Chinese

Journal of
Natural
Chinese Journal of Natural Medicines 2017, 15(4): 02410254 Medicines

•Review•

Impact of Qi-invigorating traditional Chinese medicines

on intestinal flora: A basis for rational choice of prebiotics
WANG Xiao-Meng, LI Xiao-Bo, PENG Ying*
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
Available online 20 Apr., 2017

[ABSTRACT] According to the theory of traditional Chinese medicine (TCM), Qi (vital energy) is regarded as a driving force of bio-
logical activities in human body, including both nutrient substances and organ functions. Qi-invigorating TCMs are widely used to treat
various symptoms and disorders, such as fatigue, obesity, immunosuppression, intestinal flora imbalance, and gastrointestinal diseases, in
which Qi is considered to be reduced or depleted. Interestingly, abundant clinical evidences suggest that these disorders are associated
with the alternation of intestinal flora, which directly affects disease status. Herein we review the interaction between gut microbiota and
Qi-invigorating TCMs under healthy and disease conditions and discuss the mechanisms of action and applications of Qi-invigorating
TCMs in enhancing health status through microbial alternation. A better understanding of the role of Qi-invigorating TCMs in modulating
microbial composition and the association between intestinal microbiota and diseases would help reveal the clinical consequences of
microbiota alteration and explore opportunities to harness this symbiotic relationship to improve public health.

[KEY WORDS] Gut microbiota; Traditional Chinese medicine; Qi

[CLC Number] Q5; R965 [Document code] A [Article ID] 2095-6975(2017)04-0241-14

Introduction the interaction between gut microbiota and immune system

The adult human gastrointestinal tract is colonized by
about 1014 microorganisms, consisting of at least 160 species
per individual [1] which are dominated by Bacteroides,
Prevotella and Ruminococcus [2]. Amazingly, it is estimated that
the gut microbiota contains 150-fold more genes than the hu-
man genome [3]. Given their vital impact on nutritional,
metabolic, physiological and immunological processes, intes-
tinal flora is also referred to as the ‘‘forgotten organ” [4]. Un-
der normal physiological conditions, those microbes can di-
gest food and harvest energy, prevent pathogens from invad-
ing the organs or tissues, and enhance immunity [5]. It is indi-
cated that the strong evolutionary force has driven the estab-
lishment of intestinal flora as indispensable human symbionts,
because not only its digestive function benefits the human
host, but the microbiota can also take in energy sources to
nourish itself, thereby producing a great variety of metabo-
lites with potential impacts on human health [4]. Additionally,
[Received on] 21-May-2016
[Research funding] This work was supported by the National Natural
Science Foundation of China (Nos. 30973962 and 81473318).
[*Corresponding author] E-mail: ypeng@sjtu.edu.cn
These authors have no conflicts of interest to declare.
Published by Elsevier B.V. All rights reserved
contributes to the maintenance of normal immune functions
as well as maturation of immune cells [1]. However, the im-
balance in the composition of intestinal flora will interrupt the
normal interaction with human host, thus leading to diseases
[5]
. Many diseases are observed to be associated with gut mi-
crobiota disorder, including inflammatory bowel disease
(IBD), Crohn’s disease, gastric cancer, allergy, type 2 diabetes,
obesity, and autism [6]. The involvement of gut microbiota in
pathophysiology of human diseases has aroused great interest
and has been intensively studied in recent years.
Traditional Chinese medicine (TCM), also known as
Chinese materia medica, is one of the oldest medicine prac-
tices in human history. The essence of TCM is the “Yin/Yang
Theory” (a philosophical concept that views the universe as
a result of two opposing but interacting principles), which is
extensively applied to the clinical diagnosis and treatments. In
general, Yin represents the “female” or negative features
while Yang represents the “male” or positive ones. Yin and
Yang are complementary, exchangeable, and interdepend-
ent. According to the TCM theory, if the Yin/Yang balance
of a human body is broken, in other words, deficiency
occurs in Yin or Yang, the individual will become sick or
turn into a sub-healthy status. Qi (vital energy) and Xue
(blood) are two fundamental substances supporting daily

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activities, according to the TCM theory. Qi is generated
when Yin and Yang interact with each other. Referring to
the nutritive and refined substances flowing in the body as
well as the functional status of tissues and organs, Qi
represents longevity and its depletion is linked to death [7].
The deprivation of Qi can be caused by many factors such
as malnutrition, aging, fatigue, chronic diseases and
long-term surgery, leading to symptoms such as cough,
dizziness, diarrhea, pale complexion, short breath, muscle
weakness, obesity, and immune-deficiency.
In TCM practice, tonic herbs, along with a few animal
sourced medicines (e.g., deer blood), are used for strengthen-
ing the body and curing diseases caused by Qi deficiency.
Some tonic herbs, such as the Dioscoreae Rhizoma (yam), are
also common in Chinese diet. In fact, food therapy has earned
its reputation throughout history by its function and conven-
ience of use. Based on their uses, tonic medicines are classi-
fied into four categories: Qi-invigorating, Xue-enriching,
Yin-nourishing, and Yang-promoting. Typical Qi-invigorating
herbs include Astragali Radix, Ginseng Radix et Rhizoma
(ginseng), yam, Codonopsis, Coicis Semen, Atractylodis
Macrocephalae Rhizoma, Glycyrrhizae Radix et Rhizoma (lico-
rice), and Schisandra Chinensis Fructus, and exemplary
Qi-invigorating multi-ingredient decoctions (called Tang in
Chinese) include “Dai-Kenchu-To”, “Sijunzi Tang”, “Lizhong
Tang”, “Buzhong Yiqi Tang”, and “Shenlingbaizhu San”.
In clinical practice, TCMs are usually made into decoc-
tions by boiling the herbs in water, according to a particular
weight proportion of active ingredients. Qi-invigorating
TCMs are mostly relevant to intestinal flora because they are
often administrated orally used to treat diseases with gut mi-
crobial dysbiosis [8]. Since those TCMs inevitably interact
with gut microbiota when passing through the gastrointestinal
tract, many researchers have investigated metabolites of
Qi-invigorating TCMs by intestinal flora and realized that
indeed these metabolites have important pharmacological
activities and play various roles in the disease treatment [8].
On the other hand, Qi-invigorating TCMs also have an impact
on the quantity or abundance of gut microbiota [9].
In this article, we will briefly review the interaction be-
tween gut microbiota and Qi-invigorating TCMs from two
aspects: the metabolism of Qi-invigorating TCM by intestinal
flora and the change of local microflora after TCM treatment.
The mechanisms by which Qi-invigorating TCMs enhance
health status through microbial alternation are also discussed.
A better understanding of gut microbiota changes before and
after receiving Qi-invigorating TCMs would be helpful to
elucidate the mechanism of action for tonic drugs and provide
guidance for drug design, including decoction formation and
dosage form.
Metabolism of Qi-invigorating TCM by gut mi-
crobiota
An interesting phenomenon noticed by many researchers
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in the last century is that a lot of herbs or their ingredients
with strong activities in vivo do not show significant pharma-
cological activities in vitro [10]. It is quite clear now that the
gut microbiota is crucial for treatment outcome and metabo-
lism of herbs by gut microbiota is an integrant part of drug
biotransformation. A considerable proportion of orally ad-
ministered herbal preparations are transformed by intestinal
flora to their corresponding metabolites, some of which are
bioactive metabolites, before being absorbed in the gastroin-
testinal tract [9-12]. For example, the major ginsenosides (gin-
senosides Rb1, Rb2, and Rc) from ginseng are metabolized to
20-O-β-D-glucopyranosyl-20(S)- protopanaxadiol, named com-
pound K (CK), which exhibits anti-allergic, anti-inflammatory,
and antitumor activities more potently than the parental gin-
senoside Rb1, suggesting that CK is responsible for the
pharmacological effects observed for orally administered
ginseng [9]. Astragaloside IV (AST) is a constituent of Astra-
gali Radix that shows poor bioavailability in vivo. However,
the gut microbiota can transform AST into cycloastragenol, a
highly bioavailable triterpenoid sapogenin that has significant
telomerase activating and antioxidant activities, making it an
ideal functional food and anti-aging drug [10]. Glycyrrhizin,
which also has the same problem of low bioavailability, can
be metabolized by intestinal flora into glycyrrhetinic acid that
is easily absorbed [11]. Liquiritin, another main component in
glycyrrhiza, can be metabolized by hydrolysis, hydrogenation,
methylation, deoxygenation and acetylation under microbiota
metabolism, with the major pathway being the conversion of
liquiritigenin [12].
Alternation of gut microbiota after treatment
with Qi-invigorating TCMs
Impact of Qi-invigorating herbs on gut microbiota
The interaction between Qi-invigorating TCMs and
gut microbiota has been highlighted by pharmacognostic
scientists. As mentioned above, intestinal flora is involved in
the absorption and transformation of TCMs, and the latter
can influence the activity and composition of gut micro-
biome through affecting the growth and abundance of spe-
cific bacteria. The variations in bacteria affected by
Qi-invigorating TCMs have been observed in many studies
with either in vitro culture [8, 16, 25-26] or gut microbiota
from mammals [13-15, 17-24, 27-30] . In general, Qi-invigorating
TCMs are able to promote the growth of probiotic bacteria
or/and inhibit pathogen colonization in the intestines, im-
proving health, and therefore are considered as prebiotics.
Exemplary changes in gut microbiota by Qi-invigorating
herbs are listed in Table 1.
For example, yam, an extensively cultivated food in Asia,
is used in treating diarrhea, diabetes, anorexia, spermatorrhea,
and leukorrhagia [8]. An early research has demonstrated that
a great deal of lactose-fermenting bacteria is found in feces of
rats fed with Chinese yam extract, suggesting that yam could
induce or convert some intestinal flora into health benefiting
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Table 1 Impact of Qi-invigorating herbs on gut microbiome

