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PersPecTives

OPINION

The immune system and the gut


microbiota: friends or foes?
Nadine Cerf-Bensussan and Valrie Gaboriau-Routhiau

Abstract | The mammalian intestine is home to a complex community of trillions of


bacteria that are engaged in a dynamic interaction with the host immune system.
Determining the principles that govern hostmicrobiota relationships is the focus
of intense research. Here, we describe how the intestinal microbiota is able to
influence the balance between pro-inflammatory and regulatory responses and
shape the hosts immune system. We suggest that improving our understanding of
the intestinal microbiota has therapeutic implications, not only for intestinal
immunopathologies but also for systemic immune diseases.
Initially, all microorganisms were viewed as
pathogens that cause and propagate infectious
diseases and, as a field, immunology was built
around the paradigm that the host immune
system should recognize and eliminate these
intruders (non-self) while tolerating selfmolecules to preserve homeostasis. However,
the persistent association of animal and plant
species with obligate and facultative symbionts
now shows that both bacteria and their
eukaryote hosts benefit from their cooperative relationships. These benefits suggest that
co-evolution has selected mechanisms that
promote and maintain associations between
bacteria and eukaryotes. In humans, trillions
of bacteria are distributed in complex and
site-specific communities on the skin
and at mucosal surfaces, and the largest
community is found in the distal gut. As these
bacteria encode hundreds of genes that are
absent in the human genome1, the idea has
emerged that together with our microbiota,
we form superorganisms in which energy and
metabolites can be exchanged2 and homeostasis is maintained by the immune system3.
Therefore, a new paradigm proposes that the
immune system has evolved to accommodate
colonization by symbiotic bacterial communities of increasing complexity while retaining
the capacity to fight pathogens.
The gastrointestinal tract is the primary
site of interactions between the host and the
microbiota. How bacterial colonization of

the gut might influence the development


and functions of the immune system has
become a major focus of interest. A prevalent
theory, derived from hypotheses that were
first postulated by Metchnikoff a century
ago, proposes that individual members of
the microbiota might influence the balance
between pro-inflammatory and regulatory
host responses and that alterations in the
composition of the microbiota (a process that
is known as dysbiosis) could jeopardize host
immune responses and promote the development of various inflammatory disorders.
Here, we discuss the principles that govern
the interactions between the intestinal microbiota and the host immune system, both in
health and in disease. Moreover, we stress
how the complexity of the gut ecological system and the reciprocal nature of the regulation of the immune system and of microbial
community structures must be considered
before one can draw any conclusions about
the role of the microbiota in disease and
propose therapeutic interventions.
The hostmicrobiota interaction in the gut
The intestine is an open ecological system
that is colonized immediately after birth
by a microbial population that reaches
an impressive density of 1012 bacteria per
gram of luminal content in the distal gut.
Colonization is initiated by maternally
acquired bacteria during birth; these

