Fmicb 13 956378

TYPE Review
PUBLISHED 29 September 2022

DOI 10.3389/fmicb.2022.956378
Potential roles of gut microbes in

OPEN ACCESS biotransformation of natural
products: An overview
EDITED BY
Laurent Dufossé,
Universitéde la Réunion,
France
REVIEWED BY Yucui Zhao 1,2,3, Xinqin Zhong 1,2,3, Junyuan Yan 1,2,3,
Jakub P. Piwowarski,
Medical University of Warsaw, Poland
Congying Sun 1,2,3, Xin Zhao 1,3* and Xiaoying Wang 1,2,3*
Jaehong Han, 1
Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae,
Chung-Ang University, Tianjin University of Traditional Chinese Medicine, Tianjin, China, 2 School of Chinese Materia
South Korea Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China, 3 State Key Laboratory of
*CORRESPONDENCE Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin,
Xin Zhao China
x.zhao26@tjutcm.edu.cn
Xiaoying Wang
wxy@tjutcm.edu.cn Natural products have been extensively applied in clinical practice,
SPECIALTY SECTION characterized by multi-component and multi-target, many pharmacodynamic
This article was submitted to substances, complex action mechanisms, and various physiological activities.
Food Microbiology,
a section of the journal For the oral administration of natural products, the gut microbiota and clinical
Frontiers in Microbiology efficacy are closely related, but this relationship remains unclear. Gut microbes
RECEIVED 30 May 2022 play an important role in the transformation and utilization of natural products
ACCEPTED 29 August 2022 caused by the diversity of enzyme systems. Effective components such as
PUBLISHED 29 September 2022
flavonoids, alkaloids, lignans, and phenols cannot be metabolized directly
CITATION
through human digestive enzymes but can be transformed by enzymes
Zhao Y, Zhong X, Yan J, Sun C, Zhao X and
Wang X (2022) Potential roles of gut produced by gut microorganisms and then utilized. Therefore, the focus is
microbes in biotransformation of natural paid to the metabolism of natural products through the gut microbiota. In the
products: An overview.
Front. Microbiol. 13:956378. present study, we systematically reviewed the studies about gut microbiota
doi: 10.3389/fmicb.2022.956378 and their effect on the biotransformation of various components of natural
COPYRIGHT products and highlighted the involved common bacteria, reaction types,
© 2022 Zhao, Zhong, Yan, Sun, Zhao and pharmacological actions, and research methods. This study aims to provide
Wang. This is an open-access article
distributed under the terms of the Creative
theoretical support for the clinical application in the prevention and treatment
Commons Attribution License (CC BY). The of diseases and provide new ideas for studying natural products based on gut
use, distribution or reproduction in other biotransformation.
forums is permitted, provided the original
author(s) and the copyright owner(s) are
credited and that the original publication in KEYWORDS
this journal is cited, in accordance with
accepted academic practice. No use, natural products, gut microbes, enzyme system, biotransformation, bioavailability
distribution or reproduction is permitted
which does not comply with these terms.
Introduction
The gut microbiota is composed of 1,000–1,250 kinds of bacteria that interact with
humans in various forms, such as symbiosis and parasitism, and this interaction greatly
affects human health via microbial metabolites as signal molecules (Liu et al., 2017; de Vos
et al., 2022). The gut microbes constitute a dynamic and diversified micro-ecosystem,
which is a natural barrier to resisting pathogenic bacteria (Chopyk and Grakoui, 2020;
Zhao and Maynard, 2022). Gut microbes have abundant enzyme systems, including
glucosidase, reductase, lyase, transferase, etc., and greatly expand the metabolic response
pool in the human body (Wilson and Nicholson, 2017; Fushinobu and Abou
Hachem, 2021).
Frontiers in Microbiology 01 frontiersin.org

Zhao et al. 10.3389/fmicb.2022.956378
GRAPHICAL ABSTRACT
Biotransformation and metabolism of natural products based on gut microbes. Created with BioRender.com.
Natural products are small molecules produced naturally by mechanisms and utilization of natural products. In this review,
any organism including primary and secondary metabolites.1 This we introduce the resident gut microbes that contribute to the
article mainly describes natural products of plant origin, including transformation of natural products and summarize the
nutrients and drugs. They easily interact with gut microbiota transformation pathways between natural products and specific
because of their complex components and long residence time in microbes classified by the reactions. Moreover, the advantages,
the gut. Generally, the residence time for exogenous substances is research methods, and future directions of gut microbial in the
1–6 h in the small intestine and 1–3 days in the colon (Chu and conversion of natural products are discussed to provide a
Traverso, 2022). Specific gut microbes decompose and transform theoretical basis for the modern application of natural products
natural products to produce rich metabolites and functional and the precise treatment through gut microbiota.
compounds with physiological activities that cannot
be synthesized by the host itself (Koppel et al., 2017; Xie et al.,
2020). Microbial transformation in natural products usually refers Key gut microbes in the
to the chemical reactions that are used to modify the structure of biotransformation of natural
natural products substrates, such as hydrolysis, methylation, products
demethylation, redox, and cyclization reaction (Morgan et al.,
2022; Rocchetti et al., 2022). Gut microbiota remarkably affects Oral administration is the preferred route for drug delivery, and
the chemical modification, pharmacological activity, and oral drugs account for 84% of the top 50 best-selling drugs in the US
metabolic mechanism of natural products. The potential utility of and European markets (Lennernäs and Abrahamsson, 2005; Vinarov
gut microbes for large-scale synthesis of active metabolites and et al., 2021). In recent years, the influence of gut microbiota on the
production of compounds has not been investigated. Studying stability of oral administration of natural products has received
these gut microbes, metabolites, and the reactions involved in the much attention. The intestinal tract has abundant bacteria that help
interactions between natural products and gut microbiota is of with normal digestive function, in which about 98% of gut microbes
great significance in the exploration of the pharmacological in healthy subjects can be classified into four phyla, Firmicutes,
Bacteroidetes, Proteobacteria, and Actinobacteria (Manor et al.,
2020; Ye et al., 2021; de Vos et al., 2022). Some gut microbes such as
1 https://www.nature.com/subjects/natural-products
Escherichia coli, Bifidobacterium, Eubacterium, Lactobacillus,
Bacteroides, and Streptococcus participate in the biotransformation
of natural products, and part of their metabolites are conducive to
Abbreviations: DHC, dihydrocurcumin; THC, tetrahydrocurcumin; CurA, intestinal absorption and play a notable pharmacological role (Al-
NADPH-dependent curcumin/dihydrocurcumin reductase; CHA, chlorogenic Ishaq et al., 2021; Augusti et al., 2021; Figure 1).
acid; CA, caffeic acid; GL, glycyrrhizin; 18β-GA, 18β-glycyrrhetinic acid; PM-I,
paeonimetabolin-I; GAMG, 18β-glycyrrhetinic acid-3-O-β-D-glucuronic
acid; SGG, Streptococcus gallolyticus subsp. Gallolyticus; DDAs, diester Escherichia coli
diterpenoid alkaloids; MDAs, monoester diterpene alkaloids; DHENL,
(−)-dihydroxyenterolactone; 3′-DMAG, 3′-desmethylarctigenin; BBR, Escherichia coli is a Gram-negative, spore-free, facultative
Berberine; dhBBR, dihydroberberine; DMC, demethoxycurcumin; bDMC, anaerobic bacterium, which mainly inhabits the intestines of
bis-demethoxycurcumin; CK, compound K; UA, Urolitin A. vertebrates (Foster-Nyarko and Pallen, 2022). Part of E. coli

Zhao et al. 10.3389/fmicb.2022.956378
FIGURE 1
Biotransformation of natural products by key gut microbes. (A) β-glucuronidase of E. coli HGU-3 catalyzes hydrolysis of baicalin to yield baicalein
(Han et al., 2016; Li D. et al., 2019). (B) Feruloyl esterases from B. animalis, L. reuteri, L. helveticus, and L. fermentum catalyzes hydrolysis of
chlorogenic acid into caffeic acid (Raimondi et al., 2015; Pang et al., 2016; Aguirre Santos et al., 2018). (C) β-glucosidase of Eubacterium L-8 and
Streptococcus LJ-22 catalyzes hydrolysis of glycyrrhizin to 18β-glycyrrhetinic acid (Kim et al., 1999; Chen B. et al., 2021). (D) α-L-rhamnosidase
from Bacteroides sp. 45 catalyzes hydrolysis of rutin to quercetin 3-O-glucoside (Riva et al., 2020). (E) O-Methyltransferase from Blautia sp. MRG-
PMF1 catalyzes the demethylation of curcumin to demethoxycurcumin (Burapan et al., 2017a,b). Created with BioRender.com.
can produce glycosidase to participate in the transformation release hydroxycinnamic acids through the hydrolysis of conjugated
of exogenous substances, resulting in its beneficial role (Rodríguez- hydroxycinnamates and free hydroxycinnamates exhibit antioxidant
Daza et al., 2021; Candeliere et al., 2022). For example, E. coli and anticancer properties both in vitro and in vivo (Couteau et al.,
HGU-3 produces β-glucuronidase to hydrolyze the O-glycosidic 2001). At present, a good understanding of the genetic and
bond in baicalin to produce baicalein (Kim et al., 1996, 1998; Han biochemical characteristics of E. coli may contribute to the synthesis
et al., 2016). Baicalein depresses histamine-induced scratching of natural product derivatives with various health activities in vitro.
behavior more effectively than baicalin at the same dose and
presents anti-inflammatory and anti-oxidant effects by inhibiting
Nrf2-ARE and NF-κB signaling pathway (Chen et al., 2000; Trinh Bifidobacterium
et al., 2010; Ye et al., 2014). Some E. coli strains have high specific
activity for curcumin conversion. Curcumin is reduced to Bifidobacterium is a widespread and abundant genus
dihydrocurcumin (DHC) and tetrahydrocurcumin (THC) by the belonging to the phylum Actinobacteria and is among the first
highly expressed NADPH-dependent curcumin/dihydrocurcumin colonizers of gut microbiota for humans (Satti et al., 2021; He
reductase (CurA) of E. coli DH10B, whose whole-genome sequence et al., 2022). The most common Bifidobacterium in the human gut
had already been determined (Hassaninasab et al., 2011; Tan et al., include B. adolescentis, B. angulatum, B. bifidum, B. breve,
2014). DHC and THC (20 μM) reduce triglyceride levels in B. catenulatum, B. dentium, B. longum, B. pseudocatenulatum, and
OA-induced L02 and HepG2 cells by regulating mRNA and protein B. pseudolongum (Turroni et al., 2009; Hidalgo-Cantabrana et al.,
expression levels of SREBP-1C and PPARα and attenuate 2017), accounting for <10% of the adult human microbiome, but
OA-induced liver adipogenesis in an AMPK-dependent manner; they are linked to host health (Turroni et al., 2008). Certain species
DHC and THC have novel therapeutic benefits over curcumin in of Bifidobacterium can generate phenolic acids by expressing
hepatic steatosis (Chen et al., 2018; Yu et al., 2018). E. coli Nu, E. coli feruloyl esterase. For example, the feruloyl esterase of B. animalis
MC, and E. coli WC-1 have cinnamyl esterase activity, which can can hydrolyze chlorogenic acid (CHA) into caffeic acid (CAA;

