Vol. 4, No.

3 2007
Drug Discovery Today: Therapeutic Strategies

Editors-in-Chief
Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK
Eliot Ohlstein – GlaxoSmithKline, USA
DRUG DISCOVERY
TODAY
THERAPEUTIC
STRATEGIES Gastrointestinal diseases

The gut microbiota and disease – an

inner repository for drug discovery
Fergus Shanahan*, Barry Kiely
Alimentary Pharmabiotic Centre and Department Medicine, University College Cork, National University of Ireland and Alimentary Health Ltd., Cork, Ireland

The gut micobiota is tantamount to a hidden inner

organ, with a gene content (microbiome) exceeding
that of the human genome, a versatile metabolic capa-
city rivalling that of the liver and a source of signals
required for optimal structural and functional devel-
opment of the host. Although some disorders, such as
Crohn’s disease, might result from abnormal host–
microbe interactions, and others, such as obesity,
might be influenced by bacterial-derived metabolic
signalling from the gut, the microbiota is primarily a
health asset in defence against infectious, inflamma-
tory and probably neoplastic disorders. This inner bio-
mass is a relatively untapped repository for ‘mining’
bioactives for novel drug discovery.
Introduction
The gastrointestinal ecosystem is attracting scientific and
commercial interest, both as a target for drug therapy and
as an inner resource for drug discovery [1,2]. A landmark
event, recently acknowledged with the award of the Nobel
Prize to its discoverers, was the role of Helicobacter pylori in the
pathogenesis of peptic ulcer disease. This opened minds to
the possibility of a microbial contribution to other chronic
diseases. It also served a lesson that the solution to some
diseases might never be found if research is centred exclu-
sively on mammalian pathophysiology, without due atten-
tion to the interface between the host and its microbial
environment.
*Corresponding author: F. Shanahan (f.shanahan@ucc.ie)
Section Editor:
Gareth J. Sanger – Immuno-Inflammation Centre of
Excellence for Drug Discovery, GlaxoSmithKline, Stevenage,
Hertfordshire, UK
Another advance that accelerated research into host–
microbe interactions in the gut was the first identification
of a susceptibility gene (NOD 2/CARD 15) for Crohn’s disease
[3,4]. This illustrated the molecular nexus of the three main
interacting factors involved in the pathogenesis of Crohn’s
disease: genetic risk factors, environmental (microbial) mod-
ifying factors and immune-mediated tissue damage. It was
the first time that a mutant gene coding for an intracellular
sensor of microbes was directly linked with risk of chronic
inflammatory disease, and it prompted a search for other
genetic risk factors for Crohn’s disease that involve the
interpretation or handling of the microbial environment
[5,6].
Additional drivers of the resurgence of interest in the gut
microbiota include the desire to manipulate the gastrointest-
inal microenvironment with probiotics or prebiotics, the
recognition of the relevance of the commensal microbiota
to the emergence of the global problem of antibiotic resis-
tance and the current epidemic of Clostridium difficile-asso-
ciated enteric disease. Finally, deterrents to the study of the
microbiota, such as a dependency on traditional culture-
based techniques that are limited by the inability to grow
most intestinal bacteria on available culture media, have
been circumvented with the advent of molecular strategies
[7].
The purpose of this article is to provide a perspective on
opportunities for drug discovery by exploitation of microbe–
microbe and microbe–host interactions within the gut. To

