CELLULAR AND INFECTION MICROBIOLOGY
The adult human intestine is home to an
almost inconceivable number of microor-
ganisms. Their population is up to 100 tril-
lion, nearly 10 times larger than the total
number of our somatic and germ cells. All
three domains, including bacteria, archaea,
and eukarya, are contained in the adult
human gastrointestinal (GI) tract and the
bacteria achieve the highest cell densities and
phylogenetic diversities (Whitman et al.,
1998). Such gut microbiome can be viewed as
a microbial organ placed within a host organ
and the genomes of our affiliated microbial
partners (the microbiome) may contain
more than 100 times the number of genes
in our genome. Once established, the indig-
enous microbiota provides many crucial
functions to the host endows us with func-
tional features that we have not had to evolve
ourselves (MacDonald and Monteleone,
2005). These have been reviewed elsewhere
(Ley et al., 2009; Neish, 2009) and include
the contribution to digestion (such as the
ability of microbes to break down host non-
digestible polysaccharides) and its second-
ary benefits (the generation of SCFA), the
metabolism of xenobiotics, the development
of human immune system, and the coloniza-
tion resistance. Generally, a healthy human
state is a homeostasis between the micro-
biota and the host. Maladies such as Crohn’s
disease, chronic periodontitis, and bacterial
vaginosis are characterized by a disruption
of this homeostasis, a state known as dys-
biosis (Tamboli et al., 2004). Meanwhile, the
composition of the intestinal microbiota can
undergo dynamic changes as a result of its
interactions with diet, genotype/epigenetic
composition, and immune-metabolic func-
tion (Kau et al., 2011). We envision a future
in which new therapeutics and diagnostics
enable the management of our microbiota to
treat and prevent disease. Here, the relation-
ship between gut microbiome and diseases
and the effort in adjusting the gut microbi-
ome will be discussed briefly.
use of probiotics, prebiotics, and synbiotics
suggested the potential for controlling these
diseases through manipulation of the com-
position of the gut microbiota, and direct
interactions with the gut immune system
(MacFarlane et al., 2009).
Obesity and type 2 diabetes (T2D), the
most prevalent metabolic diseases world-
wide, are considered to be induced by
impact of the microbiota on our metabolic
health. Turnbaugh et al. (2009) observed
that obesity is associated with phylum-level
changes in the microbiota, reduced bacterial
diversity, and altered representation of bac-
terial genes and metabolic pathways. The
hypothesis is that the microbiota in obese
individuals can harvest the more energy
from food than the one in lean individuals.
And another hypothesis is that gut micro-
biota can modulate plasma LPS levels which
triggers chronic low-grade inflammation
leading to obesity and diabetes (Cani et al.,
2007). Another disease that related with
obese tightly is non-alcoholic fatty liver.
The intestinal microbiota may contribute
to the development of non-alcoholic fatty
liver disease through the complex and coop-
erative activities of two microbe-sensing
protein families, namely nucleotide oli-
gomerization domain receptors (NLRs) and
Toll-like receptors (TLRs; Mukhopadhyay
et al., 2011; Yeretssian, 2012), and through
inflammasomes (Henao-Mejia et al., 2012)
that shape metabolic pathway such as lipid
The gut microbiota has a considerable
impact on the host’s intestinal immunity
and immune responses. Rheumatoid
Arthritis (RA), a systemic autoimmune
disease, is considered to be linked with gut
microbiome. The antibodies to P. gingivalis
have been reported to be more frequent in
RA subjects compared with controls and
that the titer of RA-related autoantibod-
ies and C-reactive protein concentrations
are also higher in individuals infected with
The human GuT microbioTa and
The human gut harbors diverse microbes
that play a fundamental role in the health
of their host. It differs from person to per-
son depending on the unique species of
bacteria accumulated over a lifetime. This
means that every person’s health is dis-
tinctly influenced by the specific byprod-
ucts created by their particular microbiota
(Goodacre, 2007). Microbiome, considered
as our “forgotten organ,” has been studied
by some large-scale international projects
such as HMP (Turnbaugh et al., 2007;
Peterson et al., 2009) and MetaHIT (Qin
et al., 2010). Based on an increasing number
of studies on human microbiome, includ-
ing the microbial community structure and
function (Huttenhower et al., 2012), the
researchers are shifting their concerns to the
role of human microbiota in development
of some acute or chronic diseases, especially
GI Disorder. And the understanding that
pathogenesis of some diseases is associated
with result of complex interactions between
microbiota and host was accepted more and
The most frequently reported disease
that has been proved to associate with
dramatic changes in the gut microbiota
is Inflammatory Bowel Disease (IBD;
Dicksved et al., 2008). MacFarlane et al.
