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290

Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, 14, 290-299

Structure and Functions of the Gut Microbiome

Suchita Panda1, Francisco Guarner1,2 and Chaysavanh Manichanh1,2,*
1

Digestive System Research Unit, Vall dHebron Research Institute, Barcelona, Spain; 2Centro de Investigacin
Biomdica en Red en el rea temtica de Enfermedades Hepticas y Digestivas (CIBERehd), Instituto de Salud Carlos
III, Madrid, Spain
Abstract: Over the last decade our understanding of human gut microbiology underwent a tremendous transformation.
The limitations of culture-based methods have given way to Next Generation Sequencing techniques, allowing us to
understand the microbial gut community in greater depth. The human GI-tract harbours one of the most complex and
abundant ecosystems colonized by more than 100 trillion microorganisms, among which Firmicutes and Bacteroidetes are
the major phyla. Although stable over long periods, the composition and functions of the microbiome may be influenced
by a number of factors including genetics, mode of delivery, age, diet, geographic location and medical treatments.
Dysbiosis, changes in microbiome structure, has been linked to inflammatory, functional and metabolic disorders such as
IBD, IBS and obesity. However, it is still not clear whether these changes are a contributing factor or a result of the
disease. This synopsis provides a chronological overview of the techniques used to study the gut microbiota and the
current knowledge with respect to the stability and variability of microbiome composition and functions.

Keywords: 16S rRNA, composition, diversity, gastrointestinal tract, human gut microbiota, metagenomics, microbiome,
sequencing.
INTRODUCTION
METHODS EMPLOYED TO STUDY THE GUT
MICROBIOTA
Classical Approaches
A complex assemblage of microorganisms, including
eukaryotes, archaea, bacteria, and viruses, colonizes the
human gastrointestinal tract (GI-tract) [1, 2]. Together, these
microorganisms are known as the gut microbiota, and they
outnumber human eukaryotic cells. Traditionally, studies
addressing microbiota were done using culture methods [3,
4]. These techniques rely on the biochemical and physical
capacity of the organism of interest to grow and multiply in
either liquid or solid medium infused with nutrients. Given
that various microorganisms show exceptional growth under
the nutrient, temperature and humidity conditions provided,
this culture procedure has remained a standard method for
microbial studies. However, in the 1990s, new techniques
demonstrated that culture was not able to detect most of the
microorganisms present in the GI-tract [5-10]. To overcome
this limitation, culture-independent approaches were developed,
including dot-blot hybridization, quantitative PCR amplification
(qPCR), Temperature Gradient Gel Electrophoresis (TGGE)
and Denaturing Gradient Gel Electrophoresis (DGGE),
Fluorescence In-Situ Hybridization (FISH) techniques, and
microarrays.
In dot-blot hybridization, the nucleic acids are blotted
onto a membrane, where the hybridization is performed with
*Address correspondence to this author at the Digestive System Research
Unit, Vall dHebron Institut de Recerca, Ciberehd, 08035 Barcelona, Spain;
Tel: +34 934894036; Fax: +34 934894032; E-mail: cmanicha@gmail.com
2212-3873/14 $58.00+.00

universal or specific oligonucleotide probes to semi-quantify

sequences present in a sample [11-13]. Amplification
methods such as qPCR are used to detect and quantify a
target DNA sequence using a small amount (as small as 10
pg/l DNA) of sample and specific or universal primers as
probes [14-16]. TGGE and DGGE have the capacity to
separate DNA fragments of the same length but with
different sequences, and they are useful to broadly compare
diversity between microbial communities [7, 17-22]. FISH is
used to detect DNA sequences inside microbial cells. It
involves fluorescently labeled probes, thus enabling the
identification and enumeration of specific microbial groups
within a sample [5, 7, 23-26]. Microarrays involve hybridization
between nucleic acids (the target) to various oligonucleotide
probes attached to a solid support. This approach allows the
detection of target sequences present in a sample. It is also
used to uncover variations in the sequence or expression of a
gene [16, 27-36]. The Human Intestinal Tract Chip microarray
(HITChip) is a phylogenetic microarray that contains a
duplicate set of probes based on 16S ribosomal RNA (16S
rRNA) gene sequences covering more than 1,100 intestinal
bacterial phylotypes, as proposed by Rajili-Stojanovi [37].
This assay has been and continues to be extensively used for
studying microbiota [38-41].
Revolution from Sanger Sequencing
Generation Sequencing Techniques

and

Next-

The study of the microbial ecosystem of the GI-tract

changed dramatically upon the introduction of sequencing
technologies. The sequence of nucleotides from different
organisms or microorganisms can be used to identify a
specific organism and its functions in a community sample.
2014 Bentham Science Publishers

Human Gut Microbiome

Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 4

Developed by Frederick Sanger and colleagues in 1977

[42], Sanger DNA sequencing is based on the selective
incorporation of chain-terminating dideoxynucleotides
(ddNTPs) by DNA polymerase and primers during DNA
replication. Sequence data are then analysed through various
informatics tools based on ecological laws. To analyze
microbial composition, the Sanger method involves either
PCR amplification or cloning of each microbial fragment
into a vector before its sequencing. This method is laborious
and expensive compared to Next-generation sequencing
techniques (NGS) such as 454 pyrosequencing and Illumina
sequencing.
NGS arrived with the technology of pyrosequencing
developed by Mostafa Ronaghi and Pl Nyrn in 1998 [43,
44] and was later commercialized by 454 Life Sciences
(Roche). This sequencing technique relies on the detection of
pyrophosphate release upon nucleotide incorporation through
emission of light. The use of universal primers amplifying
various regions of the 16S rRNA gene (phylogenetic marker)
in long reads ensures the specificity required to match the
generated sequences against DNA databases. This method
has been used in more than 4000 studies (as searched in
PubMed during the time of writing). NGS offers a great
advantage over the Sanger technique in that multiple samples
(up to several hundreds) [45] can be processed in a
single sequencing run using barcoded primers. To date,
pyrosequencing allows up to 1 million simultaneous
sequence reads of 450700 bp (454 FLX XL+).

291

When the microbe of interest cannot be isolated, then

shotgun sequencing of the genomic DNA from all organisms
in an environmental sample is applied. An example of such a
sample is faeces, in this case, DNA is extracted and purified
from the samples and then processed for shotgun sequencing.
Bioinformatics tools are then used to assemble and overlap
the reads, which are compared to relevant databases.
Exploited in several recent metagenomic studies, this method
has allowed a comprehensive description of the microbial
gene content of the GI-tract in health and in disease [58-60].
Future Directions

Developed in 2008, Illumina (Solexa) is another highthroughput sequencing technology [46]. This technique is
based on reversible dye-terminator technology and engineered
polymerases, and it uses massive parallel sequencing
technology generating "DNA Clusters". This technology
currently allows 4000 million simultaneous sequence reads
of 300600 bp (Illumina HiSeq 2500).

Although still in their early days, metatranscriptomics,

metaproteomics, and metabolomics are considered to be the
analytical tools of the future. Metatranscriptomics is the
study of the expression of genes found in total extracted
RNA/mRNA of a sample. cDNA is synthesized from RNA
and sequenced. This technique presents additional technical
challenges (depletion of over 90% of ribosomal RNA), but
has already been used to describe faecal communities in
samples from healthy individuals and from patients, where
the former were found to have highly divergent expression
profiles that fluctuated over time [61]. Perez-Cobas et al.,
using metatranscriptomic methods, demonstrated that
antibiotics alter interactions between the gut microbial
community and host metabolism [62]. Metaproteomics, an
emerging field of study devoted to community proteins, has
shown that the proteins involved in translation, energy
production, and carbohydrate metabolism are produced in
part by the gut microbiome [63]. Recently applied to patients
suffering from Crohns disease, metabolomics has revealed
pathways differentiating them from healthy subjects, including
pathways involved in the metabolism and/or synthesis of
amino acids, fatty acids, bile acids, and arachidonic acid
[64]. A summary of the methods used is provided in Table 1.

16S rRNA Gene Survey Versus Shotgun Sequencing

HUMAN GUT MICROBIOME

The 16S ribosomal RNA (16S rRNA) is a component

of the 30S small subunit of prokaryotic ribosomes, and its
gene is highly conserved in 10 regions among different
species of bacteria and archaea, while in 9 others it is
variable [47-49]. Due to these unique properties, the 16S
rRNA gene is used as the basis for evolutionary comparisons
in community cloning-sequencing and NGS sequencing
studies [8, 45].

Structure

In whole genome shotgun sequencing, microbial genomic

DNA from an isolated microorganism is broken up randomly
into numerous small segments of a given range (40007000bp). Multiple overlapping reads for the target DNA are
then obtained by performing several rounds of this
fragmentation and sequencing. Using assembly methods, the
overlapping ends of reads are reconstructed into a continuous
sequence. Pair-wise end sequencing, also known as doublebarrel shotgun sequencing, augmented the application of this
technique, which was used for studying whole genomes such
as those of Haemophilus influenzae in 1995 [50], Drosophila
melanogaster (fruit fly) in 2000 [51] and also the human
genome in 2003 [52, 53]. This method continues to be
widely used for this purpose [54-57].

The human gut microbial community is composed of 1013

to 1014 microbes, and their total genome (microbiome)
contains greater than 100 times more genes than the human
genome [66, 67]. Due to its high complexity two international
consortiums, the Metagenomics of the Human Intestinal
Tract (MetaHIT) [58], in Europe, and the Human Microbiome
Project (HMP) [68], in the US, were launched initially in
2008 to provide a comprehensive characterization of the
structure of the microbiome.

Jo Handelsman first used the term "metagenomics" after

cloning and sequencing genomic fragments from the
microbial community of soil samples [65]. The term
metagenomics and 16S rRNA studies have since been used
interchangeably in many fields of research, including gastrointestinal microbiota studies.

A foetus is believed to be sterile, but upon delivery the

infant is exposed for the first time to a wide array of
microbes from a variety of sources, including maternal
bacteria [69]. The microbiome of the infant differs depending
upon the type of delivery, the presence of vagina-dominating

292 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 4

Table 1.

Panda et al.

Methods used to study the human gut microbiome.