Zhao et al. 10.3389/fmicb.2022.956378
Raimondi et al., 2015). CAA (10–30 mg/kg) can prevent airway allergic inflammation by inhibiting NF-κB phosphorylation
acetaminophen-induced acute liver injury in mice by increasing and enhancing the Nrf2/HO-1 pathway (Liu et al., 2022). These
Nrf2 transcription (Raimondi et al., 2015; Pang et al., 2016). The metabolic transformations provide more information about the
participation of partial Bifidobacterium promotes the metabolism diverse array of benefits that humans derive from Eubacterium
of flavanones, glycosides, and saponins in the gut. β-glucosidase spp. However, further in vivo studies are necessary to maximize
and demethylase in B. longum R0175 promote the potential benefits the Eubacterium genus has to offer.
3-(3′-hydroxyphenyl) propionic acid and 3-(phenyl) propionic
acid production from hesperidin through ring-cleavage and
demethylation (Pereira-Caro et al., 2018). B. longum SBT2928 Lactobacillus
hydrolyzes six major human and two animal bile salts (Tanaka
et al., 2000). Thus, Bifidobacterium may regulate bile acid The genus Lactobacillus belongs to the phylum Firmicutes,
metabolism and reduce cholesterol levels in vivo. In addition, which can balance the micro-community and protect
B. breve ATCC 15700 produces β-glucosidase to cleave glycoside gastrointestinal mucosa (Dempsey and Corr, 2022). Some
at the C-3 and C-20 positions of ginsenoside Rd. to generate Lactobacillus species are rich in metabolic enzymes, such as
deglycosylated ginsenoside compound K (Zhong et al., 2016; α-rhamnosidases, tannase, gallate decarboxylases, etc. and they
Zhang R. et al., 2019). These metabolic characteristics make transform exogenous substances (Reverón et al., 2017; Li
Bifidobacterium a prime candidate for the development of B.C. et al., 2019; Ferreira-Lazarte et al., 2021). L. rhamnosus NCTC
symbiosis to make natural products potentially beneficial. 10302, which has both β-glucosidase and α-rhamnosidase
activities, converts hesperetin-7-O-rutinoside and naringenin-7-
O-rutinoside to their respective aglycones and 3-(phenyl)
Eubacterium propionic acid by hydrolysis, ring fission, and dehydroxylation
(Pereira-Caro et al., 2018). L. plantarum expresses tannase to
The genus of Eubacterium strains is Gram-positive, which hydrolyze gallate, protocatechuate esters with a short aliphatic
forms one of the core genera of the human gut microbiota and alcohol substituent, and complex gallic tannins to produce gallic
shows widespread colonization of the human gut (Mukherjee acid (Jiménez et al., 2014). Gallic acid (11.5–46 μg/ml) plays a
et al., 2020). Some Eubacterium species produce glycosidase, protective role in LPS-induced inflammation and oxidative stress
reductase, etc., and participate in the metabolism of exogenous by inhibiting the MAPK/NF-κB pathway and activating the Akt/
substances (Zhang J. et al., 2019; Ellenbogen et al., 2021). AMPK/Nrf2 pathway (Tanaka et al., 2018). Fang et al. observed
E. ramulus is one of the most widely studied flavonoid-degrading that gallic acid and pyrogallol are produced by the degradation of
gut bacteria, and it is prevalent in the human intestine. Chalcone gallotannins by gallotannin-metabolizing enzymes in L. plantarum
isomerase and flavanone-/flavanonol-cleaving reductase from WCFS1. This study implies the potential role of prebiotic-probiotic
E. ramulus degrade certain flavonoids to produce chalcone, and interactions in the prevention of diet-induced metabolic disorders
dihydrochalcone (Gall et al., 2014). Dihydrochalcone and its (Reverón et al., 2015; Fang et al., 2019). Daidzein is reduced to
metabolites have anti-inflammatory and antioxidant effects, which dihydrodaidzein by Lactobacillus sp. Niu-O16 with daidzein
can down-regulate the secretion of pro-inflammatory cytokines in reductase activity (Wang et al., 2007; Heng et al., 2019).
RAW 264.7 and rescue LPS-induced oxidative phosphorylation Dihydrodaidzein (2.5–5 μM) inhibits NF-κB activation and
(Choi et al., 2021). Braune et al. investigated the degradation of MAPK phosphorylation, thereby improving osteoporosis (Kim
flavonol quercetin and flavone luteolin by E. ramulus strain wK1 et al., 2019). L. casei, L. plantarum, and L. acidophilus highly
and found that resting cells and enzyme preparations convert influence the deglycosylation of piceid to resveratrol (Basholli-
these flavonoids into 3, 4-dihydroxyphenylacetic acid, and 3-(3, Salihu et al., 2016). This conversion is important for increasing the
4-dihydroxyphenyl) propionic acid via the reduction of 2, bioavailability and bioactivity of piceid. Feruloyl esterases from
3-position double bonds and subsequent ring fission (Braune L. reuteri, L. helveticus, and L. fermentum hydrolyze chlorogenic
et al., 2001). Phloretin hydrolase from E. ramulus strain wK1 acid to release caffeic acid (Aguirre Santos et al., 2018). These
hydrolytically cleaves the C-C bond, which is adjacent to the findings open a new perspective on the role of Lactobacillus in
aromatic A-ring of phloretin to 3-(4-hydroxyphenyl)-propionic health-promoting pharmaceutical and food product applications.
acid and phloroglucinol (Schoefer et al., 2004; Braune et al., 2019). However, the underlying transformation mechanism deserves
E. cellulosolvens ATCC 43171T may contribute to the further study.
deglycosylation of flavonoid O- and C-glucosides (luteolin
6-C-glucoside and apigenin 6-C-glucoside) through the
fermentation of the liberated glucose portion. The deglycosylation Bacteroides
of C-glucosides is exclusively catalyzed by bacterial enzymes
(Braune and Blaut, 2012; Braune et al., 2016). Eubacterium L-8 Members of the genus Bacteroides are Gram-negative obligate
hydrolyzed terpenoid glycyrrhizin (GL) to 18β-glycyrrhetinic acid anaerobes, which account for 25% of the total bacteria in the colon
(18β-GA; Kim et al., 2000). 18β-GA prevents OVA-induced and play multiple roles in the human gut bacteriome (Zafar and

