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]^[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]^{[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]^[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]^[20][21]. In the past, it has been supposed that a single drug is appropriate for a single symptom for any individual. However, wresearchers 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.

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]^[25]. As typical herbal-origin compounds, glycosides consist of one/several sugar(s) combined with an aglycone [33]^[26]. These phytochemicals are secondary plant metabolites and can be present along with phenols, alcohols, flavonoids, saponins, and anthraquinone [34]^[27]. However, the herb-derived glycosides are usually inactive due to their conjugated sugar moiety [35]^[28]; therefore, they are classified as prodrugs [36]^[29]. Nonactivated glycosides can be degraded/metabolized by the GM by their enzymes, producing bioactive aglycones [37]^[30]. 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]^[31]. 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]^[32]. 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]^[31]. The efficacy of herbal compounds can be modulated by changing their oral bioavailability [40]^[33]. In some cases, smaller molecules produced by digestion exhibit stronger efficacy than their parent molecules [31]^[34]. The GM also regulates the toxicity of HMs by metabolizing toxic substances [31]^[34]. The alteration of herbal toxicity by GM metabolism remains unclear and requires further investigation.

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]^[35]. The GM biotransformation process on ginseng saponins and its influence on host health have been extensively studied [70]^[36]. 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]^[37]. 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]^[36][38]. 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]^{[36][39][40][41][42][43][44][45][46][47][48]}. Among these bacterial metabolites, compound K, which is a hydrophobic and absorbable compound [73]^[45], has the most potent activity against numerous diseases, including various metabolic disorders [46]^[43].

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]^[49][50]. The typical compounds in Puerariae Radix include puerarin, daidzin, and daidzein [79]^[51]. Daidzin and puerarin are metabolized into daidzein and, further, into equol, which is promising for estrogenic activities [80]^[52]. 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]^[53]. 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]^[54]. Other flavonoids are found in Pueraria flos, including kakkalide and tectoridin, which also have estrogenic effects similar to those of equol [50]^[55]. 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]^[55][56].

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]^[57]. Although it is an essential compound from Coptidis rhizoma with many properties, berberine has extremely low bioavailability (<1%) [83]^[58], and its absorption is largely attributed to the activity of GM [84]^[59]. Berberine can be metabolized by the GM into dihydroberberine, berberrubine, demethyleneberberine, jatrorrhizine, and oxyberberine [85]^[60]. The biotransformation of berberine into the reduced form, dihydroberberine, is achieved by Enterobacter cloacae and Enterococcus faecalis by nitroreductase, improving its absorption rate [86]^[61]. 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]^[62]. Another metabolite, oxyberberine, is metabolized by the intestinal microbiota, showing greater effects than berberine [53]^[63].

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]^[64]. Baicalin is hydrolyzed into its aglycone, baicalein, by β-glucuronidase from E. coli [57]^[65] and is thereby easily absorbed in the intestine [88]^[66]. Absorbed baicalein can be reconjugated into baicalin by UDP-glucuronosyltransferase in the host’s liver and intestine and exert beneficial activities [56,84]^[59][67]. 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]^[68]. 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]^[69]. 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]^[70]. Intestinal bacteria of the Lactobacillus spp. and their glucuronidase enzymes are reported to be involved in these enzymatic reactions [58^[71][72],59], which also increases the bioavailability of compounds.

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]^[73][74]. As a polyphenol, curcumin has low bioavailability as demonstrated by its in vivo pharmacokinetic data [104]^[75]. The main reasons for the low bioavailability of curcumin are its poor absorption, instability, rapid metabolism, and rapid excretion [105]^[76]. However, curcumin can be metabolized by the human gut bacteria Blautia sp. MRG-PMF1 into demethylcurcumin and bisdemethylcurcumin [62]^[77]. 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]^[78]. 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]^[75].

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]^[79]. These compounds are distributed in some common traditional medicinal herbs and foods, like Mori folium, Bupleurum Radix, and Houttuyniae Herba [65,107,108]^[80][81][82]. Like other flavonoids, quercetin glycosides are not bioavailable due to their structures [84]^[59]; however, intestinal microbiota including Bacillus subtilis and Fusobacterium K-60 can metabolize quercitrin to produce quercetin through dioxygenase or α-L-rhamnosidase [63,109]^[83][84]. Among the aglycones, quercetin possesses ubiquitous effects of hypoglycemic, hypolipidemic, and hypotensive and anti-obesity with multifaceted mechanisms [110]^[85]. 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]^[86].

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]^[87][88]. 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]^[89]. 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]^[90].

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