid accumulation. Br. J. Nutr. 2014, 112, 8–14. [Google Scholar] [CrossRef] [Green Version]
  112. Dai, X.; Ding, Y.; Zhang, Z.; Cai, X.; Bao, L.; Li, Y. Quercetin but not quercitrin ameliorates tumor necrosis factor-alpha-induced insulin resistance in C2C12 skeletal muscle cells. Biol. Pharm. Bull. 2013, 36, 788–795. [Google Scholar] [CrossRef] [Green Version]
  113. Takeda, S.; Ishthara, K.; Wakui, Y.; Amagaya, S.; Maruno, M.; Akao, T.; Kobashi, K. Bioavailability study of glycyrrhetic acid after oral administration of glycyrrhizin in rats; relevance to the intestinal bacterial hydrolysis. J. Pharm. Pharmacol. 1996, 48, 902–905. [Google Scholar] [CrossRef]
  114. Park, M.; Lee, J.H.; Choi, J.K.; Hong, Y.D.; Bae, I.H.; Lim, K.M.; Park, Y.H.; Ha, H. 18β-glycyrrhetinic acid attenuates anandamide-induced adiposity and high-fat diet induced obesity. Mol. Nutr. Food Res. 2014, 58, 1436–1446. [Google Scholar] [CrossRef]
  115. Yan, T.; Wang, H.; Cao, L.; Wang, Q.; Takahashi, S.; Yagai, T.; Li, G.; Krausz, K.W.; Wang, G.; Gonzalez, F.J.; et al. Glycyrrhizin Alleviates Nonalcoholic Steatohepatitis via Modulating Bile Acids and Meta-Inflammation. Drug Metab. Dispos. 2018, 46, 1310–1319. [Google Scholar] [CrossRef]
  116. Kim, K.A.; Jung, I.H.; Park, S.H.; Ahn, Y.T.; Huh, C.S.; Kim, D.H. Comparative analysis of the gut microbiota in people with different levels of ginsenoside Rb1 degradation to compound K. PLoS ONE 2013, 8, e62409. [Google Scholar] [CrossRef] [PubMed]
  117. Matsumoto, M.; Ishige, A.; Yazawa, Y.; Kondo, M.; Muramatsu, K.; Watanabe, K. Promotion of intestinal peristalsis by Bifidobacterium spp. capable of hydrolysing sennosides in mice. PLoS ONE 2012, 7, e31700. [Google Scholar] [CrossRef] [Green Version]
  118. Brooks, A.W.; Priya, S.; Blekhman, R.; Bordenstein, S.R. Gut microbiota diversity across ethnicities in the United States. PLoS Biol 2018, 16, e2006842. [Google Scholar] [CrossRef]
  119. Kim, C.Y.; Lee, M.; Yang, S.; Kim, K.; Yong, D.; Kim, H.R.; Lee, I. Human reference gut microbiome catalog including newly assembled genomes from under-represented Asian metagenomes. Genome Med. 2021, 13, 1–20. [Google Scholar] [CrossRef]
  120. Zhang, X.; Zhao, Y.; Zhang, M.; Pang, X.; Xu, J.; Kang, C.; Li, M.; Zhang, C.; Zhang, Z.; Zhang, Y. Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. PLoS ONE 2012, 7, e42529. [Google Scholar] [CrossRef] [Green Version]
  121. Zhang, B.; Sun, W.; Yu, N.; Sun, J.; Yu, X.; Li, X.; Xing, Y.; Yan, D.; Ding, Q.; Xiu, Z.; et 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, 256–267. [Google Scholar] [CrossRef]
  122. Cani, P.D.; Delzenne, N.M. The role of the gut microbiota in energy metabolism and metabolic disease. Curr. Pharm. Des. 2009, 15, 1546–1558. [Google Scholar] [CrossRef] [Green Version]
  123. Ansari, M.H.R.; Saher, S.; Parveen, R.; Khan, W.; Khan, I.A.; Ahmad, S. Role of gut microbiota metabolism and biotransformation on dietary natural products to human health implications with special reference to biochemoinformatics approach. J. Tradit. Complement. Med. 2022. [Google Scholar] [CrossRef]
  124. Oliphant, K.; Allen-Vercoe, E. Macronutrient metabolism by the human gut microbiome: Major fermentation by-products and their Impact on host health. Microbiome 2019, 7, 1–15. [Google Scholar] [CrossRef]
  125. McCoubrey, L.E.; Thomaidou, S.; Elbadawi, M.; Gaisford, S.; Orlu, M.; Basit, A.W. Machine Learning Predicts Drug Metabolism and Bioaccumulation by Intestinal Microbiota. Pharmaceutics 2021, 13, 2001. [Google Scholar] [CrossRef]
Table 1. Herbal compounds and their microbial metabolites formed by host GM.
Table 1. Herbal compounds and their microbial metabolites formed by host GM.
Herbal MedicineCompoundRelated MicrobiotaMicrobial MetabolitesMechanismsRef.
Ginseng Radix Ginsenoside Rb1Bifidobacterium longum H-1Ginsenoside Rd
Compound K
β-D-glucosidase[41]