nATuRE REvIEws | Immunology

bacteria are then followed by hundreds


of environmentally acquired species,
which differ between individuals but
mainly belong to two bacterial phylotypes,
Firmicutes spp. and Bacteroidetes spp.2,4.
A growing number of studies support
the view that eukaryotic hosts and their
symbionts have co-evolved towards mutualistic interactions that are based on the
nutritional benefits that each partner gains
from the association5 (BOX 1). However,
the huge collection of bacteria at the gut
surface is also a major threat to host integrity and has driven the selection of highly
flexible defence mechanisms, which enable
eukaryotic hosts to cope with their microbial environment and compensate for their
less rapid genetic adaptation.
The gut immune system. Recent reviews
have highlighted how the microbiota elicits
innate and adaptive immune mechanisms
that cooperate to protect the host and maintain intestinal homeostasis6,7. Epithelial cells
are a central component of the immune
system of the gut. In a similar manner to
immune cells, epithelial cells express receptors for microbial-associated molecular
patterns (MAMPs). These receptors activate
signalling cascades that finely tune epithelial
cell production of antimicrobial products
and chemokines, depending on the signals
that are delivered by the microbiota (FIG. 1).
Thus, gut epithelial cells form a potent and
inducible physico-chemical barrier, which
limits microbial growth and access to the
gut surface. They can also recruit leukocytes
to complement their barrier function or to
participate in the activation of gut adaptive immune responses. In mammals, the
development of gut-associated lymphoid
tissues (GALTs) is initiated before birth by
a genetic programme8. However, GALT
maturation and the recruitment of IgAsecreting plasma cells and activated T cells
to mucosal sites only occurs after birth and
is strictly dependent on microbiota-derived
signals; these signals influence the crosstalk
between epithelial cells and gut dendritic
cells (DCs), thereby modulating the nature
and intensity of intestinal B and T cell
responses7,9 (FIG. 2). In immunocompetent
mice, intestinal colonization stimulates
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PersPectives
Box 1 | mutualistic relationships between hosts and their intestinal microbiota
The human intestine harbours an estimated 100 trillion bacteria, 7080% of which cannot yet be
cultured. Each individual is thought to host several hundred species of bacteria from only 7 to 9
phylotypes; these are mainly Gram-positive Firmicutes spp. (most notably Clostridium spp.,
Enterococcus spp. and Lactobacillus spp.) and Gram-negative Bacteroidetes spp. Recent
metagenomics studies predict a core of ~1,200 prevalent species and a total intestinal
microbiome that contains 150-fold more genes than the human genome4. The gut microbiome
encodes a core of redundant bacterial genes that are likely to be needed to resist stressful
conditions in the host intestine63 and to harvest nutrients that are necessary for bacterial
growth2,4. Competition between bacteria with distinct metabolic requirements might explain the
massive and rapid shifts in the structure of the intestinal microbial community that are provoked
by changes in host diet64. In addition to the genes that are necessary for microbial adaptation to
the host environment, the gut microbiome encodes multiple biosynthetic pathways that are
predicted to greatly increase the hosts capacity to metabolize glycans and xenobiotics and to
synthesize vitamins2,4. Moreover, studies in gnotobiotic mice have shown the broad influence of
the gut microbiota on host physiology. Intestinal colonizaton induces a spectrum of intestinal
and metabolic changes, which promote the digestion and absorption of nutrients and stimulate
fat storage65,66, accelerate gut epithelial renewal and alter epithelial locomotor activity67. The
signalling pathways that are involved remain largely elusive, but recent observations suggest
that overlapping mechanisms have been selected during hostmicrobiota co-evolution that
simultaneously control host metabolic and innate immune responses to the microbiota. In mice,
inactivation of Toll-like receptor 5 (TLR5), which is a receptor for bacterial flagellin that has an
established role in host innate immune responses, results in severe obesity and profound
alterations in the microbiota structure68. Furthermore, peroxisome proliferator-activated
receptor- (PPAR), which is a transcription factor that has a central role in glucidolipidic
metabolism, can control the production of microbicidal peptides by colonocytes and serves
as a feedback mechanism for the activation of nuclear factor-B (NF-B) in enterocytes69.

the production of secretory IgA, the differentiation of effector T helper 1 (TH1),


TH2 and TH17 cells, and the development of
regulatory T (TReg) cells10.
It is increasingly clear how these adaptive immune elements cooperate with innate
immune cells to strengthen the gut barrier
and protect the host from invading pathogens. An outstanding issue now is to define
how individual members of the microbiota
or microbiota-derived products can affect
the balance between pro-inflammatory and

regulatory immune responses, and to establish


whether the composition of the microbiota
can influence the development of inflammatory diseases in and beyond the gut. Before
considering the possible role of the microbiota
in disease, we will first highlight how the different colonization strategies of individual
members of the microbiota can influence the
development and function of the gut immune
system and show that, ultimately, it is the host
immune system that determines whether a
bacterium is a friend or a foe.

Anti-inflammatory roles of the microbiota.


Current results indicate that a trade-off is
established between the host immune system and the bulk of the microbiota, so that
in a healthy individual, intestinal colonization stimulates host production of microbicidal peptides11 and secretory IgA, which
in turn contain the microbiota within the
intestinal lumen and neutralize MAMPs12.
These mechanisms protect the host from
the systemic translocation of bacteria or
bacterial products and from the outburst of
pro-inflammatory cascades in intestinal epithelial and innate cells13. Conversely, the resident bacteria also benefit from the symbiotic
relationship and can thrive in the mucus,
thus minimizing destruction by host-derived
inflammatory mediators. Hosts and bacteria
have evolved additional strategies to maintain friendly relationships. Thus, signalling
cascades that occur downstream of Toll-like
receptors (TLRs) can be desensitized by
continuous exposure to lipopolysaccharide
(LPs)14 or can be attenuated by other soluble
mediators that are produced by the microbiota (FIG. 1). Furthermore, some microbiotaderived soluble products can promote the
functions of TReg cells15,16.
The mechanism that maintains this
friendly relationship has been elucidated
in the case of Bacteroides fragilis, which is a
common culturable member of the microbiota15. This bacterium possesses an unusual
capsular polysaccharide A (PsA) that is able
to drive the differentiation of interleukin-10
(IL-10)-secreting TReg cells. Colonization by
a wild-type B. fragilis, but not by a mutant
strain that lacks PsA, protected mice from
the severe experimental colitis that is induced

glossary
Ankylosing enthesopathy

IgE-associated allergies

An inflammatory autoimmune disease of the joints


that naturally occurs in mice on a C57BL/10 genetic
background; the disease is similar to human ankylosing
spondylitis. The pathology is characterized by the
proliferation of cartilage and connective tissue, which
culminates in ankylosis of the joints.

Type 1 hypersensitivity reactions that are mediated by


IgE, which induces mast cell activation and degranulation.
Such immune reactions are seen in asthma, allergic rhinitis,
systemic anaphylaxis and food allergies.

Germinal centres
Highly specialized and dynamic microenvironments that
are located in secondary lymphoid tissues and give rise
to secondary B cell follicles during an immune response.
Germinal centres are the main sites of B cell proliferation
and differentiation, which leads to the generation of
memory B cells and plasma cells that produce high-affinity
antibodies.

Obligate and facultative symbionts


Obligate microbial symbionts need to colonize a host
to develop and multiply, unlike facultative microbial
symbionts, which can also develop outside a host.

Pathobionts
Microbial symbionts that can cause defined disease in
predisposed hosts following changes in the gastrointestinal
environment.

Germ-free mice are born and raised in sterile isolators


and are devoid of colonization by any microorganisms,
but after they have been experimentally colonized by
known bacteria, they are said to be gnotobiotic. They
are kept in isolators to control their bacterial status.

Proteobacteria
Gram-negative microorganisms that colonize very distinct
environments and are the second largest group of bacteria
on earth. Proteobacteria that colonize the intestine include
commensal, pathogenic and opportunistic species, such as
Salmonella, Shigella and Helicobacter spp. and Escherichia
coli strains. In healthy adults, proteobacteria represent less
than 1% of the enteric microbiota, but they are a major
cause of intestinal and extraintestinal diseases.

Type VI secretion system

The whole genome of all of the microorganisms that


colonize a specific environment.

(T6SS). Like T3SS and T4SS, T6SS is a multi-subunit


complex that acts like a needle and syringe to
translocate bacterial products across the
double-membrane of Gram-negative bacteria into
the cytoplasm of eukaryotic cells.

Peyers patches

Xenobiotics

Collections of lymphoid follicles that are located in the


intestinal mucosa and are particularly abundant in the ileal

Chemical compounds that are foreign to a living organism


and that can be toxic, even at low concentrations.

Microbiome
Gnotobiotic mice

mucosa. Together with mesenteric lymph nodes, they form


the inductive compartment for intestinal immune responses.