(2009) revealed significant reductions
in Bifidobacterium populations in rectal
biopsies from IBD patients. Zhang et al.
(2007) have shown that bacterial diver-
sity of Lactobacilli varied greatly between
ulcerated tissue and non-ulcerated tissue in
the same UC individuals. The number of
mucosal adherent bacteria, such as invasive
E. coli, Proteobacteria, Enterobacteriaceae are
increased in IBD patients’ gut (Nagalingam
and Lynch, 2012). Despite the involvement of
microorganisms in inflammatory processes,
antibiotic therapy was unsuccessful in IBD.
However, recent studies demonstrated the
Human gut microbiota: dysbiosis and manipulation
Dongqian Shen*, Chuan Liu, Ran Xu and Faxing Zhang
Beijing Genomics Institute-Shenzhen, Shenzhen, China
Lorenza Putignani, Children’s Hospital and Research Institute Bambino Gesù, Italy
Lorenza Putignani, Children’s Hospital and Research Institute Bambino Gesù, Italy
Frontiers in Cellular and Infection Microbiology www.frontiersin.org September 2012 | Volume 2 | Article 123 | 1
published: 27 September 2012
the complex gut composition and its influ-
ence on human health. Several challenges
remain to be overcome in a near future.
Firstly, the list of the diseases that related
to the gut microbiome is just growing and
growing, and these diseases are usually
complex in terms of both pathogenesis
and complication, while sequencing and
computational technologies would be a
bottleneck in large-scale correlation analysis
between the human microbiome and dis-
eases. Secondly, despite a growing number
of researches discovered the relationship
between alterations in the gut microbiome
and diseases, it remains to be established
whether these are causes or effects. Further
studies are required to distinguish disease-
associated changes from a mass of inter-
individual variations that observed in the
microbiome. Thirdly, time-series studies of
individuals to monitor the status alter pro-
cess from health to disease and back to the
health is necessary for exploring the change-
able human microbiome. High-resolution
time-series studies provide a feasibility to
discriminate between “normal” perturba-
tions and pathologic states, and between
organisms that are simply passing through
a body habitat and are entrenched resi-
dents of an ecosystem (Eckburg et al., 2005;
Palmer et al., 2007; Koenig et al., 2011). In
some studies, (Huse et al., 2008; Dethlefsen
and Relman, 2010) rapid decreases in alpha
diversity and a characteristic shift in com-
munity composition were observed in
association with antibiotic therapy, fol-
lowed by a rapid post-antibiotic increase
in diversity as the gut community returned
to a state similar (but not identical) to the
pre-treatment state. Furthermore, despite
a large number of reports have showed the
different gut microbiome between patient
and healthy person, the definition of “the
healthy gut microbiome” remains unclear.
And the methodologies that can change the
unhealthy gut microbiome to a healthy one
are still in investigation.
In terms of its application of human
gut microbiome for human health devel-
opment, we propose to monitor the micro-
biome when being healthy, and to establish
a baseline indicating healthy, with more
intensive monitoring when being sick and
during treatment period. Such method
demands the development of new diag-
nostic tools that are both accurate and suf-
ficiently rapid to inform decisions regarding
microbiome. Modern medicine is struggling
to seek methods of treating these multi-
component diseases. The ancient medical
philosophies and practices of Asia – particu-
larly those of traditional Chinese medicine
(TCM) – can offer an alternative approach.
TCM’s reliance on complex mixtures of
compounds and its philosophy – complete
system needs to be balanced – of treating
the human body, match up well with the
synergistic properties of the gut microbi-
ome (Crow, 2011). In addition, most herbal
medicines are orally administered, which
will result in the unavoidable exposure of
these medicines to the microorganisms in
the gut. During this process, some of them
are selectively metabolized into active or
absorbable components by enzymes derived
from intestinal microbiota. Then the thera-
peutic effects can be achieved.