Herb Formation Experimental subject Change of gut microbiome Refence
Dioscoreae Rhi- Yam polysaccharide Strains cultivated by culture Bifidobacteria↑ Lactobacilli↑ [8]
zoma (yam) medium Escherichia coli↓ Enterococcus faecalis↓
Yam ethanol extract Pathogen-free male Sprague- Lactobacillus plantarum-Enterobacter [13]
Dawley rats, strains cultivated cloacae-Bacteroides fragilis↓
by culture medium The intestinal floral mix shifted toward lactose-
fermenting bacteria after a 6-Week-diet featuring
2% Chinese yam extract.
Yam powder BALB/c mice Total bacteria concentrations↑ Bifidobacteria↑ [14]
Clostridium perfringens↓
Glycyrrhizae Radix Liquiritin Healthy human Enterobacter↓ Enterococcous↓ Clostridium↓ [12]
et Rhizoma (lico- Bacteroides↓ Lactobacilli & Bifidobacteria: not
rice) much affected
Panax ginseng Panax ginseng extracts Obese (body mass index (BMI) The dominant genera switched from Blautia, [31]
≥ 25 kg·m2) Korean women Bifidobacterium, and Anaerostipes to
aged 40−60 Bifidobacterium, Blautia, and
Faecalibacterium. Significant abundance
change was observed only in Anaerostipes.
Korean ginseng White Korean ginseng Male Sprague-Dawley rats Total bacteria↑ Lactobacillus↑ [15]
powder (WG), red Korean
ginseng powder (RG)
Red ginseng Red ginseng leaching Male Wistar rats with ulcerative In vitro: Bifidobacterium animalis↑ [17]
liquor colitis caused by trinitro- Bifidobacterium longum↑ Lactobacillus
benzene-sulfonic acid, rhamnosum↑ Escherichia coli↓ Staphylococcus
strains cultivated by culture aureus↓ Salmonella spp.↓
medium In vivo: Bifidobacterium↓ Lactobaccillus↑
Escherichia coli↓
Red ginseng leaching Strains cultivated by culture In vitro: Bifidobacterium↑ Lactobacillus [16]
liquor medium rhamnosum↑ Salmonella↓ Escherichia coli↓
Male Wistar rats with ulcerative In vivo: Lactobacillus↑ Escherichia coli↓
colitis caused by trinitro-
benzene-sulfonic acid (TNBS)
Coicis Semen Coicis Semen leaching Male Wistar rats with ulcerative In vitro: Bifidobacterium animalis, [17]
liquor colitis caused by trinitro- Bifidobacterium longum, Lactobacillus
benzene-sulfonic acid/ethanol, rhamnosum, Salmonella spp., Escherichia coli:
strains cultivated by culture depend on dosage.
medium Staphylococcus aureus↑
In vivo: Lactobaccillus↑ Escherichia coli↑
Atractylodis Mac- Unfermented Atractylodis Male, high-fat diet induced obese UAMR & FAMR: Bifidobacterium↑ [21]
rocephalae Rhi- Macrocephalae Rhizoma Sprague-Dawley rats Akkermansia↑ Bacteriodetes/Firmicutes ratio↑
zoma (AMR) (UAMR), Lactobacillus FAMR: Bacteriodetes↑ Lactobacillus↑
plantarum fermented
Atractylodis Macrocephalae
Rhizoma (FAMR)
Atractylodis Macrocepha- Male KM mice Bifidobacterium↑ Lactobacillus↑ Enterobacter↓ [22]
lae Rhizoma Enterococcus-
powder
Atractylodis Macrocepha- Male Sprague-Dawley rats with The intestinal flora presented a certain degree of [23]
lae Rhizoma intestinal flora disorder caused by recovery in each treatment group.
polysaccharide Cassia angustifolia,
Astragali Radix Astragali Radix leaching Strains cultivated by culture Bifidobacterium longum↑ [25]
liquor medium, Mice Bifidobacterium bifidus↑
Escherichia coli: first week↑ 2nd-4th week↓
Schisandra Schisandra Chinensis Strains cultivated by culture Bacillus proteus↑ Escherichia coli↑ Shigella [26]
Chinensis Fructus Fructus leaching liquor medium flexneri↑
Schisandra Chinensis Wistar rats with cirrhosis Enterococcus↑ Enterobacteria↑ [27]
Fructus powder Bacteroides↑ Bifidobacterium↑
Lactobacillus↑
Codonopsis Radix Codonopsis Radix BALB/c mice Bifidobacterium-, Lactobacillus↑ Escherichia [30]
powder coli↓ Enterococcous-
Codonopsis Radix KM mice with intestinal flora In vitro: Bifidobacteria↑ Escherichia coli: no [29]
polysaccharide disorder caused by lincomycin significant change
hydrochloride, In vivo: Bacillus bifidus↑ Bacillus acidi lactici↑
strains cultivated by culture medium Enterococcus↓ Enteric bacilli↓

bacteria [13]. Subsequent experiments have proven that fecal of these effects might be exerted by yam polysaccharides,
total bacteria and Bifidobacteria concentrations are increased which has been observed to promote Bifidobacteria and Lac-
significantly, while Clostridium perfringens concentrations are tobacilli, while inhibiting Escherichia coli and Enterococcus
decreased significantly in mice receiving yam diets [14]. Some faecalis in vitro [8]. Yam’s soluble dietary fibers, including ara-