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PersPectives
by Helicobacter hepaticus15,17. Furthermore,
administration of PsA reduced the severity of disease in a model of trinitrobenzene
sulphonic acid (TnBs)-induced colitis17.
Therefore, B. fragilis may represent a prototype peace-keeper strain. Yet the outcome
of hostmicrobiota interactions cannot be
predicted from only the bacterium itself, and
a bacterium that is beneficial for an immunocompetent host can become a dangerous foe
when the immune system is weakened. This
is illustrated by the fact that B. fragilis causes
severe sepsis in immunocompromised hosts.
Likewise, normally harmless members of the
microbiota can initiate intestinal inflammation in individuals who cannot mount efficient intestinal humoral responses18,19 and in
individuals with impaired intestinal immunoregulation, most notably in those who lack a
functional IL-10 signalling pathway 20,21.
Promotion of effector immune responses.
Although certain members of the microbiota
have adopted peace-keeper activities to colonize the intestine, others are, undoubtedly,
endowed with pro-inflammatory properties.
one such group, which has recently attracted
much attention, is segmented filamentous
bacteria (sFB). These unculturable species
settle in the rodent intestine at the time of
weaning and stimulate the postnatal maturation of immune responses in the mouse
gut. Mice that are colonized by a microbiota
that lacks sFB have weaker IgA antibody
responses22 and much poorer intestinal
T cell responses compared with mice that
are colonized with sFB. notably, mice that are
colonized by an sFB-deficient microbiota
lack mucosal TH17 cells10,23. Furthermore,
these animals cannot control colonization by
the invasive pathogen Citrobacter rodentium,
which suggests that microbiota-induced
immune responses participate in the barrier function of the flora23. This hypothesis
is also supported by recent work that shows
that the destruction of the microbiota following treatment with antibiotics can jeopardize innate immune responses in the gut
and promote colonization by pathogens24.
A striking feature of sFB is their strong
adherence to the surface epithelium of the
ileum and the Peyers patches shortly after
weaning 25. This is in contrast with most other
members of the microbiota, which remain
entrapped within the mucus and have little
or no physical contact with host epithelium25.
This attachment, which is perhaps necessary
to initiate the replication of sFB, is likely to
facilitate the sampling and presentation of
sFB antigens to T cells by DCs in the Peyers
patches and to stimulate pro-inflammatory

PAMP

Bacterium

TLR

Intestinal lumen
Intestinal
epithelial cell

MYD88
Expression of IRAK1
decreased by LPS
from microbiota

IRAK1

ROS induced by
microbiota inhibit
ubiquitin ligases
IB ubiquitylated and
targeted to the proteasome
for degradation

IB
p50 p65
NF-B
Nuclear translocation
of NF-B

p50 p65

p65 PPAR

PPAR

NF-B transcribes
pro-inflammatory
cytokines and
chemokines and
defensins

PPAR induced in
response to microbiota
LPS diverts NF-B
from nucleus
PPAR upregulates
colonic -defensins
to sustain gut barrier

Pathway impaired
in patients with
Crohns disease

Figure 1 | modulation of intestinal epithelial cell pro-inflammatory responses by the microbiota.


in a similar manner to immune cells, epithelial cells detect microbes throughNature
pattern-recognition
recepReviews | Immunology
tors, including Toll-like receptors (TLrs). Upon TLr ligation, adaptor proteins, such as myeloid differentiation primary-response protein 88 (MYD88), are recruited and activate signalling cascades, notably
the nuclear factor-B (NF-B) pathway, which stimulates the transcription of antimicrobial proteins,
pro-inflammatory cytokines and chemokines. in resting cells, NF-B is sequestered in the cytoplasm by
its inhibitor iB. Following TLr activation, iB is phosphorylated, ubiquitylated and degraded by the
proteasome, which allows nuclear translocation of NF-B and transcription of NF-B target genes. This
pathway can be modulated by microbiota-derived factors, preventing excessive and potentially deleterious host pro-inflammatory responses. immediately after birth, expression of the interleukin-1 receptorassociated kinase 1 (irAK1), which is the proximal activator of the NF-B cascade, is downregulated by
microbiota-derived lipopolysaccharide (LPs)14. The polyubiquitylation and degradation of iB can be
inhibited by commensal bacteria, which inhibit a common ubiquitin ligase by inducing reactive oxygen
species (rOs)70. Peroxisome proliferator- activated receptor- (PPAr), which is induced in response to
TLr4 activation by LPs71, can also divert NF-B from the nucleus72. checkpoints that are controlled by
the microbiota are indicated by T bars. interestingly, PPAr positively controls the expression of the
colonic microbicidal peptide defensin 1 (rEF. 69) and thus can simultaneously sustain the gut barrier
and prevent excessive inflammation. This mechanism may be impaired in a subset of patients with
colonic crohns disease69. PAMP, pathogen-associated molecular pattern.

signalling pathways in epithelial cells and


DCs, resulting in robust innate and adaptive immune responses in the intestine10,23.
such behaviour is characteristic of bona fide
pathogens, which use host inflammatory
responses to eliminate the resident flora and
to colonize the remaining niches26,27. This
attachment might enable sFB to settle in the

nATuRE REvIEws | Immunology

mouse intestine, but it also benefits the host


by strengthening the gut barrier. strikingly,
on the basis of morphological studies, sFB
have been detected in all species studied from
arthropods to mammals, including humans,
and closely related 16s rRnA sequences have
been found in chickens, trout and rodents25,28.
Therefore, it is tempting to speculate that this
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PersPectives
a
M cell

Intestinal lumen
Bacterium

MHC
Peptide
Intestinal epithelium
TCR
Naive T cell

CX3CR1expressing
phagocyte

Transcytosed bacteria are


acquired by DCs, which activate
adaptive immune responses

CD103+ DCs acquire


bacterial antigens

Direct sampling of
bacteria in lumen?
Antigen transfer?

Lamina propria

CD103+

Peyers patch

Peyers patch and CD103+ DCs


migrate to MLNs and initiate
adaptive immune responses

DC

c
IgA molecules are
transcytosed by polymeric
IgA receptors and retain
bacteria in the mucus

B. fragilis

TLR
Mucus layer

Dimeric
secretory
IgA

IgA+ plasma cell

SFB

Microbiotaderived products
activate TLRs

BAFF,
APRIL

TSLP,
TGF,
retinoic
acid

ATP
SAA

Bacterial ATP and


bacteria-induced
SAA activate DCs

TReg cell
induction

Epithelial
cell

BAFF and APRIL


promote T celldependent and
T cell-independent
IgA class-switching

B. fragilis capsular
polysaccharide A

Tolerogenic DC

Inflammatory
DCs

FOXP3
TReg cell
+

IL-12

IL-1, IL-6,
IL-23

TReg cells maintain


tolerance to food
and commensals

TH17 cell

SFB induce
IL-12-producing
DCs by unknown
mechansims

TH1 cell

TH1 and TH17 cells sustain intestinal barrier


by recruiting macrophages and neutrophils
and inducing antibacterial defensins

Figure 2 | | modulation of adaptive immune responses in the gut by the


microbiota. a | intestinal adaptive immune responses can be initiated in
Peyers patches or in mesenteric lymph nodes (MLNs). Activated T and B cells
subsequently leave these lymphoid tissues and home to the intestinal lamina
propria via the bloodstream. Bacteria are mainly sampled by Peyers patch
dendritic cells (Dcs) after transcytosis across the specialized epithelium that
overlays these lymphoid organs. it has also been suggested that a population
of cX3c-chemokine receptor 1 (cX3cr1)+ lamina propria cells with both Dcand macrophage-like characteristics can send dendrites into the intestinal
lumen and directly capture bacteria. Their role in antigen presentation
remains controversial73,74, but they may pass antigens to lamina propria
cD103+ Dcs, which can migrate to the MLNs and present antigens to T cells74.
b | Microbiota-derived products activate Toll-like receptors (TLrs) that are
expressed by intestinal epithelial cells, which leads to the production of
B cell-activating factor (BAFF) and a proliferation-inducing ligand (APriL);
these cytokines promote both T cell-dependent and T cell-independent igA
class-switching responses in the intestine75,76. Plasma cells produce dimeric
igA molecules that are transcytosed into the intestinal lumen by the epithelial polymeric ig receptor, the expression of which is upregulated by the
microbiota. The extracellular part of this receptor remains associated with
igA following release into the lumen and forms secretory igA. These

secretory igA molecules form immune complexes with bacteria, which are
then retained in the mucus. c | cD103+ Dcs are conditioned by epithelial
cell-derived factors, such as thymic stromal lymphopoietin (TsLP), transforming growth factor- (TGF) and retinoic acid, to acquire a tolerogenic phenotype; these Dcs can promote the induction of forkhead box P3 (FOXP3)+
regulatory T (Treg) cells77. Bacteria-derived products, such as the capsular
polysaccharide A from Bacteroides fragilis, can further
induction
Naturepromote
Reviews the
| Immunology
of interleukin-10 (iL-10)-producing Treg cells through a TLr2-dependent
mechanism15,17. However, some commensal bacteria can stimulate the differentiation of inflammatory mucosal T cells. T helper 17 (TH17) cell differentiation can be promoted by bacteria-derived ATP, which activates a subset of
Dcs that produce iL-1, iL-6 and iL-23 (rEF. 78), or by serum amyloid A protein (sAA), which is an acute phase protein that is produced in response to
segmented filamentous bacteria (sFB)23. sFB can also drive the expansion of
mucosal TH1 cell populations11, presumably by inducing iL-12 production by
Dcs. in addition, inflammatory Dcs might stimulate the conversion of
Treg cells into TH17 and/or TH1 cells in the lamina propria (not shown)79. TH1
and TH17 cells maintain the intestinal barrier by recruiting and activating
macrophages and neutrophils that eliminate penetrating bacteria. iL-22 that
is produced by a subset of TH17 cells can also promote the production of
antibacterial defensins by epithelial cells. M cell, microfold cell.

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PersPectives
unusual symbiont has a particularly important role in shaping the gut immune system
across evolution. However, again, the outcome of sFBhost interactions depends on
the immune status of the host; sFB has been
associated with the development of intestinal
inflammation29 or arthritis30 in mice with
impaired immunoregulation and can also
aggravate experimental autoimmune encephalomyelitis31 (FIG. 3). Interestingly, sFB alone
were not able to induce intestinal inflammation in immunodeficient mice and instead
synergized with a pathogen-free flora. This
finding highlights how interactions in the
microbiota community can influence host
immune responses, thereby adding an
additional level of complexity.
The case of pathobionts. A particular subset of bacteria further exemplifies how the
behaviour of the microbiota is dependent on
the immune status of the host. Although these
bacteria, which are known as pathobionts,
colonize the gastrointestinal tract of many
individuals asymptomatically, they also have
the potential to cause disease. A recent study
showed that Helicobacter hepaticus, which
is a member of the epsilon subgroup of
proteobacteria, uses its type VI secretion system
(T6ss) to regulate bacterial colonization and
inhibit host innate and adaptive immune
responses, thereby actively maintaining
symbiotic relationships with immunocompetent hosts32. However, this bacterium can
cause severe typhocolitis in Il10/ mice or
in the severe combined immunodeficient
(sCID) transfer model of colitis. These
findings highlight the central role of host
adaptive regulatory responses in maintaining symbiotic relationships with the
microbiota32.
In humans, the most classical example
of a pathobiont is Helicobacter pylori, which
uses various mechanisms to dampen host
immune responses and persist in the stomach. Gastric colonization by this bacterium
remains asymptomatic in most individuals and has even been suggested to protect
against the development of oesophageal
carcinomas owing to downmodulation of
gastric acid secretion. Yet this bacterium
is the major cause of gastritis and gastric
cancers. The circumstances that lead to this
bacterium becoming a serious health concern are not completely understood but are
thought to include the selection of specifically aggressive strains and/or host predisposing factors, notably polymorphisms in
gene promoters that increase the production
of tumour necrosis factor (TnF) or IL-1,
which is a pro-inflammatory cytokine

Intestinal colonization by SFB

Effects on intestinal compartment


Stimulation of innate immune
responses e.g. Reg III/ production
Stimulation of CD4+ T cell responses e.g.
TH1, TH2, TH17 and TReg cells
Induction of IgA responses
Recruitment and activation of IELs

