Current Pharmaceutical Design, 2009, 15, 2051-2065 2051

The Intestinal Environment in Health and Disease – Recent Insights on the

Potential of Intestinal Bacteria to Influence Human Health

Sam Possemiers1,#,*, Charlotte Grootaert1,#, Joan Vermeiren1,#, Gabriele Gross1,2,#,

Massimo Marzorati1, Willy Verstraete1 and Tom Van de Wiele1,#

1
Laboratory of Microbial Ecology and Technology (LabMET), Ghent University, Belgium and 2Advanced Food
Microbiology, Unilever R&D Vlaardingen, The Netherlands

Abstract: The human intestine is colonized by a complex microbial ecosystem, which could be considered as a separate
organ within the human host, having a coding capacity which exceeds the liver by a factor 100. On the one hand, this ex-
tensive microbiome is closely involved in the first-pass metabolism and bioavailability of food and drug compounds. Un-
derstanding to which extent each individual’s gut microbiota affects the bioavailability and response to orally adminis-
tered drugs is therefore a first important challenge towards novel drug development strategies. On the other hand, as our
microbiota is directly or indirectly involved in the onset of a number of disease states, a new generation of therapeutics
may be developed that affect the structure and functioning of the intestinal microbiota and interfere with their specific
cross-talk with the human host. Ultimately, the intestinal microbiota may even be used as a biomarker for impending dis-
eases inside or outside the gastrointestinal tract and for the evaluation of responses to specific therapeutic interventions.
This review will therefore highlight the importance of the indigenous microbial community and its enormous metabolic
potential, microbe-microbe interactions, mechanisms of host-bacterium cross-talk and will discuss the onset of obesity, a
specific disease state in which the role of intestinal bacteria becomes more and more apparent. Understanding the impor-
tance of the intestinal ecosystem in these phenomena may open the door for new strategies which target the management
of the intestinal microbiome into the desired direction and therefore to a completely new type of nutrition research and
pharmaceutical design.

1. INTRODUCTION Driven by selection forces at both microbial and host

For many years, it was believed that the main function of
the large intestine was the resorption of water and salt by the
body and the facilitated disposal of waste materials. How-
ever, this task definition proved to be far from complete, as it
did not consider the activity of the microbial content of the
large intestine. Indeed, the human colon harbors a highly
complex microbial ecosystem of about 200 g living cells, at
concentrations of 1012 microorganisms per gram gut content,
the highest recorded for any microbial habitat [1]. As this
number is approximately 10 times greater than the total
number of our somatic and germ cells, it seems appropriate
to view ourselves as a composite of human cells and bacteria
and our genetic landscape as a ‘metagenome’, an amalgam
of genes embedded in our genome and in the genomes of all
our microbial partners [2]. It is estimated that the collection
of all microbial genomes in the gut comprises between 2
million and 4 million genes, which is 70-140 times more
than that of their host. This ‘microbiome’ encompasses all
genes that are responsible for numerous processes such as
substrate breakdown, protein synthesis, biomass production,
production of signaling molecules, antimicrobial compounds
and encodes biochemical pathways that humans have not
evolved [3]. Thus, the intestinal microbiota can be regarded
as a separate organ within the human host, which is capable
of even more conversions than the human liver.
*Address correspondence to this author at the LabMET – UGent. Coupure
Links 653, B-9000 Gent, Belgium; Tel: +32 9 264 59 76; Fax: + 32 9 264
62 48; E-mail: sam.possemiers@ugent.be
#
These authors equally contributed to the manuscript.
level, the microbial community has coevolved in a mutualis-
tic relation with the human host with the capacity to commu-
nicate with other species and with the host. Due to this sig-
naling system, the microbiome is closely involved in the
host’s health, for instance by the extraction of energy from
otherwise indigestible compounds [4], the stimulation of the
gut immune system [5], the regulation of cell proliferation
[6], the synthesis of essential vitamins K and B [7] and by
enhancing pathogen resistance [8]. On the other hand, spe-
cific community assemblage may also be seen as a risk fac-
tor contributing to a disease state. This is shown by recent
reports linking intestinal bacteria with diseases ranging from
allergies [9] to bowel inflammation [10] and obesity [11].
When we consider our body therefore as the host of a
complex and prominent microbiome, this opens up a totally
new dimension of potential therapeutic strategies. On the one
hand, the extensive gene pool present in the intestinal micro-
biome is closely involved in the first-pass metabolism of
compounds that are poorly or incompletely absorbed by the
gut. Understanding to which extent each individual’s gut
microbiota affects the bioavailability and response to orally
administered drugs is therefore a first important challenge
towards new drug development strategies. On the other hand,
as our microbiota is directly or indirectly involved in the
onset of a number of disease states, a new generation of
therapeutics may be developed that affects the structure and
functioning of the intestinal microbiota and interferes with
their specific cross-talk with the human host. Ultimately, the
intestinal microbiota may even be used as a biomarker for

1381-6128/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

2052 Current Pharmaceutical Design, 2009, Vol. 15, No. 18
impending diseases inside or outside the gastrointestinal tract
and for the evaluation of responses to specific therapeutic
interventions. This review will therefore highlight the impor-
tance of the indigenous microbial community and its enor-
mous metabolic potential, the mechanisms of bacterium-host
interaction and a specific disease state in which the role of
intestinal bacteria becomes more and more apparent.
2. THE INTESTINAL MICROBIOTA: A WORLD IN-
SIDE US
2.1. Structure and Functional Organization
One of the most important accomplishments of Life Sci-
ences in the last decades was the completion of the Human
Genome Project, which characterized over 25 000 genes in
the human cell. Five years ago, the US National Institutes for
Health started another ambitious project which has the aim
of exploring the vast microbial community that interacts with
the human host: the Human Microbiome Project [2]. The use
of advanced culture-independent approaches [12, 13] and of
new ecological theories about evolutionary forces shaping
the microbial community in the intestine [6, 14, 15] have
already provided new insights into the structure of our mi-
crobial ecosystem. The adult human gastrointestinal tract
contains all three domains of life, bacteria, archaea and eu-
karya, with the largest community residing in our colon. Al-
though 55 and 13 divisions of respectively bacteria and ar-
chaea have been described, only 8 bacterial divisions have
been identified so far in the gastrointestinal tract and the gut
microbiota is dominated by only two bacterial divisions, the
Cytophaga-Flavobacterium-Bacteroides (bacteroides) and
Firmicutes (clostridia, eubacteria, …), with lower levels of
Actinobacteria (bifidobacteria), and by mainly one member
of the archaea, Methanobrevibacter smithii. At this level, the
intestinal communities of all humans therefore appear quite
similar. However, within these divisions, a limited number
of lineages terminate in broad, shallow radiations comprising
hundreds of species and thousands of strains, making the
microbiota of an individual as personalized as a fingerprint
[14, 15].
The unique shape of this microbial ecosystem is related
to a specific functional organization. The structure and com-
position of this ecosystem reflects a natural selection at both
microbial and host levels, which promote a mutual coopera-
tion in the search of a functional stability [16]. Indeed, a re-
cent paper from Turnbaugh et al. [17] showed that, although
the community composition may be as individual as a fin-
gerprint, a ‘core’ gut microbiome would exist at the level of
shared functional genes. It has been proposed that such equi-
librium requires a series of evolved, nested equilibria to
achieve the overall homeostasis, in analogy with the ‘Evolu-
tionary Stable Strategy’ theory. In other words, microbial
success in a host requires the ability to grow and overcome
the host’s defenses, yet cannot affect the fitness of the host,
as this would ultimately reduce the number of hosts and
thereby lead to loss of the bacteria’s own habitat [16]. Such a
selection primarily occurs along mucosal surfaces via a host-
microbiota cross-talk that leads to the modulation of host
immunity. The gastrointestinal system has to constantly deal
with a large number of bacteria and only those recognized as
“friendly” are considered to be tolerated. Commensal bacte-
Possemiers et al.
ria are thus allowed to have a direct contact with the host
(adhesion), thereby positively activating innate and adaptive
immunity [18]. The diversity found in the gastrointestinal
tract, namely a few divisions represented by very tight clus-
ters of related bacteria, may therefore reflect strong host se-
lection for specific bacteria whose emergent collective be-
havior is beneficial for the host [14].
2.2. Mechanisms of Cross-Talk between the Colonic Mi-
crobiota and Its Host
The gastrointestinal tract is the site in the body where the
divergent needs of nutrient absorption on the one hand and
host defense and host-bacterium cross-talk on the other hand
collide. Whereas nutrient absorption requires a thin epithe-
lium and large surface area, optimal communication with
commensal bacteria and simultaneous protection against
pathogen invasion requires an extensive and selective de-
fense system. The investment by the gut in protecting itself
is evident in the abundant lymphoid tissue and immune cells
it harbors. At the same time, multiple mechanisms exist for
host-bacterium cross-talk, ultimately influencing human
health. It is therefore important to understand how these ef-
fects are mediated, and how bacteria communicate with
epithelial cells in the intestine.
In general, gut bacteria can interact with the host by
common mechanisms like attachment to the mucosal surface
or by excretion of soluble factors, but many species have
developed unique approaches of bacterial-epithelial cros-
stalk, thereby inducing specific immune responses [19, 20].
It has been proposed that this cross-kingdom cell-to-cell sig-
naling could also involve small molecules, such as hormones
that are produced by the eukaryotes (adrenaline, noradrena-
line,…) and hormone-like chemicals (autoinducer signal 3 -
AI-3 and acyl homoserine lactones) that are produced by
bacteria for quorum sensing purposes [21]. In many cases
however, the varying underlying molecular mechanisms are
not yet completely understood. Importantly, innate immune
recognition of endogenous bacteria plays a crucial role in
maintaining intestinal homeostasis under healthy conditions
[22, 23]. To sense bacteria that are present in the intestinal
tract, the host innate immune system is able to recognize
specific molecular structures that are unique to pathogenic as
well as non-pathogenic microorganisms, referred to as Mi-
crobe-Associated Molecular Patterns [24]. The best-charac-
terized class of pattern recognition receptors are the Toll-like
receptors (TLR) that elicit adequate inflammatory and antim-
icrobial responses after activation by their microbial ligands
[24, 25]. For example, lipoteichoic acids and bacterial DNA
can exert immunomodulatory properties towards the host
mediated by respectively TLR2 and TLR9 [26-28]. Currently
known molecular modes of action of probiotic bacteria -
added to functional food products to improve host health and
well-being - have been reviewed elsewhere [29]. For ins-
tance, interactions of lactobacilli with the pattern-recogni-
tion receptor DC-SIGN (dendritic cell-specific intercellular
adhesion molecule 3-grabbing non-integrin) and with man-
nose-residues on the epithelial surface have been described
[30, 31]. Although recently various studies have been pub-
lished on cross-talk of intestinal bacteria with the host im-
mune system, the complex connections between the diversity
of bacterial triggers and the various components of possible
Intestinal Bacteria and Human Health Current Pharmaceutical Design, 2009, Vol. 15, No. 18 2053

host responses are not yet fully understood (reviewed in Due to the use of germ-free animals in the majority of
Corthesy et al. [18] and Medhzitov et al. [24]). studies, evidence on the impact of similar mechanisms in the
presence of an endogenous microbiota in conventional ani-
After the initial contact between microbes and epithelial
mals is limited. However, modulation of host gene expres-
cells, the host organism may react to these bacterial signals.
Different bacterial triggers in the intestine can induce a vari- sion by commensal species in germ-free animals demon-
strates the importance of the composition of the intestinal
ety of host responses, which are reflected in changes in gene
microbiota for physiological functions of the host [35, 37].
expression and can be detected simultaneously by for exam-
Mucosal immune responses are highly adapted to the pres-
ple transcriptome analyses. Several studies using this ap-
ence of large numbers of endogenous bacteria in the lower
proach have been performed with pathogenic, commensal
intestine, constantly present in close proximity to host tissues
and probiotic bacterial species, employing different host
models [30, 32-34]. Colonization of germ-free mice with [41]. This is indicated by the fact that germ-free mice pos-
sess small and underdeveloped Peyer’s patches and that the
commensal and probiotic bacteria such as B. thetaiotaomi-
restitution of these mice with a microbial microbiota is suffi-
cron, Bifidobacterium longum and some Lactobacillus spp.
cient to restore the mucosal immune system [9]. One of the
has been shown to cause substantial changes in gene expres-
future challenges of gastrointestinal microbiology research
sion of the host, including the induction of host genes in-
will be to study the regulatory mechanisms within this con-
volved in innate immunity, mucosal barrier function, nutrient
absorption, and intestinal maturation [35-37]. stant co-existence and its implications for health in more
detail.
One interesting example of a gene whose expression has
been shown to be differently affected by interactions with 2.3. Towards an Integrative Approach to Study the Intes-
various bacterial species in different animal models is tinal Microbiota and Host-Microbe Interactions
RegIII
(human counterpart: pancreatitis-associated protein,
PAP). RegIII
/PAP has been proposed to be directly antimi- As many specific interactions of intestinal bacteria with
the host have not been elucidated yet, molecular approaches
crobial and could therefore play a role during increased bac-
are needed to identify mechanisms at both bacterial and host
terial-epithelial contact to limit potential microbial penetra-
level (Fig. 1) by which specific bacteria may confer defined
tion and maintain mucosal integrity [38]. RegIII
/PAP
health benefits [29]. Genome sequence analyses of an in-
(mRNA) expression has been shown to be up- or downregu-
creasing number of bacterial strains provide the tools to
lated, respectively, by B. thetaiotaomicron, E. coli and Sal-
monella, segmented filamentous bacteria, Schaedler’s E. study genetic parameters that determine their functions re-
lated to host health [57-59]. Currently, specific bacterial
coli, Listeria innocua, Lactobacillus plantarum, and B.
genes can be characterized by the construction of (multiple)
longum [30, 32, 37-40]. Interestingly, the ability of bacteria
gene-specific mutant strains in an isogenic background [60].
to repress host expression of this bactericidal protein may
This offers much more elegant and targeted research strate-
possibly promote their own survival in the gut and influence
gies than the former use of spontaneous mutants with unde-
the microbial ecology [37].

Fig. (1). Schematic overview of host-microbe interactions in the intestine and currently available (molecular) methods to investigate various
factors involved. References indicate studies for which a similar approach has been applied.
2054 Current Pharmaceutical Design, 2009, Vol. 15, No. 18
fined genetic alterations [53, 61]. Furthermore, it has become
possible to assess responses of particular strains to gastroin-
testinal conditions in terms of bacterial gene expression dur-
ing passage through the gastrointestinal tract [43, 62].
With regard to gut microbial ecology, several molecular
high-throughput techniques are currently available to moni-
tor intestinal bacterial population dynamics such as 16S ribo-
somal DNA terminal restriction fragment pattern analysis
(T-RFLP), denaturing gradient gel electrophoresis (DGGE),
phylogenetic microarrays as well as metagenomics and
metaproteomics approaches [12, 47, 63-65]. Most of these
culture-independent methods are based on phylogenetic
analysis of rRNA genes and can provide important insights
into the types of bacteria present in the gastrointestinal tract,
their distribution, functionality and development under cer-
tain conditions [66]. At present, comparative metagenomics
have been used e.g. in the Human Microbiome Project to
find out whether all humans have an identifiable ‘core’ mi-
crobiome (see above) and to compare intestinal microbial
community composition among different populations [2].
Linking gut microbial community composition profiles to
e.g. host metabolomics data can indicate key functional mi-
crobiome members that are particularly important for host
metabolism and health [67].
Concerning the host, the rapidly progressing develop-
ment of whole genome sequences and commercially avail-
able microarrays for increasing numbers of species improves
the possibilities to study transcriptomes which illustrate host
responses upon environmental and e.g. bacterial stimuli [32,
68, 69]. However, truly integrated approaches, which focus
on both specific bacterial genes potentially involved in a
particular cross-talk mechanism as well as on their molecular
effects on the host, are still scarce [30, 50].
In order to gain more insight in this complex host-
bacterium interplay and to understand how this can affect
human health, the development and application of appropri-
ate model systems will be very important. Several in vitro
model systems have been developed to study the intestinal
microbiota as a complex ecosystem and its metabolic poten-
tial. Examples of well-designed models are the Simulator of
the Human Intestinal Microbial Ecosystem (SHIME) [70,
71], a similar three-step colon model [72] and the EnteroMix
model [73]. Such systems enable fast reproducible experi-
ments under controlled conditions and can be used to study
the metabolic potential of intestinal bacteria and microbe-
microbe interactions such as horizontal gene transfer. Vali-
dation of the results may be obtained by using well-
controlled in vivo models for the human gut, such as germ-
free and human microbiota-associated animal models [74].
These results should help to formulate and direct hypothesis-
based research of the microbiota’s metabolome in humans.
To study specific host-bacterium cross-talk, optimal ap-
proaches should include in vitro as well as in vivo experi-
ments to investigate possible health effects and to integrate
mechanistic exploratory indications with the complex multi-
factorial interactions that occur in vivo. To do this, a number
of in vivo models have been developed in which specific
genes are switched off (e.g. leptin-deficient ob/ob mice) or
which are colonized with specific microbiota. One particu-
larly interesting example of an in vitro model to study host-
Possemiers et al.
bacterium interactions was developed to study the joint me-
tabolism between liver and gut microbiota. In an elegant
two-compartment reactor, Laube et al. succeeded in the co-
culture of hepatocytes and fecal microbiota under aerobic
and anaerobic conditions, respectively [75]. This way, the
sequential metabolism of 7-ethoxycoumarin and a thiadiazi-
non derivative by hepatocytes and fecal bacteria was investi-
gated in vitro.
Strategies which target the intestinal microbiota may
consist of affecting or introducing specific bacterial species
or strains, or may lead to modulation of the composition or
activity of the general microbial ecosystem. A typical exam-
ple of the introduction of specific bacterial strains is the use
of engineered lactic acid bacteria as mucosal-delivery vehi-
cles and vaccine carriers, expressing immunomodulatory
proteins [76]. Several applications of lactic acid bacteria
delivery have already been tested in animal models, targeting
the possible prevention and treatment of Inflammatory
Bowel Disease (IBD), allergies and different infections (re-
viewed in [77]). In many cases however, the final health ef-
fect cannot be attributed to one specific species, but is the
result of a complex interplay between various bacteria,
which interact through various mechanisms with the host. In
analogy with the recently developed ecological concept of
Microbial Resource Management [78, 79], which provides a
number of tools that can help in the interpretation of ecologi-
cal surveys, we therefore introduce the concept of Gastroin-
testinal Resource Management (GRM), i.e. the management
of the complex gut microbiota and its metabolism with the
aim of improving the health of the host (Fig. 2).
The rationale behind this is that microorganisms acting as
consortia are comparable with human beings working to-
gether in organizations and firms, requiring human resource
management. To put the basics of GRM in perspective one
needs to know:
a) Who is there? The genomic methods currently allow the
listing of the various organisms present. Besides the mo-
lecular analysis of microbial communities, one should
also explore new ways to isolate new species by new cul-
tivation approaches.
b) Who is doing what? There are a variety of new ap-
proaches to identify the actuators [43-47]. All these
methods will allow making up the “catalogues” of the
species involved in the different processes. Yet, they will
only give a limited picture of the overall ”happiness” and
”functioning” of the microbial consortia involved.
c) Who is doing what with whom? To deal with complex
groups of living entities, it is required to know the inter-
relationships. We need to learn about the standard type
exchanges between different groups of organisms, par-
ticularly about types of “trading” of electron donors
and/or acceptors.
If we can link the answer to those three questions to-
gether, this will allow to understand, and therefore also to
manage, what makes the intestinal community to act in mu-
tualism with the host and which factors trigger the intestinal
microbiome to become a pathogenic one. Understanding the
structure and function of the intestinal ecosystem as a whole,
will therefore be an important step in finding new drug tar-
Intestinal Bacteria and Human Health
Fig. (2). Introducing the ecological concept of Gastrointestinal Resource Management, the management of the complex gut microbiome with
the aim to improve host health. Central questions are who is there, who is doing what with whom and how can one adjust, control and/or
steer these mixed cultures and communities.
gets which help to manage and steer the intestinal micro-
biome into the desired direction.
3. METABOLIC POTENTIAL OF INTESTINAL MI-
CROBIOTA AND ITS IMPLICATIONS FOR HUMAN
HEALTH
3.1. Microbial Metabolism in the Intestine
As the colon microbial community receives a large diver-
sity of non- or partly digested food components and host
excretion products as nutrient and energy source, the set of
bacterial genes that code for metabolic enzymes is highly
diverse and redundant to ensure the metabolism of many
different substrates under the fluctuating nutritional condi-
tions. Carbohydrates, resistant to digestion, drive colonic
bacterial fermentation and the resulting end products (SCFA)
are considered beneficial for the host. In contrast, when pro-
teins are fermented, the end products include toxic com-
pounds, such as amines and phenols [80]. Besides carbohy-
drates and proteins, many other components, such as plant
chemicals, food or environmental contaminants and xenobi-
otics in general also become available to the gut microbiota.
It has been shown that the gut microbial community has the
ability to metabolize xenobiotics far more extensively than
any other part of the body (reviewed by [81]). This microbial
factor in the metabolism of ingested chemicals has often
been overlooked, yet the last decade of scientific research
has brought new insights and surprising findings. Ilett dem-
onstrated that gut bacterial metabolism has a strong potential
for both bioactivation and detoxification of xenobiotics [82].
Table 1 presents the different types of microbial enzymes in
the gut. In contrast to the oxidative and conjugative nature of
liver metabolism, which generates hydrophilic high molecu-
lar weight biotransformation products, the metabolic nature
of the gut microbial community in an anaerobic environment
is mainly reductive and hydrolytic, generating non-polar low
molecular weight byproducts [81]. Yet, oxidative reactions
can also occur.
3.2. Implications for the Activity of Dietary Constituents
Foodstuffs represent a significant source of components
that have the potential to positively or negatively influence
Current Pharmaceutical Design, 2009, Vol. 15, No. 18 2055
human health. A selected class of food compounds that will
shortly be described here as a good example of biologically
active compounds, is the group of (poly-)phenols. The daily
intake ranges from 100 mg to over 2 g and primarily origi-
nates from the consumption of coffee, black tea, fruits and
vegetables. From the ingested polyphenols, only 5% is ab-
sorbed in the duodenum and only 5% of the absorbed frac-
tion, mainly flavanols, reaches the blood circulation intact.
The rest of the absorbed fraction is conjugated through the
liver biotransformation process. The 90 to 95% of the in-
gested compounds together with the biliary secreted conju-
gated compounds reach the colon where they become avail-
able to the resident microbiota (reviewed by Clifford [83]).
The extensive transformations taking place include the re-
moval of sugars, removal of phenolic hydroxyl groups, fis-
sion of aromatic rings, and further degradation [84]. Many
microbial metabolites have been found and include phenols
and aromatic/phenolic acids/lactones possessing 0, 1 or 2
phenolic hydroxyl groups and up to five carbons in the side
chain (reviewed by [83]).
Flavonoids are the best studied polyphenols and can be
divided into several groups, of which flavanols and proan-
thocyanidins are generally unconjugated, whereas the other
substances normally occur as glycosides [83]. Amongst
these, isoflavones, some flavanones and stilbenes, some lig-
nans and some coumarins are characterized as phytoestro-
gens for their putative estrogenic and/or anti-androgenic
properties. These phytoestrogens (isoflavones from soy,
prenylflavonoids from hop, coumestans and lignans from
fruits and cereals) are typically considered as a good exam-
ple of the importance of intestinal metabolism of food com-
pounds. This is related to the fact that the potency of phy-
toestrogens to prevent or modulate hormone-dependent dis-
eases such as breast- and prostate cancer, or osteoporosis and
menopausal complaints, is largely governed by the presence
of specific intestinal microorganisms. Lignans only show
estrogenic properties after metabolism by colon microorgan-
isms. Hop contains the most powerful phytoestrogen known
thus far, namely 8-prenylnaringenin (8-PN). Rowland et al.
discussed the role of the gut microbial community in the
bioavailability and metabolism of estrogens in general and
2056 Current Pharmaceutical Design, 2009, Vol. 15, No. 18 Possemiers et al.

Table 1. Metabolic Potency of Human Gastrointestinal Microbiota (After: Ilett et al. [82])

Reactions Enzyme Bacterial Species / Origin of Sample

Hydrolysis

Glucuronides
-Glucuronidase Escherichia coli

Glycosides
-Glucosidase Enterococcus faecalis, Eubacterium rectale, Clostridium sphenoides

Amides Amide hydrolase E. coli, Bacillus subtilis

Esters Deacetylase E. faecalis

Sulfamates Arylsulfotransferase Clostridia, enterobacteria, enterococci

Reduction

Azo-compounds Azoreductase Clostridia, lactobacilli

Unsaturated lacton Unsat. glycoside hydrogenase Eubacterium lentum

Aliphatic double bounds Unsat. fatty acid hydrogenase E. faecalis

Nitro-compounds Nitroreductase E. coli, bacteroides

N-oxides N-oxide reductase Human colon

S-oxides Sulfoxide reductase E. coli

Ketones Hydrogenase Rat caecum

Hydroxylamines Nitroreductase Rat GIT

Dehydroxylation

Demethylaton Demethylase Enterococci, lactobacilli, clostridia

Deamination Deaminase Bacteroides, clostridia

Decarboxylation Decarboxylase E. faecalis

Dehydrogenation Dehydrogenase Clostridium welchii

Dehalogenation Dehalogenase E. coli, Aerobacter aerogenes

Synthetic Reactions

Esterification Acetyltransferase E. coli

N-nitrosation E. faecalis, E. coli

Other Reactions

Oxidation Oxidase E. coli, E. faecalis

Isomerization Isomerase E. rectale, C. sphenoides

Fission aliphatic Tryptophanase E. coli, Bacillus alvei

Activity towards cystein or GSH conjugates C-S lyase Pig GIT, Eubacterium aerofaciens

phytoestrogens more in particular [85]. Intestinal bacteria
contribute to the bioavailability and biological activity of
phytoestrogens in a number of ways. Firstly, intestinal bacte-
ria produce ß-glucosidases thereby cleaving the naturally
occurring glycosylated phytoestrogens into an aglycon. Sec-
ondly, the gut bacteria elicit glucuronidase and sulfatase ac-
tivity, thereby deconjugating phase II metabolites from the
liver and releasing aglycons again. Thirdly and most impor-
tantly, intestinal bacteria are capable of transforming the
original components to metabolites that have a higher bio-
logical activity (Fig. 3) [86]. For example, equol, 8-PN and
enterodiol and enterolacton are bacterial metabolites from
daidzein (soy) [87], isoxanthohumol (hop) [88] and secoiso-
lariciresinol diglucoside (fruit/cereal lignans) [89, 90], re-
spectively and have a much higher biological activity than
their precursor product. A remarkable aspect of the microbial
conversion of daidzein into equol and of isoxanthohumol
into 8-PN is the large interindividual variability in the con-
version efficiency [52]. This was nicely illustrated for equol
[91] and 8-PN production [92].
Intestinal Bacteria and Human Health
Fig. (3). The most relevant groups of phytoestrogens, the isoflavones, lignans and prenylflavonoids, are present in food as less active precur-
sors. Inside the human body, they can be activated into the respective active metabolites equol, enterodiol + enterolacton and 8-
prenylnaringenin. Although some transformations are of chemical origin (C) or catalyzed by human enzymes (H), microbial enzymes (M)
have a crucial role in the generation of the final metabolites for each group of phytoestrogens (after Possemiers, et al. [86]).
Other examples of gut microbial polyphenol metabolism
include for instance proanthocyanidins, which are complex
flavonoid polymers naturally present in fruits, legume seeds,
cereal grains, and different beverages (wine, tea, cocoa/
chocolate, cider) (reviewed by Santos-Buelga et al. [93]),
and are, therefore, an integral part of the human diet. The
most common proanthocyanidins are procyanidins, which
consist of flavan-3-ol (catechin, epicatechin) elementary
units with the typical C6-C3-C6 flavonoid skeleton. Procya-
nidins are not/poorly absorbed through the intestinal barrier,
but they are degraded by the colonic microbiota into low
molecular weight phenolic acids [94], which are more read-
ily absorbed.
3.3. Implications for the Activity of Xenobiotics
Besides the interest in the microbial conversion of health-
promoting components from ingested foodstuffs, much at-
tention is also given to the role of intestinal bacteria in the
conversion of ingested drugs, environmental or food con-
taminants or xenobiotics in general. Firstly, the intestinal
microbiota may interfere with the clearance of ingested
xenobiotics through deconjugation reactions of phase II
biotransformation products from enterocytes and primarily
hepatocytes. This results in the enterohepatic circulation of
xenobiotic compounds. Compounds absorbed in the intestine
and subsequently detoxified are usually conjugated with po-
lar groups (glucuronic acid, glycine, sulfate, glutathion and
taurine) in the liver prior to secretion with the bile [82]. Once
released in the intestinal lumen, bacterial enzymes such as
-
glucuronidase, sulfatase and other glycosidases may hydro-
lyze these conjugates again. This would negate the detoxifi-
cation cycle and delay the excretion of many exogenous
compounds since the original compounds or phase I metabo-
lites are more prone to intestinal absorption than their phase
II conjugates. In one particular study, it was shown that gut
microbial
-glucuronidase activity increased the genotoxicity
of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) [95], a
food-borne carcinogen that is formed in meat and fish during
Current Pharmaceutical Design, 2009, Vol. 15, No. 18 2057
cooking. Additionally, guinea pig experiments showed that
the hydrolysis of benzo(a)pyrene conjugates by the intestinal
microbiota resulted in de novo production of toxic
benzo(a)pyrene intermediates which caused the formation of
DNA adducts in the colon [96].
The ability of gut bacteria to metabolize drugs came un-
der the attention of pharmaceutical companies since an acci-
dent in 1993 with the antiviral drug orivudine revealed that
its gut microbial metabolite (E)-5-(2-bromovinyl)uracil in-
terfered with the clearance of a co-administered anti-cancer
drug 5-fluoro-uracil. This resulted in the death of 18 patients
[97]. Recently, Sousa et al. reviewed the conversion of over
30 drug compounds by gut microorganisms and the related
consequences for their biological effect in the human body
[81]. Examples are the reduction of omeprazole and digoxin,
hydrolysis of lactulose and sorivudine, acetylation of 5-
aminosalicylic acid, proteolysis of insulin and calcitonin and
N-demethylation of methamphetamine. Additionally, de-
methylation, deamination, decarboxylation and dehalogena-
tion reactions have also been described, next to other reac-
tions such as aromatization, esterification and N-nitrosation
[82].
Quite remarkably, gut bacteria can also perform oxida-
tive reactions despite a reducing intestinal environment. For
instance, Enterococcus faecalis can use micromolar amounts
of oxygen, diffusing across the epithelium from the serosal
to the luminal side, to form hydroxylated radicals from D-
phenylalanine and N-tert-butylnitrone. This may increase the
oxidative stress on the intestinal epithelium [98]. Further-
more, IQ is converted to the direct acting mutagen 7-
hydroxy-IQ [99] by bacteria belonging to predominant intes-
tinal populations, such as B. thetaiotaomicron, Clostridium
clostridiiforme and E. coli [100], although a large interindi-
vidual variability exists. As a third example, oxidative reac-
tions were also described with the hydroxylation of poly-
cyclic aromatic hydrocarbons (PAH) by in vitro cultured
intestinal microbiota [101]. Hydroxylation of PAH gives
these compounds an affinity for the human estrogen recep-
2058 Current Pharmaceutical Design, 2009, Vol. 15, No. 18
tor, so that they may interfere with normal hormone-driven
processes in the body. Therefore, microbial oxidation prod-
ucts of PAH may actively interfere with the host’s physiol-
ogy.
Finally, also the microbial modifications of food con-
taminants may interfere with intestinal health. For example,
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a
carcinogenic heterocyclic aromatic amine formed in meat
products during cooking, is converted to PhIP-M1 by En-
terococcus faecium strains and Lactobacillus reuteri [102].
Whether it is a detoxification is still a matter of debate, since
PhIP-M1 has been shown to be cytotoxic toward Caco-2
cells but is not mutagenic in the Ames assay [103]. As a sec-
ond example, incubation of arsenobetaine, an important or-
ganoarsenical compound in fish and shellfish, with intestinal
microorganisms results in dimethylarsinic acid, dimethylars-
inoylacetic acid and trimethylarsine oxide production. The
toxicological consequences of these metabolites in the colon
environment are not known. In addition, metal(loid)s such as
As, Se, Te, Bi have been shown to be volatilized through
methylation (e.g. As(CH3)3) and hydride formation (AsH3 )
(Diaz and Van de Wiele, submitted). Methanoarcheae such
as M. smithii are now proposed as an important player in this
process [104]. This is of important toxicological significance
as volatile metal(loid)s easily diffuse across the gut epithe-
lium and thus become bioavailable to the host.
3.4. Indirect Effects of the Intestinal Microbiota on Host
Metabolism
During their research of microbe-host interactions,
Hooper et al. made an important observation concerning the
effect from gut bacteria towards the host [105]. Colonization
of germ-free rats by B. thetaiotaomicron resulted in modula-
tion of epithelial cell gene expression involved in several
important functions. This not only involved mucosal barrier
formation, angiogenesis and nutrient absorption but, impor-
tantly, also xenobiotic metabolism. In addition, Li et al. de-
monstrated a "transgenomic" approach to link gut micro-
biome and metabolic phenotype (metabotype) variation.
Combining spectroscopic, microbiomic, and multivariate
statistical tools, they analyzed fecal and urinary samples
from different individuals and modeled the microbe-host
metabolic connectivity. They introduced the concept of func-
tional metagenomics by which they characterized key func-
tional members of the microbiome, such as Faecalibacte-
rium prausnitzii, that most influence host metabolism and
hence health [48]. Other examples of bacterial modulation of
host metabolism include the studies performed by Villarini et
al. who recently showed that Lactobacillus casei decreased
the production of liver xenobiotic metabolizing enzymes
thereby lowering the genotoxicity of 1,2-dimethylhydrazine
[106]. Additionally, lactulose fermentation products influ-
ences the activities of liver and intestinal xenobiotic metabo-
lizing enzymes in rats inoculated with Clostridium parapu-
trificum [107]. Furthermore, Humblot et al. showed that
Brussels sprouts, oligosaccharides, and fermented milk low-
ered the genotoxicity of 2-amino-3-methylimidazo[4,5-
f]quinoline by changing not only the composition of the in-
testinal microbial community, but also the xenobiotic me-
tabolizing enzymes [108]. Thus, supplementation of func-
tional foods under form of dietary fibers, probiotics or other
Possemiers et al.
food constituents may modulate the gut microbial commu-
nity composition, thereby affecting the metabolic potency of
the microbiota as such, but also influencing the host
biotransformation capacity.
3.5. Perspectives
In summary, the true scale of the metabolic potential of
the gut microorganisms is only recentlty becoming evident.
Not only is this important for e.g. the biological activity of
many functional food components, but it also has toxicologi-
cal consequences when assessing the risks from ingested
contaminants or the pharmacological effects of administerd
drugs. Mikov pointed out the importance of gut microbiota
stating that the gut microbial metabolism must be considered
an integral part of drug/xenobiotic metabolism and toxicity
studies [109]. New developments in metabonomics covering
the metabolic potency of the entire gut microbiome will re-
veal new metabolites and pathways of biotransformation and
biodegradation. Additionally, emphasis needs to be put on
the interindividual variability in terms of microbial commu-
nity composition and hence, also in its metabolic capabili-
ties. Li et al. concluded from their work that interindividual
differences in xenobiotic metabolism are associated to a
large extent with the gut microbiota composition, which pre-
disposes a different pathophysiological outcome upon die-
tary factors or chemical stimuli [110]. Clearly, unraveling
the metabolic pathways of the gut microbiota but also ex-
ploring the interindividual differences presents an enormous
challenge for the scientific community.
4. HOST-BACTERIUM CROSS-TALK: GUT BACTE-
RIA AND OBESITY
4.1. Obesity and the Intestinal Microbial Community
Obesity has been recognized as one of the most important
growing problems in our current society leading towards
health problems such as diabetes type II, certain types of
cancer and cardiovascular diseases [111]. Besides an im-
paired balance between energy uptake and physical activity,
the composition of the intestinal microbiota has recently
been presented as a factor playing a substantial role in the
development of obesity. Ley et al. showed that the state of
obesity determines the composition of the intestinal micro-
bial community [112]. Both mice and human trials revealed
that obese individuals had a decrease of up to 50% in the
abundance of bacteria belonging to the division of the Bac-
teroidetes, and a proportional increase in Firmicutes, com-
pared to lean individuals. Moreover, this proportion of Bac-
teroidetes to Firmicutes increased with weight loss on low-
calorie diets [113]. A corresponding decrease in the propoer-
tion of Bacteroidetes was also observed in a recent study on
154 individuals with, in this case, also a significant increase
in Actinobacteria [17]. It has also been demonstrated that the
composition of the microbial community may also determine
the state of obesity [114]. In this study, the intestinal content
of both lean and genetically modified ob/ob mice (with
leptin deficiency and thus developing obesity) was isolated,
and transplanted in normal, germ-free mice. It was observed
that mice, conventionalized with microbiota originating from
obese mice, had a higher percentage increase in body fat
over two weeks than mice conventionalized with intestinal
Intestinal Bacteria and Human Health
bacteria from lean mice. Furthermore, it was shown that a
high fat diet alone is not sufficient to induce obesity [11],
indicating that host-bacterium cross-talk may play an essen-
tial role in the host’s fat storage.
Given this potentially crucial role of intestinal bacterial
in the process of metabolic homeostasis, i.e. the control of
energy uptake and metabolism in the body, the next para-
graphs will discuss the potential mechanisms of this host-
bacterium cross-talk and which future strategies may be en-
visaged to prevent or treat obesity and metabolic disorders
by targeting the intestinal microbiota (Table 2).
4.2. Gut Peptides Involved in Appetite Control
Appetite control is a first important factor in the concept
of metabolic homeostasis and involves the production of a
number of gut peptides. Glucagon-like peptide 1 (GLP-1)
and peptide YY (PYY) are satiety stimulating hormones,
released in response to nutrient ingestion by L-cells in
mainly ileum and colon. GLP-1 promotes insulin secretion
and pancreatic
-cell proliferation and controls glycogen
synthesis in muscle cells [115], while PYY slows down gas-
tric emptying. In contrast, ghrelin stimulates appetite and is
mainly produced by P/D1 cells in the stomach and -cells of