1740-6773/$ ß 2008 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddstr.2008.02.006 195
 Drug Discovery Today: Therapeutic Strategies | Gastrointestinal diseases
that end, some of the pivotal concepts and gaps in knowledge
in relation to the microbiota will be addressed in overview
but, for more detailed reviews and specific aspects of the gut
microbiota, the reader is referred elsewhere [7–10].
Scale and complexity of the microbial inner organ
The human gut is the most densely populated ecosystems on
the planet. It is a hidden biomass, tantamount to an inner
organ with a metabolic capacity on the scale of that of the
liver. The bacterial load and diversity (>1000 species)
increases distally with the largest gradient being across the
ileocaecal valve, where there are approximately 108 bacteria/g
of ileal content rising to 1012/g of colonic content. Cross-
sectional variation is also evident with the ratio of anaerobes
to aerobes being lower for mucosa-adherent bacteria versus
luminal populations.
Collectively, the microbiota is a repository of genetic
information (microbiome) exceeding that of the host gen-
ome. Indeed, the host genome encodes insufficient informa-
tion for full development of the gut. Sterile before birth,
optimal development of the gut is dependent upon signals
from the microbiota colonising the lumen immediately after
birth. The composition of these pioneering commensals is
determined by several factors that include the mode of birth
delivery, maternal microbiota, diet and environmental
hygiene. In different individuals, the composition of the
microbiota appears to be distinct, and perhaps unique, by
molecular fingerprinting. A variety of molecular techniques,
mainly nucleic acid-based strategies, has revealed a scale and
diversity of the human microbiota greater than previously
contemplated (reviewed in references [7,11]). For example,
the acidity of the human stomach was thought by many to
create an almost sterile microenvironment, once cleared of
H. pylori, but a metagenomic approach has revealed an
extraordinary range of bacterial residents, some of which
were not previously thought to be present in the human
body [12].
The application of culture-independent metagenomics to
the gut microbiota is escalating and has already provided new
insights into the metabolic capacity of the normal microbiota
in diseases, such as obesity, and is being applied to the
apparent compositional changes in the microbiota in disor-
ders such as inflammatory bowel disease and irritable bowel
syndrome [13–15]. Major consortia on both sides of the
Atlantic are underway to apply metagenomics to enhancing
the understanding of the normal microbiota in health and
disease at various ages and different dietary conditions [11].
Host–microbe dialogue
Comparative studies of germ-free versus conventionally colo-
nised animals first performed several decades ago showed the
conditioning influence of the microbiota on intestinal struc-
ture and function [10]. Germ-free animals have rudimentary
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Vol. 4, No. 3 2007
lymphoid tissue with sparse lamina propria cellularity, low
epithelial cell turnover and digestive enzyme activity,
reduced muscle wall thickness with impaired peristalsis, in
comparison with colonised littermates. By contrast, life
without bacteria (germ-free) is associated with increased
enterochromaffin cell area and increased dietary caloric
requirements. This suggests that the microbiota is a source
of both positive and negative regulatory signals acting a
multiple levels within the host, the identities of which are
being pursued with techniques such as laser microdissection
and gene array analysis [16].
Germ-free animals are more susceptible to infection, have
defective immune function and disturbed stress responses
[10,17]. However restoration to normality occurs with resti-
tution of the intestinal microbiota; colonisation with the
single species, Bacteroides thetaiotaomicron, is sufficient to
influence the expression of host genes regulating nutrient
uptake, metabolism, angiogenesis, barrier function and the
development of the enteric nervous system [18].
Host–microbial dialogue occurs over a huge surface area
within the gut (400 m2), with only a single layer of epithe-
lium separating the lumen from the internal milieu.
Although this adaptation of structure to function is optimal
for nutrient absorption, it becomes a potential vulnerability
in the setting of enteric infection. Hence, there is a require-
ment for continual maintenance of mucosal homoeostasis;
multiple mechanisms are required and involve contributions
from both the host and the resident microbiota (reviewed in
references [9,10]). Breakdown in homoestasis through defec-
tive host–microbe exchange is thought to underlie the patho-
genesis of some chronic inflammatory disorders, such as
Crohn’s disease [5].
The challenge for the host is the requirement for exquisite
precision in distinguishing harmless commensal microbes
from episodic challenge with pathogens. This is achieved
by continual sampling of the microenvironment and distinct
cellular and molecular immunosensory processes. Immuno-
logical sampling of the lumen takes place across the epithe-
lium at several sites. M cells overlying lymphoid follicles
transport microbial antigens to subjacent antigen-presenting
cells, whereas surface enterocytes sample soluble antigens
and elaborate a range of chemokines, thereby alerting the
host and directing the innate and acquired immune systems
to the site of any breach in the mucosal barrier. Dendritic cells
might directly sample the contents of the lumen by extend-
ing dendrites between the surface enterocytes; they can
ingest and retain live bacteria and migrate to the mesenteric
lymph node where an immune response is induced. In this
way, the mesenteric lymph node serves as the gatekeeper,
limiting access by luminal bacteria to the systemic immune
compartment [19].
At a molecular level, discrimination of pathogenic
and commensal bacteria by dendritic and other immunosen-
 Vol. 4, No. 3 2007
sory cells is mediated, partly, by two major host pattern
recognition receptor (PRR) systems – the family of surface
Toll-like receptors (TLRs) and the intracellular nucleotide-
binding oligomerization domain/caspase recruitment
domain isoforms (NOD/CARD) [9,10]. These systems are
under precise regulation, the details of which are not fully
understood. The complexity of the process is shown by the
fact that commensals and pathogens share many PRR ligands,
but the normal mucosal immune response to commensals is
restrained. In addition, continual signalling by ligands from
the resident microbiota using host TLRs is essential for main-
tenance of intestinal homeostasis and barrier function [20].
Furthermore, some commensal bacteria attenuate the pro-
inflammatory effects of pathogens using various mechanisms
[10,21].
Therapeutic strategies
Humankind has exploited microbes for many purposes ran-
ging from producing insulin to cleaning up oil slicks. Envir-
onmental microbes also continue to be used for isolation of
novel antibiotics, immunomodulatory drugs and other
bioactives, but the inner gut ecosystem is a relatively
untapped frontier. However, a ‘bugs to drugs’ discovery strat-
egy can be designed from current understanding of the
normal microbiota, particularly the lessons derived from
studying life without bacteria, and as summarised below,
some predictions are already fulfilled.
Commensal-derived novel antimicrobial drugs – bacteriocins
Because bacterial numbers within different segments of the
gut are constrained not only by the host and by mutual
competitive interactions but also by microbe–microbe signal-
ling, the potential to mine novel antimicrobial factors from
the microbiota arises. A highly conserved antimicrobial sys-
tem in living organisms is the production of antimicrobial
peptides, such as bacteriocins and defensins. Bacteriocins are
ribosomally synthesised antimicrobial peptides produced by
one bacterium that are active against other bacteria but to
which the producer organism has a specific resistance
mechanism. They might exhibit either narrow- or broad-
spectrum antibacterial activity and have been used for
decades by the food industry where bacteriocin-producing
food-grade bacteria are deployed for food preservation
(reviewed in reference [22]).
More recently, a bacteriocin from a specific probiotic lac-
tobacillus has been shown to account for the protective
mechanism of probiotic action against Listeria infection
[23]. Bacteriocins have also been shown to have clinical
potential in animal husbandry and in human conditions
such as Clostridium difficile [24]. The pursuit of human com-
mensal-derived bacteriocins with potency and a narrow spec-
trum of activity against C. difficile is a particularly appealing
strategy in view of the emergence of a highly virulent form of
Drug Discovery Today: Therapeutic Strategies | Gastrointestinal diseases
this disease and the widespread resistance of the organism to
currently available drugs.
Commensal-derived immunomodulatory drugs
Given that germ-free mice have defective immune develop-
ment that is restored upon colonisation with conventional
microbiota, it follows that the gut microbiota must be a source
of immunomodulatory molecules influencing the structural
and functional development of the immune system. This
prediction was fulfilled by the demonstration that colonisa-
tion with Bacteroides fragilis produces a zwitterionic polysac-
charide that directs and corrects maturational deficits in the
developing immune system [25,26]. Particularly noteworthy
was the observation that this microbial-derived polysaccharide
not only influenced development of mucosal lymphoid tissue
but also corrected structural and functional systemic immune
deficits after colonisation of germ-free animals [25].
Bacterial products or constituents, other than polysacchar-
ides, might also modulate immune function. For example,
bacterial DNA and oligonucleotides containing hypomethy-
lated CpG dinucleotides, in contrast to eukaryotic DNA
and methylated oligonucleotides, have immunomodulatory
properties that are mediated by ligation of TLR9 on host cells
[10]. Indeed, the beneficial effects of probiotics in murine
models of inflammatory bowel disease have been attributed
to the actions of probiotic DNA on TLR9 [27]. However, bacteria
vary in their immunomodulatory DNA content, and CpG DNA
motifs might have unexpected or undesirable effects in experi-
mental models of colitis depending on the timing of admin-
istration. Thus, in contrast to the prophylactic effect of CpG
DNA before the onset of inflammation, exposure during acute
inflammation has been reported to aggravate the inflammatory
disease in a murine model of inflammatory bowel disease [28].
Microbial-derived anti-inflammatory inflammatory activity
In addition to immunomodulatory and immunostimulatory
polysaccharides and nucleotides, bacteria in the gut have
been shown to produce a variety of proteins and peptides
with actions on the host that are broadly cytoprotective or
anti-inflammatory [29,30].
With intact whole bacteria, the impact on host cytokine
production is highly variable even for different strains within
a given species. However, in the case of lactobacilli, it has
been shown that a major determinant of anti-inflammatory
activity is the composition of the cell envelope constituent,
lipotechoic acid, specifically its D-alanine content [31]. Lipo-
techoic acids are docked in the bacterial cell membrane by a
glycolipid anchor and represent amphiphilic polymers of
repeating units of glycerophosphate speckled with D-alanine
and glycosyl residues. D-alanine content might become a
selection criterion for probiotics for some disease indications
and has implications for future mining of microbial-derived
anti-inflammatory compounds.
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 Drug Discovery Today: Therapeutic Strategies | Gastrointestinal diseases Vol. 4, No. 3 2007