Zhao et al. 10.3389/fmicb.2022.956378
Saier, 2021). Bacteroides species such as B. fragilis, B. distasonis, anti-oxidant effect (Agunloye et al., 2019). Streptococcus strains
B. ovatus, and B. thetaiotaomicron are commonly detected in the might be a commensal, pathogenic, and opportunistic pathogen
clinic (Wexler, 2007). Bacteroidetes spp. possesses a series of in the gut, and more information is needed about its effect on
hydrolases and participates in inter-species cross-feeding human health. A better understanding of how Streptococcus
relationships with their microbial neighbors by converting foreign metabolizes natural products may allow the regulation of the gut
substances (Sonnenburg et al., 2004; Zafar and Saier, 2021). In microbiome to improve therapeutic efficacy.
vitro co-incubation experiments showed that certain Bacteroides
species are involved in the biotransformation of flavonoids.
Bacteroides sp. 45 expresses α-L-rhamnosidase and β-rutinosidase Blautia
for the hydrolysis of rutin into quercetin 3-O-glucoside, quercetin,
and leucocyanidin (Yang et al., 2012; Riva et al., 2020; Ferreira- Blautia species are strictly anaerobic, nonmotile, usually
Lazarte et al., 2021). Quercetin 3-O-glucoside is better absorbed spherical or oval, and widely found in the gut and feces of
than other forms of quercetin and can suppress the inflammatory mammals (Liu X. et al., 2021). There is increasing evidence for the
response in mice with TNBS-induced colitis via the inhibition of probiotic properties of Blautia on the biotransformation of natural
the NF-κB and MAPK signaling pathways (Zhang D. et al., 2019). products (Tremaroli and Bäckhed, 2012). In the course of
Bacteroides sp. 54 metabolizes quercitrin to hydroxyquercitrin and flavonoid biotransformation, the reactions catalyzed by Blautia
desmethylquercitrin. Quercitrin is also degraded to quercetin by include demethylation, O-and C- deglycosylation, and C-ring
α-L-rhamnosidase and undergoes further ring-cleavage to yield cleavage (Braune and Blaut, 2016), which may be catalyzed by the
3,4-dihydroxybenzoic acid by Bacteroides sp. 45 (Jiang et al., corresponding enzymes, such as O-glycosidase and β-glucosidases
2014). β-glucuronidase, which is expressed by Bacteroidetes J-37, (Braune et al., 2016). Research indicates that the strain Blautia sp.
metabolizes GL to 18β-GA (Kim et al., 1999; Guo et al., 2018). MRG-PMF1 has a hydrolytic ability on aryl methyl ether
Based on the review of existing studies, natural products are functional groups by converting 5,7-dimethoxyflavone and
biotransformed under the action of Bacteroidetes to produce 5,7,4-trimethoxyflavone into bioactive chrysin and apigenin,
metabolites with different functional activities. It is important to respectively. Blautia sp. MRG-PMF1 also possesses deglycosylation
understand the whole process of natural products occurring in the activity, and various isoflavones, flavones, and flavones were found
body to assess the effect on human health. to be metabolized into the corresponding aglycones (Kim et al.,
2014). Besides, under anaerobic conditions, Blautia sp.
MRG-PMF1 strain metabolizes icariin further to desmethylicaritin
Streptococcus with estrogenic effects (Wu et al., 2016). The strain can also
catalyze curcumin to produce demethoxycurcumin with anti-
The Streptococcus species are Gram-positive, spherical, or inflammatory and anti-cancer properties (Burapan et al., 2017a;
ovoid cells, which are usually arranged in chains or pairs and Hatamipour et al., 2019). In addition, Blautia sp. AUH-JLD56 is
widely exist in human feces and nasopharynx (Lannes-Costa capable of solely biotransforming arctiin or arctigenin into
et al., 2021). Meta-transcriptomic analysis indicates that the demethylated products with better antioxidant capacity (Liu et al.,
phosphotransferase system is majority expressed by 2013). Recently, a growing academic interest has been witnessed
Streptococcus, suggesting that these bacteria are the main in the biotransformation and metabolism of herbal plants and
utilizers of the available carbohydrates in the small intestinal functional foods by Blautia. Exploring the biotransformation of
(Zoetendal et al., 2012). Streptococcus LJ-22 expresses Blautia is of great significance for the development of new
β-glucuronidase to metabolize GL to 18β-glycyrrhetinic acid-3- enzymes and bioactive metabolites (Meng et al., 2020).
O-β-D-glucuronic acid (GAMG; Kim et al., 2000; Park et al.,
2004; Guo et al., 2018). GAMG has anti-allergic activity against
LPS-induced RAW264.7 cells with IC50 value of 0.28 mM (Park Key transformation types involved
et al., 2004). In addition, tannic acid is degraded by tannase of in natural products microbial
Streptococcus gallolyticus subsp. Gallolyticus (SGG) to produce metabolism
pyrogallol. SGG may contribute to the development of colorectal
cancer by eliminating the toxicity of tannic acid to tumor cells Complex microbial enzymes catalyze the metabolism of
(Oehmcke-Hecht et al., 2020). Therefore, further in vivo studies natural products in the gut, resulting in lipophilic and
are necessary to determine whether the elimination of these low-molecule-weight metabolites conducive to host utilization/
tannic acid-degrading microbes can support the effective excretion (Weersma et al., 2020). Unlike human genetics, the gut
treatment of colorectal cancer. S. thermophilus GIM 1.321 has a microbiome is modifiable in terms of characteristics, making it a
high production capacity of β-glucosidase for the degradation of potential therapeutic target to optimize therapy. After oral natural
fructus anthocyanins into CHA, CAA, and ferulic acid (Cheng products enter the digestive tract, they will first come into contact
J.R. et al., 2016). The administration of CAA and CHA with a large number of gut microbes and the active enzymes
(10/15 mg/kg/day) can lower blood pressure and exert an produced by them. Therefore, natural products’ gut

Zhao et al. 10.3389/fmicb.2022.956378
biotransformation may occur before the first-pass effect through hydrolyzing xylose and glucose groups in epimedium B to obtain
the liver (Xie et al., 2020). Natural products can be modified/ baohuoside I and sagittatoside B (Tong et al., 2021). Flavanones
deconjugated by the gut microbiome, and can also be transported have a 2,3-dihydro-2-phenylchromen-4-one structure.
to the liver to modify/bind and then excreted into the gut to react Hesperidin is converted to its active form hesperetin by
with gut microbes to form a series of metabolites (Koppel et al., α-L-rhamnosidase, which is expressed by B. pseudocatenulatum
2017). The metabolites transformed by the host-microbial (Mas-Capdevila et al., 2020). Isoflavones are mainly found in
co-metabolic system may be functionally novel and not clearly legumes. B. breve MCC1274 possesses the highest β-glucosidase
defined. Therefore, the combination of specific strains, specific activity for the conversion of daidzin to daidzein (Yao et al.,
metabolic pathways, and specific enzymes associated with health/ 2019). The anthocyanin cyanidin 3-glucoside is converted to
disease is important for the determination of the effect of gut cyanidin by E. ramulus and Clostridium saccharogumia (Hanske
microbes on the host. et al., 2013). Human gut enzymes such as β-glucuronidase play
a key role in the hydrolysis of wogonoside to its aglycone form
wogonin (Xing et al., 2014). Theasinensin A, a bioactive catechin
Hydrolysis dimer found in black tea, is degalloylated to yield theasinensin
C by human fecal microbiota (Liu Z. et al., 2021). In the present
Certain natural products have high molecular weight and study, we observed the metabolic differences in flavane-3-ols,
low lipid solubility, and they are difficult to be absorbed by the and the results suggest that steric hindrance may limit the
body in the intestine and have low bioavailability (Hostetler degradation of partial flavane-3-ols C-ring by bacterial enzymes
et al., 2017). Through gut microbes-mediated hydrolysis, their during gut microbial fermentation. Many other flavonoids can
physical properties are changed, and their biological activity and also undergo hydrolysis reactions under the action of gut
bioavailability are greatly improved (Wu and Tan, 2019). microbes, as shown in Table 1. Notably, considering the
Slámová et al. indicated that most glycosides have low activity structural differences of flavonoids, the degree of degradation of
and are considered “natural prodrugs” (Slámová et al., 2018). flavonoids by gut microbes varies greatly, thus affecting their
After interacting with gut microbes, the sugar groups of bioaccessibility. Further efforts are required to investigate the
glycosides are removed, and then, the aglycone portion is role of gut metabolism in the bioavailability and absorption of
absorbed by intestinal cells to exert physiological effects (Wilson flavonoids and the possible bacteria-flavonoid interaction
and Nicholson, 2017; Murota et al., 2018). The hydrolysis ctivities.
reaction is required for further transformation, and the products
(e.g., sugars) participate in promoting the growth and survival Terpenoids
of gut microorganisms (Theilmann et al., 2017). Figure 2 shows Terpenoids are the largest class of natural products with anti-
the hydrolysis reaction of partial natural products under the cancer, anti-inflammatory, and neuroprotective effects
action of gut microbes. (Agatonovic-Kustrin et al., 2020; El-Baba et al., 2021). Part of
terpenoids can also be hydrolyzed by gut microbes. Geniposide
Flavonoids produces genipin with the action of β-glucosidase expressed by
Flavonoids are natural phenolic compounds found Eubacterium sp. A-44 (Akao et al., 1994; Jiang et al., 2016).
abundantly in fruits and vegetables. Gut microbes may be partly Paeoniflorin is transformed into PM-I under the action of
responsible for the efficacy of flavonoids (glycoside forms), β-glucosidase, which is expressed by L. brevis and B. fragilis
which have low bioavailability because of the presence of water- (Abdel-Hafez et al., 1999; He et al., 2007). By incubating with rat
soluble sugar components (Murota et al., 2018; Al-Ishaq et al., anaerobic gut microbiota, paeoniflorin is also deglucosed and
2021). Flavanols with 3-hydroxyflavone base (3-hydroxy-2- dephenyled into albiflorin and acyl albiflorin with a small
phenylchromen-4-one) and planar ring system constitute a molecular weight (Ke et al., 2016). Peng et al. demonstrated that
significant class of flavonoids. In the study of Du et al., several Bifidobacteria species with esterase can hydrolyze albiflorin
isorhamnetin-3-O-neohesperidoside was first deglycosylated to to benzoic acid in vitro (Peng et al., 2022). In vitro study shows
isorhamnetin-3-O-glucoside and subsequently to the aglycone that asiaticoside is gradually deglycosylated by glycoside bond
isorhamnetin by Escherichia sp. 23 (Du et al., 2017). The gut hydrolase and produces corresponding aglycones (Weng et al.,
microbes and derived enzymes (lactase phlorizin hydrolase) 2006). Saikosaponin B1 is gradually hydrolyzed to prosaikogenin
jointly controlled the metabolism of epimedium koreanum and saikogenin A under the action of β-glucosidase and β-D-
nakai-prenylated flavonoids as determined by in vitro assays. In focusidase, which are expressed by Eubacterium sp. A-44 (Kida
the present study, gut enzymes metabolized flavonoids faster et al., 1998). Except for the compounds mentioned above,
than gut microbes (Zhou et al., 2013). Wu et al. found that terpenoids ginsenoside Rh2 (Guo et al., 2019), ardipusillosides
α-L-rhamnosidase from Bacteroides thetaiotaomicron VPI-5482 I (Cao et al., 2015), mogroside III (Yang et al., 2007), and
could hydrolyze the α-1,2 glycosidic bond of epimedin C to pedunculoside (Wu et al., 2019) can also undergo hydrolysis
produce icariside (Wu et al., 2018). β-xylosidase Dt-2,286, which reactions under the action of gut microbes (Table 1). Therefore,
is derived from Dictyoglomus turgidum, is highly active in gut microbes play an important role in terpenoid metabolism, and

Zhao et al. 10.3389/fmicb.2022.956378
FIGURE 2
Hydrolysis of natural products under the action of gut microbes. (A–E) Hydrolysis of hesperidin (Mas-Capdevila et al., 2020), geniposide (Jiang
et al., 2016), aconitine (Zhang et al., 2015), theasinensin A (Liu Z. et al., 2021), sennoside A or B (Matsumoto et al., 2012).
the effects of their metabolites on gut microbiome and human Chinensis is commonly used in Asia, and its major saponin
health need to be further studied. anemoside B4 can be degraded by gut microbes to produce
deglycosylation products (Wan et al., 2017). Table 1 shows that the
Other compounds alkaloids scopolamine (Wu et al., 2019), steroid compound
Ellagitannins, which have a very low bioavailability perform a pulsatilla saponin D (Yan et al., 2018), and cycasin (Goldin, 1990)
pharmacological role only when it is hydrolyzed into derivatives undergo hydrolysis reactions under the action of gut microbes.
such as ellagic acid and uroliths under the action of tannase from The hydrolysis reaction is an important step in the metabolism of
Gordonibacter urolithinfaciens, Gordonibacter pamelaeae, and natural products by gut microbes and is required for the
Ellagibacter isourolithinifaciens (Beltrán et al., 2018; García- expression of biological activity and further biotransformation.
Villalba et al., 2020; Tang et al., 2021). The anthraquinone The specific microorganisms and enzymes involved in this
glycosides extracted from rhubarb are hydrolyzed into reaction should be focused on to fully understand the ultimate fate
anthraquinone aglycones by gut microbes (Li Q. et al., 2020). of natural products and their impact on human health and provide
Sennoside A, a major component of rhubarb extract, is a basis for personalized treatment.
metabolized into rhein anthrone by β-glucosidase of
Bifidobacterium sp. strain SEN (Matsumoto et al., 2012; Kon et al.,
2014). Under the action of carboxylesterase (CEs), which are Methylation and demethylation
expressed by gut microbes, diester diterpenoid alkaloids (DDAs,
such as aconitine) hydrolyze the ester bonds of C-8 and C-14 to Gut microbes can express transferases and move functional
produce monoester diterpene alkaloids (MDAs, such as groups between the two substrates through nucleophilic
hypaconitine), which are less toxic (Zhang et al., 2015). Pulsatilla substitution reactions (Koppel et al., 2017). The addition of methyl

Zhao et al. 10.3389/fmicb.2022.956378
TABLE 1 Hydrolysis reaction of gut bacteria to natural products.
Classification Gut microbiota Enzyme Substrate End-product Changes Ref.