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binogalactans, konjacglucomannan, and guar gum, have also
been demonstrated to act like prebiotic viscous dietary fi-
bers [14].
Licorice is widely used as sweetening, flavoring and
foaming agents in tobacco, candy, and food industries in
Western countries [12]. It is one of the oldest and most fre-
quently prescribed tonic TCMs for effects of neuroprotection,
detoxification, and tumor-suppression. Liquiritin, one of the
major phenolics, is clinically beneficial as it provides anti-
oxidant, anti-inflammatory, antiviral, antidiabetic, antithrom-
botic, and neuroprotective activities. In addition, liquiritin is
likely to benefit the host by inhibiting the growth of patho-
gens, such as Clostridium and Bacteroides, regulating com-
mensal bacteria such as Enterobacter and Enterococcus, and
stimulating probiotics such as Lactobacillus and Bifidobacte-
ria; and it could therefore be considered as a prebiotic [12].
Ginseng has the history of being a popular tonic for at
least 1 000 years in Asia. The effects of ginseng on inflamma-
tion, obesity, cancer, and metabolic diseases such as diabetes,
hypertension, and hyperlipidemia have been widely observed
[15]
. It has been reported that ginseng can stimulate Lactoba-
cillus in vitro and in both healthy and ulcerative colitis (UC)
rats. Escherichia coli is suppressed by ginseng in vitro and in
UC rats. Moreover, ginseng can promote the growth of
Bifidobacterium and inhibit pathogens such as Staphylococcus
aureus and Salmonella in vitro [15-17]. Coicis Semen, the herb
used in the treatment of micturition difficulty [18], neuropathic
pain [19], functional dysmenorrhea [20]. And diarrhea, can also
stimulate Lactobacillus proliferation significantly in vivo,
although the relative abundance of Escherichia coli increases
simultaneously [16].
Atractylodis Macrocephalae Rhizoma (AMR) is used as
digestive, diuretic and antihidrotic agent in eastern Asia. Bi-
fidobacterium is found to be enhanced by AMR in healthy
mice [22] and obese rats [21]. Besides, AMR can promote Lac-
tobacillus and repress Enterobacter in healthy mice [22]. In
obese rats, AMR has displayed promoting effects on Akker-
mansia abundance and the ratio of Bacteriodetes/ Firmicutes
[21-22]
. Moreover, polysaccharides of AMR are shown to
intensify the ability of intestinal flora to digest reducing
sugar in rats with microbiota dysbiosis, indicating a recov-
ery of the gut microbial community by TCM treatments [23].
Astragali Radix, which possesses hepatoprotective and
anticancer functions [24], can increase Bifidobacterium longum
and Bifidobacterium bifidus in vitro. Bifidobacterium promo-
tion by Astragali Radix has also been observed in vivo, along
with suppression of Escherichia coli [25]. For treating gastro-
intestinal diseases as well as asthma and gonorrhea, Schisan-
dra chinensis can increase not only Escherichia coli and
Shigella flexneri in vitro [26], but also Enterococcus, Entero-
bacteria, Bacteroides, Bifidobacterium and Lactobacillus in rats
with cirrhosis [27]. Codonopsis Radix is used for improving
gastrointestinal function, decreasing blood pressure, and
strengthening the immune system [28]. It has been found that
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Codonopsis Radix can promote Lactobacillus and suppress
Escherichia coli in normal mice. In mice with intestinal flora
disorder, Bacillus bifidus and Bacillus acidi lactici are pro-
moted by Codonopsis Radix, whereas Enterococcus and En-
teric bacilli are restrained [29-30].
Impact of Qi-invigorating decoctions on gut microbiota
Due to the synergetic effect of multiple components in
TCM decoction, many Qi-invigorating decoctions have
stronger treatment effects than single herb [7]. Actually, most
hospitals specialized in TCM usually prescribe decoctions to
patients rather than single herb. It is common that specific
herb composition and proportion may be different for the
same prescription name, owing to the genuineness of regional
drugs and the prescription habits of individual hospitals. The
influence of decoctions on gut microbiota has been widely
observed in many animal disease models, and the results are
listed in Table 2. For example, Dai-Kenchu-To (DKT) is used
for treatment of adhesive bowel obstruction and cold feeling
in the abdomen. With ginseng as a cardinal remedium, DKT
is revealed to prevent the reduction of microbiome diversity
in rat’s fast stress model, suggesting a new anti-inflammatory
mechanism of DKT through intestinal flora [32].
A lot of Qi-invigorating decoctions can be used to cure diar-
rhea and gastroenteritis, including Qiweibaizhu San, Jianpiy-
ichang Tang, Jianpishenshi Tang, Changfukang Tang,
Shenlinbaizhu San, Sijunzi Tang, Lizhong Tang, Buzhongyiqi
Tang, and Qihuang Oral Liquid. Using ginseng as principal
composition, Qiweibaizhu San has enhancing effects on lactic
acid bacteria [33], making it especially helpful for treatment of
UC and antibiotic-associated diarrhea. Jianpishenshi Tang can
restore gut microbiome to normal condition in the elderly
with intestinal flora disturbance [34] and promote Lactobacil-
lus and Bifidobacteria in both spleen-deficient patients and
patients with colorectal cancer. In spleen-deficient patients,
Jianpishenshi Tang has inhibitory effects on Enterobacteriaceae
and Enterococcus [35-36]. Changfukang Tang can enhance Lac-
tobacillus and Bifidobacteria in patients with chronic diarrhea
[37]
. Shenlinbaizhu San recovers gut microbiota diversity in
UC rats [38] and the proportion of bacilli and cocci in patients
with intestinal flora disorder [39]. In spleen-deficient mice,
Shenlinbaizhu San can stimulate the proliferation of Lactoba-
cillus, Bifidobacteria, and Bacteroides, and suppress Es-
cherichia coli and Enterococcus [46]. It is reported that Sijunzi
Tang can recover gut microbiota diversity in
spleen-deficiency animal models [40-41]. These controversial
and contradictory results in bacterial variation induced by
Sijunzi Tang are discussed in later sessions.
Used for curing gastroenteritis, both Buzhongyiqi Tang
and Lizhong Tang can recover the diversity of gut microbiota
in rats with Qi-deficiency [42], while Buzhongyiqi Tang can
promote Lactobacillus, Bifidobacterium, Enterococcus and
Bacillus subtilis in mice with intestinal flora disorder [43].
Other indications of Buzhongyiqi Tang include bacillary dys-
entery, archoptosis and descensus uteri, and Lizhong Tang has
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Table 2 Impact of Qi-invigorating decoctions on gut microbiome