Method

Material Used

Experimental Design

Type of Result

References

Culture

Tissue/
environmental sample

Diluted sample incubated in enriching medium

followed by microscopy/ biochemical analysis

Physical/ biochemical details of

different microbes

[3,4]

Dot-Blot hybridisation

DNA extracted from

sample

DNA blotted in a membrane which is subjected to

hybridisation with oligonucleotides

Semi-quantification and detection of

certain sequences in sample

[11-13]

qPCR

DNA extracted from

sample

Amplification of sequences using

specific dye-labelled primers

Quantification as either an absolute

number of copies or a relative amount
when normalized to DNA input

[14-16]

DGGE

Total environmental
DNA extracted from
sample

PCR amplification of 16S rRNA (prokaryotic) or 18S

rRNA (eukaryotic) gene from total extracted DNA.
Amplicons are then subjected to changing chemical
denaturing conditions in a gel. DNA strands denature
completely within the gel depending on the sequence
composition, which are visualised as bands.

Possibility to discern differences in

DNA sequences and similarity
comparison giving an estimate of
microbial richness

[17-19, 21]

TGGE

Total environmental
DNA extracted from
sample

PCR amplification of 16S rRNA (prokaryotic) or 18S

rRNA (eukaryotic) gene from total extracted DNA.
Temperature gradient used to separate amplicon bands
in a gel depending on sequence content
(GC vs. AT content).

Gel band patterns used to visualize

variations in microbial genetic diversity
and provide a rough estimate of the
richness of predominant microbial
community members

[7, 20-22]

FISH

DNA in tissues

Use of fluorescent probes to bind to DNA targets (in

tissues) showing high degree of sequence
complementarity after which fluorescence microscopy
is used to locate the bound probes in tissues

Fluorescence probe hybridisation

coupled with fluorescence microscopy
enables the identification and
enumeration of specific microbial
groups within a sample

[5, 7, 19, 23,

24-26]

Microarray

Total environmental
DNA extracted from
sample

A solid substrate (chip) contains embedded labelled

specific DNA sequences (probe) to which sample DNA
(target) is added. Complementary strands undergo
hybridisation that is detected and quantified to
determine relative abundance of nucleic acid
sequences in the target

Detection and measurement of specific

sequences present in sample

[16, 27-41]

Metagenomics

Total environmental
DNA extracted from
sample

Microbial genomic DNA is broken up randomly into

numerous small segments that are then sequenced.
Bioinformatic assembly methods are used to reconstruct
overlapping ends of reads into a continuous sequence
that are compared to databases.

Comprehensive description of the

microbial gene content

[54-60, 62,
79, 91, 101,
106, 123]

16S rRNA gene

survey

Total environmental
DNA extracted from
sample

PCR amplification of 16S rRNA (prokaryotic) gene

from total extracted DNA. Amplicons are then
sequenced, and compared to 16S rRNA gene databases

Composition and diversity of microbial

groups present in a sample based on the
16S rRNA gene

[62, 67, 70,

72, 73, 76-87,
92, 100, 103107, 126]

Metatranscriptomics

Total environmental
RNA / mRNA
extracted from
sample

Synthesis and further sequencing of cDNA from total

RNA or mRNA (after rRNA removal from total RNA).
Bioinformatic assembly methods are then used to
reconstruct the sequences which are then
compared to databases

Gene expression and functions carried

out by microbes present in the sample

[61, 62, 106,

126]

Metaproteomics

Total environmental
proteins isolated from
sample

Gel-based and non gel-based chromatography based

separation of proteins with a further step of mass
spectrometry based peptide identification

Quantitation of protein expression,

protein structure information

[62, 63]

Total environmental
metabolites extracted
from sample

Liquid / gas chromatography coupled to mass

spectrometry. Metabolite identification and further
pathway detection

Analyses of interactions and functions

using molecular metabolic pathways

Metabolomics

[62, 64]

Human Gut Microbiome

Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 4

bacteria upon natural birth and dominance of skinharbouring bacteria upon C-section delivery [70]. Apart from
the delivery mode, feeding methods and even country of
birth influence the faecal microbiome of infants [69, 71, 72].
Firmicutes is dominant in the neonate gut microbiome after
birth but is replaced by Bacteroidetes upon the intake of
formula food. By the age of 3, the gut microbial diversity is
comparable to that of an adult [73]. The microbiome of
children becomes more complex with age [74].
The human gut microbiome comprises four dominant phyla:
Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria.
In addition, Fusobacteria, and Verrucomicrobia could also be
detected [67]. The most dominant phyla are Firmicutes and
Bacteroidetes, which make up more than 90% of the total
bacterial population [58, 67, 75-77]. The composition of the
intestinal microbes (as provided by 16S rRNA gene survey)
varies between intestinal sites in the same individual and also
among individuals [8, 67]. While the microbiome is shared
among family members, each persons gut microbial
community varies, through time and diet [59, 78, 79]. Deep
metagenomic sequencing allowed the MetaHIT consortium
to explore the possibility of the presence of a common set of
microorganisms called the core microbiome. Using shotgun
sequencing and a 90% identity threshold, 13 species were
found to be common in more than 90% of individuals and 35
species in more than 50% [58]. From another perspective, the
HMP consortium estimated that the total human microbiome
contained between 3,500 and 35,000 Operational Taxonomic
Units (OTUs). Several signatures at the genus level were
observed across nearly all individuals, but specific taxa were
highly variable and almost never universal [59].
Modulation of the Microbial Composition
The composition of the gut microbiota is influenced by
several known factors, such as genetics, mode of delivery
[70], age [73, 74, 80, 81], geographical location [71, 82, 83],
lifestyle (diet or smoking) [83-88] and medical treatments
[89], and a number of as yet unknown ones.
Western or rural diet has been shown to affect the
structure of the gut microbiota [90, 91]. In this regard, diets
containing mostly protein and animal fat lead to the
dominance of Bacteroidetes, while long-term diets rich in
carbohydrates favor mainly Firmicutes [85]. Studies
performed on adult human gut microbiomes of lean and
obese mono- and dizygotic twins showed that despite having
common microbial species, they presented different
phenotypes, suggesting that host genetics might not be the
only cause of obesity [79]. These results were also confirmed
in animal models [62, 78, 92].
The microbiota of elderly people displays greater interindividual variation than that of younger adults [81]. Also,
there is greater similarity of faecal microbiota among family
members than with non-members [82, 83].
Recently, many diseasesdigestive and non-digestive
have been associated with dysbiosis or alterations in
microbial communities. Whether the diseases themselves
alter the community or vice versa is still speculative, but an
association between dysbiosis and certain conditions has

293

been found. Inflammatory Bowel Diseases (IBDs) [93-95]

such as Crohns Disease [96-98] and Ulcerative Colitis [99],
Intestinal Bowel Syndrome (IBS) [100], and diabetes [101]
have been associated with a decrease in the diversity of the
intestinal microbial community.
Antibiotics are commonly prescribed to treat infections.
However, depending on the type of antibiotics and the route
of administration, this treatment can have an immediate or
even a long-term effect on the composition of the gut
microbial community. Studies have shown that resilience is
not complete months after cessation of an antibiotic
treatment [102-106]. Apart from the change in diversity,
microbial load, as an immediate effect of antibiotic use, does
not decrease, as would be expected, but instead tends to
increase [107].
More modern treatments, including prebiotics and
probiotics, have shown potential to transiently modulate the
gut microbial composition. Probiotics are defined as live
microorganisms which when administered in adequate
amounts confer a health benefit on the host [108] and are
generally marketed as functional foods or dietary supplements.
Commonly used probiotics include Lactobacillus and
Bifidobacterium species [89], and mixtures of various strains
from these genera are also being used. [109-111]. Due to the
low probability of the probiotic bacteria to survive the
journey till the intestines, a significant change in the
microbial composition is in debate [112]. However, a study
of infants showed that feeding with Lactobacillus promoted
other known probiotic species "characteristic of communities
that are more resistant to perturbation and outgrowth of
pathogens" [113]. Furthermore, animal model studies [111]
and clinical trials with probiotics, cited above, have been
carried out [114, 115] and have shown to be beneficial to
alleviate symptoms of IBS [114-116]. Recently, it has been
speculated that probiotics need not be live microorganisms;
their cellular components, such as cell wall peptidoglycans,
could be beneficial by themselves. [112].
Gibson and Roberfroid in 1995 introduced the term
prebiotic [117], which is defined as selectively fermented
ingredients that allow specific changes, both in the composition
and/or activity in the GI microflora that confer benefits upon
host well-being and health. [118]. Widely used prebiotics are
oligosaccharides, including lactulose, galacto-oligosaccharides,
fructo-oligosaccharides,
malto-oligosaccharides,
xylooligosaccharides and soya bean oligosaccharides. Prebiotics
are said to help micronutrient absorption. Their fermentation
leads to increased short-chain fatty acid production that
decreases the pH, increases mineral solubility and enlarges
the enterocyte absorption surface. However, high-dosage
could lead to adverse effects such as an accumulation of
microbial fermentation products and gas that could cause
bowel discomfort. Several studies on both animal models
and human subjects have shown positive effects with
oligosaccharides. [119-122].
Concept of Enterotypes
To classify microbial communities in human populations,
Arumugam et al. [123] proposed three groups of enterotypes
or microbial communities that are determined mostly by

294 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 4

species composition, but also take into account the molecular

functions of these species. Bacteroides (enterotype 1),
Prevotella (enterotype 2) and Ruminococcus (enterotype 3)
are the three dominant genera in each of the respective
enterotypes. It is proposed that each individual falls into one
of these categories. The enterotypes do not correlate with
host properties such as nationality, age, gender, or body mass
index (BMI). Other authors, reporting two enterotypes rather
than three among their study population, found that
enterotypes were strongly associated with the predominant
composition of long-term diets: protein and animal fat
(Bacteroides), or carbohydrates (Prevotella) [85]. To date,
the environmental or genetic factors that cause the clustering
are unclear; however, elucidation of these factors may reveal
why or how certain individuals or groups of individuals
respond differently to diet or drug administration.
Core Gut Microbiome and it Functions
The core gut microbiome could be defined as the
microorganisms, genes, or functional capacity present in the
GI-tract of all or the vast majority of individuals. The use of
shotgun sequencing along with KEGG (Kyoto Encyclopedia
of Genes and Genomes) [124] pathways and COGs (Clusters
of Orthologous Groups) databases [125] has allowed us to
gather information about the activities of this microbiome.
Functions are defined on the basis of genes of various
metabolic or synthesis pathways.
Qin et al. [58] proposed a minimal gut metagenome,
understood as the set of genes present in the gut microbial
community of almost all individuals. This metagenome
codes for 6,313 functions, of which 80% are poorly
characterized. The known functions include (pro)phagerelated proteins, proteins involved in the biodegradation of
complex sugars and glycans, and enzymes with the capacity to
ferment mannose, fructose, cellulose, and sucrose. Similarly,
other authors have reported that the core microbiome
consists of genes encoding for transcription, translation,
nucleotide charging and ATP synthesis, glycolysis, synthesis
of cellular components, and genes related to complex
carbohydrate and amino acid metabolism [59, 61, 79, 106, 126].
In the human gut, Firmicutes were proposed to be
enriched in genes involved in transport systems while
Bacteroidetes were found to be enriched in a number of
carbohydrate metabolism pathways and had a significantly
higher functional diversity [79]. In the Firmicutes,
Ruminococcaceae, Lachnospiraceae and Clostridiaceae were
identified as the most active families, while in the
Bacteroidetes; this role was attributed to Bacteroidaceae,
Rikenellaceae, Porphyromonadaceae and Prevotellaceae
[126]. Furthermore, functions carried out by the microbes are
more consistent among individuals than are microbial
diversity and abundance [58, 59, 61, 79, 106, 126, 127].

Panda et al.

enzyme classes have been reported to be similar in infants

and adults, the number of uncharacterized enzymes is greater
in the latter population; this observation may reflect an agerelated increase in diversity [59, 83]. It has been reported
that the microbiome at the early age is enriched in genes
facilitating lactate utilization and that it gradually evolves to
genes involved in plant polysaccharide metabolism upon the
introduction of solid food [73]. Infants showed higher levels
of folate-producing enzymes than adults, while biosynthetic
capacity for the vitamins cobalamin, thiamine, and biotin
increases with age.
Geographical location, related to diet and lifestyle, also
affects the functions of the gut microbiome, as demonstrated
in a study comparing Malawians, Amerindians and Americans
[83]. The lifestyle and high-fat and high-protein diet of
Americans increased gut microbial capacity for degradation
of glutamine and other amino acids as compared to the other
populations. These findings are consistent with studies
comparing the intestinal microbial community of carnivores
and herbivores [86].
During an antibiotic (beta-lactam) treatment, genes of
proteins belonging to the glycolysis pathway, pyruvate
metabolism, and energy metabolism are more highly
expressed [62]. The phospho-transferase system is involved
in stress response in bacteria and is also observed to be
elevated during antibiotic treatment. Furthermore, differences
have been reported in the gene expression levels between
bactericidal (endospore formation) and bacteriostatic
(lipopolysaccharide synthesis, catabolism of fatty acids and
phospholipids) types of treatment [106].
Given the high complexity of the gut microbiome in
terms of its composition and functions, an intense and
collective effort by the scientific community will be required
to unravel the role of this microbial community in disease
and thus facilitate the development of efficient diagnostic or
prognostic tools and treatments.
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
Declared none.
LIST OF ABBREVIATIONS
cDNA

complementary DNA

ddNTPs

dideoxy Nucleotide Tri-Phosphates

DGGE

Denaturing Gradient Gel Electrophoresis

FISH

Fluorescence In-Situ Hybridization

Variability and Modulation of the Functions

IBD

Inflammatory Bowel Disease

Variation in the functions performed by the gut

microbiome may depend on the immune, environmental, or
dietary exposure of these individuals.

IBS

Intestinal Bowel Syndrome

NGS

Next-generation sequencing techniques

Age is a factor that leads not only to a diverse gut

microbial structure but also to diverse functions. Although

OTUs

Operational Taxonomic Units

Human Gut Microbiome

Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 4

qPCR

quantitative Polymerase Chain Reaction

TGGE

Temperature
phoresis

Gradient

Gel

[19]

Electro[20]

REFERENCES
[1]
[2]
[3]
[4]

[5]

[6]
[7]

[8]

[9]

[10]
[11]
[12]

[13]

[14]

[15]

[16]

[17]
[18]

Drasar, B.S.; Hill, M.J. Human Intestinal Flora; Academic Press:

London, 1974.
Ducluzeau, R. Role of experimental microbial ecology in
gastroenterology. In: Microbial Ecology and Intestinal Infections;
Bergogne-Berezin, E.N., Ed.; Springer: Paris, 1989; pp 7-26.
Moore, W.E. and Holdeman, L.V. (1974) Human fecal flora: the
normal flora of 20 Japanese-Hawaiians. Appl. Microbiol. 27(5),
961-979.
Finegold, S.M.; Sutter, V.L. and Mathisen, G.E. Normal
indigenous intestinal flora. In: Human Intestinal Microbiota In
Health & Disease; Hentges; D.J., Ed.; Elsevier Science: 1983; pp.
3-31.
Langendijk, P.S.; Schut, F.; Jansen, G.J.; Raangs, G.C.; Kamphuis,
G.R.; Wilkinson, M.H. and Welling, G.W. (1995) Quantitative
fluorescence in situ hybridization of Bifidobacterium spp. with
genus-specific 16S rRNA-targeted probes and its application in
fecal samples. Appl. Environ. Microbiol., 61(8), 3069-3075.
Wilson, K.H. and Blitchington, R.B. (1996) Human colonic biota
studied by ribosomal DNA sequence analysis. Appl. Environ.
Microbiol., 62(7), 2273-2278.
Zoetendal, E.G.; Akkermans, A.D. and De Vos, W.M. (1998)
Temperature gradient gel electrophoresis analysis of 16S rRNA
from human fecal samples reveals stable and host-specific
communities of active bacteria. Appl. Environ. Microbiol., 64(10),
3854-3859.
Suau, A.; Bonnet, R.; Sutren, M.; Godon, J.J.; Gibson, G.R.;
Collins, M.D. and Dore, J. (1999) Direct analysis of genes
encoding 16S rRNA from complex communities reveals many
novel molecular species within the human gut. Appl. Environ.
Microbiol., 65(11), 4799-4807.
Hayashi, H.; Sakamoto, M. and Benno, Y. (2002) Phylogenetic
analysis of the human gut microbiota using 16S rDNA clone
libraries and strictly anaerobic culture-based methods. Microbiol.
Immunol., 46(8), 535-548.
Shanahan, F. (2002) The host-microbe interface within the gut.
Best Pract Res. Clin. Gastroenterol., 16(6), 915-931.
Bergmans, H.E. and Gaastra, W. (1988) Dot-blot hybridization
method. Methods Mol. Biol., 4, 385-390.
Stahl, D.A.; Flesher, B.; Mansfield, H.R. and Montgomery, L.
(1988) Use of phylogenetically based hybridization probes for
studies of ruminal microbial ecology. Appl. Environ. Microbiol., 54
(5), 1079-1084.
Dore, J.; Sghir, A.; Hannequart-Gramet, G.; Corthier, G. and
Pochart, P. (1998) Design and evaluation of a 16S rRNA-targeted
oligonucleotide probe for specific detection and quantitation of
human faecal Bacteroides populations. Syst. Appl. Microbiol., 21
(1), 65-71.
Bartosch, S.; Fite, A.; Macfarlane, G.T. and McMurdo, M.E.
(2004) Characterization of bacterial communities in feces from
healthy elderly volunteers and hospitalized elderly patients by
using real-time PCR and effects of antibiotic treatment on the fecal
microbiota. Appl. Environ. Microbiol., 70(6), 3575-3581.
Malinen, E.; Rinttila, T.; Kajander, K.; Matto, J.; Kassinen, A.;
Krogius, L.; Saarela, M.; Korpela, R. and Palva, A. (2005) Analysis of
the fecal microbiota of irritable bowel syndrome patients and healthy
controls with real-time PCR. Am. J. Gastroenterol., 100(2), 373382.
Carey, C.M.; Kirk, J.L.; Ojha, S. and Kostrzynska, M. (2007)
Current and future uses of real-time polymerase chain reaction and
microarrays in the study of intestinal microbiota, and probiotic use
and effectiveness. Can J. Microbiol., 53(5), 537-550.
Fischer, S.G. and Lerman, L.S. (1979) Length-independent
separation of DNA restriction fragments in two-dimensional gel
electrophoresis. Cell, 16(1), 191-200.
Myers, R.M.; Fischer, S.G.; Lerman, L.S. and Maniatis, T. (1985)
Nearly all single base substitutions in DNA fragments joined to a
GC-clamp can be detected by denaturing gradient gel
electrophoresis. Nucleic Acids Res., 13(9), 3131-3145.

[21]

[22]

[23]
[24]
[25]
[26]

[27]

[28]
[29]

[30]
[31]

[32]
[33]
[34]

[35]

[36]

[37]

295

Collins, M. and Myers, R.M. (1987) Alterations in DNA helix

stability due to base modifications can be evaluated using
denaturing gradient gel electrophoresis. J. Mol. Biol., 198(4), 737744.
Rosenbaum, V. and Riesner, D. (1987) Temperature-gradient gel
electrophoresis. Thermodynamic analysis of nucleic acids and
proteins in purified form and in cellular extracts. Biophys. Chem.,
26(2-3), 235-246.
Muyzer, G. and Smalla, K. (1998) Application of denaturing
gradient gel electrophoresis (DGGE) and temperature gradient gel
electrophoresis (TGGE) in microbial ecology. Antonie Van
Leeuwenhoek, 73(1), 127-141.
Seksik, P.; Lepage, P.; de la Cochetiere, M.F.; Bourreille, A.;
Sutren, M.; Galmiche, J.P.; Dore, J. and Marteau, P. (2005) Search
for localized dysbiosis in Crohn's disease ulcerations by temporal
temperature gradient gel electrophoresis of 16S rRNA. J. Clin.
Microbiol., 43(9), 4654-4658.
Amann, R.I.; Ludwig, W. and Schleifer, K.H. (1995) Phylogenetic
identification and in situ detection of individual microbial cells
without cultivation. Microbiol. Rev., 59(1), 143-169.
Ames, J.M.; Wynne, A.; Hofmann, A.; Plos, S. and Gibson, G.R.
(1999) The effect of a model melanoidin mixture on faecal
bacterial populations in vitro. Br. J. Nutr., 82(6), 489-495.
Collins, M.D. and Gibson, G.R. (1999) Probiotics, prebiotics, and
synbiotics: approaches for modulating the microbial ecology of the
gut. Am. J. Clin. Nutr., 69(5), 1052S-1057S.
Harmsen, H.J.; Gibson, G.R.; Elfferich, P.; Raangs, G.C.;
Wildeboer-Veloo, A.C.; Argaiz, A.; Roberfroid, M.B. and Welling,
G.W. (2000) Comparison of viable cell counts and fluorescence in
situ hybridization using specific rRNA-based probes for the
quantification of human fecal bacteria. FEMS Microbiol. Lett., 183
(1), 125-129.
Maskos, U. and Southern, E.M. (1992) Oligonucleotide
hybridizations on glass supports: a novel linker for oligonucleotide
synthesis and hybridization properties of oligonucleotides
synthesised in situ. Nucleic Acids Res., 20(7), 1679-1684.
Schena, M.; Shalon, D.; Davis, R.W. and Brown, P.O. (1995)
Quantitative monitoring of gene expression patterns with a
complementary DNA microarray. Science, 270(5235), 467-470.
Schena, M.; Shalon, D.; Heller, R.; Chai, A.; Brown, P.O. and
Davis, R.W. (1996) Parallel human genome analysis: microarraybased expression monitoring of 1000 genes. Proc. Natl. Acad. Sci.
USA, 93(20), 10614-10619.
Shalon, D.; Smith, S.J. and Brown, P.O. (1996) A DNA microarray
system for analyzing complex DNA samples using two-color
fluorescent probe hybridization. Genome Res., 6(7), 639-645.
Bates, M.D.; Erwin, C.R.; Sanford, L.P.; Wiginton, D.; Bezerra,
J.A.; Schatzman, L.C.; Jegga, A.G.; Ley-Ebert, C.; Williams, S.S.;
Steinbrecher, K.A.; Warner, B.W.; Cohen, M.B. and Aronow,
B.J. (2002) Novel genes and functional relationships in the adult
mouse gastrointestinal tract identified by microarray analysis.
Gastroenterology, 122(5), 1467-1482.
Roy, S.; Khanna, S.; Bentley, K.; Beffrey, P. and Sen, C.K. (2002)
Functional genomics: high-density oligonucleotide arrays. Methods
Enzymol., 353, 487-497.
Liu-Stratton, Y.; Roy, S. and Sen, C.K. (2004) DNA microarray
technology in nutraceutical and food safety. Toxicol. Lett., 150(1),
29-42.
Larocque, R.C.; Harris, J.B.; Dziejman, M.; Li, X.; Khan, A.I.;
Faruque, A.S.; Faruque, S.M.; Nair, G.B.; Ryan, E.T.; Qadri, F.;
Mekalanos, J.J. and Calderwood, S.B. (2005) Transcriptional
profiling of Vibrio cholerae recovered directly from patient
specimens during early and late stages of human infection. Infect.
Immun., 73(8), 4488-4493.
Kovatcheva-Datchary, P.; Zoetendal, E.G.; Venema, K.; de Vos,
W.M. and Smidt, H. (2009) Tools for the tract: understanding the
functionality of the gastrointestinal tract. Therap. Adv.
Gastroenterol., 2(4), 9-22.
Tottey, W.; Denonfoux, J.; Jaziri, F.; Parisot, N.; Missaoui, M.;
Hill, D.; Borrel, G.; Peyretaillade, E.; Alric, M.; Harris, H.M.;
Jeffery, I.B.; Claesson, M.J.; O'Toole, P.W.; Peyret, P. and Brugere,
J.F. (2013) The human gut chip "HuGChip", an explorative
phylogenetic microarray for determining gut microbiome diversity
at family level. PLoS One, 8(5), e62544.
Rajilic-Stojanovic, M.; Heilig, H.G.; Molenaar, D.; Kajander, K.;
Surakka, A.; Smidt, H. and de Vos, W.M. (2009) Development and

296 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 4

[38]

[39]
[40]

[41]

[42]
[43]
[44]
[45]

[46]

application of the human intestinal tract chip, a phylogenetic

microarray: analysis of universally conserved phylotypes in the
abundant microbiota of young and elderly adults. Environ.
Microbiol., 11(7), 1736-1751.
Biagi, E.; Nylund, L.; Candela, M.; Ostan, R.; Bucci, L.; Pini, E.;
Nikkila, J.; Monti, D.; Satokari, R.; Franceschi, C.; Brigidi, P. and
De Vos, W. (2010) Through ageing, and beyond: gut microbiota
and inflammatory status in seniors and centenarians. PLoS One,
5(5), e10667.
Nikkila, J. and de Vos, W.M. (2010) Advanced approaches to
characterize the human intestinal microbiota by computational
meta-analysis. J. Clin. Gastroenterol., 44 Suppl 1, S2-S5.
Van den Abbeele, P.; Grootaert, C.; Marzorati, M.; Possemiers, S.;
Verstraete, W.; Gerard, P.; Rabot, S.; Bruneau, A.; El Aidy, S.;
Derrien, M.; Zoetendal, E.; Kleerebezem, M.; Smidt, H. and Van
de Wiele, T. (2010) Microbial community development in a
dynamic gut model is reproducible, colon region specific, and
selective for Bacteroidetes and Clostridium cluster IX. Appl.
Environ. Microbiol., 76(15), 5237-5246.
Rajilic-Stojanovic, M.; Heilig, H.G.; Tims, S.; Zoetendal, E.G. and
de Vos, W.M. (2012) Long-term monitoring of the human
intestinal microbiota composition. Environ. Microbiol., 15(4),
1146-1159.
Sanger, F.; Nicklen, S. and Coulson, A.R. (1977) DNA sequencing
with chain-terminating inhibitors. Proc. Natl. Acad. Sci. USA,
74(12), 5463-5467.
Ronaghi, M.; Karamohamed, S.; Pettersson, B.; Uhlen, M. and
Nyren, P. (1996) Real-time DNA sequencing using detection of
pyrophosphate release. Anal Biochem., 242(1), 84-89.
Ronaghi, M.; Uhlen, M. and Nyren, P. (1998) A sequencing
method based on real-time pyrophosphate. Science, 281(5375),
363, 365.
Caporaso, J.G.; Lauber, C.L.; Walters, W.A.; Berg-Lyons, D.;
Huntley, J.; Fierer, N.; Owens, S.M.; Betley, J.; Fraser, L.; Bauer,
M.; Gormley, N.; Gilbert, J.A.; Smith, G. and Knight, R. (2012)
Ultra-high-throughput microbial community analysis on the
Illumina HiSeq and MiSeq platforms. ISME J., 6(8), 1621-1624.
Bentley, D.R.; Balasubramanian, S.; Swerdlow, H.P.; Smith, G.P.;
Milton, J.; Brown, C.G.; Hall, K.P.; Evers, D.J.; Barnes, C.L.;
Bignell, H.R.; Boutell, J.M.; Bryant, J.; Carter, R.J.; Keira
Cheetham, R.; Cox, A.J.; Ellis, D.J.; Flatbush, M.R.; Gormley,
N.A.; Humphray, S.J.; Irving, L.J.; Karbelashvili, M.S.; Kirk, S.M.;
Li, H.; Liu, X.; Maisinger, K.S.; Murray, L.J.; Obradovic, B.; Ost,
T.; Parkinson, M.L.; Pratt, M.R.; Rasolonjatovo, I.M.; Reed, M.T.;
Rigatti, R.; Rodighiero, C.; Ross, M.T.; Sabot, A.; Sankar, S.V.;
Scally, A.; Schroth, G.P.; Smith, M.E.; Smith, V.P.; Spiridou, A.;
Torrance, P.E.; Tzonev, S.S.; Vermaas, E.H.; Walter, K.; Wu, X.;
Zhang, L.; Alam, M.D.; Anastasi, C.; Aniebo, I.C.; Bailey, D.M.;
Bancarz, I.R.; Banerjee, S.; Barbour, S.G.; Baybayan, P.A.; Benoit,
V.A.; Benson, K.F.; Bevis, C.; Black, P.J.; Boodhun, A.; Brennan,
J.S.; Bridgham, J.A.; Brown, R.C.; Brown, A.A.; Buermann, D.H.;
Bundu, A.A.; Burrows, J.C.; Carter, N.P.; Castillo, N.; Chiara,
E.C.M.; Chang, S.; Neil Cooley, R.; Crake, N.R.; Dada, O.O.;
Diakoumakos, K.D.; Dominguez-Fernandez, B.; Earnshaw, D.J.;
Egbujor, U.C.; Elmore, D.W.; Etchin, S.S.; Ewan, M.R.; Fedurco,
M.; Fraser, L.J.; Fuentes Fajardo, K.V.; Scott Furey, W.; George,
D.; Gietzen, K.J.; Goddard, C.P.; Golda, G.S.; Granieri, P.A.;
Green, D.E.; Gustafson, D.L.; Hansen, N.F.; Harnish, K.;
Haudenschild, C.D.; Heyer, N.I.; Hims, M.M.; Ho, J.T.; Horgan,
A.M.; Hoschler, K.; Hurwitz, S.; Ivanov, D.V.; Johnson, M.Q.;
James, T.; Huw Jones, T.A.; Kang, G.D.; Kerelska, T.H.; Kersey,
A.D.; Khrebtukova, I.; Kindwall, A.P.; Kingsbury, Z.; KokkoGonzales, P.I.; Kumar, A.; Laurent, M.A.; Lawley, C.T.; Lee, S.E.;
Lee, X.; Liao, A.K.; Loch, J.A.; Lok, M.; Luo, S.; Mammen, R.M.;
Martin, J.W.; McCauley, P.G.; McNitt, P.; Mehta, P.; Moon, K.W.;
Mullens, J.W.; Newington, T.; Ning, Z.; Ling Ng, B.; Novo, S.M.;
O'Neill, M.J.; Osborne, M.A.; Osnowski, A.; Ostadan, O.;
Paraschos, L.L.; Pickering, L.; Pike, A.C.; Chris Pinkard, D.;
Pliskin, D.P.; Podhasky, J.; Quijano, V.J.; Raczy, C.; Rae, V.H.;
Rawlings, S.R.; Chiva Rodriguez, A.; Roe, P.M.; Rogers, J.; Rogert
Bacigalupo, M.C.; Romanov, N.; Romieu, A.; Roth, R.K.; Rourke,
N.J.; Ruediger, S.T.; Rusman, E.; Sanches-Kuiper, R.M.; Schenker,
M.R.; Seoane, J.M.; Shaw, R.J.; Shiver, M.K.; Short, S.W.; Sizto,
N.L.; Sluis, J.P.; Smith, M.A.; Ernest Sohna Sohna, J.; Spence,
E.J.; Stevens, K.; Sutton, N.; Szajkowski, L.; Tregidgo, C.L.;
Turcatti, G.; Vandevondele, S.; Verhovsky, Y.; Virk, S.M.;

[47]

[48]
[49]

[50]

[51]

[52]

Panda et al.
Wakelin, S.; Walcott, G.C.; Wang, J.; Worsley, G.J.; Yan, J.; Yau,
L.; Zuerlein, M.; Mullikin, J.C.; Hurles, M.E.; McCooke, N.J.;
West, J.S.; Oaks, F.L.; Lundberg, P.L.; Klenerman, D.; Durbin, R.
and Smith, A.J. (2008) Accurate whole human genome sequencing
using reversible terminator chemistry. Nature, 456(7218), 53-59.
Fox, G.E.; Magrum, L.J.; Balch, W.E.; Wolfe, R.S. and Woese,
C.R. (1977) Classification of methanogenic bacteria by 16S
ribosomal RNA characterization. Proc. Natl. Acad. Sci. USA,
74(10), 4537-4541.
Pace, N.R. and Waugh, D.S. (1991) Design of simplified
ribonuclease P RNA by phylogenetic comparison. Methods
Enzymol., 203, 500-510.
Blaut, M.; Collins, M.D.; Welling, G.W.; Dore, J.; van Loo, J. and
de Vos, W. (2002) Molecular biological methods for studying the
gut microbiota: the EU human gut flora project. Br. J. Nutr., 87
Suppl 2, S203-S211.
Fleischmann, R.D.; Adams, M.D.; White, O.; Clayton, R.A.;
Kirkness, E.F.; Kerlavage, A.R.; Bult, C.J.; Tomb, J.F.; Dougherty,
B.A.; Merrick, J.M. and et al. (1995) Whole-genome random
sequencing and assembly of Haemophilus influenzae Rd. Science
269 (5223), 496-512.
Adams, M.D.; Celniker, S.E.; Holt, R.A.; Evans, C.A.; Gocayne,
J.D.; Amanatides, P.G.; Scherer, S.E.; Li, P.W.; Hoskins, R.A.;
Galle, R.F.; George, R.A.; Lewis, S.E.; Richards, S.; Ashburner,
M.; Henderson, S.N.; Sutton, G.G.; Wortman, J.R.; Yandell, M.D.;
Zhang, Q.; Chen, L.X.; Brandon, R.C.; Rogers, Y.H.; Blazej, R.G.;
Champe, M.; Pfeiffer, B.D.; Wan, K.H.; Doyle, C.; Baxter, E.G.;
Helt, G.; Nelson, C.R.; Gabor, G.L.; Abril, J.F.; Agbayani, A.; An,
H.J.; Andrews-Pfannkoch, C.; Baldwin, D.; Ballew, R.M.; Basu,
A.; Baxendale, J.; Bayraktaroglu, L.; Beasley, E.M.; Beeson, K.Y.;
Benos, P.V.; Berman, B.P.; Bhandari, D.; Bolshakov, S.; Borkova,
D.; Botchan, M.R.; Bouck, J.; Brokstein, P.; Brottier, P.; Burtis,
K.C.; Busam, D.A.; Butler, H.; Cadieu, E.; Center, A.; Chandra, I.;
Cherry, J.M.; Cawley, S.; Dahlke, C.; Davenport, L.B.; Davies, P.;
de Pablos, B.; Delcher, A.; Deng, Z.; Mays, A.D.; Dew, I.; Dietz,
S.M.; Dodson, K.; Doup, L.E.; Downes, M.; Dugan-Rocha, S.;
Dunkov, B.C.; Dunn, P.; Durbin, K.J.; Evangelista, C.C.; Ferraz,
C.; Ferriera, S.; Fleischmann, W.; Fosler, C.; Gabrielian, A.E.;
Garg, N.S.; Gelbart, W.M.; Glasser, K.; Glodek, A.; Gong, F.;
Gorrell, J.H.; Gu, Z.; Guan, P.; Harris, M.; Harris, N.L.; Harvey,
D.; Heiman, T.J.; Hernandez, J.R.; Houck, J.; Hostin, D.; Houston,
K.A.; Howland, T.J.; Wei, M.H.; Ibegwam, C.; Jalali, M.; Kalush,
F.; Karpen, G.H.; Ke, Z.; Kennison, J.A.; Ketchum, K.A.; Kimmel,
B.E.; Kodira, C.D.; Kraft, C.; Kravitz, S.; Kulp, D.; Lai, Z.; Lasko,
P.; Lei, Y.; Levitsky, A.A.; Li, J.; Li, Z.; Liang, Y.; Lin, X.; Liu,
X.; Mattei, B.; McIntosh, T.C.; McLeod, M.P.; McPherson, D.;
Merkulov, G.; Milshina, N.V.; Mobarry, C.; Morris, J.; Moshrefi,
A.; Mount, S.M.; Moy, M.; Murphy, B.; Murphy, L.; Muzny,
D.M.; Nelson, D.L.; Nelson, D.R.; Nelson, K.A.; Nixon, K.;
Nusskern, D.R.; Pacleb, J.M.; Palazzolo, M.; Pittman, G.S.; Pan,
S.; Pollard, J.; Puri, V.; Reese, M.G.; Reinert, K.; Remington, K.;
Saunders, R.D.; Scheeler, F.; Shen, H.; Shue, B.C.; Siden-Kiamos,
I.; Simpson, M.; Skupski, M.P.; Smith, T.; Spier, E.; Spradling,
A.C.; Stapleton, M.; Strong, R.; Sun, E.; Svirskas, R.; Tector, C.;
Turner, R.; Venter, E.; Wang, A.H.; Wang, X.; Wang, Z.Y.;
Wassarman, D.A.; Weinstock, G.M.; Weissenbach, J.; Williams,
S.M.; WoodageT; Worley, K.C.; Wu, D.; Yang, S.; Yao, Q.A.; Ye,
J.; Yeh, R.F.; Zaveri, J.S.; Zhan, M.; Zhang, G.; Zhao, Q.; Zheng,
L.; Zheng, X.H.; Zhong, F.N.; Zhong, W.; Zhou, X.; Zhu, S.; Zhu,
X.; Smith, H.O.; Gibbs, R.A.; Myers, E.W.; Rubin, G.M. and
Venter, J.C. (2000) The genome sequence of Drosophila
melanogaster. Science, 287(5461), 2185-2195.
Venter, J.C.; Adams, M.D.; Myers, E.W.; Li, P.W.; Mural, R.J.;
Sutton, G.G.; Smith, H.O.; Yandell, M.; Evans, C.A.; Holt, R.A.;
Gocayne, J.D.; Amanatides, P.; Ballew, R.M.; Huson, D.H.;
Wortman, J.R.; Zhang, Q.; Kodira, C.D.; Zheng, X.H.; Chen, L.;
Skupski, M.; Subramanian, G.; Thomas, P.D.; Zhang, J.; Gabor
Miklos, G.L.; Nelson, C.; Broder, S.; Clark, A.G.; Nadeau, J.;
McKusick, V.A.; Zinder, N.; Levine, A.J.; Roberts, R.J.; Simon,
M.; Slayman, C.; Hunkapiller, M.; Bolanos, R.; Delcher, A.; Dew,
I.; Fasulo, D.; Flanigan, M.; Florea, L.; Halpern, A.; Hannenhalli,
S.; Kravitz, S.; Levy, S.; Mobarry, C.; Reinert, K.; Remington, K.;
Abu-Threideh, J.; Beasley, E.; Biddick, K.; Bonazzi, V.; Brandon,
R.; Cargill, M.; Chandramouliswaran, I.; Charlab, R.; Chaturvedi,
K.; Deng, Z.; Di Francesco, V.; Dunn, P.; Eilbeck, K.; Evangelista,
C.; Gabrielian, A.E.; Gan, W.; Ge, W.; Gong, F.; Gu, Z.; Guan, P.;

Human Gut Microbiome

[53]

[54]
[55]
[56]

[57]

[58]

Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 4

Heiman, T.J.; Higgins, M.E.; Ji, R.R.; Ke, Z.; Ketchum, K.A.; Lai,
Z.; Lei, Y.; Li, Z.; Li, J.; Liang, Y.; Lin, X.; Lu, F.; Merkulov,
G.V.; Milshina, N.; Moore, H.M.; Naik, A.K.; Narayan, V.A.;
Neelam, B.; Nusskern, D.; Rusch, D.B.; Salzberg, S.; Shao, W.;
Shue, B.; Sun, J.; Wang, Z.; Wang, A.; Wang, X.; Wang, J.; Wei,
M.; Wides, R.; Xiao, C.; Yan, C.; Yao, A.; Ye, J.; Zhan, M.;
Zhang, W.; Zhang, H.; Zhao, Q.; Zheng, L.; Zhong, F.; Zhong, W.;
Zhu, S.; Zhao, S.; Gilbert, D.; Baumhueter, S.; Spier, G.; Carter,
C.; Cravchik, A.; Woodage, T.; Ali, F.; An, H.; Awe, A.; Baldwin,
D.; Baden, H.; Barnstead, M.; Barrow, I.; Beeson, K.; Busam, D.;
Carver, A.; Center, A.; Cheng, M.L.; Curry, L.; Danaher, S.;
Davenport, L.; Desilets, R.; Dietz, S.; Dodson, K.; Doup, L.;
Ferriera, S.; Garg, N.; Gluecksmann, A.; Hart, B.; Haynes, J.;
Haynes, C.; Heiner, C.; Hladun, S.; Hostin, D.; Houck, J.;
Howland, T.; Ibegwam, C.; Johnson, J.; Kalush, F.; Kline, L.;
Koduru, S.; Love, A.; Mann, F.; May, D.; McCawley, S.;
McIntosh, T.; McMullen, I.; Moy, M.; Moy, L.; Murphy, B.;
Nelson, K.; Pfannkoch, C.; Pratts, E.; Puri, V.; Qureshi, H.;
Reardon, M.; Rodriguez, R.; Rogers, Y.H.; Romblad, D.; Ruhfel,
B.; Scott, R.; Sitter, C.; Smallwood, M.; Stewart, E.; Strong, R.;
Suh, E.; Thomas, R.; Tint, N.N.; Tse, S.; Vech, C.; Wang, G.;
Wetter, J.; Williams, S.; Williams, M.; Windsor, S.; Winn-Deen,
E.; Wolfe, K.; Zaveri, J.; Zaveri, K.; Abril, J.F.; Guigo, R.;
Campbell, M.J.; Sjolander, K.V.; Karlak, B.; Kejariwal, A.; Mi, H.;
Lazareva, B.; Hatton, T.; Narechania, A.; Diemer, K.;
Muruganujan, A.; Guo, N.; Sato, S.; Bafna, V.; Istrail, S.; Lippert,
R.; Schwartz, R.; Walenz, B.; Yooseph, S.; Allen, D.; Basu, A.;
Baxendale, J.; Blick, L.; Caminha, M.; Carnes-Stine, J.; Caulk, P.;
Chiang, Y.H.; Coyne, M.; Dahlke, C.; Mays, A.; Dombroski, M.;
Donnelly, M.; Ely, D.; Esparham, S.; Fosler, C.; Gire, H.;
Glanowski, S.; Glasser, K.; Glodek, A.; Gorokhov, M.; Graham,
K.; Gropman, B.; Harris, M.; Heil, J.; Henderson, S.; Hoover, J.;
Jennings, D.; Jordan, C.; Jordan, J.; Kasha, J.; Kagan, L.; Kraft, C.;
Levitsky, A.; Lewis, M.; Liu, X.; Lopez, J.; Ma, D.; Majoros, W.;
McDaniel, J.; Murphy, S.; Newman, M.; Nguyen, T.; Nguyen, N.;
Nodell, M.; Pan, S.; Peck, J.; Peterson, M.; Rowe, W.; Sanders, R.;
Scott, J.; Simpson, M.; Smith, T.; Sprague, A.; Stockwell, T.;
Turner, R.; Venter, E.; Wang, M.; Wen, M.; Wu, D.; Wu, M.; Xia,
A.; Zandieh, A. and Zhu, X. (2001) The sequence of the human
genome. Science, 291(5507), 1304-1351.
Istrail, S.; Sutton, G.G.; Florea, L.; Halpern, A.L.; Mobarry, C.M.;
Lippert, R.; Walenz, B.; Shatkay, H.; Dew, I.; Miller, J.R.;
Flanigan, M.J.; Edwards, N.J.; Bolanos, R.; Fasulo, D.;
Halldorsson, B.V.; Hannenhalli, S.; Turner, R.; Yooseph, S.; Lu,
F.; Nusskern, D.R.; Shue, B.C.; Zheng, X.H.; Zhong, F.; Delcher,
A.L.; Huson, D.H.; Kravitz, S.A.; Mouchard, L.; Reinert, K.;
Remington, K.A.; Clark, A.G.; Waterman, M.S.; Eichler, E.E.;
Adams, M.D.; Hunkapiller, M.W.; Myers, E.W. and Venter, J.C.
(2004) Whole-genome shotgun assembly and comparison of human
genome assemblies. Proc. Natl. Acad. Sci. USA, 101(7), 19161921.
Staden, R. (1979) A strategy of DNA sequencing employing
computer programs. Nucleic Acids Res., 6(7), 2601-2610.
Anderson, S. (1981) Shotgun DNA sequencing using cloned DNase
I-generated fragments. Nucleic Acids Res., 9 (13), 3015-3027.
Edwards, A.; Voss, H.; Rice, P.; Civitello, A.; Stegemann, J.;
Schwager, C.; Zimmermann, J.; Erfle, H.; Caskey, C.T. and
Ansorge, W. (1990) Automated DNA sequencing of the human
HPRT locus. Genomics, 6(4), 593-608.
Sunagawa, S.; Mende, D.R.; Zeller, G.; Izquierdo-Carrasco, F.;
Berger, S.A.; Kultima, J.R.; Coelho, L.P.; Arumugam, M.; Tap, J.;
Nielsen, H.B.; Rasmussen, S.; Brunak, S.; Pedersen, O.; Guarner, F.;
de Vos, W.M.; Wang, J.; Li, J.; Dore, J.; Ehrlich, S.D.; Stamatakis, A.
and Bork, P. (2013) Metagenomic species profiling using universal
phylogenetic marker genes. Nat. Methods, 10(12), 1196-1199.
Qin, J.; Li, R.; Raes, J.; Arumugam, M.; Burgdorf, K.S.;
Manichanh, C.; Nielsen, T.; Pons, N.; Levenez, F.; Yamada, T.;
Mende, D.R.; Li, J.; Xu, J.; Li, S.; Li, D.; Cao, J.; Wang, B.; Liang,
H.; Zheng, H.; Xie, Y.; Tap, J.; Lepage, P.; Bertalan, M.; Batto,
J.M.; Hansen, T.; Le Paslier, D.; Linneberg, A.; Nielsen, H.B.;
Pelletier, E.; Renault, P.; Sicheritz-Ponten, T.; Turner, K.; Zhu, H.;
Yu, C.; Jian, M.; Zhou, Y.; Li, Y.; Zhang, X.; Qin, N.; Yang, H.;
Wang, J.; Brunak, S.; Dore, J.; Guarner, F.; Kristiansen, K.;
Pedersen, O.; Parkhill, J.; Weissenbach, J.; Bork, P. and Ehrlich,
S.D. (2010) A human gut microbial gene catalogue established by
metagenomic sequencing. Nature, 464(7285), 59-65.

[59]
[60]

[61]

[62]

[63]

[64]

[65]

[66]
[67]

[68]
[69]
[70]

[71]

[72]

[73]

[74]
[75]

297

Human Microbiome Project Consortium (2012) Structure, function

and diversity of the healthy human microbiome. Nature,
486(7402), 207-214.
Le Chatelier, E.; Nielsen, T.; Qin, J.; Prifti, E.; Hildebrand, F.;
Falony, G.; Almeida, M.; Arumugam, M.; Batto, J.M.; Kennedy,
S.; Leonard, P.; Li, J.; Burgdorf, K.; Grarup, N.; Jorgensen, T.;
Brandslund, I.; Nielsen, H.B.; Juncker, A.S.; Bertalan, M.;
Levenez, F.; Pons, N.; Rasmussen, S.; Sunagawa, S.; Tap, J.; Tims,
S.; Zoetendal, E.G.; Brunak, S.; Clement, K.; Dore, J.;
Kleerebezem, M.; Kristiansen, K.; Renault, P.; Sicheritz-Ponten,
T.; de Vos, W.M.; Zucker, J.D.; Raes, J.; Hansen, T.; Bork, P.;
Wang, J.; Ehrlich, S.D. and Pedersen, O. (2013) Richness of human
gut microbiome correlates with metabolic markers. Nature,
500(7464), 541-546.
Booijink, C.C.; Boekhorst, J.; Zoetendal, E.G.; Smidt, H.;
Kleerebezem, M. and de Vos, W.M. (2010) Metatranscriptome
analysis of the human fecal microbiota reveals subject-specific
expression profiles, with genes encoding proteins involved in
carbohydrate metabolism being dominantly expressed. Appl.
Environ. Microbiol., 76(16), 5533-5540.
Perez-Cobas, A.E.; Gosalbes, M.J.; Friedrichs, A.; Knecht, H.;
Artacho, A.; Eismann, K.; Otto, W.; Rojo, D.; Bargiela, R.; von
Bergen, M.; Neulinger, S.C.; Daumer, C.; Heinsen, F.A.; Latorre,
A.; Barbas, C.; Seifert, J.; dos Santos, V.M.; Ott, S.J.; Ferrer, M.
and Moya, A. (2013) Gut microbiota disturbance during antibiotic
therapy: a multi-omic approach. Gut, 62(11), 1591-1601.
Verberkmoes, N.C.; Russell, A.L.; Shah, M.; Godzik, A.;
Rosenquist, M.; Halfvarson, J.; Lefsrud, M.G.; Apajalahti, J.; Tysk,
C.; Hettich, R.L. and Jansson, J.K. (2009) Shotgun metaproteomics
of the human distal gut microbiota. ISME J., 3(2), 179-189.
Jansson, J.; Willing, B.; Lucio, M.; Fekete, A.; Dicksved, J.;
Halfvarson, J.; Tysk, C. and Schmitt-Kopplin, P. (2009)
Metabolomics reveals metabolic biomarkers of Crohn's disease.
PLoS One, 4(7), e6386.
Handelsman, J.; Rondon, M.R.; Brady, S.F.; Clardy, J. and
Goodman, R.M. (1998) Molecular biological access to the
chemistry of unknown soil microbes: a new frontier for natural
products. Chem. Biol., 5(10), R245-R249.
Backhed, F.; Ley, R.E.; Sonnenburg, J.L.; Peterson, D.A. and
Gordon, J.I. (2005) Host-bacterial mutualism in the human
intestine. Science, 307(5717), 1915-1920.
Eckburg, P.B.; Bik, E.M.; Bernstein, C.N.; Purdom, E.; Dethlefsen,
L.; Sargent, M.; Gill, S.R.; Nelson, K.E. and Relman, D.A. (2005)
Diversity of the human intestinal microbial flora. Science,
308(5728), 1635-1638.
Turnbaugh, P.J.; Ley, R.E.; Hamady, M.; Fraser-Liggett, C.M.;
Knight, R. and Gordon, J.I. (2007) The human microbiome project.
Nature, 449(7164), 804-810.
Fanaro, S.; Chierici, R.; Guerrini, P. and Vigi, V. (2003) Intestinal
microflora in early infancy: composition and development. Acta
Paediatr. Suppl., 91(441), 48-55.
Dominguez-Bello, M.G.; Costello, E.K.; Contreras, M.; Magris,
M.; Hidalgo, G.; Fierer, N. and Knight, R. (2010) Delivery mode
shapes the acquisition and structure of the initial microbiota across
multiple body habitats in newborns. Proc. Natl. Acad. Sci. USA,
107(26), 11971-11975.
Fallani, M.; Young, D.; Scott, J.; Norin, E.; Amarri, S.; Adam, R.;
Aguilera, M.; Khanna, S.; Gil, A.; Edwards, C.A. and Dore, J.
(2010) Intestinal microbiota of 6-week-old infants across Europe:
geographic influence beyond delivery mode, breast-feeding, and
antibiotics. J. Pediatr. Gastroenterol. Nutr., 51(1), 77-84.
Fan, W.; Huo, G.; Li, X.; Yang, L.; Duan, C.; Wang, T. and Chen,
J. (2013) Diversity of the intestinal microbiota in different patterns
of feeding infants by Illumina high-throughput sequencing. World
J. Microbiol. Biotechnol., 29(12), 2365-2372.
Koenig, J.E.; Spor, A.; Scalfone, N.; Fricker, A.D.; Stombaugh, J.;
Knight, R.; Angenent, L.T. and Ley, R.E. (2011) Succession of
microbial consortia in the developing infant gut microbiome. Proc.
Natl. Acad. Sci. USA, 108 Suppl 1, 4578-4585.
Hopkins, M.J.; Sharp, R. and Macfarlane, G.T. (2002) Variation in
human intestinal microbiota with age. Dig. Liver Dis., 34 Suppl 2,
S12-18.
Hayashi, H.; Sakamoto, M. and Benno, Y. (2002) Fecal microbial
diversity in a strict vegetarian as determined by molecular analysis
and cultivation. Microbiol. Immunol., 46(12), 819-831.

298 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 4
[76]

[77]

[78]
[79]
[80]
[81]

[82]

[83]

[84]

[85]

[86]

[87]
[88]
[89]
[90]
[91]

[92]

[93]

Hold, G.L.; Pryde, S.E.; Russell, V.J.; Furrie, E. and Flint, H.J.
(2002) Assessment of microbial diversity in human colonic
samples by 16S rDNA sequence analysis. FEMS Microbiol. Ecol.,
39(1), 33-39.
Wang, X.; Heazlewood, S.P.; Krause, D.O. and Florin, T.H. (2003)
Molecular characterization of the microbial species that colonize
human ileal and colonic mucosa by using 16S rDNA sequence
analysis. J. Appl. Microbiol., 95(3), 508-520.
Ley, R.E.; Backhed, F.; Turnbaugh, P.; Lozupone, C.A.; Knight,
R.D. and Gordon, J.I. (2005) Obesity alters gut microbial ecology.
Proc. Natl. Acad. Sci. USA., 102(31), 11070-11075.
Turnbaugh, P.J. and Gordon, J.I. (2009) The core gut microbiome,
energy balance and obesity. J. Physiol., 587(Pt 17), 4153-4158.
Costello, E.K.; Lauber, C.L.; Hamady, M.; Fierer, N.; Gordon, J.I.
and Knight, R. (2009) Bacterial community variation in human body
habitats across space and time. Science, 326(5960), 1694-1697.
Claesson, M.J.; Jeffery, I.B.; Conde, S.; Power, S.E.; O'Connor,
E.M.; Cusack, S.; Harris, H.M.; Coakley, M.; Lakshminarayanan,
B.; O'Sullivan, O.; Fitzgerald, G.F.; Deane, J.; O'Connor, M.;
Harnedy, N.; O'Connor, K.; O'Mahony, D.; van Sinderen, D.;
Wallace, M.; Brennan, L.; Stanton, C.; Marchesi, J.R.; Fitzgerald,
A.P.; Shanahan, F.; Hill, C.; Ross, R.P. and O'Toole, P.W. (2012)
Gut microbiota composition correlates with diet and health in the
elderly. Nature, 488(7410), 178-184.
De Filippo, C.; Cavalieri, D.; Di Paola, M.; Ramazzotti, M.;
Poullet, J.B.; Massart, S.; Collini, S.; Pieraccini, G. and Lionetti, P.
(2010) Impact of diet in shaping gut microbiota revealed by a
comparative study in children from Europe and rural Africa. Proc.
Natl. Acad. Sci. USA, 107(33), 14691-14696.
Yatsunenko, T.; Rey, F.E.; Manary, M.J.; Trehan, I.; DominguezBello, M.G.; Contreras, M.; Magris, M.; Hidalgo, G.; Baldassano,
R.N.; Anokhin, A.P.; Heath, A.C.; Warner, B.; Reeder, J.;
Kuczynski, J.; Caporaso, J.G.; Lozupone, C.A.; Lauber, C.;
Clemente, J.C.; Knights, D.; Knight, R. and Gordon, J.I. (2012)
Human gut microbiome viewed across age and geography. Nature,
486(7402), 222-227.
Biedermann, L.; Zeitz, J.; Mwinyi, J.; Sutter-Minder, E.; Rehman,
A.; Ott, S.J.; Steurer-Stey, C.; Frei, A.; Frei, P.; Scharl, M.;
Loessner, M.J.; Vavricka, S.R.; Fried, M.; Schreiber, S.; Schuppler,
M. and Rogler, G. (2013) Smoking cessation induces profound
changes in the composition of the intestinal microbiota in humans.
PLoS One, 8(3), e59260.
Wu, G.D.; Chen, J.; Hoffmann, C.; Bittinger, K.; Chen, Y.Y.;
Keilbaugh, S.A.; Bewtra, M.; Knights, D.; Walters, W.A.; Knight,
R.; Sinha, R.; Gilroy, E.; Gupta, K.; Baldassano, R.; Nessel, L.; Li,
H.; Bushman, F.D. and Lewis, J.D. (2011) Linking long-term
dietary patterns with gut microbial enterotypes. Science, 334(6052),
105-108.
Ley, R.E.; Hamady, M.; Lozupone, C.; Turnbaugh, P.J.; Ramey,
R.R.; Bircher, J.S.; Schlegel, M.L.; Tucker, T.A.; Schrenzel, M.D.;
Knight, R. and Gordon, J.I. (2008) Evolution of mammals and their
gut microbes. Science, 320(5883), 1647-1651.
Ley, R.E.; Lozupone, C.A.; Hamady, M.; Knight, R. and Gordon,
J.I. (2008) Worlds within worlds: evolution of the vertebrate gut
microbiota. Nat. Rev. Microbiol., 6(10), 776-788.
Albenberg, L.G. and Wu, G.D. (2014) Diet and the Intestinal
Microbiome: Associations, Functions, and Implications for Health
and Disease. Gastroenterology, 146(6), 1564-1572.
Steer, T.; Carpenter, H.; Tuohy, K. and Gibson, G.R. (2000)
Perspectives on the role of the human gut microbiota and its
modulation by pro- and prebiotics. Nutr. Res. Rev., 13(2), 229-254.
Mai, V. (2004) Dietary modification of the intestinal microbiota.
Nutr. Rev., 62(6 Pt 1), 235-242.
Schwartz, S.; Friedberg, I.; Ivanov, I.V.; Davidson, L.A.; Goldsby,
J.S.; Dahl, D.B.; Herman, D.; Wang, M.; Donovan, S.M. and
Chapkin, R.S. (2012) A metagenomic study of diet-dependent
interaction between gut microbiota and host in infants reveals
differences in immune response. Genome Biol., 13(4), r32.
Turnbaugh, P.J.; Backhed, F.; Fulton, L. and Gordon, J.I. (2008)
Diet-induced obesity is linked to marked but reversible alterations
in the mouse distal gut microbiome. Cell Host Microbe, 3(4), 213223.
Cucchiara, S.; Iebba, V.; Conte, M.P. and Schippa, S. (2009) The
microbiota in inflammatory bowel disease in different age groups.
Dig Dis., 27(3), 252-258.

[94]
[95]

[96]

[97]

[98]
[99]

[100]

[101]

[102]
[103]
[104]

[105]

[106]

[107]

[108]
[109]

[110]

Panda et al.
Manichanh, C.; Borruel, N.; Casellas, F. and Guarner, F. (2012)
The gut microbiota in IBD. Nat. Rev. Gastroenterol. Hepatol.,
9(10), 599-608.
Thorkildsen, L.T.; Nwosu, F.C.; Avershina, E.; Ricanek, P.;
Perminow, G.; Brackmann, S.; Vatn, M.H. and Rudi, K. (2013)
Dominant fecal microbiota in newly diagnosed untreated
inflammatory bowel disease patients. Gastroenterol. Res. Pract.,
2013, 636785.
Manichanh, C.; Rigottier-Gois, L.; Bonnaud, E.; Gloux, K.;
Pelletier, E.; Frangeul, L.; Nalin, R.; Jarrin, C.; Chardon, P.;
Marteau, P.; Roca, J. and Dore, J. (2006) Reduced diversity of
faecal microbiota in Crohn's disease revealed by a metagenomic
approach. Gut, 55(2), 205-211.
Joossens, M.; Huys, G.; Cnockaert, M.; De Preter, V.; Verbeke, K.;
Rutgeerts, P.; Vandamme, P. and Vermeire, S. (2011) Dysbiosis of
the faecal microbiota in patients with Crohn's disease and their
unaffected relatives. Gut, 60(5), 631-637.
Dey, N.; Soergel, D.A.; Repo, S. and Brenner, S.E. (2013)
Association of gut microbiota with post-operative clinical course in
Crohn's disease. BMC Gastroenterol., 13, 131.
Sokol, H.; Seksik, P.; Furet, J.P.; Firmesse, O.; Nion-Larmurier, I.;
Beaugerie, L.; Cosnes, J.; Corthier, G.; Marteau, P. and Dore, J.
(2009) Low counts of Faecalibacterium prausnitzii in colitis
microbiota. Inflamm. Bowel. Dis., 15(8), 1183-1189.
Manichanh, C.; Eck, A.; Varela, E.; Roca, J.; Clemente, J.C.;
Gonzalez, A.; Knights, D.; Knight, R.; Estrella, S.; Hernandez, C.;
Guyonnet, D.; Accarino, A.; Santos, J.; Malagelada, J.R.; Guarner,
F. and Azpiroz, F. (2014) Anal gas evacuation and colonic
microbiota in patients with flatulence: effect of diet. Gut, 63(3),
401-408.
Qin, J.; Li, Y.; Cai, Z.; Li, S.; Zhu, J.; Zhang, F.; Liang, S.; Zhang,
W.; Guan, Y.; Shen, D.; Peng, Y.; Zhang, D.; Jie, Z.; Wu, W.; Qin,
Y.; Xue, W.; Li, J.; Han, L.; Lu, D.; Wu, P.; Dai, Y.; Sun, X.; Li,
Z.; Tang, A.; Zhong, S.; Li, X.; Chen, W.; Xu, R.; Wang, M.; Feng,
Q.; Gong, M.; Yu, J.; Zhang, Y.; Zhang, M.; Hansen, T.; Sanchez,
G.; Raes, J.; Falony, G.; Okuda, S.; Almeida, M.; LeChatelier, E.;
Renault, P.; Pons, N.; Batto, J.M.; Zhang, Z.; Chen, H.; Yang, R.;
Zheng, W.; Yang, H.; Wang, J.; Ehrlich, S.D.; Nielsen, R.;
Pedersen, O. and Kristiansen, K. (2012) A metagenome-wide
association study of gut microbiota in type 2 diabetes. Nature,
490(7418), 55-60.
Jernberg, C.; Lofmark, S.; Edlund, C. and Jansson, J.K. (2007)
Long-term ecological impacts of antibiotic administration on the
human intestinal microbiota. ISME J., 1(1), 56-66.
Dethlefsen, L.; Huse, S.; Sogin, M.L. and Relman, D.A. (2008) The
pervasive effects of an antibiotic on the human gut microbiota, as
revealed by deep 16S rRNA sequencing. PLoS Biol., 6(11), e280.
Jakobsson, H.E.; Jernberg, C.; Andersson, A.F.; Sjolund-Karlsson,
M.; Jansson, J.K. and Engstrand, L. (2010) Short-term antibiotic
treatment has differing long-term impacts on the human throat and
gut microbiome. PLoS One, 5(3), e9836.
Fouhy, F.; Guinane, C.M.; Hussey, S.; Wall, R.; Ryan, C.A.;
Dempsey, E.M.; Murphy, B.; Ross, R.P.; Fitzgerald, G.F.; Stanton,
C. and Cotter, P.D. (2012) High-throughput sequencing reveals the
incomplete, short-term recovery of infant gut microbiota following
parenteral antibiotic treatment with ampicillin and gentamicin.
Antimicrob. Agents Chemother., 56(11), 5811-5820.
Perez-Cobas, A.E.; Artacho, A.; Knecht, H.; Ferrus, M.L.;
Friedrichs, A.; Ott, S.J.; Moya, A.; Latorre, A. and Gosalbes, M.J.
(2013) Differential effects of antibiotic therapy on the structure and
function of human gut microbiota. PLoS One, 8(11), e80201.
Panda, S.; El khader, I.; Casellas, F.; Lpez Vivancos, J.; Garca
Cors, M.; Santiago, A.; Cuenca, S.; Guarner F. and Manichanh, C.
(2014) Short-term Effect of Antibiotics on Human Gut Microbiota.
PLoS One, 9(4) e95476.
Pineiro, M. and Stanton, C. (2007) Probiotic bacteria: legislative
framework-- requirements to evidence basis. J. Nutr., 137(3 Suppl
2), 850S-853S.
Kadooka, Y.; Sato, M.; Imaizumi, K.; Ogawa, A.; Ikuyama, K.;
Akai, Y.; Okano, M.; Kagoshima, M. and Tsuchida, T. (2010)
Regulation of abdominal adiposity by probiotics (Lactobacillus
gasseri SBT2055) in adults with obese tendencies in a randomized
controlled trial. Eur. J. Clin. Nutr., 64(6), 636-643.
Chapman, C.M.; Gibson, G.R. and Rowland, I. (2011) Health
benefits of probiotics: are mixtures more effective than single
strains? Eur. J. Nutr., 50(1), 1-17.