Ginsenoside Rb1Fusobacterium K-60Compound Kβ-Glucosidase[42]
Ginsenosides
Ra1 and Ra2
Bifidobacterium breve K-110Ginsenosides Rb2, Rcβ-D-Xylosidase[43]
Ginsenoside Rb1Microbacterium esteraromaticumGinsenoside Rd
Ginsenoside 20(S)-Rg3
β-Glucosidase[44]
Ginsenoside Rb1Eubacterium sp. A-44Ginsenoside Rd
Ginsenoside F2
Compound K
β-D-glucosidase[45]
Ginsenoside RcBifidobacterium K-103
Eubacterium A-44
Ginsenoside Rd (intermediate)
Compound K
Hydrolysis[46]
Bacteriodes HJ-15
Bifidobacterium K-506
Ginsenoside Mb (intermediate)
Compound K
Hydrolysis
Ginsenoside Rb1Prevotella oris20-O-/J-o-glucopyranosyl-20(S)-protopanaxadiolβ-Glucosidase hydrolysis[47]
Puerariae Radix
And
Puerariae Flos
PuerarinDorea longicatena PUEDaidzeinDeglycosylation[48]
DaidzeinSlackia isoflavoniconvertens.EquolNot identified[49]
Kakkalide
Tectoridin
Bifidobacterium breve K-110Irisolidone
tectorigenin
β-D-Xylosidase[50]
Puerarin
Daidzin
Bacteroides sterocoris HJ-15
Bifidobacterium longum H-1
Eubacterium rectale A-44
Streptococcus faecium S-9
DaidzeinHydrolysis[51]
Kakkalide
Irisolidone
Not identifiedIrisolidone
Biochanin A
Hydrolysis
Dehydroxylation
Demethoxylation
Demethylation
Hydroxylation
Decarbonylation
Reduction
[52]
Coptidis RhizomaBerberineEscherichia coli
Streptococcus faecalis
Lactobacillus acidophilus
OxyberberineOxidation[53]
BerberineNot identifiedThalifendine
Berberrubine
Jatrorrhizine
Not identified[54]
BerberineEnterobacter cloacae
Enterococcus faecium
DihydroberberineNitroreductase[55]
Scutellaria RadixBaicalinNot identifiedBaicaleinNot identified[56]
BaicalinEscherichia coliBaicaleinBeta-D-glucuronidase[57]
Baicalin
Wogonoside
Lactobacillus delbrueckii Rh2Baicalein
Wogonin
β-glucuronidase[58]
Baicalin
Wogonoside
Lactobacillus brevis RO1Baicalein
Wogonin
β-glucuronidase[59]
Curcumae RadixCurcumin
Demethoxycurcumin
Bis-demethoxycurcumin
Escherichia fergusonii
Escherichia coli ATCC 8739
Escherichia coli DH10B
Dihydrocurcumin
Tetrahydrocurcumin
Ferulic acid
Reduction
(CurA)
[60]
CurcuminE. Coli strain DH10BDihydrocurcumin
Tetrahydrocurcumin
Reduction
(CurA)
[61]
Curcumin (1)
Demethoxycurcumin (2)
Bisdemethoxycurcumin (3)
Blautia sp. MRG-PMF1Dimethylcurcumin (from 1)
Bisdemethylcurcumin (from 1)
Demethyldemethoxycurcumin (from 2)
Reduction[62]
Mori folium/
Bupleurum Radix/
Houttuyniae Herba
QuercitrinBacillus subtilisQuercetinDioxygenase
(C-ring cleavage)
[63]
QuercitrinFusobacterium K-60QuercetinHydrolysis
(α-L-Rhamnosidase)
[64]
QuercitrinFusobacterium K-60Quercetin
3,4-Dihydroxyphenylacetic acid
4-Hydroxylphenylacetic acid
Not identified[65]
Glycyrrhizae
Radix
GlycyrrhizinEubacterium sp. GLH18β-Glycyrrhetinic acid monoglucuronide
18β-Glycyrrhetinic acid
Deglycosylation[66]
GlycyrrhizinNot indicated
(human feces sample)
18β-Glycyrrhetic acidb-D-glucuronidases[67]
GlycyrrhizinRuminococcus sp. PO1-318β-Glycyrrhetic acid
3-Oxo-glycyrrhetic acid
b-D-glucuronidases
3β-Hydroxysteroid dehydrogenase
[68]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Lim, D.-W.; Wang, J.-H. Gut Microbiome: The Interplay of an “Invisible Organ” with Herbal Medicine and Its Derived Compounds in Chronic Metabolic Disorders. Int. J. Environ. Res. Public Health 2022, 19, 13076. https://doi.org/10.3390/ijerph192013076

AMA Style

Lim D-W, Wang J-H. Gut Microbiome: The Interplay of an “Invisible Organ” with Herbal Medicine and Its Derived Compounds in Chronic Metabolic Disorders. International Journal of Environmental Research and Public Health. 2022; 19(20):13076. https://doi.org/10.3390/ijerph192013076

Chicago/Turabian Style

Lim, Dong-Woo, and Jing-Hua Wang. 2022. "Gut Microbiome: The Interplay of an “Invisible Organ” with Herbal Medicine and Its Derived Compounds in Chronic Metabolic Disorders" International Journal of Environmental Research and Public Health 19, no. 20: 13076. https://doi.org/10.3390/ijerph192013076

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop