1. FOCUS ON GUT MICROBIOTA
OPINION certainly, other diseases, including some
forms of colorectal cancer, have a micro-
The gut microbiota—a clinical bial aetiology.3 Second, the story showed
the value of traditional culture-based
perspective on lessons learned techniques and the wisdom of working
with model organisms to understand
Fergus Shanahan disease mechanisms. Third, after decades
of missing a trans­ issible cause of peptic
m
Abstract | Once considered obscure and largely ignored by microbiologists, the human ulceration, the discovery exposed the limi-
microbiota has moved centre-stage in biology. The gut microbiota is now a focus of tations of ‘risk factor epidemiology’ without
disparate research disciplines, with its contributions to health and disease ready for taking into account the disease mecha-
translation to clinical medicine. The changing composition of the microbiota is linked nisms, whilst it also highlighted the impor-
with changes in human behaviour and the rising prevalence of immunoallergic and tance of thinking across the boundaries
metabolic disorders. The microbiota is both a target for drug therapy and a repository of traditional research disciplines to solve
for drug discovery. Its secrets promise the realization of personalized medicine and important biological problems. Finally, as
nutrition, and will change and improve conventional dietary management. the prevalence of H. pylori was in decline
in developed countries long before its exist-
Shanahan, F. Nat. Rev. Gastroenterol. Hepatol. 9, 609–614 (2012); published online 14 August 2012; ence was known, the story poses important
doi:10.1038/nrgastro.2012.145
clinical questions regarding the changing
nature of the human microbiota.
Introduction This judgement from one so closely
Few developments in biology promise as linked with the human genome is par- Microbiota change—disease risk
much to the advancement of medicine as the ticularly pertinent to the human micro- An abrupt rise in the frequency of immuno­
exploration of the indigenous human micro- bia l environ­ ent. Gast rointest ina l
m allergic disorders, such as IBD and asthma,
biota. Since the publication of historic exper- patho­ hysiology cannot be conclusively
p occurs with socioeconomic develop-
iments performed with germ-free animals, examined outside the context of the ment. This association has been attrib-
it has been evident that the microbiota is relation­ship with our microbial selves. Over uted to reduced environmental exposure
a source of trophic, metabolic and protec- the past decade, a convergence of research to microbes (the hygiene hypothesis), but
tive signals, from which the host benefits. interest from disparate cognitive disciplines more accurately might be related to changes
Host–microbe interactions are now known has greatly enhanced the understanding of in microbial colonization during the earliest
to be bidirectional and disturb­ances of these the human microbiota and of host–microbe stages of life, when the immune system is
interactions contribute to gastrointestinal interactions. Progress has been acceler- maturing. Microbial signalling is required,
and extraintestinal disorders. Mining host– ated by metagenomics, which combines not only for mucosal homeo­ tasis, but also
s
microbe signalling has long promised much, high-throughput DNA sequencing and for full development of extra­ ntestinal
i
but several pivotal discoveries and advances computational methods to define the com- systems, including the brain–gut axis
in mol­ cular microbiology are now poised
e position of complex microbial communities and the immune response. Loss of ances-
for translation to clinical medicine. This without needing to culture the constituents. tral organisms, such as H. pylori and hel-
article focuses on the clinical implications Microbial genes (the microbiome) numeri- minths, is associated with socio­ conomic
e
of advances in human microbial ecology; the cally exceed those of the human genome development, and is a risk factor for certain
lessons learned extend beyond the gut and by 100‑fold, and microbes from the three diseases. Reduced microbial diversity
are germane to all clinical specialties. domains of life (Bacteria, Archaea and accompanies many gastrointestinal and
Eukarya), along with viruses, are repre- extraintestinal disorders, but reduced levels
Features of the gut microbiota sented within the normal human micro­ of specific organisms, such as Lactobacilli
In 2007, J. Craig Venter wrote that “Without biota, including species that were unknown spp., Bifidobacterium spp., Akkermansia
understanding the environment in which until recently.2,3 Work from various labora- muciniphilia and Faecalibacterium praus-
cells or species exist, life cannot be under- tories has revealed the complexity, majesty nitzii, might confer a particular risk of
stood. An organism’s environment is and diversity of the microbiota (Table 1).2,3 developing IBD.2–5
ultimately as unique as its genetic code.”1 The discovery of Helicobacter pylori by The earlier the exposure to a modern
clinicians refusing to accept dogma is argu- lifestyle in a developed country, the greater
ably the field’s greatest success story and is the risk of disease. This finding is con-
Competing interests has yielded several lessons of continuing sistent with the onset of many immuno­
The author declares associations with the
clinical relevance. First, it showed that the allergic disorders in adolescence or early
following companies: Alimentary Health,
GlaxoSmithKline, Procter & Gamble. See the solution to some diseases cannot be found adulthood, and is confirmed by migration
article online for full details of the relationships. by focussing exclusively on the host. Almost studies5 (Figure 1). Many of the elements of
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY VOLUME 9 | OCTOBER 2012 | 609
© 2012 Macmillan Publishers Limited. All rights reserved

2. PERSPECTIVES
Table 1 | Overview of the gut microbiota*
Feature Comment
High diversity and density Loss of microbial diversity predisposes to pathogenic infections and is linked with several immunoallergic and metabolic
disorders
Individuality Variation arises at species and strain levels with limited variability at phylum level; members of two phyla (Firmicutes and
Bacteroidetes) contribute to ~90% of the species in the distal gut
Maternal transmission Colonization at birth is influenced by mode of delivery (vaginal versus caesarean section)
Age-dependent variability Rapid diversification during infancy influenced by diet and environment, including antibiotics, reaching relative stability with
idiosyncrasy in adulthood, and changing in the elderly depending on physiological status, diet, drugs and morbidity
Variation over long axis of gut After the oral cavity, complexity and numbers increase distally
Variation over cross-sectional The aerobe:anaerobe ratio is greater at the mucosal surface than at the lumen
axis of gut
Resilience The microbiota tends to return to normal after antibiotic challenge, but some strains might be eliminated, particularly after
repeated or prolonged antibiotic exposure, with the greatest effect in infancy
Plasticity and adaptability On a background of relative stability, there are continual variations in metabolic behaviour and composition depending on
diet, other lifestyle variables and disease
Host–microbe interactions Bidirectional; microbial, immunoinflammatory and metabolic cascades are interactive
Spatial segregation and Microbes have restricted access to the small intestinal epithelia because of host-derived factors, such as the antibacterial
compartmentalization lectin RegIII-γ; and in the colon, the structure of the inner layer of colonic mucin ensures that it is microbe-free; if
commensal organisms penetrate the mucosa they are restricted from the systemic circulation by a gatekeeper effect of the
mesenteric lymph node
Experimental transferrable ‘Colitogenic’ microbiota from animal models of colitis can transfer disease to naive genetically wild-type recipients;
microbiota transplants of microbiota have similarly revealed transferrable metabolic phenotypes
*Source material reviewed, in part, in references 2 and 3.
a modern lifestyle in a developed country metabolites that promote atherosclerosis the gut, including diabetes, obesity and
influence the composition of the indigenous after absorption and hepatic metabolism.10 related complications (Figure 3). The first
microbiota, disturbances of which have This finding has brought personalized intersection of microbes, immunity and
been reported in several diseases of devel- nutrition a step closer to reality but, as dis- metabolism arises at the intestinal epithe-
oped society. The most obvious lifestyle or cussed below, is only one part of an unfold- lium. The immune and metabolic functions
environmental modifier of the microbiota ing story linking the microbiota with both of the epithelium (for example, IgA release
is increased antibiotic exposure, particu- immunoinflammatory and metabolic and lipid absorption, respectively) are func-
larly in infancy, which has been linked with signalling in the host. tionally interconnected and inversely regu-
an increased risk of IBD in childhood in lated.14 IgA influences the composition of
population-based studies. 6,7 Early anti­ Microbe–host signalling the commensal microbiota and, if deficient,
biotic exposure might also increase the risk Microbe–host signalling is reciprocal, and the commensal bacteria drive interferon-
of asthma, and perhaps even metabolic and occurs at several levels: with the immune dependent expression of genes controlling
obesity-related disease, in later life. system; with host metabolic processes; immunity, at the expense of those regulat-
Dietary intake is another prominent and with the enteric nervous system and ing metabolism. This effect might contrib-
modifier of the microbiota (Figure 2). For brain–gut axis. Interdependency within ute to lipid malabsorption in some forms of
example, dietary polysaccharides and oligo­ this network is shown by the mutual regula- immune deficiency.