Human Gut Microbiome

[111]

[112]
[113]

[114]

[115]

[116]

[117]
[118]

[119]

[120]

Endocrine, Metabolic & Immune Disorders - Drug Targets, 2014, Vol. 14, No. 4

Park, D.Y.; Ahn, Y.T.; Park, S.H.; Huh, C.S.; Yoo, S.R.; Yu, R.; Sung,
M.K.; McGregor, R.A. and Choi, M.S. (2013) Supplementation of
Lactobacillus curvatus HY7601 and Lactobacillus plantarum
KY1032 in diet-induced obese mice is associated with gut
microbial changes and reduction in obesity. PLoS One, 8(3),
e59470.
Collins, S.M. (2014) A role for the gut microbiota in IBS. Nat Rev
Gastroenterol Hepatol. [Epub ahead of Print]
Cox, M.J.; Huang, Y.J.; Fujimura, K.E.; Liu, J.T.; McKean, M.;
Boushey, H.A.; Segal, M.R.; Brodie, E.L.; Cabana, M.D. and Lynch,
S.V. (2010) Lactobacillus casei abundance is associated with profound
shifts in the infant gut microbiome. PLoS One, 5(1), e8745.
Williams, E.A.; Stimpson, J.; Wang, D.; Plummer, S.; Garaiova, I.;
Barker, M.E. and Corfe, B.M. (2009) Clinical trial: a multistrain
probiotic preparation significantly reduces symptoms of irritable
bowel syndrome in a double-blind placebo-controlled study.
Aliment. Pharmacol. Ther., 29(1), 97-103.
Zeng, J.; Li, Y.Q.; Zuo, X.L.; Zhen, Y.B.; Yang, J. and Liu, C.H.
(2008) Clinical trial: effect of active lactic acid bacteria on mucosal
barrier function in patients with diarrhoea-predominant irritable
bowel syndrome. Aliment. Pharmacol. Ther., 28(8), 994-1002.
Sinn, D.H.; Song, J.H.; Kim, H.J.; Lee, J.H.; Son, H.J.; Chang,
D.K.; Kim, Y.H.; Kim, J.J.; Rhee, J.C. and Rhee, P.L. (2008)
Therapeutic effect of Lactobacillus acidophilus-SDC 2012, 2013 in
patients with irritable bowel syndrome. Dig. Dis. Sci., 53(10),
2714-2718.
Gibson, G.R. and Roberfroid, M.B. (1995) Dietary modulation of
the human colonic microbiota: introducing the concept of
prebiotics. J. Nutr., 125(6), 1401-1412.
Gibson, G.R.; Probert, H.M.; Loo, J.V.; Rastall, R.A. and
Roberfroid, M.B. (2004) Dietary modulation of the human colonic
microbiota: updating the concept of prebiotics. Nutr. Res. Rev., 17
(2), 259-275.
Scholz-Ahrens, K.E.; Ade, P.; Marten, B.; Weber, P.; Timm,
W.; Acil, Y.; Gluer, C.C. and Schrezenmeir, J. (2007) Prebiotics,
probiotics, and synbiotics affect mineral absorption, bone mineral
content, and bone structure. J. Nutr., 137(3 Suppl 2), 838S-846S.
Whisner, C.M.; Martin, B.R.; Schoterman, M.H.; Nakatsu, C.H.;
McCabe, L.D.; McCabe, G.P.; Wastney, M.E.; van den Heuvel,
E.G. and Weaver, C.M. (2013) Galacto-oligosaccharides increase
calcium absorption and gut bifidobacteria in young girls: a doubleblind cross-over trial. Br. J. Nutr., 110(7), 1292-1303.

Received: 21 April, 2014

Accepted: 11 July, 2014

[121]
[122]

[123]

[124]
[125]

[126]

[127]

299

Halmos, E.P.; Power, V.A.; Shepherd, S.J.; Gibson, P.R. and Muir,
J.G. (2014) A diet low in FODMAPs reduces symptoms of irritable
bowel syndrome. Gastroenterology, 146(1), 67-75 e65.
Sheridan, P.O.; Bindels, L.B.; Saulnier, D.M.; Reid, G.; Nova, E.;
Holmgren, K.; O'Toole, P.W.; Bunn, J.; Delzenne, N. and Scott,
K.P. (2014) Can prebiotics and probiotics improve therapeutic
outcomes for undernourished individuals? Gut Microbes., 5(1), 74-82.
Arumugam, M.; Raes, J.; Pelletier, E.; Le Paslier, D.; Yamada, T.;
Mende, D.R.; Fernandes, G.R.; Tap, J.; Bruls, T.; Batto, J.M.;
Bertalan, M.; Borruel, N.; Casellas, F.; Fernandez, L.; Gautier, L.;
Hansen, T.; Hattori, M.; Hayashi, T.; Kleerebezem, M.; Kurokawa,
K.; Leclerc, M.; Levenez, F.; Manichanh, C.; Nielsen, H.B.;
Nielsen, T.; Pons, N.; Poulain, J.; Qin, J.; Sicheritz-Ponten, T.;
Tims, S.; Torrents, D.; Ugarte, E.; Zoetendal, E.G.; Wang, J.;
Guarner, F.; Pedersen, O.; de Vos, W.M.; Brunak, S.; Dore, J.;
Antolin, M.; Artiguenave, F.; Blottiere, H.M.; Almeida, M.;
Brechot, C.; Cara, C.; Chervaux, C.; Cultrone, A.; Delorme, C.;
Denariaz, G.; Dervyn, R.; Foerstner, K.U.; Friss, C.; van de
Guchte, M.; Guedon, E.; Haimet, F.; Huber, W.; van HylckamaVlieg, J.; Jamet, A.; Juste, C.; Kaci, G.; Knol, J.; Lakhdari, O.;
Layec, S.; Le Roux, K.; Maguin, E.; Merieux, A.; Melo Minardi,
R.; M'Rini, C.; Muller, J.; Oozeer, R.; Parkhill, J.; Renault, P.;
Rescigno, M.; Sanchez, N.; Sunagawa, S.; Torrejon, A.; Turner, K.;
Vandemeulebrouck, G.; Varela, E.; Winogradsky, Y.; Zeller, G.;
Weissenbach, J.; Ehrlich, S.D. and Bork, P. (2011) Enterotypes of
the human gut microbiome. Nature, 473(7346), 174-180.
Kanehisa, M.; Goto, S.; Kawashima, S.; Okuno, Y. and Hattori, M.
(2004) The KEGG resource for deciphering the genome. Nucleic
Acids Res., 32(Database issue), D277-280.
Tatusov, R.L.; Fedorova, N.D.; Jackson, J.D.; Jacobs, A.R.;
Kiryutin, B.; Koonin, E.V.; Krylov, D.M.; Mazumder, R.;
Mekhedov, S.L.; Nikolskaya, A.N.; Rao, B.S.; Smirnov, S.;
Sverdlov, A.V.; Vasudevan, S.; Wolf, Y.I.; Yin, J.J. and Natale,
D.A. (2003) The COG database: an updated version includes
eukaryotes. BMC Bioinformatics, 4, 41.
Gosalbes, M.J.; Durban, A.; Pignatelli, M.; Abellan, J.J.; JimenezHernandez, N.; Perez-Cobas, A.E.; Latorre, A. and Moya, A.
(2011) Metatranscriptomic approach to analyze the functional
human gut microbiota. PLoS One, 6(3), e17447.
Burke, C.; Steinberg, P.; Rusch, D.; Kjelleberg, S. and Thomas, T.
(2011) Bacterial community assembly based on functional genes
rather than species. Proc. Natl. Acad. Sci. USA, 108(34), 14288-14293.