Flavonoid glycosides E. coli HGU-3; β-glucuronidase Baicalin Baicalein; Bioavailability↑ Yim et al. (2004), Trinh
L. brevis RO1 oroxylin A anti-inflammation↑ et al. (2010) and Han
et al. (2016)
E. cellulosolvens β-glucosidase Luteolin 7-O- Luteolin; Bioavailability↑ Braune and Blaut
ATCC 43171T glucoside; apigenin (2012) and Braune
apigenin 7-O- et al. (2016)
glucoside
E. cellulosolvens NA Luteolin 6-C- Luteolin; Bioavailability↑ Braune and Blaut
ATCC 43171 T
glucoside; apigenin (2012) and Braune
apigenin 6-C- et al. (2016)
glucoside
Human gut microbes β-glucuronidase Wogonoside Wogonin Anti-inflammation↑ Xing et al. (2014)
Bacteroides JY-6; β-glucosidase Rutin Quercetin-3-O- Bioavailability↑ Riva et al. (2020) and
Fusobacterium K-60 α-L-rhamnosidase glucoside; anti-oxidant↑ Ferreira-Lazarte et al.
β-rutinosidase quercetin; (2021)
leucocyanidin
Escherichia sp. 23 β-glucosidase Isorhamnetin-3-O- Isorhamnetin-3-O- Bioavailability↑ Du et al. (2017)
neohesperidoside glucoside; anti-inflammation↑
isorhamnetin
Rat gut microbes; β-glucosidase Epimedin A, B, C Icariin II; Anti-osteoporosis↑ Cui et al. (2013), Cui
B. thetaiotaomicron α-L-rhamnosidase icariin A, B et al. (2014) and Wu
VPI-5482 et al. (2018)
Dictyoglomus β-xylosidase Dt-2,286 Epimedium B Baohuoside I; Anti-osteoporosis↑ Tong et al. (2021)
turgidum sagittatoside B
B. animalis subsp. β-glucosidase Quercetin 3-O- Quercetin; Anti-tumor↑ Youn et al. (2012)
lactis AD011 glucoside isorhamnetin anti-inflammatory↑
isorhamnetin 3-O-
glucoside
Lactobacillus β-glucosidase Kaempferol-3-O- Kaempferol Anti-aging↑ Shimojo et al. (2018)
paracasei A221 sophoroside
Enterococcus. sp. 8B, β-glucosidase Astilbin Taxifolin Cardiovascular Zhao et al. (2014) and
8-2,9-2 protection↑ Zhao et al. (2021)
anti-tumor↑
anti-inflammatory↑
Human gut microbes; α-L-rhamnosidase; Hesperidin Hesperetin Anti-oxidant ↑ Mas-Capdevila et al.
B. pseudocatenulatum β-glucosidase anti-inflammatory ↑ (2020)
Rat gut microbes β-glucosidase Calycosin-7-O-β-D- Calycosin Neuroprotection↑ Ruan et al. (2015)
glucoside anti-oxidant ↑
E. ramulus; β-glucosidase Daidzin Daidzein Neuroprotection↑ Mace et al. (2019) and
B. breve MCC1274 Yao et al. (2019)
Dorea species PUE C-deglycosylation 3″-oxo-puerarin Daidzein Bioavailability↑ Nakamura et al. (2020)
enzymes (DgpB-C)
E. ramulus; β-glucosidase Cyanidin 3-glucoside Cyanidin Bioavailability↑ Hanske et al. (2013)
Clostridium
saccharogumia
Human gut microbes Tannase Theasinensins A Theasinensins C Bioavailability↑ Liu Z. et al. (2021)
Bacillus sp. KM7-1; C-C glucosyl-cleaving Mangiferin Norathyriol Anti-cancer↑anti- Hasanah et al. (2021)
Bacteroides sp. enzyme diabetes↑
MANG
Strain CG19-1 NA Mangiferin Norathyriol Braune and Blaut
(2011)
(Continued)

Zhao et al. 10.3389/fmicb.2022.956378
TABLE 1 (Continued)
Terpenoids Eubacterium. sp. A-44 β-glucosidase, Geniposide Genipin; Bile secretion↑ Akao et al. (1994),
carboxylesterases geniposidic acid anti-hepatitis↑ Jiang et al. (2016) and
Tian et al. (2013)
B. fragilis; β-glucosidase Paeoniflorin PM-I; Anti-convulsant↑ He et al. (2007) and Ke
L. brevis; albiflorin and its Bioavailability↑ et al. (2016)
rat gut microbes aglycone;
Deacyl-
paeonifloridin
Rat gut microbes Glycoside hydrolases Asiaticoside Corresponding Bioavailability↑ Weng et al. (2006)
aglycones
Eubacterium sp. A-44 β-glucosidase; Saikosaponin B1 Prosaikogenin; Anti-inflammatory↑ Kida et al. (1998)
β-D-fucosidase saikogenin A Anti-oxidant↑
Eubacterium L-8; β-glucuronidase GL 18β-GA; Anti-platelet Kim et al. (1999), Kim
Bacteroidetes J-37; GAMG aggregation↑ et al. (2000), Park et al.
Streptococcus LJ-22 anti-allergic↑ (2004) and Guo et al.
anti-tumor↑ (2018)
anti-bacterial↑
Eubacterium sp. A-44; β-glucosidase Ginsenoside Rh2 Ginsenoside F2; Bioavailability↑ Zhong et al. (2016),
B. breve ATCC 15700 compound K Zhang R. et al. (2019)
and Kim (2018)
B. breve; Esterases Albiflorin Benzoic acid Anti-depression↑ Zhao et al. (2018) and
B. longum Peng et al. (2022)
Human/rat gut β-glucosidase; Ardipusillosides I Deglycosylated Bioavailability↑ Cao et al. (2015)
microbes α-L-rhamnosidase product
Human gut microbes NA Mogroside III Mogroside II Bioavailability↑ Yang et al. (2007)
mogrol
B. adolescentis; NA Pedunculoside Deglycosylated Bioavailability↑ Wu et al. (2019)
B. breve products
Rat gut microbes NA Capilliposide C Deglycosylated Cheng Z. et al. (2016)
products
esterolysis products
Anthraquinones Bifidobacterium sp. β-glucosidase Sennoside A and B Sennidin A/B-8- Purgation↑ Matsumoto et al.
strain SEN monoglucoside (2012)
Alkaloids Human gut microbes CEs DDAs MDAs Toxicity↓ Zhang et al. (2015)
Phenols Rat gut microbes NA Scopolamine Scopine Anti-tumor↑ Dey (2019)
L. plantarum Tannase Gallic tannins Gallic acid Anti-oxidant↑ Jiménez et al. (2014)
Akkermansia Tannase Ellagitannins Ellagic acid Neuroprotection↑ Luca et al. (2020)
muciniphila
Rat gut microbes β-glucosidase Amygdalin Mandelonitrile; Toxicity↑ Kim et al. (2008) and
prunasin; Qin et al. (2021)
phenylacetonitrile;
hydrogen cyanide
B. animalis Feruloyl esterase CHA CAA Anti-oxidant↑ Raimondi et al. (2015)
L. plantarum; Feruloyl esterases CAA; ferulic acid Anti-oxidant↑ Fritsch et al. (2017)
L. johnsonii; p-coumaric acids
L. acidophilus
E. coli Nu; Cinnamyl esterase Conjugated Free Anti-oxidant↑ Couteau et al. (2001)
E. coli MC; hydroxycinnamates hydroxycinnamates anti-cancer↑
E. coli WC-1
(Continued)