Nutrient and bioactive metabolite production
Although the enteric microbiota play a central role in diges-
tion and nutrient provision and this is of commercial rele-
vance particularly to the food industry, it is beyond the scope
of the present overview. However, some bacterial metabolites
in the gut serve not only a nutrient function but also have
intrinsic bioactive properties that can be mined for use either
as a functional food ingredient or perhaps as a drug. An
example is the generation of bioactive isomers of conjugated
linoleic acid (CLA) by the commensal microbiota that exhibit
peroxisome proliferator-activated receptor (PPAR) agonist
activity [32,33].
Microbial-derived metabolic signals for host metabolism and obesity
Germ-free animals must consume more calories than colo-
nised animals to maintain body weight. It follows that manip-
ulation of the composition or metabolic activity of the
microbiota might have a bearing on the approach to obesity.
Convincing evidence that the microbiota is a regulator of fat
storage has been shown by Gordon and colleagues [34]. Two
mechanisms are involved: the first being the induction of
hepatic lipogenesis following enhanced absorption of mono-
saccharides released by microbial metabolism of non-digesti-
ble polysaccharides and the second being the enhanced
deposition of lipid in adipocytes promoted by microbial-
induced suppression of fasting-induced adipocyte factor (Fiaf,
also known as ANGPTL4), which is a member of the angio-
poietin-like family of proteins and an inhibitor of lipoprotein
lipase. In a series of elegant studies, the same group of inves-
tigators showed that the microbiota of obese leptin-deficient
mice and of obese humans extract and make available more
energy to the host from a given diet than do the microbiota of
their lean counterparts, and this was associated with reversible
compositional differences in the microbiota [7].
This body of work shows that the impact of the gut
microbiota in health and disease extends well beyond the
gut. To underscore this, others have used metabolic profiling
to show a contribution of the gut microbiota to fatty liver

Table 1. Representative examples of bacterial actions in the gut that might be suited to a ‘bugs to drugs’ programme of
discovery for development of bioactive ingredients in functional foodsa
Bacterial action
1 Microbe–microbe
communication
Examples: quorum
sensing and
antimicrobial
production
2 Bacterial stimulation
or modulation of
host immunity
3 Commensal (and probiotic)
anti-inflammatory effects on
host tissues
4 Nutrient production
5 Metabolic signals
6 Neuroactive signals
7 Genetically engineered enteric
bacteria to produce bioactives
a
Note this table is intended to be representative not comprehensive. The well-established potential of microbial ecosystems outside the gut microbiota is acknowledged but is beyond the
scope of this overview.
Opportunity
Isolation of novel
antibiotics
(e.g. bacteriocins)
Example: lacticin
Bacterial-derived
immunoregulatory
polysaccharides
Bacterial
immunostimulatory
(CpG) DNA
Anti-inflammatory drugs
from bacterial components
(e.g. lipotechoic acid)
Bacterial-derived vitamins
& fatty acid nutrients
Example: bioactive
isomers of CLA
Obesity prevention by
reducing dietary caloric
bioavailability
Analgesic effects for
irritable bowel syn.
Bioactive of choice
is probably unlimited
Advantages Potential limitations Anyone interested? Refs
Naturally occurring Sensitive to digestive The food industry [22]
Low level of resistance enzymatic degradation Alimentary
Dual mechanism of action Topical action only unless Health Ltd.
enteric-coated (targeting C. difficile)
Potential applications for Might involve complex [26]
immunodeficiency disorders and expensive carbohydrate
chemistry
Macromolecules might be
required as end products
Applications to inflammatory Might be proinflammatory Coley [28]
and neoplastic disorders in certain settings Pharmaceuticals
Pfizer Corp.
Relevant bacteria are readily Evidence base to date [31]
available and culturable in vitro is still very preliminary
Sound evidence base The food industry [33]
Gut microbiota might be
exploited to favourably
influence the fatty acid
composition of host tissues
Seemingly a potentially safe Will probably require The food industry [34]
but long-term strategy if live microbes
developed
Exploitation of endogenous Needs independent [36]
analgesic mechanism confirmation
Site-specific delivery Public health and Actigenix [38]
Inexpensive environmental concerns
regarding containment