The Chinese microbiologist Zhao (2012)
adopted a regimen involving Chinese yam
and bitter melon – fermented prebiotic
foods – that are believed to change the
growth of bacteria in the digestive system.
When he adopted the regimen by comb-
ing these prebiotics with diet composed
of whole grains, he lost 20 kg in 2 years.
Furthermore, his blood pressure, heart
rate, and cholesterol level came down as
well. The content of Faecalibacterium praus-
nitzii, a bacterium with anti-inflammatory
properties, increased from an undetectable
level to 14.5 percentage. of his total gut
bacteria. The animal experiments showed
that when rats were given a high fat diet
(HFD) together with berberine, the major
pharmacological component of the Chinese
herb Coptis chinensis or Huanglian, they did
not develop obesity or insulin resistance.
What is more, the populations of known
pathogens decreased while those of known
beneficial bacteria increased in the gut.
Other studies in mice also showed that the
change from a low fat, plant polysaccharide
diet to a western diet high in sugar, and fat
would rapidly and profoundly reconfigure
the composition of microbes in the gut. The
gut microbiota in response to HFD feeding
may allow the host to harvest more energy
from food (Ley et al., 2005; Ley et al., 2006;
Sanderson et al., 2006).
challenGe and ProsPecT
Though the development of human gut
microbiome research burst in the last dec-
ade, we are still unenlightened in facing to
P. gingivalis suggesting that this organism
plays a role in disease risk and progression
in RA (Mikuls et al., 2009). Furthermore,
RA is closely related to periodontal disease.
In a case-control study, serum antibodies
against disease-producing periodontal
bacteria were identified more frequently in
subjects affected by RA and periodontitis
than control subjects (Ogrendik et al., 2005;
Moen et al., 2006).
Commensal gut bacteria are essen-
tial to immune system development, and
exposures disrupting the infant gut micro-
biota have been considered to be linked to
asthma. The western diet has been found
associated with increased risk of asthma for
children (Nagel et al., 2010), and fast food
consumption might counteract the pro-
tective effects of prolonged breastfeeding
(Mai et al., 2009). Following birth, exclu-
sive breastfeeding confers “beneficial” gut
microbiota to infants, including increased
colonization by Bifidobacteria and reduced
prevalence and abundance of C. difficile
compared to formula-fed infants (Penders
et al., 2007; Fallani et al., 2010; Roger and
McCartney, 2010). Infants who are not suf-
ficiently exposed to Bifidobacteria in breast
milk may have inappropriate immune
responses to microbial exposures later
in childhood, leading to atopic disorders
including asthma. Beside of breast milk
and other nutritional supplements, anti-
biotics affecting colonization of the intes-
tinal bacteria by suppressing commensal
bacteria, and causing the emergence of
asthma-associated pathogens such as C. dif-
ficile are the next most commonly ingested
substances by infants. The research shows
that antibiotic use in the immediate period
after birth can severely alter the composi-
tion and population of gut microbiota in
infants (Fallani et al., 2010). Additional, the
perinatal prevention from asthma via the
intestinal microbiome is a relatively new
perspective that has evolved long side mod-
ern technologies for the study of microbial
communities (Azad and Kozyrskyj, 2012).
The Pursue of maniPulaTe The GuT
The increasingly serious chronic health
issues, ranging from obesity and diabetes
to bowel disease and RA, are being demon-
strated to be linked with perturbations in
gut flora. Hence, it is feasible to treat these
complex diseases through adjusting the gut
Shen et al. Human gut microbiome and diseases
Frontiers in Cellular and Infection Microbiology www.frontiersin.org September 2012 | Volume 2 | Article 123 | 2
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published online: 27 September 2012.
Citation: Shen D, Liu C, Xu R and Zhang F (2012) Human
gut microbiota: dysbiosis and manipulation. Front. Cell. Inf.
Microbio. 2:123. doi: 10.3389/fcimb.2012.00123
Copyright © 2012 Shen, Liu, Xu and Zhang. This is an
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