Zhao et al. 10.3389/fmicb.2022.956378
TABLE 1 (Continued)
Steroids Human gut microbes NA Pulsatilla saponin D Corresponding Bioavailability↑ Yan et al. (2018)
deglycosylation
products
Other Mouse gut microbes β-glucosidase Cycasin Diazomethane Toxicity↑ Goldin (1990)
to exogenous substances by gut microbes requires chemically Lignans

activated co-substrates, such as acetyl coenzyme A, adenosine Dietary lignans are phytoestrogens that are mostly found in
triphosphate, or S-adenosylmethionine, while demethylation seeds, nuts, legumes, and vegetables. Arctiin can be demethylated
requires cofactors that can undergo nucleophilic catalysis, such as to (−)-dihydroxyenterolactone (DHENL) and other products by
COB (I) alamin, and tetrahydrofolate (Kumano et al., 2016). Eubacterium sp. ARC-2 strain (Jin et al., 2007, 2013; Seyed
Methylation modification can optimize the physiological activity Hameed et al., 2020). Liu et al. isolated a bacterium named Blautia
of natural products, and demethylation can release polar groups sp. AUH-JLD56 from human fecal bacteria, and this species could
for further binding and excretion from the body, and provide a efficiently transform arctiin or arctigenin into a demethylation
carbon source for the growth of gut microbes (Ticak et al., 2014). metabolite 3′-desmethylarctigenin (3′-DMAG; Liu et al., 2013).
Figure 3 shows the methylation and demethylation of natural Secoisolariciresinol, which is one of the most common lignans
products under the action of gut microbes. found in flaxseed, can be demethylated in the presence of Blautia
producta, Gordonibacter and Lactonifactor longoviformis to form
Flavonoids enterolactone and enterodiol (Bess et al., 2020; Tse et al., 2022).
The methylation modification can be carried out at the C-2, Sesamin is metabolized into mammalian lignan enterolactone and
C-3, C-4, C-5, C-6, C-7, and C-8 positions in the structure of enterodiol through methylation, demethylation, and other
flavonoids, and the bioavailability of methylated flavonoids is reactions by gut microbes (Peñalvo et al., 2005). Matairesinol and
greatly improved (Wen and Walle, 2006). Bernini et al. found that phillygenin can also be demethylated to produce enterolactone
O-methylated flavonoids have remarkable anti-cancer activity and (Clavel et al., 2006; Yamawaki et al., 2011; Michalak et al., 2018).
resistance to hepatic metabolism (Bernini et al., 2011; Choi, 2019). Silybin A and B are demethylated into demethylsilybin A and
After oral administration of rutin in rats, many methylated demethylsilybin B by human fecal microbiota (Zhang et al., 2014;
metabolites, such as methylrutin, methylisoquercetin, and Valentová et al., 2020).
methylquercetin sulfate, are detected in fecal samples (Yang et al.,
2012; Wu et al., 2017; Riva et al., 2020). Methoxylated isoflavonoids Other compounds
formononetin and biochanin A undergo demethylation to produce Polyphenol compound curcumin is demethylated by Blautia
daidzein and genistein under the action of E. limosum ATCC 8486 sp. MRG-PMF1 to produce metabolites demethoxycurcumin
(Hur and Rafii, 2000). Isoxanthohumol yields demethylation (DMC) and bis-demethoxycurcumin (bDMC; Burapan et al.,
products 8-prenylnaringenin by E. limosum (Paraiso et al., 2019). 2017a,b). The demethylated products of dihydro-isoferulic acid,
Hesperidin, hesperetin (Pereira-Caro et al., 2018; Jiao et al., 2020), such as dihydrocaffeic acid, are also obtained in fecal metabolites
5,7-dimethoxyflavone, xanthohumol (Paraiso et al., 2019), and (Kay et al., 2017). Wang et al. found that the methylation reaction
5,7,4′-trimethoxyflavone (Kim et al., 2014) can also undergo occurs at the internal and external glucuronic acid residues of the
demethylation reactions under the action of gut microbes (Table 2). licorice saponins 22β-acetoxyl glycyrrhizin sugar chain, yielding
22β-acetoxyl glycyrrhizin-6″-methyl ester (Wang et al., 2015).
Alkaloids Compounds such as polyphenols danshensu (Gu et al., 2014),
Alkaloids are nitrogen-containing compounds, which are terpenoids genipin (Akao et al., 1994), stilbenoids thunalbene
biosynthesized by both marine and terrestrial organisms, and they (Jarosova et al., 2019), and steroids pulsatilla saponin B3 (Liu et al.,
have anti-cancer (Tse et al., 2022) and anti-viral activity (Abookleesh 2015) undergo methylation and demethylation under the action of
et al., 2022). Under the action of enzymes expressed by gut microbes, gut microbes, as shown in Table 2. Methylation and demethylation
quassic ketone, the main alkaloid component in bitter wood, is reactions are important pathways of gut microbial metabolism, and
methylated into quassic alkali butyl (Fan et al., 2013; Chen et al., have been confirmed in many studies. However, the genes/enzymes
2021). Isoquinoline alkaloid palmatine yields demethylation that mediate this reaction have not been fully characterized.
products such as columbamine, jatrorrhizine, demethyleneberberine,
and demethyleneberberine via in vitro anaerobic incubation (He
et al., 2017; Liao et al., 2021). The demethylation of aconitine by gut Redox reaction
microbes is demonstrated by ion trap electrospray ionization tandem
mass spectrometry, and 16-O-demethylaconitine is produced (Zhao Gut microbes can express many oxidoreductases and
et al., 2008; Zhang et al., 2017). transform natural compounds by adjusting various functional

Zhao et al. 10.3389/fmicb.2022.956378
FIGURE 3
Methylation and demethylation of natural products under the action of gut microbes. (A) Methylation of rutin (Wu et al., 2017); (B–F)
Demethylation of aconitine (Zhang et al., 2017), arctigenin (Jin et al., 2013), 5,7,4-trimethoxyflavone (Kim et al., 2014), 22β-acetoxyl glycyrrhizin
(Wang Q. et al., 2015), isoxanthohumol (Paraiso et al., 2019).
groups, such as olefins, carboxylic acid derivatives, nitro, 2019). By using UPLC-ESI-Q-TOF-MS/MS analysis, compounds
N-oxides, and a, b-unsaturated carboxylic acid derivatives, which such as the deoxidized metabolites kaempferol and the C2-C3
influence the activity of natural products in vivo (Lavrijsen et al., double bond hydrogenation reduction product taxifolin were
1995; Haiser et al., 2013; Abookleesh et al., 2022). Various identified in the culture solution of rat gut fluid by incubation with
cofactors such as NADH, NADPH, flavin, Fe/S cluster, heme, and quercetin under anaerobic conditions (Qin et al., 2017). Yang et al.
molybdenum cofactor are involved in the mediation of the discovered a flavone reductase from Flavonifractor plautii ATCC
transfer of electron or hydride equivalent (H+, 2e−) to the 49531, and this enzyme specifically catalyzes the hydrogenation of
substrate (Vanoni, 2021; Lubner et al., 2022). Figure 4 shows the the C2-C3 double bound of flavones/flavanols C-ring and acts
oxidation and reduction reactions of natural products under the during the initial step of the entire biodegradation pathway of
action of gut microbes. flavonoid (Goris et al., 2021; Yang et al., 2021).
O-desmethylxanthohumol, a chalcone compound, is reduced to
Flavonoids O-desmethyl-α, β-dihydroxanthohumol by E. ramulus (Paraiso
Daidzein is reduced to dihydrodaidzein and further et al., 2019).
tetrahydrodaidzein under the action of Clostridium sp. strain
HGH6 and Lactobacillus. sp. Niu-O16 (Zhao et al., 2011; Heng Alkaloids
et al., 2019). The reduced product dihydrogenistein is produced Nitroreductase, which is produced by gut microbes,
by genistein under the action of human fecal bacteria (Mace et al., catalyzes ether and coordination bond reactions in alkaloids.

Zhao et al. 10.3389/fmicb.2022.956378
TABLE 2 Methylation and demethylation reaction of gut microbes to natural products.

Flavonoids Rat gut microbes Methyltransferase Rutin Methylrutin; Bioavailability↑ Wu et al. (2017)
Methyl-isoquercetin;
methylquercetin
sulfate
Mice gut microbes NA Myricetin Mono- and di- Toxicity↓ Zhang et al. (2020)
methylated myricetin
Rat gut microbes NA Hesperidin; Demethylated Bioavailability↑ Pereira-Caro et al.
hesperetin products (2018) and Jiao et al.
(2020)
E. limosum O-demethylase Formononetin; Daidzein; Estrogen effect↑ Hur and Rafii (2000)
biochanin A genistein
Blautia sp. MRG- Methyltransferase 5,7-dimethoxyflavone; Chrysin; Anti-oxidant↑ Kim et al. (2014)
PMF1 5,7,4′-trimethoxyflavone apigenin anti-inflammatory↑
anti-cancer↑
Blautia sp. MRG- Methyltransferase Icariin Desmethylicaritin Estrogenic effects↑ Wu et al. (2016)
PMF1
E. limosum O-demethylase Isoxanthohumol 8-prenylnaringenin Anti-androgen↑ Paraiso et al. (2019)
anti-osteoporosis↑
Alkaloids Human gut microbes Methyltransferase Quassic ketone Quassic alkali butyl Chen F.Z. et al. (2021)
Rat gut microbes Methyltransferase Palmatine Columbamine; Bioavailability↑ He et al. (2017) and
Jatrorrhizine; Liao et al. (2021)
demethyleneberberine
Human gut microbes O-demethylase Aconitine 16-O- Toxicity↓ Zhao et al. (2008) and
demethylaconitine Zhang et al. (2017)
Lignans Eubacterium O-demethylase Arctiin; DHENL; Anti-oxidant↑ Jin et al. (2007), Jin
sp. ARC-2; arctigenin 3′-DMAG estrogen effect↑ et al. (2013), Liu et al.
Blautia sp. AUH- (2013) and Seyed
JLD56 Hameed et al. (2020)
Blautia producta Guaiacol lignan Secoisolariciresinol Enterolactone; Estrogen effect↑ Bess et al. (2020) and
DSM3507; methyltransferase; enterodiol Tse et al. (2022)
Gordonibacter strains catechol lignan
3C and 28C; dehydroxylase;
Lactonifactor enterodiol
longoviformis lactonizing enzyme
DSM17459T
Human gut microbes SesA Sesamin Enterolactone; Estrogen effect↑ Peñalvo et al. (2005)
enterodiol
Rat gut microbes O-demethylase Matairesinol 2,3-bis(3,4- Anti-inflammatory↑ Clavel et al. (2006),
dihydroxybenzyl) estrogen effect↑ Yamawaki et al. (2011)
butyrolactone; and Michalak et al.
enterolactone (2018)
Human/rat gut O-demethylase Phillygenin Enterolactone Anti-inflammatory↑ Michalak et al. (2018)
microbes estrogen effect↑
E. limosum ZL-II; O-demethylase Silybin A and B Demethylsilybin A; Anti-Alzheimer’s Zhang et al. (2014) and
human gut microbes demethylsilybin B disease↑ Valentová et al. (2020)
Diketones Blautia sp. MRG- Co O- Curcumin DMC; Anti-tumor↑ Burapan et al.
PMF1 Methyltransferase bDMC anti-inflammatory↑ (2017a,b)
Phenols Rat gut microbes NA Danshensu 3-(3-O-methyl-4- Bioavailability↑ Gu et al. (2014)
hydroxyphenyl)-2-
hydroxypropanoic
acid
(Continued)