the pancreas [126]. Non-digestible carbohydrates, such as
oligofructose [127], lactitol [128] and resistant starch [117],
are effective to induce satiety by modulating the production
of the gut peptides GLP-1, PYY and ghrelin through a
mechanism that also involves modulation of the intestinal
microbial community [129]. Rat studies demonstrated that an
oligofructose-enriched diet significantly increased GLP-1
and decreased ghrelin production, and doubled the number
of GLP-1-expressing cells in the proximal colon [127, 130].
Lactitol mainly increased PYY production in rats and hu-
mans [128], while resistant starch significantly affected both
PYY and GLP-1 production [117]. The latter authors also
demonstrated that bacterial regulation of gut peptides is me-
diated by short chain fatty acids produced from indigestible
substrates. Physiological concentrations of acetate, propion-
ate and butyrate, but also a pH decrease from 7.5 to 6, sig-
nificantly increased proglucagon and PYY in the entero-
endocrine colon cell line STC-1 [117]. Furthermore, the
Table 2. Examples of Mechanisms, Conventional Drugs, Potential Microbial Alternatives and Possible Advantages of a Microbial
Approach to Prevent or Treat Obesity
Example of
Mechanism Target
Conventional Drugs
GLP-1
GLP-1, PYY
Satiety gut peptides PYY
and analogues
Ghrelin
Fenofibrate,
Lipase inhibitors FIAF
thiazolidinediones
Cholesterol,
Liver lipogenesis Statines
Fatty acids
Liver gluconeogenesis Glucose, Insuline Metformin
Current Pharmaceutical Design, 2009, Vol. 15, No. 18 2059
presence of glucose in the intestine also enhances the GLP-1
production in the L-cells [116]. These mechanisms may ex-
plain why gut peptide modulation is only observed with
highly fermentable fibers [131].
4.3. Gut Peptides Involved in fat Storage
In vivo studies with germ-free and conventionalized mice
revealed that intestinal bacteria may not only impact the in-
take of energy but that they may also modulate the host’s fat
storage by repressing the intestinal production of a cytokine
involved in this process, called the fasting-induced adipose
factor (FIAF) [4]. Once secreted in the blood, FIAF inhibits
the activity of lipoprotein lipase, an enzyme responsible for
the conversion of triglycerides to monoglycerides and fatty
acids from circulating lipoproteins [118, 132]. As a conse-
quence, these triglycerides cannot be stored in the fat tissue,
resulting in a lower body weight [4]. The fact that germ-free
mice showed elevated serum FIAF concentration and that
conventionalization of these animals with intestinal bacteria
decreased FIAF levels and increased fat storage and weight
gain, led to the conclusion that intestinal bacteria may impact
metabolic homeostasis through this process and may there-
fore be a potentially important future target in the protection
against obesity [11]. Until now, it is not known which
mechanisms in this host-bacterium cross-talk occur during
the repression of FIAF production by the gut epithelium. It
was observed that, when conventionalizing germ-free mice
with B. thetaiotaomicron and/or M. smithii, FIAF production
was more repressed by the presence of a combination of both
micro-organisms, than by each of them separately [11].
However, the mechanism remains unclear. Furthermore, it is
not known whether different microbial species have the same
FIAF repressing potential.
4.4. Interference with Lipid Metabolism and Nutrient
Uptake
Several pro- and prebiotics have been shown to alter se-
rum cholesterol and lipid levels, thereby not only affecting
fat storage, but also the development of cardiovascular dis-
eases [133]. These effects are often attributed to the produc-
tion of propionate, which inhibits hepatic cholesterol synthe-
Potential Microbial Advantages of the
References
Alternative Microbial Alternative
Pre/probiotics stimulating glucose No rapid degradation,
[115-117]
release and SCFA production no injection needed
Only intestinal, not in
Intestinal microbiota [4, 118, 119]
other organs
Prebiotics stimulating propionate,
No muscle damage [120-123]
bile salt-degrading probiotics
No lactic acidosis,
Prebiotics [124, 125]
no hypoglycemia
2060 Current Pharmaceutical Design, 2009, Vol. 15, No. 18
sis from acetate [123, 134, 135]. Furthermore, intestinal bac-
teria interfere with cholesterol absorption from the gut by
deconjugating bile salts [136] or by directly assimilating
cholesterol, as reviewed by St-Onge et al. [122]. Examples
of probiotic bacteria influencing cholesterol and lipid me-
tabolism are Lactococcus lactis [137], Streptococcus ther-
mophilus [138, 139], Lactobacillus acidophilus [140], E.
faecium [139], Bifidobacterium bifidum [141, 142] and B.
longum [143]. Bacteria present in fermented foods, such as
bacteroides, bifidobacteria, fusobacteria, clostridia, pep-
tostreptococci, lactobacilli, and streptococci are known to
hydrolyze conjugated bile acids [144]. Several in vivo stud-
ies confirmed the cholesterol and lipid lowering effects of
oligofructose [120, 145-147] and resistant starch [148, 149],
representing a prebiotic approach.
Hepatic lipogenesis is not only regulated by short chain
fatty acids, but also by serum glucose and insulin levels
[150]. Enhanced sugar uptake has been observed in presence
of gut bacteria compared to germ-free conditions, which can
be explained by several mechanisms. First of all, the pres-
ence of an intestinal microbial community leads towards an
increase in the amount of capillaries that underlie the small
intestinal villus epithelium [151]. Secondly, host monosac-
charide transporters are induced by the polysaccharide-
processing activity of the microbiota, as was demonstrated
by studies with germ-free mice colonized with B. thetaio-
taomicron [35]. The monomers generated from indigestible
polysaccharides are delivered as substrates for lipid produc-
tion in the liver. Besides, they can also activate the lipogenic
enzymes in the liver by ChREBP- and SREBP-1- mediated
mechanisms [4]. Hence, the polysaccharide-degrading poten-
tial of an intestinal microbial community is considered an
important determinant for hepatic lipid production. In obese
ob/ob mice, the intestinal microbial community is enriched
for genes that are able to harvest calories from complex
plant-derived polysaccharides compared to lean mice. These
genes code for enzymes involved in sugar degradation, sugar
transport and acetate and butyrate production [114]. Al-
though more and more insight is gained in the importance of
polysaccharide degradation in the host’s fat production and
storage, it is neither evident nor desirable to modulate the
composition of the microbial community to completely in-
hibit polysaccharide degradation and thus obesity. However,
modulation of the sugar uptake by bacteria so that a slower
glucose release and glycemic response is obtained, might be
of interest. Several studies demonstrate that both oligofruc-
tose and resistant starch are effective against obesity-induced
diabetes type II, because they reduce glycemia [152], im-