saccharides, including fibres, are bifido- tion of the microbiota and immune system. By contrast, disturbed host metabolism
genic (that is, they enhance the growth of Microbial signalling is required for immune with excess fat storage might arise from
beneficial bifidobacteria), whereas micro- development and homeostasis, whereas defects in innate immunity. Experimental
bial compositional changes have been an intact immune system is necessary for mice lacking Toll-like receptor (TLR)5, the
linked with high levels of dietary fat, iron maintenance of a healthy microbiota. A immunosensory receptor for microbial
and protein (casein).8 Of note, increased depleted microbiota might result in an flagellin, develop obesity and insulin resist-
consumption of dietary fat in Japan, partic- immune deficit, whereas defects in innate ance.12 This result seems to be attributable
ularly animal fat and n‑6 polyunsaturated immunity lead to an altered gut micro- to alterations in the composition of the gut
fatty acids, has been closely correlated with biota, which might transfer inflammatory microbiota, which induce proinflamma-
increases in the incidence of both Crohn’s and metabolic disease phenotypes upon tory cytokines, leading to desensitization of
disease and ulcerative colitis.9 faecal transplantation.11–13 insulin receptor signalling with consequent
Dietary modification of the intestinal Interactions between inflammatory and hyperphagia and weight gain. Defects at the
microbiota has also been linked with meta- metabolic cascades are well established. level of the inflammasomes are also associ-
bolic and cardiovascular disease. A striking Modulation of both of these processes ated with changes in microbial composi-
example is the discovery of a microbial- by the microbiota has added an intrigu- tion, activation of inflammatory cascades
dependent pathway for the metabolism ing layer of complexity, with therapeutic and progression of metabolic disease.13,15,16
of dietary phospholipids that generates implications for several diseases beyond Inflammasomes, as discussed later, are
610 | OCTOBER 2012 | VOLUME 9 www.nature.com/nrgastro
© 2012 Macmillan Publishers Limited. All rights reserved

3. FOCUS ON GUT MICROBIOTA
intracellular sensors of microbial-induced Migration from developing (low-risk) regions to developed (high-risk) regions
damage, but also sense metabolic disturb­
ance in the host and might determine why
some patients with obesity are metaboli-
cally normal and why others progress to
multi­ rgan complications, including steato­
o
hepatitis and insulin resistance. 15,16 The High-risk
microbiota might confound host metab­ High-risk
region
olism by additional mechanisms (Figure 3). region
Low-risk
However, the microbiota also intersects host regions
metabolism and inflammatory tone by regu-
lating fatty-acid composition within fat tissue,
the bioactivity of which influences the pro-
duction of inflammatory cytokines.17 Thus,
the microbiota has a regulatory influence on
both fat quantity and quality in the host.
As microbial, inflammatory and meta-
bolic signalling pathways are interlinked
and each limb of this triangular network is
influenced by diet, it follows that identifi-
cation and manipulation of the microbial
signals and/or alteration of the inflam-
matory response offer new therapeutic Age at time of migration
adjuncts to the management of obesity-
related disease. The molecular details
underpinning this prospect have been
addressed elsewhere,8 and proof of princi- Risk of acquiring disease of new world
ple for an improved metabolic outcome by
Figure 1 | Migration and disease risk. Migration studies confirm that lifestyle factors exert their
targeted manipulation of gut microbiota in influence at the earliest stages of life (when the microbiota is becoming established and whilst
diet-induced obesity has been established.18 the immune system is maturing). The risk of various immunoallergic disorders is greater the
earlier a migrant moves from a region of low-risk (‘developing’ socioeconomically) to one of high-
The sensory conundrum risk (developed) and is low if they migrate in later life.
What defines a commensal and how does
the host distinguish harmless commensals
from dangerous or opportunistic patho- against reflux-associated complications, host.19 Whether other commensals deploy
gens? The distinction is not always clear, including metaplasia and neoplasia at the symbiosis-associated molecular patterns
even at a clinical level. The simplest answer gastro­ sophageal junction, in later life.
e is unclear, but the host has an intracellular
is that all commensals probably have patho- How does the host interpret the micro- surveillance system to detect danger within
genic potential, depending on the context bial environment in terms of risk and the microbiota and to respond and maintain
and host susceptibility, and some organisms benefit or what are traditionally referred compositional equilibrium.
might be both beneficial and hazardous. For to as pathogens versus commensals? As Intracellular inflammasomes are multi­
premature babies, colonization with other- the molecular patterns involved in recog- protein complexes, partly comprised of
wise harmless commensals before optimal nition of pathogens are also expressed by Nod-like receptors (NLRs), which sense
development of immunity and mucosal nonpathogenic microbes, detection is only exogenous or endogenous stress or damage.
barrier function poses a pathogenic threat. part of the process. The response decision The epithelium mobilizes the NLRP6
Risk and benefit are also well represented is complex and seems to be based partly inflammasome in response to pathogenic
in the H. pylori story, 3 with some clini- on specific inputs or symbiosis-associated components of the microbiota and triggers
cians taking the view that ‘the only good molecular patterns from the microbiota 19 a cascade of events including: activation
H. pylori is a dead H. pylori’. However, the and partly by sensing danger or damage- of caspase 1; conversion of pro­ nterleukin
i
outcome of the Helicobacter–host inter- associated molecular patterns by epithe- IL‑18 to mature IL‑18; recruitment of
action varies depending on the bacterial lial and other host cells 13 (Figure 4). An γ‑interferon-producing NK and T cells;
strain, the host susceptibility and the age example of the former is the production and enhanced bacteriocidal activity of local
of the host. Acquired in childhood, with a of an immunomodulatory polysaccharide macrophages.13 This inflammasome mobi-
latent period of apparent health, H. pylori (polysaccharide A) by Bacteroides fragilis. In lization has a conditioning influence on the
might cause peptic ulceration in adulthood contrast to other TLR2 ligands that promote composition of the gut microbiota, which
in some individuals, lymphoma in others clearance of pathogens, poly­ accharide A
s becomes evident when NLRP6 is defi-
and gastric cancer at a later age. By contrast, signals though TLR2 on regulatory T cells cient and the commensal bacteria become
the same organism might confer protec- and suppresses T‑helper 17 effector cells, colito­ enic. Intestinal macrophages and
g
tion against asthma and possibly infections thereby avoiding an adverse immune dendritic cells have also been reported to
in early life, and almost certainly protects response and favouring colonization of the have divergent responses to commensals
NATURE REVIEWS | GASTROENTEROLOGY HEPATOLOGY VOLUME 9 | OCTOBER 2012 | 611
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4. PERSPECTIVES
exposure to bacteria in the distal gut, an
increasing list of drugs and other xeno­
biotics are substrates for bacterial enzymes
and might arrive at the distal gut because
■ Smaller family size of delayed release formulations or after
■ Delayed infections
Antibiotics/ biliary excretion. This delay might result
vaccinations in metabolites with more or less activity, a
Hygiene and
water quality desirable example of the former being the
release of aminosalicylate from the parent
prodrug, sulphasalazine, whereas a classic
example of the latter is microbial action on
Microbiota Metabolic
signalling digoxin. In other instances, toxins might be
Lifestyle
(early life) generated by microbial enzymatic action on
drugs. A particularly informative example
of the clinical effect of bacterial action
on drugs has been shown in the case of
Immune the colon cancer chemotherapeutic agent
priming and
inflammatory CPT‑11.22 After parenteral administration,
signalling
this drug is activated in vivo to generate the
antineoplastic topoisomerase I toxin and is
inactivated by glucuronidation in the liver,
after which it arrives in the intestine by
■ Diet and nutrition Urban life biliary excretion, where it is reactivated by
■ Cooking and refrigeration
bacterial glucuronidase. This process leads
Figure 2 | Lifestyle, microbiota and disease. The link between the elements of a modern lifestyle
to dose-limiting diarrhoea, a problem that
in developed countries and risk of immune and metabolic disorders in later life might be through
an influence on the microbiota, particularly in infancy. Microbial, immune and metabolic
can be circumvented using inhibitors that
signalling events are interactive. are specific to the bacterial enzyme. Thus,
the microbiota metabolizes some drugs and
is a target for others.
a b
Mining the microbiota
Mankind has exploited microbes with
Microbiota Inflammatory
tone ingenuity, from cleaning up oil slicks to
production of monoclonal antibodies and
Satiety, life-saving drugs. New therapeutic oppor-
behaviour
tunities arise as the molecular basis of
host–microbe interactions unfold. These
Diet
include mining the microbiota for bio­
active compounds that might be formu-
Immunity Metabolism lated as functional food ingredients or novel
drugs (Table 2).
The diversity of microbial metabolites
Bioavailability storage
of dietary nutrients and signalling molecules is testimony to the
Figure 3 | A signalling internet a | Diet influences each component of a triangular network of richness of the microbiota as a repository
signalling among the microbiota, host immunity and host metabolism. b | Mechanisms by which for drug discovery, but the pressing need
the microbiota influences host metabolism include: harvest of energy from dietary nutrients, for exploring this avenue is perhaps best
production of short-chain fatty acids (which signal via G protein-coupled receptors expressed by illustrated by increasing bacterial resist-
the epithelium), and promotion of lipid storage in adipose tissue by suppressing fasting-induced ance from overuse of antibiotics and dimin-
adipocyte factor, an inhibitor of lipoprotein lipase; modification of satiety and behaviour by ished pharmaceutical research.23 Concerns
signalling through the brain–gut–microbe axis; and influencing the host’s inflammatory tone,
about the long-term consequences of anti­
including the ratio of proinflammatory and anti-inflammatory cytokines.
bacterial action on the commensal micro-
biota also call for agents with a narrower
versus pathogens, which are driven by the promise new therapeutic targets. Failure of spectrum of activity. An approach to these
NLRC4 inflammasome.20 the checkpoints for modifying the response problems is shown by the discovery that a
Once an antimicrobial immune response to microbes might underpin or contribute Bacillus thuringiensis strain, isolated from
is launched, the host must determine the to chronicity of inflammatory disease.21 human faeces, produces thuricin CD, a
scale of the threat and adapt accordingly potent anti­ icrobial peptide with narrow-
m
to limit inflammatory collateral damage. The ‘drugable’ microbiota spectrum efficacy against Clostridium dif-
The molecular mechanisms by which this Although most drugs are absorbed in the ficile. This peptide is a naturally occurring,
effect is achieved are becoming clear and upper gastrointestinal tract with little potential adjunct to existing antibiotics, of
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© 2012 Macmillan Publishers Limited. All rights reserved

5. FOCUS ON GUT MICROBIOTA
comparable efficacy, but with little resist- Commensal bacteria Pathogens
ance evident to date. More importantly, ?
unlike antibiotics currently used against
C. difficile, thuricin CD has a narrow spec-
trum of activity without collateral damage
to the commensal microbiota.24
Rebooting the system
Clinicians often make a therapeutic leap
before basic science catches up, the story
of H. pylori and peptic ulceration being
Microbial factors Host factors Context
one example. Faecal microbial transplanta- Symbiosis-associated Damage-associated Wrong place at wrong time
tion is an old remedy undergoing a resur- molecular patterns (SAMPS) molecular patterns (DAMPS) or host susceptibility
gence of interest because of promising
results in various conditions, particularly
C. difficile-associated disease (CDAD). The TLR2
problem of CDAD has escalated because
of increasing antibiotic resistance, emer-
gence of an epidemic hypervirulent strain
(NAP1/B1/027) and recurrence rates of Mucosal Born too soon
TREG cell Inflammasome —premature baby
about 20–25%.25 Curiously, the appendix
might act as a sanctuary for the resident Figure 4 | The sensory conundrum—friend or foe? The distinction between a harmless
microbiota that protects against C. difficile commensal and a potential pathogen occurs at different levels. Microbial factors: although the
immune system does not express specific receptors to discriminate pathogens from
recurrence, with increased rates of recur-
commensals, some microbes produce molecules that act directly on regulatory T cells that
rence reported in patients who have had promote colonization by the organism. Host factors: epithelial inflammasomes are multiprotein
an appendicectomy.26 It has been suggested intracellular sensors of cellular stress or damage that activate an immune response, thereby
that the appendix might be both a locus of modifying the composition of the microbiota. Context: the host will respond to any commensal
mucosal lymphoid tissue and a reservoir of found in the wrong place at the wrong time; for example, premature babies are colonized with
normal microbiota, from which the colon commensals that have pathogenic potential because the mucosal barrier, immune function and
can be re-populated to restore homeostasis blood–brain barrier are not yet completely developed.
after challenge from antibiotics, disease and
perhaps phage viruses.
Different centres have wide variability Table 2 | Microbial activity translated to drug discovery or to functional foods 4,24,33–37
concerning the acquisition, storage, prepa- Bacterial action Potential drug category Representative examples
ration and mode of administration of faecal Microbe–microbe Antimicrobial (bacteriocin) Lactococcus lactis and Bacillus thuringiensis-derived
material to patients, although a standard- signalling broad and narrow-spectrum bacteriocins against
ized preparation and protocol has been Clostridium difficile
described.27 Critics claim that the bacterial Microbe–host Anti-inflammatory: Protective in experimental models of IBD
components of the administered material signalling Bacteroides fragilis-
derived anti-inflammatory
should be well defined and their interac- polysaccharide antigen;
tions with other microbes established prior Lactobacillus-derived cell
to making this therapy a routine practice. wall peptide
Others raise safety concerns, which will Microbe–host Cytoprotective Inhibition of cytokine-induced epithelial cell apoptosis
increase as faecal microbial transplantation signalling by a probiotic (Lactobacillus rhamnosus)-derived
soluble protein acting as an epidermal growth factor
becomes more widespread or is applied to
receptor agonist
less serious or trivial conditions. Concern
Microbe–host Analgesic Probiotic-derived analgesic effect in experimental
might even become crisis if reports linking
signalling functional bowel disorder
specific bacteria with colorectal cancer
Microbial Vitamins and short-chain Short-chain fatty acids, conjugated linoleic acid
are replicated and if the risk of cancer is
metabolism fatty acids
shown to be transferrable.3 An alternative
Genetically Delivery of vaccines or Reversal of autoimmune diabetes with L. lactis
strategy now underway in several centres
modified bioactive agents to gut engineered to deliver proinsulin and IL‑10; treatment
is to define the minimal microbiota, that organisms of colitis with Bacteroides ovatus engineered to
is, the combination(s) of strains sufficient secrete TGF‑β1 under control of dietary xylan
to safely confer protection against recur-
rence of CDAD and which can be char-
acterized, stored and safely prepared for probiotics and pharmabiotics, in CDAD and Conclusions
human administration without the risk of other disorders, have been addressed else- Helpful recommendations for filling
human–human disease transmission. where, the most important lesson being the persisting gaps in our knowledge of
More nuanced approaches to mimic the need to match the selection of the probiotic host–microbe interactions in health
normal microbiota, including prebiotics, strain with the clinical indication.28 and disease have been offered by several
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6. PERSPECTIVES
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