Zhao et al. 10.3389/fmicb.2022.956378
TABLE 2 (Continued)
Rat gut microbes O-demethylase Dihydro-isoferulic acid Dihydrocaffeic acid Anti-oxidant↑ Kay et al. (2017)
anti-apoptosis↑
Terpenoids Rat gut microbes NA 22β-acetoxyl 22β-acetoxyl Bioavailability↑ Wang Q. et al. (2015)
glycyrrhizin glycyrrhizin-6″-
methyl ester
Eubacterium sp. A-44 NA Genipin Geniposidic acid Anti-oxidant↑ Akao et al. (1994)
Stilbenoids Human gut microbes O-demethylase Thunalbene Isoresveratrol Anti-oxidant↑ Jarosova et al. (2019)
Steroids Human gut microbes NA Pulsatilla saponin B3 Corresponding Bioavailability↑ Liu et al. (2015)
Deglycosylation
products
FIGURE 4
Oxidation and reduction of natural products under the action of gut microbes. (A–C, E, F) Reduction of genistein (Mace et al., 2019), berberine
(Feng et al., 2015), curcumin (Hassaninasab et al., 2011), resveratrol (Pallauf et al., 2019), digoxin (Kumar et al., 2018); (D) glycyrrhetinic acid.
Berberine (BBR), as the main component of Coptis Chinensis, high polarity. dhBBR could be absorbed in the intestine and
can be reduced to dihydroberberine (dhBBR) by nitroreductase then oxidized into the prototype BBR into the blood. The
expressed by gut microbes, and this reduction product has absorption rate of dhBBR in the intestine is five times that of

Zhao et al. 10.3389/fmicb.2022.956378
BBR (Feng et al., 2015). Li et al. found that the gut microbes iridoid glycoside, can be hydrolyzed to gentianaldehyde by gut
could transform BBR into oxyberberine via oxidation (Li microbial β-glucosidase, and then to nitrogen-containing
et al., 2020). Oxyberberine, a novel metabolite of BBR, may compounds via N-heterocyclic reaction (el-Sedawy et al.,
be a promising bioactive agent worthy to be explored. 1989). The partial ring-opening of genipin acetone alcohol
Coptisine is a natural protoberberine alkaloid with the same results in the formation of dialdehyde by gut microbes (Kang
maternal structure as BBR. After oral administration of et al., 2012). Quinic acid can be aromatized to hippuric acid
coptisine, the C-O bond is opened and cracked, followed by a in the presence of gut microbes (Pero and Lund, 2011). Maren
reduction reaction to produce hydrogenated BBR (Cui et al., et al. incubated kaempferol-O-glycosides and apigenin-C-
2018). Avenanthramide-C is reduced by mice and the human glycosides with human fecal samples to generate
gut microbiota into dihydroavenanthramide-C (Wang 3-(4-hydroxyphenyl) propionic acid, 3-phenyl propionic acid,
et al., 2015). and phenylacetic acid through deglycosylation, ring fission
and other reactions (Vollmer et al., 2018). The main hydrolytic
Phenylpropanoids and ring-cleaved metabolites, namely, benzoic acid,
Caffeic acid (CAA), as the main dietary polyphenol in food 2-(3,4-dihydroxy phenyl) acetic acid, and 5-(3,4-dihydroxy
and beverage, can easily enter the colon and react with gut phenyl)-γ-valerolactone were obtained via in vitro
microbiota after esterification. CAA is transformed to fermentation of flavan-3-ols procyanidin B2 and A2 with
3-hydroxyphenylpropionic acid through C4 double bond human gut
reduction and dehydroxylation, and then rapidly converted to microbes (Stoupi et al., 2010; Ou et al., 2014; Le Bourvellec
3-phenyl propionic acid via the β-oxidation of gut microbes in et al., 2019). Sulfated and hydrogen-reduced metabolites have
vitro (Gonthier et al., 2006). CAA can also be dehydroxylated to been detected in the fecal samples of rats after oral
m-coumaric acid or hydrogenated to dihydrocaffeic acid administration of luteolin (Li et al., 2017; Káňová et al., 2020).
(García-Villalba et al., 2020). Danshensu, the major monomer The conversion of daidzein to equol, which is facilitated by gut
phenolic acid of Salvia Miltiorrhiza, undergo dehydrogenation microbes is another interesting example (Li et al., 2000; Hur
and deoxygenation by gut microbiota to produce 3-phenyl-2- et al., 2002; Mayo et al., 2019). Eggerthella lenta and
hydroxy propionic acid, 3-(3,4-dihydroxy phenyl) 2-acrylic acid Flavonifractor plautii reductively cleaved the heterocyclic
(caffeic acid), and 3-(3,4-dihydroxy phenyl)-propionate (Gu C-ring of both (−)-epicatechin and (+)-catechin giving rise to
et al., 2014). 1-(3,4-dihydroxyphenyl)-3-(2,4,6-trihydroxyphenyl) propan-
2-ol, δ-(31,41-dihydroxyphenyl)-γ-valerolactone, and
Other compounds δ-(31,41-dihydroxyphenyl)-γ-valeric acid (Ozdal et al., 2016).
Glycyrrhetic acid generates 3-oxo-glycyrrhetinic acid by Tea polyphenols are metabolized by gut microbiota (Liu et al.,
3β-hydroxysteroid dehydrogenase of Ruminococcus sp. po1-3 in 2018). Tea polyphenols first undergo structural modifications
the cecum. Sennosides, a class of natural anthraquinone such as methylation and sulfation in the small intestine and
derivative and dimeric glycosides, are first hydrolyzed by then enter the colon to be cleaved into small phenolic acids,
β-glucosidase to produce sennoside-8-O-monoglycoside, and which is conducive to absorption (Cheng et al., 2018). SesA, a
then reduced to rhubaranthrone with purgative effect by sesamin-metabolizing enzyme from Sinomonas sp. no. 22,
Streptococcus in vivo (Hattori et al., 1988). Stilbenoids resveratrol catalyzes the methylene group transfer from sesamin or
is reduced to dihydroresveratrol by Slackia equolifaciens and sesamin monocatechol to tetrahydrofolate with ring
Eggerthella lenta ATCC 4305 (Bode et al., 2013; Pallauf et al., cleavage, yielding sesamin mono- or di-catechol and
2019) Moreover, diketones curcumin (Hassaninasab et al., 2011; 5,10-methylenetetrahydrofolate (Kumano et al., 2016). The
Tan et al., 2014), steroid compounds digoxin (Kumar et al., 2018) terpenoids astragaloside A (He et al., 2019), flavonoids
and other compounds aristolochic acid (Feng et al., 2019) can quercitrin (Jiang et al., 2014) and myricetin (Zhang et al.,
also be reduced in the presence of gut microbes (Table 3). Gut 2019), the phenol anthocyanidin (Aura et al., 2005), the
microbial flavone reductase and nitroreductase have special alkaloid strychnine N-oxide (el-Mekkawy et al., 1993) and the
catalytic selectivity, filling key gaps in gut microbial aliphatic myristic acid (Du et al., 2014) can all undergo
transformation pathways. However, the specific genes and biotransformation reactions to generate active metabolites
enzymes that mediate gut microbial reduction have not been under the action of gut microbes. These studies demonstrate
fully determined. the enormous metabolic potential of various gut microbiomes.
The gut microbial metabolism of natural products and their
role in host health should be the focus of future research.
Other reactions This section summarizes the biotransformation of gut
microbiota-mediated natural products from a single reaction.
As shown in Table 4, natural products are also transformed However, some limitations are observed. Firstly, considering the
by gut microbes through ring fission, sulfuration, complexity of gut microbes and the diversity of gut microbial
aromatization, and other reactions. Gentiopicroside, a natural enzymes, natural products undergo complex transformations in

Zhao et al. 10.3389/fmicb.2022.956378
TABLE 3 Reduction and oxidation reaction of gut microbes to natural products.
Enterobacterial
Classification Gut microbiota metabolic Substrate End-product Changes Ref.
enzyme
Flavonoids Clostridium sp. strain Dihydrodaidzein Daidzein Dihydrodaidzein; Anti-osteoporosis↑ Wang et al. (2007) and
HGH6; reductase; tetrahydrodaidzein Heng et al. (2019)
Lactobacillus sp. tetrahydrodaidzein
Niu-O16 reductase
Aeroto Niu-O16 NA Genistein Dihydrogenistein Bioavailability↑ Mace et al. (2019)
Rat gut microbes Flavone reductase Quercetin Kaempferol; Bioavailability↑ Qin et al. (2017)
E. ramulus taxifolin
E. ramulus Flavanone-/ Xanthohumol; α, β-dihydroxanthohumol; Anti-bacterial↑ Paraiso et al. (2019)
flavanonol-cleaving O- O-desmethyl-α,
reductase desmethylxanthohumol β-dihydroxanthohumol
Alkaloids Mouse gut microbes Nitroreductase BBR; dhBBR; Bioavailability↑ Feng et al. (2015) and
coptisine hydrogenated berberine anti-inflammatory↑ Cui et al. (2018)
Mouse gut microbes NA BBR Oxyberberine Anti-fungal↑ Li C. et al. (2020)
Mouse/human gut NA Avenanthramide-C Dihydroavenanthramide-C Anti-inflammation↑ Wang P. et al. (2015)
microbes anti-atherogenesis↑
Phenolic acids Human gut microbes NA CAA Dihydrocaffeic acid Bioavailability↑ Gonthier et al. (2006)
and García-Villalba
et al. (2020)
Rat gut microbes NA Isoferulic acid Dihydrocaffeic acid Anti-oxidant↑ Kay et al. (2017)
anti-apoptosis↑
Rat gut microbes NA Dansensu 3-phenyl-2-hydroxy Bioavailability↑ Gu et al. (2014)
propionic acid;
3-(3,4-dihydroxy phenyl)
2-acrylic acid;
3-(3,4-dihydroxy phenyl)-
propionate
Gordonibacter Catechol- Chlorogenic acid; Dihydro-chlorogenic acid; Bioavailability↑ García-Villalba et al.
urolithinfaciens dehydroxylase rosmarinic acid dihydro-rosmarinic acid (2020)
Terpenoids Ruminococcus sp. 3β-hydroxysteroid Glycyrrhetinic acid 3-oxo-glycyrrhetinic acid Anti-inflammatory↑
po1-3 dehydrogenase
Anthraquinone Human gut microbes; NA Sennoside-8-O- Rhubaranthrone Purgation↑ Hattori et al. (1988)
Streptococcus spp. monoglycoside and Matsumoto et al.
(2012)
Stilbenes Slackia equolifaciens; NA Resveratrol Dihydroresveratrol Anti-oxidant↑ Jung et al. (2009), Bode
Eggerthella lenta et al. (2013) and Pallauf
ATCC 4305 et al. (2019)
Diketones E. coli strain K-12; CurA Curcumin DHC; Anti-oxidant↑ Hassaninasab et al.
E. fergusonii ATCC THC lipid-lowering↑ (2011) and Tan et al.
35469; (2014)
E. coli strains ATCC
8739 and DH10B
Steroids Eubacterium lenta Cardiac glycoside Digoxin Dihydrodigoxin Bioavailability↓ Kumar et al. (2018)
reductase
Other classes Human gut microbes NA Aristolochic acid Aristololactams Anti-cancer↑ Feng et al. (2019)
the intestinal tract. A single reaction can only describe a certain biotransformation reactions underplayed by natural products can
process of metabolism. Therapy can be optimized by activating/ be expected from gut microbes. To elucidate how gut microbial
inhibiting this process. In addition, considering that gut microbes metabolism affects human health, researchers should link the
contain various potentially multifunctional enzymes, more functions of interest to genes and enzymes. A deep understanding