Decoction Formation Experimental subject Change of gut microbiome Reference
Dai-Kenchu-To Ginseng Radix et Rhizoma, Zanthoxyli fruc- Male Wister rats received fast DKT maintained the diversity of [32]
(DKT) tus and Zingiberis Recens Rhizome in the stress microbiome lost from fast stress.
ratio of 3 : 2 : 5
Qiweibaizhu San Ginseng Radix et Rhizoma, Aucklandiae Mice with intestinal flora disorder Total bacteria↑ Yeast↑ Mildew↓ [33]
Radix, Poria, fried Atractylodis Macrocephalae caused by mixture of lincomycin Colibacillus↑ Lactic acid
Rhizoma, agastache leaf, Puerariae lobatae hydrochloride, cefradine and bacteria↑ Bifidobacteria↑
Radix and Glycyrrhizae Radix et Rhizoma in ampicillin sodium
the ratio of 6 : 6 : 10 : 10 : 10 : 10 : 3
Jianpiyichang Ginseng Radix et Rhizoma, Atractylodis The elderly with intestinal flora There were more patients whose [34]
Tang Macrocephalae Rhizoma, Dioscoreae Rhizoma, disorder gram-positive cocci, gram-
Nelumbinis Semen, Amomi Fructus, Poria, negative cocci, gram-positive
Astragali Radix, Cimicifugae Rhizoma, bacillus, and gram-negative
Scutellariae Radix, Coptidis Rhizoma, Citri bacillus recovered to normal
Reticulatae Pericarpium, Coicis Semen, and range in TCM group than
Glycyrrhizae Radix et Rhizoma in the ratio of control group and showed
5 : 4 : 4 : 4 : 5 : 4 : 10 : 4 : 4 : 4 : 4 : 5 : 3 significant difference.
Jianpishenshi Codonopsis Radix, Atractylodis Macrocephalae Spleen-deficiency patients Enterobacter↓ Enterococcus↑ [35]
Tang Rhizoma, Poria, Glycyrrhizae Radix et Rhi- Lactobacillus↑ Bifidobacteria↑
zoma, Dioscoreae Rhizoma, Lablab Semen
Album, Nelumbinis Semen, Coicis Semen,
Amomi Fructus, Schisandra Chinensis Fructus
and Platycodonis Radix in the ratio of 6 : 4 :
4:4:4:3:2:4:2:3:2
Codonopsis Radix, Atractylodis Macrocephalae Large intestine cancer patients Lactobacillus↑ Bifidobacteria↑ [36]
Rhizoma, Poria, Glycyrrhizae Radix et Rhizoma,
Dioscoreae Rhizoma, Lablab Semen Album,
Nelumbinis Semen, Coicis Semen, Amomi
Fructus, Schisandra Chinensis Fructus and
Platycodonis Radix in the ratio of 6 : 4 : 4 :
4:4:3:2:4:2:3:2
Changfukang Codonopsis Radix, deep-fried Atractylodis Chronic diarrhea patients due to Lactobacillus↑ Bifidobacteria↑ [37]
Tang Macrocephalae Rhizoma, Magnoliae Officinalis intestinal flora disorder
Cortex, Coicis Semen, Dioscoreae Rhizoma,
Poria, Polyporus, Plantaginis Semen, Setariae
Fructus Germinatus, Hordei Fructus Germinatus,
Granati Pericarpium, Portulacae Herba and
Glycyrrhizae Radix et Rhizoma in the ratio of
12 : 15 : 10 : 30 : 30 : 15 : 12 : 15 : 15 : 15 :
15 : 20 : 3
Shenlinbaizhu Not listed in paper KM mice with spleen-deficiency Lactobacillus↑ Bifidobacteria↑ [46]
San caused by Rhei Radix et Bacteroides↑ Escherichia coli↓
Rhizoma Enterococcus↓ Staphylococcus-
Ginseng Radix et Rhizoma, Atractylodis Wistar rats with ulcerative colitis Enterobacterial Repetitive [38]
Macrocephalae Rhizoma, Poria, Lablab Se- caused by trinitro-benzene- Intergenic Consensus-PCR
men Album, Nelumbinis Semen, Dioscoreae sulfonic acid/ethanol (ERIC-PCR) indicated that UC
Rhizoma, Amomi Fructus, Coicis Semen, rats had less intestinal flora
Platycodonis Radix, Glycyrrhizae Radix et diversity than normal rats.
Rhizoma, and Citri Reticulatae Pericarpium After the rats were given
in the ratio of 5 : 5 : 5 : 4 : 3 : 5 : 2 : 3 : 2 : 3 : Shenlinbaizhu San, their
3 intestinal flora diversity
increased.
Codonopsis Radix, Atractylodis Macrocephalae Patients with intestinal flora The proportion of bacilli and [39]
Rhizoma, Poria, Lablab Semen Album, Ne- disorder cocci in stool of patients
lumbinis Semen, Dioscoreae Rhizoma, recovered after treatment.
Amomi Fructus, Coicis Semen, Platycodonis
Radix and honey-fried Glycyrrhizae Radix et
Rhizoma in the ratio of 20 : 15 : 15 : 10 : 10 :
10 : 10 : 10 : 10 : 6
Sijunzi Tang Ginseng Radix et Rhizoma, Atractylodis Wistar rats with spleen- ERIC-PCR indicated that after [40]
Macrocephalae Rhizoma, Poria and Glycyrrhizae deficiency caused by Sennae treatment, the diversity of intes-
Radix et Rhizoma in the ratio of 10 : 9 : 9 : 6 Folium or Rhei Radix et tinal flora in rats increased sig-
Rhizoma nificantly.
Ginseng Radix et Rhizoma, Atractylodis Rats with spleen-deficiency Sijunzi Tang improved the di- [41]
Macrocephalae Rhizoma, Poria and honey- caused by reserpine versity of intestinal flora in
fried Glycyrrhizae Radix et Rhizoma in the diarrhea rats.
ratio of 3 : 3 : 3 : 2 Lactobacillus↑ Enterococcus↑
Ginseng Radix et Rhizoma, Atractylodis KM mice injected with D- Escherichia coli↓ Enterococcus↓ [47]
Macrocephalae Rhizoma, Poria and galactose to cause aging model Lactobacillus↑ Bifidobacteria↑
Glycyrrhizae Radix et Rhizoma

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Continued
Decoction Formation Experimental subject Change of gut microbiome Reference

Traditional decoction and nano-TCM: Gin- KM mice with intestinal flora Lactobacillus↑ Bifidobacteria↑ [48]
seng Radix et Rhizoma, Atractylodis Macro- disorder caused by lincomycin Enterococcus↓
cephalae Rhizoma, Poria and hydrochloride Nano-TCM had better effect and
Glycyrrhizae Radix et Rhizoma less dosage required compared
with the traditional liquid extract
of Sijunzi Tang.
Modified Sijunzi Tang: Codonopsis Radix, Male Sprague-Dawley rats with Bifidobacteria↑ Escherichia [49]
Atractylodis Macrocephalae Rhizoma, spleen-deficiency caused by Rhei coli↓
Poria, Glycyrrhizae Radix et Rhizoma, Radix et Rhizoma and rifampicin
Hericium erinaceus, Citri Reticulatae
Pericarpium and xylo-oligosaccharide in
the ratio of 6 : 3 : 3 : 1 : 2 : 1 : 2
Polysaccharide of Sijunzi Tang: Codonopsis Male BALB/c mice with spleen- B/E (the ratio of [50]
Radix, Atractylodis Macrocephalae Rhizoma, deficiency caused by Sennae Bifidobacterium and
Poria and Glycyrrhizae Radix et Rhizoma Folium and irregular diets Escherichia coli)↑
Buzhongyiqi Tang Astragali Radix, Ginseng Radix et Rhizoma, KM mice with intestinal flora Lactobacillus↑ Bifidobacte- [43]
Angelicae Sinensis Radix, Atractylodis disorder caused by lincomycin rium↑ Enterococcus↑ Bacillus
Macrocephalae Rhizoma, honey-fried hydrochloride and ampicillin subtilis↑
Glycyrrhizae Radix et Rhizoma, Bupleuri sodium
Radix, Cimicifugae Rhizoma and Citri
Reticulatae Pericarpium
Astragali Radix, Ginseng Radix et Rhizoma, Wister rats with spleen Qi- ERIC-PCR indicated that after [42]
Angelicae Sinensis Radix, Atractylodis deficiency caused by irregular treatment, the diversity of intes-
Macrocephalae Rhizoma, honey-fried diets and exercise fatigue tinal flora in rats increased sig-
Glycyrrhizae Radix et Rhizoma, Bupleuri nificantly.
Radix, Cimicifugae Rhizoma and Citri
Reticulatae Pericarpium in the ratio of
6:1:1:1:3:2:2:2
Lizhong Tang Codonopsis Radix, Atractylodis Wister rats with spleen Qi- ERIC-PCR indicated that after [42]
Macrocephalae Rhizoma, Zingiberis deficiency caused by irregular treatment, the diversity of intes-
Rhizoma and honey-fried Glycyrrhizae diets and exercise fatigue tinal flora in rats increased sig-
Radix et Rhizoma in the ratio of 1 : 1 : 1 : 1 nificantly.
Qihuang Oral Cooked Rhei Radix et Rhizoma, Astragali Liver cirrhosis patients Escherichia coli↓ [45]
Liquid Radix and Aucklandiae Radix in the ratio of Enterococcus↓ Bifidobacterium↑
5:9:4 Lactobacillus↑ Bacteroidetes↑

optimistic curative effects in treatment of hepatitis [42]. An-
other prescription that has similar clinical indication to
Lizhong Tang in diarrhea and liver diseases is Qihuang Oral
Liquid, which can be used to treat autoimmune diseases such
as systemic lupus erythematosus (SLE) as well [44]. The oral
liquid is reported to promote Bifidobacterium, Lactobacillus
and Bacteroidetes and suppress Escherichia coli and Entero-
coccus in patients with liver cirrhosis [44]. The stimulation of
probiotics and decrease in the intestinal endotoxin may reduce
liver damage and improve patient’s condition [45].
Mechanism of Qi-invigorating TCMs on gut microbiota
The results shown in Tables 1 and 2 have demonstrated
that most Qi-invigorating TCMs have promoting effects
on probiotic intestinal bacteria like Lactobacilli and
Bifidobacterium. Increases in Lactobacilli and Bifidobacterium
have been shown to maintain intestinal health through many
ways, such as reducing acids production which raises fecal
pH, suppressing pathogenic bacteria like Clostridium per-
fringens, promoting bowel movement, decreasing ammonia,
skatoles, and harmful amine procarcinogens formation in the
large intestine [51], adsorbing carcinogenic materials, improv-
ing intestinal epithelial cell defense integrity, competitively
inhibiting other pathogens, and preventing carcino-
gen-induced intestinal tumors [14]. Oligosaccharides and
polysaccharides are major bioactive ingredients that distribute
abundantly in Qi-invigorating herbs. Famous as prebiotics,
bioactive oligosaccharides or polysaccharides from various
plants such as soybeans [52], cereal [53], and citrus [54] are re-
ported to selectively stimulate the growth of lactic acid
bacteria, making scientists hypothesize that the oligosaccha-
rides and polysaccharides in Qi-invigorating TCM are also
the active components to enhance probiotic bacterial growth.
Further investigations are required to demonstrate the as-
sumption and find out which specific oligosaccharide or
polysaccharide is responsible for the probiotics promoting
effect.
Some opportunistic gut pathogens can be suppressed by
Qi-invigorating TCMs such as Bacteroides, Clostridium, En-
terococcus, and Enterobacteriaceae. Bacteroides species
benefit human host by limiting the colonization of potential
pathogens in gut under normal conditions. But some Bacter-
oides species are conditionally pathogenic bacteria. For ex-
ample, Bacteroides fragilis is resistant to β-lactam antibiotics
and can cause infections under peritoneal cavity, bowel