198 www.drugdiscoverytoday.com
 Vol. 4, No. 3 2007
phenotype in insulin-resistant mice [35]. Unravelling the
mechanisms at the host–microbe interface in these disorders
is likely to reveal new therapeutic targets, some of which
might be suitable for novel drug strategies.
Neuroactive signals
Of the numerous examples exhibiting the diversity of bacterial
actions within the gut that might be suited to bioprospecting
for novel drugs, the modulation of visceral pain by a subset of
commensals (L. acidophilus) is particularly intriguing in the
context of managing patients with irritable bowel syndrome
[36]. Oral administration of some, but not all, lactobacillus
strains to rodents was found to induce the expression of mu-
opioid and cannabinoid receptors on intestinal epithelia, and
in a rectal distension model of visceral pain an analgesic effect
was noted that was equivalent to 1 mg/kg morphine. Because
there is increasing scientific interest in host–microbe interac-
tions in irritable bowel syndrome [14], it might be that both the
cause and the solution can be mined from the enteric micro-
biota in this condition (Table 1).
Genetically engineered enteric bacteria for production of bioactives
The use of commensal or food-grade bacteria engineered for
delivery of therapeutically relevant molecules to the gut
mucosa is an appealing prospect with many advantages.
Proof of principle was established in murine models of
inflammatory bowel disease using a transgenic Lactococcus
lactis to deliver interleukin-10 to the gut, and preliminary
results in humans with Crohn’s disease have been encoura-
ging [37,38]. The strategy is suited to a diversity of applica-
tions, such as delivery of vaccines, trefoil factors or other
bioactive molecules. Containment of the transgenic organ-
ism has been achieved by deletion and replacement of the
thymidylate synthase gene with the chosen transgene,
thereby rendering the organism dependent on a local supply
of thymidine or thymine in the gut and unable to survive
without these in the external environment.
Conclusions
There is a long-standing tradition in drug discovery from
mining microbes and other biologic material. The gut eco-
system, long neglected or considered to be impenetrable
owing to technical obstacles, is now well suited to such
bio-prospecting. Predictions of areas that are ripe for explora-
tion and exploitation, based on comparative studies of germ-
free and conventionally colonised animals, are already being
fulfilled. This occurs on a background of an increasing list of
chronic gastrointestinal disorders, for which some distur-
bance of host–microbe interactions appears to be contribu-
tory. The importance of these conditions is reflected in
reviews of the substantial global burden of gastrointestinal
disease [39,40]. Furthermore, the influence of the gut micro-
biota extends well beyond the confines of the gastrointestinal
Drug Discovery Today: Therapeutic Strategies | Gastrointestinal diseases
tract and has a bearing on common disorders in developed
societies, such as obesity, metabolic syndrome and their
complications. Although technical hurdles continue to fall,
the greatest challenge is still the requirement for enhanced
understanding of the normal gut microbiota and its interac-
tion with the host in health and disease.
Conflict of interest statement
The authors are affiliated with a multi-departmental university
campus company, Alimentary Health Ltd. that investigates
inter alia host–microbe interactions. The content of this paper
was neither influenced nor constrained by that fact.
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