TABLE 4 Other reactions of gut microbes to natural products.
Frontiers in Microbiology
Zhao et al.
Classification Gut microbiota Biotransformation Enterobacterial Substrate End-product Changes Ref.
metabolic enzyme
Terpenoids Human gut microbes Cyclization β-glucosidase Gentiopicroside Gentisaldehyde; Anti-inflammatory↑ el-Sedawy et al. (1989)
nitrogen-containing
compounds
Human gut microbes Cyclization NA Geniposide Nitrogen-containing Bioavailability↑ Kawata et al. (1991)
compounds
Human gut microbes Deglycosylation; NA Astragaloside A Cycloastragenol Bioavailability↑ He et al. (2019)
deacetylation;
dehydrogenation
Phenolic acids Rat gut microbes Aromatization NA Quinic acid Hippuric acid Anti-cancer↑ Pero and Lund (2011)
anti-bacterial↑
anti-viral↑
Egerthella lenta Dehydroxylation Catechol dehydroxylases Dihydrocaffeic acid 3-(3-hydroxyphenyl) Bioavailability↑ Maini Rekdal et al. (2020)
propionic acid
Human gut microbes Ring cleavage; NA Tea Phenolic acids Bioavailability↑ Cheng et al. (2018)
sulfation polyphenols
methylation
16
L. plantarum WCFS1 Ring fission; Tannase; Gallotannins Gallic acid; Anti-oxidant↑ Reverón et al. (2015) and
hydrolysis gallate decarboxylase pyrogallol anti-inflammatory↑ Fang et al. (2019)
SGG Ring fission; Tannase; Gallotannins Gallic acid; Anti-cancer↓ Oehmcke-Hecht et al.
hydrolysis gallate decarboxylase pyrogallol (2020)
Gordonibacter Decarboxylation; NA Ellagic acid Urolithins Anti-cancer↑ Beltrán et al. (2018),
urolithinfaciens; lactone-ring cleavage; anti-oxidant↑ García-Villalba et al. (2020)
Goronibacter pamelaeae; dehydroxylation anti-inflammatory↑ and Tang et al. (2021)
Ellagibacter
isourolithinifacens
Flavonoids Rat gut microbes Sulfation Aryl sulfotransferase Luteolin Luteolin-3′-O-sulfate; Li et al. (2017) and Káňová
luteolin-4′-O-sulfate et al. (2020)
Clostridium sp. strain C-ring fission 2-dehydro-O- Daidzein O-desmethylangolensin Anti-cancer↑ Hur et al. (2002)
HGH136 demethylangolensin
10.3389/fmicb.2022.956378
Eggerthella sp. strain Ring-fission Dihydrodaidzein racemase Dihydrodaidzein S-equol Estroge effect↑ Yokoyama and Suzuki
YY7918; (2008) and Mayo et al.
B. breve ATCC 15700 T; (2019)
frontiersin.org
B. longum BB536;
L. paracasei CS2
(Continued)
TABLE 4 (Continued)
Frontiers in Microbiology
Zhao et al.
Classification Gut microbiota Biotransformation Enterobacterial Substrate End-product Changes Ref.
metabolic enzyme
E. ramulus Ring-fission; Chalcone isomerase; Naringenin; Naringenin chalcone; Bioavailability↑ Gall et al. (2014) and
reduction flavanone-/flavanonol- eriodictyol phloretin; anti-inflammatory↑ Braune et al. (2019)
cleaving reductase 3-hydroxyphloretin
E. ramulus strain wK1 Ring-fission Phloretin hydrolase Phloretin 3-(4-hydroxyphenyl)- Bioavailability↑ Schoefer et al. (2004) and
propionic acid; Braune et al. (2019)
phloroglucinol
Bacteroides sp. 45; Ring-fission Chalcone isomerase; Quercetin; 4-hydroxybenzoic acid Anti-platelet Jiang et al. (2014) and
B. fragilis; phloretin hydrolase luteolin 3,4-dihydroxyphenylacetic aggregation↑anti-tumor↑ Braune et al. (2001)
E. ramulus acid;
3,4-dihydroxybenzoic;
3-(3-hydroxyphenyl)
propionic acid
Rat gut microbes Ring-fission Chalcone isomerase; Myricetin 3,4,5-trihydroxyphenylacetic Anti-inflammatory↑ Zhang S. et al. (2019) and
sulfation phloretin hydrolase acid; Káňová et al. (2020)
myricetin-3′-O-sulfate
B. longum R0175 Ring-cleavage; Phloretin hydrolase; Hesperidin 3-(3′-hydroxyphenyl) Bioavailability↑ Pereira-Caro et al. (2018)
17
demethylation demethylase propionic acid;

3-(phenyl) propionic acid
Eggerthella lenta; C-ring cleavage NA (−)-epicatechin; 1-(3,4-dihydroxyphenyl)-3- Bioavailability↑ Ozdal et al. (2016)
Flavonifractor plautii (+)-catechin (2,4,6-trihydroxyphenyl)
propan-2-ol;
δ-(31,41-dihydroxyphenyl)-
γ-valerolactone;
δ-(31,41-dihydroxyphenyl)-
γ-valeric acid
Human gut microbes C-ring cleavage NA Anthocyanidin Protocatechuic acid; Bioavailability↑ Aura et al. (2005)
A-ring fission syringic acid;
dehydroxylation vanillic acid;
phloroglucinol aldehyde
10.3389/fmicb.2022.956378
Human gut microbes C-ring cleavage Tannase Procyanidin B2 and A2 2-(3,4-dihydroxyphenyl) Anti-oxidant↑ Stoupi et al. (2010), Ou
A-ring fission acetic acid; et al. (2014) and Le
dehydroxylation, etc 5-(3,4-dihydroxyphenyl)-γ- Bourvellec et al. (2019)
frontiersin.org
valerolactone;
benzoic acid
(Continued)
Zhao et al. 10.3389/fmicb.2022.956378
Bess et al. (2020)s and Xiao

of the gene sequences of functional enzymes allows organisms
el-Mekkawy et al. (1993)

with similar sequences to be assigned the same biological activity.
Moreover, in addition to the regulation of gut microbes on the
Du et al. (2014)
disposal of natural products, the regulation of natural products on
et al. (2021)
gut microecology is important as a potential mechanism
Ref.
of efficacy.
Biotransformation contributions to
mining the active substance and
Anti-apoptosis↑
Anti-oxidant↑
mechanism
Changes
Toxicity↓
The increasing research about gut microbiota gradually

reveals the relationship between high pharmacological action and
Quercetin-3-O-rhamnoside;
low oral availability of most natural products. Most glycosides

16-hydroxystrychnine
have complex parent structures and are difficult to be absorbed by

secoisolariciresinol
aglycone myricetin
End-product
the intestine cells, thus limiting their tissue-specific

Lariciresinol;
Strychnine;
bio-accessibility. These compounds are transformed into small

quercetin;
molecule metabolites/unique metabolites through degradation

reactions that are dependent on microbial/gut microbial enzymes
and thus have a wide range of effects on the host (Wardman et al.,
2022). Gut microbes also act on dietary phenolics to produce
Strychnine N-oxide
functional metabolites that contribute to host health (Loo

Myristic acid
Substrate
et al., 2020).
Pinoresinol
Importantly, the biotransformation by gut microbes

facilitates the therapeutic effects of natural products. The
typical metabolization model of ginsenosides to compound K
(CK) has been widely reported (Figure 5), with enhanced anti-
metabolic enzyme
Benzyl ether reductase

Enterobacterial
tumor, anti-inflammatory, and lipid-lowering effects (Kim

et al., 2013; Kim, 2018). At 50 μM, CK inhibits the growth of
glioblastoma cells by upregulating caspase-3-, caspase-8-,
caspase-9- and cAMP-dependent protein kinases (Lee et al.,
NA
NA
2017); At 20 μM, CK reduces hepatic lipid accumulation in

human hepatocellular carcinoma cells by activating AMPK
(Zhang et al., 2022); CK attenuates macrophage inflammation
Biotransformation
and foam cell formation via autophagy induction and by

modulating NF-κB, p38 and JNK/MAPK signaling (Lu et al.,
Dehydroxylation
2020). The bioavailability of curcumin metabolites is dependent

Ring cleavage
Ring fission
on the microbiota dependent (Hassaninasab et al., 2011). For

instance, DMC increases PPARγ expression, resulting in
autophagy and NF-κB inhibition and subsequently inhibiting
LPS-induced inflammation (Tang et al., 2021). DMC mitigates
inflammatory responses in vivo and in vitro by inhibiting the
Human gut microbes
Human gut microbes