– 246 –
 WANG Xiao-Meng, et al. / Chin J Nat Med, 2017, 15(4): 241254
surgery, appendicitis and other conditions, through the forma-
tion of abscess and inhibition of phagocytosis [55]. It is re-
ported that the growth of Bacteroides fragilis is significantly
retarded by the addition of yam [13]. Clostridium species in-
clude free-living bacteria as well as human pathogens. Clos-
tridium perfringens can cause a wide range of symptoms from
food poisoning, gas gangrene, to enterotoxemia [56]. It is
known that the increased levels of Bacteroides and Clostrid-
ium are markers for high colon cancer risks [57], suggesting the
inhibition of Bacteroides and Clostridium by yam and
liquiritin may lower the risk of colon cancer. Enterococcus, a
kind of conditional pathogenic bacteria, can cause severe
clinical infections, including urinary tract infections and bac-
teremia [58]. Yam, licorice, Codonopsis Radix, Qihuang Oral
Liquid, and Shenlinbaizhu San all show suppressing effects on
Enterococcus. The Enterobacteriaceaes are a large family
including common pathogens such as Salmonella, Es-
cherichia coli, and Enterobacter. Red ginseng shows inhibi-
tory effects on Staphylococcus aureus and Salmonella species
in vitro. Enterobacter can be suppressed by liquitin in healthy
human and decreased in spleen-deficient patients following
the treatment of Jianpishenshi Tang. Escherichia coli can be
suppressed by various Qi-invigorating TCMs such as yam,
licorice, red ginseng, Qihuang Oral Liquid, Shenlinbaizhu
San, and Sijunzi Tang. Since Staphylococcus aureus, Salmo-
nella, and Escherichia coli are human pathogens frequently
involved in foodborne illness [59] which have been reported to
develop certain level of intrinsic antibiotic resistances, the
discoveries of antibiotic properties of Qi-invigorating TCMs
on these pathogens are of great interest in the light of the
ongoing threat of bacterial resistance to conventional antibi-
otics.
Application of Qi-invigorating TCMs
The human intestinal micro-organism community is a
highly dynamic ecosystem. Many physical, chemical, and
biological factors can lead to disturbance in gut microbiota
and various diseases. Dietary change, aging, medication, and
surgery influence the composition of gut microbiota in re-
versible ways. The specific modulation of Qi-invigorating
TCMs on intestinal flora grants them great values for both
medical applications and dietary supplies. They have now
been used in many aspects, which are discussed in the fol-
lowing sections.
Qi-invigorating TCMs and antibiotics
Antibiotics are widely used in public health, livestock
cultivation, and agriculture to treat bacterial infections. How-
ever, these drugs have been found to alter the genomic, taxo-
nomic, and functional capacity of human intestinal flora, with
rapid or even persistent effects [60]. In addition, clinical uses
of broad-spectrum antibiotics reduce gut microbiota diversity,
increase chances for horizontal gene transfer, and enable in-
trusion of pathogens through depletion of natural niches [60].
For example, lincomycin treated mice have shown distur-
– 247 –
bance in intestinal flora, severe damage to the intestinal mu-
cosa, and bacterial translocation to liver [29, 33, 43].
Qi-invigorating TCMs such as Sijunzi Tang, Qiweibaizhu San,
and Buzhongyiqi Tang, can be used to adjust such intestinal
flora imbalance caused by antibiotic treatment [33, 43, 48]. Si-
junzi Tang can promote probiotics such as Lactobacillus and
Bifidobacteria, suppress the growth of Enterococcus, acceler-
ate the recovery of intestinal mucosa, and reduce liver bacte-
rial dislocation [48]. Mice with intestinal flora disorder caused
by a mixture of lincomycin hydrochloride, cefradine, and
ampicillin sodium and treated with Qiweibaizhu San are ob-
served with a significant increase in Bifidobacteria, lactic
acid bacteria, and total gut bacteria and yeast [33]. The amount
of mildew decreases in gut and Escherichia coli is restored to
normal level [33]. Buzhongyiqi Tang shows enhancing effects
on Lactobacillus, Bifidobacterium, Enterococcus, and Bacil-
lus subtilis in mice with intestinal flora dysbiosis induced by
lincomycin hydrochloride and ampicillin sodium [43]. The
injury of intestinal mucosa in model mice can be healed, and
goblet cells are increased [43]. Generally speaking, Qi-invigorating
TCMs may be a practical strategy in prevention of antibiotics
associated bowel injuries and disturbances of the intestinal
homeostasis [61].
Qi-invigorating TCMs and aging
Age-related intestinal flora alterations are associated with
immunosenescence and inflammageing. Gut microbiota im-
balances could be seen as either the causes or the conse-
quences of the inflammageing process. It is generally consid-
ered that an increase in facultative anaerobes and Gram-
negative bacteria (mainly Enterobacter) and a decrease in
beneficial bacteria such as Lactobacillus and Bifidobacterium
together mark a prominent characteristic of gut microbiota in
the elderly [62]. The consumption of Qi-invigorating TCMs
may help to prevent or treat age-related pathophysiological
conditions, such as immune dysfunctions, constipation, and
Clostridium difficile related diarrhea [34, 47]. Many Qi-invigorating
TCMs can stimulate the growth of probiotics including Lactoba-
cillus and Bifidobacterium [8, 17, 21-22, 27, 33, 35-37, 43, 45-48]. These pro-
biotics are involved in counteracting inflammation such as
improvement of colonic mucosa conditions and
down-regulation of inflammation related genes, and are be-
lieved to have the potentiality to promote longevity [62]. The
number of Lactobacillus and Bifidobacterium species isolated
from centenarians is reported to be similar to younger adults,
with the presence of Bifidobacterium longum as particular
feature in centenarians [63], indicating a vital role of probi-
otic bacteria in longevity. These results are consistent with
the anti-aging effect of Sijunzi Tang by adjusting intestinal
flora of mice, which revives Maleic Dialdehyde (MDA)
and Superoxide Dismutase (SOD) level of serum at the
same time [47].
Qi-invigorating TCMs and immune system
Human host and its gut microbiota have developed com-
plex inter-relationships throughout evolution. One important
 WANG Xiao-Meng, et al. / Chin J Nat Med, 2017, 15(4): 241254
approach to understanding the role of gut microbiota in im-
mune system is the use of germ-free animals. Raised in com-
pletely sterile environment and colonized with human intesti-
nal bacteria, these axenic animals have been widely used as
models that can provide information on how the intestinal
flora is involved in health and disease [64]. It is now accepted
that microbes regulate the function and development of the
mucosal immune system to avoid being attacked by the host’s
immune system, creating a symbiosis between microflora and
human host. Meanwhile, gut microbiota is protecting the host
from infection. The metabolites of microbes such as
short-chain fatty acids (SCFA) promote the epithelia barrier
function [65] and the production of antimicrobial molecules
like Regenerating gene Ⅲβ (REGⅢβ) and Regenerating
gene Ⅲγ (REGⅢγ) [66]. The intestinal flora affects the im-
mune homeostasis through not only regulating local intestinal
immune system, but also influencing host’s systemic immune
responses [5].
Cytokines
Although few researches have focused on the effects of
tonic TCMs on the interaction between immune system and
gut microbiota, lots of independent studies have confirmed
that Qi-invigorating TCMs can enhance immunity [50, 67-70].
For example, Atractylodis Macrocephalae Rhizoma can sup-
press the secretion of IL-6 [67]. Shenlinbaizhu San shows
downregulating effects on the expression of TNF-α, IL-1β,
and IL-6 [68]. Astragali Radix is reported to reduce IL-6 and
TNF-α in rats with acute renal ischemia-reperfusion [69].
These findings are consistent with the physiologic function of
probiotic bacterial stains, suggesting a correlation between the
therapeutic effect of TCM on immune system and its regula-
tion on gut microbiota. In a recent study of Sijunzi Tang,
polysaccharide of Sijunzi Tang can increase the B/E of
spleen-deficient mice after TCM treatment, increase the thy-
mus index, Peyer’s patches and intestinal sIgA, upregulate the
proliferation ability of lymphocyte in mesenteric lymph nodes
and spleen, and recover the ratio of peripheral blood leuko-
cyte and T/B lymphocyte in lymphoglandulae mesentericae
[50]
. Since microbiota affects the development and function of
IgA-secreting plasma cells and natural killer cells (NK cells)
[70]
, it is hypothesized that Sijunzi Tang can improve the im-
munity by reviving the intestinal microbial community. Fur-