prove glucose tolerance and insulin sensitivity [125, 149],
and lower endotoxaemia caused by lipopolysaccharides from
Gram-negative intestinal bacteria, all factors which may lead
towards obesity and type II diabetes [129].
4.5. Perspectives
Conventional anti-obesity drugs induce weight losses by
several mechanisms, such as suppressing appetite (gut pep-
tides and analogues, anorectics), interference with nutrient
absorption (pancreatic lipase inhibitors) and increasing the
host’s metabolism (cannaboid receptor antagonists) [153,
154]. Although effective, some of these drugs may cause
undesired side effects, such as oily bowel movements and a
Possemiers et al.
high blood pressure. Furthermore, the use of gut peptides is
not evident because of their rapid enzymatic degradation
after injection [115, 117]. As the previous paragraphs show
that intestinal microbiota may have an important role in both
the intake of energy (appetite control), uptake of sugars and
fat from the gut, energy metabolism in the body and fat stor-
age in the adipose tissue, alternative strategies may be devel-
oped in which the specific host-bacterium cross-talk in-
volved in these processes is targeted. Into this respect, pre-
and probiotics seem to be particularly promising as can be
deduced from rapidly expanding scientific evidence.
5. CONCLUDING REMARKS
If we accept the view of our body as a functional system
composed of both human cells and bacterial species, with a
prominent role for the intestinal microbiome, an enormous
potential for future drug development is offered. The differ-
ent topics described above clearly show that the intestinal
microbiota may have a profound role in health and disease
and the true impact of our microbial ecosystem on human
health is yet far from fully understood. Targeting the intesti-
nal microbiota may therefore offer unique prevention or
treatment strategies for a variety of disease states in which
the microbial factor is related to its metabolic potential, mi-
crobe-microbe interactions or host-bacterium cross-talk. This
review aimed at describing these factors, based on specific
disease states in which existing scientific evidence shows an
important role of the intestinal microbiota.
One of the important drivers for investigating and under-
standing the metabolic ability of gut microbiota, is the modu-
lating effect it has towards the biological activity of food and
pharmaceutical compounds. The examples described in this
review illustrate that the gut microbial metabolic potency is
sometimes a crucial variable when assessing the benefits or
risks from ingested compounds and drug substances.
Horizontal gene transfer is an important mechanism by
which bacteria may interact with each other and efficiently
exchange information (microbe-microbe interactions). This
does not only enable bacteria to adapt themselves to rapidly
changing environmental conditions, but is also an important
contributing factor to for instance the rapidly spreading anti-
biotic resistance between bacteria under clinical conditions.
Whereas antibiotic treatment is still considered a standard
treatment strategy in case of pathogen infections, thorough
understanding of microbe-microbe interactions such as gene
transfer systems may offer important alternative strategies to
counteract infectious diseases [155]. Originally susceptible
pathogens may acquire resistance factors during antibiotic
therapy, thereby reducing the treatment’s efficiency. Simul-
taneous administration of antibiotics with inhibitors of hori-
zontal gene transfer may prevent the acquisition of these
resistance factors, making that such inhibitors could offer
interesting future applications that selectively target bacteria
capable of transferring antibiotic resistance and generating
multidrug resistant strains [156]. This may be an important
step in the prevention of resistance propagation during clini-
cal treatment of bacterial infections and in extending the
lifetime of our antibiotic arsenal.
Whereas modern medicine has managed, at least in the
westernized world, to take control over most infectious dis-
Intestinal Bacteria and Human Health
ease of the gut, gastrointestinal food allergies and different
intestinal inflammatory conditions have dramatically in-
creased. Although the reason for this remains unknown, a
prevailing notion is that we now face inflammation without
infection. This may even be related to the lack of sufficient
gut infection and stimulation of the immune system (the so-
called ‘hygiene hypothesis’), thereby disturbing the balance
and the cross-talk between the normal bacteria which colo-
nize the gut and the host immune system [9]. However, more
and more evidences arise that disturbance in the microbial
ecosystem and the host-bacterium cross-talk would not only
be involved in disease states of the gut itself but also in the
rest of our body. Typical examples are the findings that in-
testinal microbiota may play a crucial role in the onset and
development of obesity [114, 157].
Recent findings on - for instance - the role of intestinal
bacteria in the latter disease states have shown that changes
occur in the general ecosystem structure rather than the
(dis)appearance of one particular species. For this reason,
treatment strategies should also target the intestinal microbi-
ota as a multi-cellular structure. A deeper insight in its popu-
lation dynamics, variability and structure-function relation-
ships will lead to a better understanding of the extent to
which each individual’s gut microbiota affects the bioavail-
ability and response to administered drugs and the impact of
interventions that alter our microbial ecology.
ACKNOWLEDGEMENTS
Sam Possemiers and Tom Van de Wiele benefit from a
post-doctoral grant from the Research foundation – Flanders
(FWO Vlaanderen). Joan Vermeiren is supported by a Con-
certed Research Action of the Flemish Community (GOA)
(GOA/24J/BAS/DOC/DOS/PDO/ZAP). Charlotte Grootaert
profits from a IWT (Institute for the Promotion of Innovation
by Science and Technology in Flanders) scholarship. We
acknowledge the financial support of the European Commu-
nity under the Marie Curie Transfer of Knowledge – Indus-
try-Academia Strategic Partnership Scheme, MTKI-CT-
2006-042786 (GUTSYSTEM), especially for the second-
ment of Gabriele Gross to Gent University.
ABBREVIATIONS
DGGE = Denaturing gradient gel electrophoresis
FIAF = fasting-induced adipose factor
GLP-1 = Glucagon-like peptide 1
GRM = Gastrointestinal resource management
IBD = Inflammatory Bowel Disease
IQ = 2-Amino-3-methylimidazo[4,5-f]quinoline
PAH = Polycyclic aromatic hydrocarbons
PAP = Pancreatitis-associated protein
PhIP = 2-Amino-1-methyl-6-phenylimidazo[4,5-
b]pyridine
8-PN = 8-Prenylnaringenin
PYY = Peptide YY
SCFA = Short-chain fatty acids
Current Pharmaceutical Design, 2009, Vol. 15, No. 18 2061
SHIME = Simulator of the Human Intestinal Microbial
Ecosystem
TLR = Toll-like receptor
T-RFLP = Terminal restriction fragment pattern analysis
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