Gut microbiota
secretion of inflammatory factors and activation of MAPK and

Eggerthella lenta
NF-κB pathways (Lu et al., 2022). The chemical stability of

DMC increases because of the absence of the methoxyl group
in their prototype benzene ring structure, thus explaining the
strong beneficial effects of curcumin (Burapan et al., 2017a).
Notably, urolithin A (UA), a natural compound that is
TABLE 4 (Continued)
produced by gut microbes from ingested ellagitannins and

Classification
ellagic acid, has significant anti-inflammatory and

neuroprotective effects. At 1 μM, UA is sufficient for the
Aliphatics
Alkaloids
decreased production of TNF-α and MCP-1 and the

Lignins
inactivation of TLR3/TRIF signaling in poly (I:C)-induced

Zhao et al. 10.3389/fmicb.2022.956378
FIGURE 5
Biotransformation of ginsenosides (Kim et al., 2008) and efficacy of metabolite compound K. Created with BioRender.com.
RAW264.7 cells (Huang et al., 2022). UA improves systemic et al., 2015; Ding et al., 2019). The digoxin-reducing type
insulin sensitivity and reduces liver IL-1β levels in high-fat diet strains of E. lenta contain cardiac glycoside reductase that can
mice (Toney et al., 2019). UA ameliorates cognitive impairment reduce the α and β-unsaturated lactone on the digoxin ring and
in APP/PS1 mice and inhibits neuroinflammation by metabolize it into dihydrodigoxin with less activity, thereby
decreasing the levels of IL-6, IL-1β, and TNF-α in the cortex inhibiting its possible cardiotoxicity (Kumar et al., 2018).
and hippocampus (Gong et al., 2019). These studies highlight However, this ability is limited, and 50% of digoxin can
the importance of identifying natural products-microbial be inactivated by gut microbial transformation (Lu et al., 2014).
metabolism. Moreover, many in vitro pharmacological activity Cardiac glycoside reductase may be an effective biomarker for
measurements should be performed in conjunction with digoxin inactivation, and its expression can be inhibited by
microbial metabolites, which actually interact with biochemical arginine (Haiser et al., 2013). Therefore, diet could explain the
receptors in vivo. inter-individual variations in digoxin reduction and may
The composition, structure, function, and metabolites of modulate microbial metabolic activity in vivo. By contrast,
gut microbes have become potential targets for natural toxic compounds can be produced by gut microbes. Cycasin is
products to exert beneficial effects and reduce toxicity as well. hydrolyzed into carcinogenicity diazomethane under the
For instance, gut microbes can catalyze the ester bond action of β-glucosidase from gut microbes (Goldin, 1990).
hydrolysis of C-8 and C-14 of DDAs through CEs or catalyze Therefore, small molecule inhibitors of microbial gut enzymes
the ester exchange of C-8 to produce less toxic MDAs (Zhang should be developed to play a regulatory role in specific

Zhao et al. 10.3389/fmicb.2022.956378
transformation in this complex habitat. The toxicity difference methods, metatranscriptomics, and metagenomics has been
between metabolites transformed by gut microbiota and used to identify and characterize the active subsets of gut
precursor substances is worthy of further study. Moreover, microbiota and determine their metabolic responses to
excessive drugs may cause imbalance and adverse reactions in natural products.
gut microbes (Lindell et al., 2022), and the effects of different
doses of natural products on gut microbes and metabolism
need further investigation. Conclusions and future remarks
The gut microbiota is a reservoir of genes that encode
Multivariate technologies for various metabolic enzymes (Flint et al., 2012). The activation
studying biotransformation of biological activities and potential health benefits of most
natural products (e.g., flavonoids, alkaloids, and lignin) are
Considering that gut microbes can increase the host’s extremely dependent on gut microbes as a substrate-machining
complex and variable response to drugs/natural products, this factory (Braune and Blaut, 2016; Seyed Hameed et al., 2020;
process is of great interest to researchers. Research on Plamada and Vodnar, 2021). Much research effort has been
biotransformation is mainly conducted via in vitro approach devoted to understanding how microbes uniquely modify
(Sousa et al., 2008) as follows: (1) Intestinal fluid transformation. natural products and the effects of these metabolites on host
The large-scale preparation of transformed products can health (Luca et al., 2020; Shabbir et al., 2021). The following
be realized by intestinal fluid biotransformation; (2) Incubation conclusions have been made: (1) gut microbes can transform
with a sample of the host microbiota. The type and quantity of natural products (Xie et al., 2020); (2) natural products can
prototype drugs and metabolites can be detected using the regulate the composition and abundance of gut microbes
method. It has the advantage of accurate representation of the (Saccon et al., 2021); and (3) gut microbes can mediate the
entire gut microbiome of the individual; (3) Incubation of multi-component synergy of natural products (Feng et al.,
representative strains. This method affords high-throughput 2019). Although high-throughput methods are being developed
potential, which is valuable for large-scale drug studies and to help people understand the importance of the gut
contributes to the industrial production of beneficial metabolites. microbiome in the metabolism of natural products, microbial
In addition, organ-on-a-chip microphysiological systems metabolism-based screening has not been adopted as part of
(Ashammakhi et al., 2020), gastrointestinal organoids (Singh the drug development process, because its mechanism remains
et al., 2020), and various predictive/computational tools unclear (Zimmermann et al., 2019). Moreover, the great
(Machado et al., 2018; Chowdhury and Fong, 2020) may help plasticity and interindividual differences of gut microbes are
improve our understanding of microbial metabolism in notable (Vujkovic-Cvijin et al., 2020). Therefore, researchers
the future. need to improve the understanding of the physiological,
In addition, the relationships between natural product chemical, and microbial contributions of gut microbes to the
metabolism and gut microbes have been studied in animal metabolism of natural products to help in explaining the
models, and the results can be used to investigate the individual differences in natural product responses and provide
distribution and form of metabolites (Yoshisue et al., 2000). support for personalized treatment (Kolodziejczyk et al., 2019;
Germ-free/antibiotic-treated animals with conventional Javdan et al., 2020). Most of the data in the present study were
animals have been compared to prove the key roles of gut obtained independently of the clinic, but clinical trials are
microbes on natural product metabolism. The limitation of already underway, and the results will influence clinical
this method is that inherent gastrointestinal and practice in the foreseeable future.
microbiological differences exist between humans and Increasing studies on the mechanism of how to exert the
rodents (Nguyen et al., 2015). Detailed microbiota and curative effect, the application of fecal transplantation, specific
metabolite analysis of feces collected from subjects in clinical bacterial transplantation, and animal models will help in
trials can comprehensively reflect the metabolic process of clarifying the role of gut microbes. Nevertheless, standardization
natural products in vivo and be used to explain individual of operation, reproducibility of experimental results, and
differences. In addition, the application of sequencing variation between species and individuals greatly reduce the
technology needs to be increased to study the microbial authenticity and stability of the research, and a standard and
transcriptional activity and metabolic profile. By using the scientific operating procedure remain to be put forward. Thus,
single-cell method, the physiological structure of gut confirming the symbolic functional extremely involved in
microbes can be characterized to determine their metabolic biotransformation and its material basis will help in exploring
activity (Zheng et al., 2022). Metatranscriptomics (RNA-Seq) the mechanism of natural products in the treatment of diseases
allows the direct analysis of gene expression profiles of and explaining the treatment mode of indirect interaction
microorganisms with strong metabolic activity in the human between natural products with low bioavailability and
gut (Berlinberg et al., 2022). The combination of single-cell gut microbiota.

Zhao et al. 10.3389/fmicb.2022.956378
Author contributions Conflict of interest

YZ contributed to the data collection and preparation of the The authors declare that the research was conducted in the
original draft. XZ, JY, and CS provided brief article ideas and absence of any commercial or financial relationships that could
language modifications. XZ and XW supervised and revised the be construed as a potential conflict of interest.
manuscripts. All authors contributed to the article and approved
the submitted version. Publisher’s note
All claims expressed in this article are solely those of the
Funding authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
This work was supported by the National Natural Science reviewers. Any product that may be evaluated in this article, or
Foundation of China under grant no. 81873104, 81830112, claim that may be made by its manufacturer, is not guaranteed or
and 82192914. endorsed by the publisher.
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TYPE Review

PUBLISHED 29 September 2022

Potential roles of gut microbes in

Frontiers in Microbiology 01 frontiersin.org

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TABLE 1 Hydrolysis reaction of gut bacteria to natural products.

Classification Gut microbiota Enzyme Substrate End-product Changes Ref.

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Classification Gut microbiota Enzyme Substrate End-product Changes Ref.

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to exogenous substances by gut microbes requires chemically Lignans

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TABLE 2 Methylation and demethylation reaction of gut microbes to natural products.

Classification Gut microbiota Enzyme Substrate End-product Changes Ref.

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TABLE 3 Reduction and oxidation reaction of gut microbes to natural products.

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demethylation demethylase propionic acid;

Bess et al. (2020)s and Xiao

el-Mekkawy et al. (1993)

The increasing research about gut microbiota gradually

low oral availability of most natural products. Most glycosides

have complex parent structures and are difficult to be absorbed by

the intestine cells, thus limiting their tissue-specific

bio-accessibility. These compounds are transformed into small

molecule metabolites/unique metabolites through degradation

functional metabolites that contribute to host health (Loo

Importantly, the biotransformation by gut microbes

Benzyl ether reductase

tumor, anti-inflammatory, and lipid-lowering effects (Kim

2017); At 20 μM, CK reduces hepatic lipid accumulation in

and foam cell formation via autophagy induction and by

2020). The bioavailability of curcumin metabolites is dependent

on the microbiota dependent (Hassaninasab et al., 2011). For

Human gut microbes

secretion of inflammatory factors and activation of MAPK and

NF-κB pathways (Lu et al., 2022). The chemical stability of

produced by gut microbes from ingested ellagitannins and

ellagic acid, has significant anti-inflammatory and

decreased production of TNF-α and MCP-1 and the

inactivation of TLR3/TRIF signaling in poly (I:C)-induced

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Author contributions Conflict of interest

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