ther researches and more evidence are needed to explain the
role of gut microbial change in improving immune status after
TCM treatment.
Gastrointestinal mucosa
Contributed to large amounts of mucin, the gastrointesti-
nal mucosal layer plays a key role in protecting mucosal cells
from harmful substances such as pathogenic bacteria. It also
participates in epithelial hydration and immune response [71].
Diet habits or diseases can affect the mucosal layer, including
the quantity of mucin-producing goblet cells and mucin gene
expression [72-73]. Thirteen mucin genes expressed in the gas-
trointestinal tract have been described so far [72]. The major
– 248 –
intestinal mucin in rats is Muc2, a gel-forming mucin pro-
duced by goblet cells [74]. It is found that the Muc2 mRNA
expression can be significantly elevated by white ginseng
diets [15]. The mRNA expression of another mem-
brane-encoding associated mucin, Muc4, is also increased
upon ginseng consumption, although the result is not statisti-
cally significant [15]. The change in mucin gene expression
may be induced by the increased beneficial bacterial strains
with the help of tonic TCMs [15]. Probiotics such as Bifido-
bacterium, Lactobacillus, and Streptococcus have been shown
to raise the luminal mucin protein content as well as mucin
gene expression [74]. Correlation analyses have shown that
expression of the Muc2 gene is significantly correlated with
the number of Lactobacillus and total bacteria [74]. And Muc4
gene expression is correlated with the amount of digesta
mucin protein [74]. The relationship among curative effects
of Qi-invigorating TCMs, gut microbiota variation and
regulation of mucin gene expression still needs further
investigation.
Other TCMs also show trophic effects on the restoration
of gastrointestinal mucosa integrity. Yam is reported to in-
crease short-chain fatty acids (SCFAs) output and thicken the
mucosa lining of caecum in mice [14]. Secreted by anaerobic
gut bacteria after glycolysis, SCFAs are crucial for maintain-
ing the morphology and function of colonic mucosal cells,
and suppressing pro-inflammatory cytokines, colitis, and
tumor proliferation [75]. Butyrate, one of SCFAs which is pro-
duced mainly by Firmicutes [76], can promote Lactobacillus
proliferation and repress the growth of Escherichia coli [77].
Recent metabonomic studies have detected SCFAs and other
gut microbiota derived metabolites in the systemic circulation,
and confirmed that these molecules constituted part of the
neurohumoral communication axes, which link the gut with
other organs such as the liver and the brain [78].
Qi-invigorating TCMs and diseases
Many diseases are associated with intestinal flora disor-
ders, and recently extensive studies are investigating whether
the intestinal flora disorders are the causes or the conse-
quences of the diseases [5-6]. These diseases include inflam-
matory bowel disease (IBD), irritable bowel syndrome, colon
cancer, liver diseases (e.g., liver cirrhosis, chronic hepatitis,
and fatty liver), obesity, diabetes, multiple organ failure, and
mental disorders such as depression and autism [5-6]. A lot of
Qi-invigorating TCMs are used to treat above diseases and
regulate the intestinal flora simultaneously, which may be
conducive to the remission [16-17, 21, 27, 31-32, 35-38, 40-41, 46]. Char-
acterizing the nature of gut microbial dysbiosis and mecha-
nisms of immune response to gut-derived factors is poten-
tially helpful for the development of alternative therapies for
diseases.
Liver diseases
The intestinal flora is closely linked to liver diseases. The
liver receives 70% of blood supply from the gut via the portal
vein, making it continually exposed to gut-derived factors
 WANG Xiao-Meng, et al. / Chin J Nat Med, 2017, 15(4): 241254
including bacteria, endotoxins (flagellin, lipoteichoic acid and
lipopolysaccharide) and peptidoglycans [79]. Animal experi-
ments and human studies have indicated that intestinal bacte-
rial products like endotoxin mediate inflammation and serve
as cofactors for the development of alcohol-related liver in-
jury [80]. The serum endotoxin levels are elevated in rats and
humans with alcoholic liver disease, and monocytes from
alcoholics are primed to produce cytokines after endotoxin
exposure [80]. Schisandra Chinensis Fructus shows modulation
on gut microbiota in cirrhosis rats induced by ethanol and
relieve cirrhosis symptoms [27]. Qihuang Oral Liquid can in-
crease gut anaerobes and lower the production and absorption
of enterogenic endotoxin, hence reducing serum endotoxin
level and improving liver damage in hepatitis B cirrhosis
patients [45]. This effect may be associated with stimulation of
probiotics which have shown promising results in ameliorat-
ing liver injury by reducing bacterial translocation and hepatic
inflammation [81].
Impaired intestinal motility and small intestine bacterial
overgrowth (SIBO)
One of the gastrointestinal indications of Qi-invigorating
TCMs is the impaired intestinal motility, which is often ac-
companied with small intestine bacterial overgrowth (SIBO),
and the lattercan lead to microflora disturbance, and is in-
ferred to be caused by the delayed orocecal transit time [82].
Yam is reported to increase gastrointestinal motility and fa-
cilitate intestinal digestion [13]. Schisandra Chinensis Fructus
(SCF) extracts could modulate pacemaker potentials in the
interstitial cells of Cajal (ICCs) in murine small intestine
through external and internal Ca2+ regulations, and via G pro-
tein and the phospholipase C (PLC) pathway [83]. The intesti-
nal transit rate is elevated by SCF extracts and the GI motility
dysfunctions are recovered [83]. Another decoction, Dai- Ken-
chu-To, also shows acceleration on the transit of gastrointes-
tinal contents [32].
Inflammatory bowel disease (IBD)
Crohn’s disease and ulcerative colitis are collectively
known as inflammatory bowel disease (IBD), a chronic and
relapsing inflammatory disorder of gut. Despite that the pre-
cise cause of IBD remains unknown, the most accepted hy-
pothesis of IBD etiology is the aberrant immune response
against intestinal flora triggered by environmental factors in a
genetically susceptible host [84]. The global composition of
intestinal flora rather than one single pathogen appears to be
more relevant for the pathogenesis of the inflammatory bowel
disease. Alteration of the microbiome in mucosal inflamma-
tion reflects a metabolic imbalance of the complex microbiota
system and severe consequences for mucosal barrier, rather
than broken defense to single microorganism [85-86]. Patients
with diarrhea or inflammatory diseases often show a higher
inter individual variability in microbiome. Microbiota diver-
sity of control group with non-inflammation has been found
higher than that of Crohn’s disease and ulcerative colitis pa-
tients, indicating that the bacterial diversity reduction is a
– 249 –
specific disease feature of IBD [87]. Therapies correcting dys-
biosis, including probiotics and fecal microbiota transplanta-
tion, produce positive outcomes in IBD treatments [84]. Red
ginseng, Coicis Semen, Dai-Kenchu-To, and Shenlinbaizhu
San can relieve the symptoms of ulcerative colitis, probably
because they are able to restore the diversity of gut microbiota
and promote the growth of probiotics [17, 32, 38].
Spleen deficiency
Spleen deficiency is a TCM concept which refers to a
type of major chronic digestive system disease. The “spleen”
here does not refer to the entitative organ located in abdomi-
nal cavity, but means the overall function of all key organs.
Therefore spleen deficiency is somewhat equivalent to Qi
deficiency, for they both represent a dysfunction status of
body. Qi-invigorating TCMs are also able to treat spleen defi-
ciency diseases. Typical spleen deficiency syndromes include
anorexia, abdominal distension, emaciation, and diarrhea,
which occur in various diseases like gastritis, IBD, dysentery,
metropathia hemorrhagica and nephritis [88]. Using modern
diagnostic techniques, pathological changes of spleen defi-
ciency are found to be correlated with abnormal gastrointes-
tinal motility and damaged gastrointestinal mucosa, including
decreased goblet cells, shorter and sparser intestinal villi [89].
The immune system can also be affected by spleen deficiency.
Spleen deficient mice are observed with diminished organ
index of spleen and thymus [90], fewer Peyer’s patch [91], re-
duction of NK cells, weakened engulfment function of
macrophage, slower proliferation of T lymphocyte and B
lymphocyte [92], and decreased T lymphocyte subgroups [93-94].
Spleen deficient rats have more peripheral blood leucocytes
and neutrophile granulocytes, fewer lymphocytes and distin-
guished levels of serum IL-1, IL-2, IL-6, and tumor necrosis
factors (TNFs), compared to normal rats [95]. In summary,
spleen deficiency has impacts on both specific and
non-specific immune responses. The composition and quan-
tity of gut microbiota also change when spleen deficiency,
partially because the faster small intestine propelling rate
would cause diarrhea, and take away bowel resident micro-
biome, which makes it more vulnerable to external patho-
genic bacteria easier invasion [88]. The notable decrease in
anaerobia and increase in aerobia is a feature of intestinal
bacteria disturbance in spleen deficiency [46]. Qi-invigorating
TCMs can improve spleen deficiency through immunor-
egulation, microbial re-composition, and gut function res-
toration [35, 40-42, 46, 49-50].
Animal models are often used to study the therapeutic
effects and mechanisms of Qi-invigorating TCMs on spleen
deficiency. Methods used to induce spleen deficiency include
drugs, physical approaches such as irregular diets, certain
food, over-exercise, damp living environment, and a combi-
nation of the above [35, 40-42, 46, 49-50]. However, it is interesting
that spleen deficiency animal models induced by different
methods will have differences in the intestinal bacterial varia-
tions [35, 40-42, 46, 49-50]. A decrease in both Lactobacillus and Bifi-
 WANG Xiao-Meng, et al. / Chin J Nat Med, 2017, 15(4): 241254
dobacterium in the gut is observed in spleen deficiency ani-
mals induced by Rhei Radix et Rhizoma [46], but induction by
Sennae Folium raises Lactobacillus and Bifidobacterium
abundance [50]. This may be related to the different mecha-
nisms of TCMs in vivo. More interestingly, several inde-
pendent studies have shown different results when using Si-
junzi Tang to treat spleen deficiency animals [40-42]. The
amount of Lactobacillus and Bifidobacterium in spleen defi-
ciency animals induced by Rhei Radix et Rhizoma is increase
after Sijunzi Decotion treatment, but falls down when Sennae
Folium is used for induction, indicating that certain TCM
might have two-way regulation effects [40].
Obesity
Though various Qi-invigorating TCMs (e.g., ginseng [31],
yam [14], glycyrrhizin of licorice [96], and Atractylodis Macro-
cephalae Rhizoma [21]) can be used to reduce body weight, it
is interesting that the reported anti-obesity efficacy varies
from person to person. Modern medical studies have found
that the oral administration of ginseng does not change the
body weight of healthy animals [97], but has other effects on
obese individuals. In a Korean study, Panax ginseng exert a
weight loss effect in all obese Korean women volunteers, but
the extent varies, depending on the composition of gut micro-
biota prior to ginseng administration [31]. Significant differ-
ences in gut microbiota between the responding and
non-responding groups are observed at both phyla and genera
level [31]. Another example is Herba ephedrae. Since obesity
is highly related with the imbalance of intestinal flora, me-
diating through accelerated energy harvest from food, pro-
motion of fat deposition, and induction of systematic in-
flammation [98-99], scientists have speculated that the
anti-obesity effect of Herba ephedrae is achieved by modula-
tion of gut microbiota [100], suggesting that the weight-loss
effect of Qi-invigorating TCMs might work in a similar way.
Other uses
Some Qi-invigorating herbs are both medicinal and edi-
ble, such as yam, ginseng, and Coicis Semen, etc. Yam is
considered as a useful digestive-aid agent because of its sup-
pression on gastric acid secretion and promotion on gastroin-
testinal motility as well as fecal quantities [13]. In addition,
under yam diets, fecal total bacteria concentrations are in-
crease significantly [14] and the intestinal flora mix shifts to
lactose-fermenting bacteria [13], indicating that yam can not
only improve digestive capability, but also alter the flora to-
ward a more beneficial bacterial composition. Additional
evidence also confirms that yam can stimulate the growth of
“helpful” microflora like Bifidobacteria and Lactobacillus,
and suppress pathogenic bacteria like Escherichia coli, En-
terococcus faecalis, and Clostridium perfringens [8, 14]. Gin-
seng has long been employed as a popular tonic agent and gift
in eastern culture. In the past, it was a precious tribute to the
emperor. In addition to prescription uses, ginseng is also con-
sumed in making tea or chicken soup as daily diet. These
recipes are all similar to decoction preparation, that is, by
– 250 –
boiling ginseng in hot water, when the bioactive polysaccha-
rides can be effectively extracted [101]. Licorice is a favorable
food additive, owing to its sweet taste, while raw licorice is
made as candy for children in northern China. Considering
their digest-aiding and weight-reducing effects, people suf-
fering from gastrointestinal malfunctions or obesity may
benefit from taking those foods as daily diets.
According to the Technical Specification for Inspection
and Evaluation of Health Food promulgated by State Food
and Drug Administration of China in 2003, many
Qi-invigorating herbs are qualified for health food or func-
tional food production because of their regulation on four
types of intestinal bacteria: Bifidobacterium, Lactobacillus, En-
terococcous, and Enterobacteriaceae. Astragali Radix and
ginseng are the most frequently used materials in health food
production, followed by yam, Schisandra Chinensis Fructus,
Codonopsis Radix, licorice and Atractylodis Macrocephalae
Rhizoma [102]. The results summarized in Tables 1 and 2
demonstrate the effects of TCMs on stimulation of the growth
of beneficial microbiome and suppression of pathogen, sug-
gesting that more Qi-invigorating TCMs could be enrolled
into the functional food industry.
Moreover, the discovery of promoting effects on probiot-
ics (such as Bifidobacterium, and Lactobacillus) by
Qi-invigorating TCMs has inspired their new applications:
proliferation factors for microbial cultivation. Yam can sig-
nificantly enhance the growth of Bifidobacterium adolescentis
when added into culture media [103]. Proliferation of both Bi-
fidobacterium longum and Bifidobacterium bifidus can be
boosted by culture media containing Astragali Radix [25]. Coi-
cis Semen and red ginseng media can promote Bifidobacte-
rium animalis, Bifidobacterium longum, and Lactobaccillus
rhamnosum. While red ginseng suppresses Staphylococcus
aureus, Salmonella, and Escherichia coli, Coicis Semen can
promote their growth at low dose but show inhibitory effects
at high dose [17]. In general, Qi-invigorating TCMs are appro-
priate for culture medium optimization because they are
commonly used as additives in food industry, familiar to the
public, and have competitive low costs.
Conclusions
The gut microbiota is a complex ecosystem which pro-
vides essential functions, including carbohydrate metabolism,
interaction with immune system, and prevention against
pathogen invasion. Various tonifying Qi-invigorating TCMs
are used to cure bowel diseases, treat intestinal flora disorder,
enhance immunity, control weight, relieve fatigue, and pro-
long lifespan either as clinical medications or daily diets.
Viewing from the studies published so far, it is inferred that
Qi-invigorating TCMs can exert above effects through inter-
acting with microbial community, since they are orally taken
and metabolized in the gastrointestinal tract where the com-
position of microbiota will change at the same time. Their
regulations on intestinal flora also suggest new choices for
 WANG Xiao-Meng, et al. / Chin J Nat Med, 2017, 15(4): 241254
prebiotics as alternative therapies. Large-scale sequencing
projects, such as the Human Microbiome Project, Human
Food Project, and the American Gut Project, will ultimately
be critical for providing a universal view of the association
between microbiota and human health, which can also pro-
vide valuable information for research about TCM effects
on intestinal flora. A combination of gnotobiotic, me-
tabolomic, metagenomic, and immunohistochemical experi-
ments is required to advance the understanding of this intri-
cate relationship in the future.
Acknowledgements
We thank LU Yuan of Shanghai Jiao Tong University for
editing the manuscript and former and current members of our
lab for their contributions to this work.
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Cite this article as: WANG Xiao-Meng, LI Xiao-Bo, PENG Ying. Impact of Qi-invigorating traditional Chinese medicines on intestinal flora: a
new choice for prebiotics [J]. Chin J Nat Med, 2017, 15(4): 241-254.

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