Physiological inflammation
strengthens gut barrier in
immunocompetent hosts

Intestinal inflammation
in SCID mice transferred
with effector T cells

Effects on peripheral compartment


Increased germinal centre
formation in the spleen
Autoantibody-secreting
IgG plasma cells
Circulating immune
complexes

Arthritis in
K/BxN mice

Enhanced
sensitization
following
challenge with
MOG peptide

Increased
severity of EAE

Figure 3 | Effects of SFB colonization on the immune system. segmented filamentous bacteria
(sFB) are spore-forming bacteria that are related to the genus Clostridium28. inherited from the
Nature Reviews | Immunology
mother microbiota, sFB develop strong interactions with the ileal mucosa and in immunocompetent mice, the bacteria can largely recapitulate the inducing effects of the whole microbiota on
the postnatal maturation of the gut immune system. sFB induce the production of reg iii/ microbicidal peptides10,23,80, which protect against colonizing pathogens24. Additionally, sFB simultaneously activate strong secretory igA responses22, induce the recruitment and activation of cytotoxic
intraepithelial lymphocytes (ieLs)81 and drive various T cell responses, including a robust T helper 17
(TH17) cell response11,23. in immunocompetent mice, sFB-induced pro-inflammatory and regulatory
responses balance each other, which results in physiological inflammation that strengthens the
gut barrier. By contrast, colonization by sFB promotes the development of colitis in severe combined immunodeficient (sciD) mice that have been reconstituted with effector T cells29. intestinal
colonization by sFB can also promote the development of inflammatory diseases outside of the
gut. sFB promote arthritis in autoimmune non-obese diabetic (NOD) mice that express a transgenic T cell receptor (Tcr) that is specific for a self peptide (known as K/BxN mice), an effect
ascribed to the induction of TH17 cells 30. sFB also enhance the severity of myelin oligodendrocyte
glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (eAe). These aggravating
effects may reflect the strong adjuvant properties of sFB. Treg cells, regulatory T cells.

with potent acid-suppressive properties33.


other recently characterized pathobionts
include enterotoxigenic B. fragilis (ETBF),
which can stimulate colonic inflammation
and tumorigenesis in predisposed multiple
intestinal neoplasia (MIn) mice34, and some
Escherichia coli strains, which can promote
gut inflammation in patients with Crohns
disease35,36.
Intestinal dysbiosis and IBDs
Inflammatory bowel diseases (IBDs) are
thought to arise owing to a combination of
genetic and environmental factors that result
in dysregulated immune responses to the gut
microbiota and the subsequent development
of gut inflammation20. Compelling evidence
from a variety of studies has shown dysbiosis
in patients with IBD compared with healthy
controls, and this suggests a causative role for
dysbiosis in gut inflammation.
several scenarios can be considered.
Pro-inflammatory bacteria, such as enteroinvasive Escherichia coli strains, are more
frequently seen in the ileal mucosa of

nATuRE REvIEws | Immunology

patients with Crohns disease than in healthy


controls, which suggests that these bacteria
can initiate disease36. Yet to induce intestinal
inflammation, the prototype E. coli LF82
strain first needs to bind to an epithelial
cell-expressed receptor. This receptor
is absent in the normal ileal mucosa but is
upregulated by interferon- (IFn) and
TnF that are produced during intestinal
inflammation35,37. An alternative hypothesis suggests that the reduced frequency
of a Firmicutes species, Faecalibacterium
prausnitzii, in the intestinal microbiota is
a causative factor of Crohns disease16. This
strain releases an unidentified soluble factor,
which inhibits pro-inflammatory epithelial
cell responses in vitro and attenuates
inflammation in a mouse model of colitis16.
other studies, however, suggest that
more global changes in the composition
of the microbiota are associated with IBD,
such as abnormal adherence of bacteria to
the gut mucosa, reduced bacterial diversity,
decreased levels of resident Firmicutes spp.
and/or Bacteroides spp. and an overgrowth
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of proteobacteria3840. strikingly, comparable
changes in the microbiota have been seen
in mice in which intestinal inflammation
was induced by either an invasive pathogen
or by the injection of transgenic T cells
that attacked the gut epithelium27. In these
two distinct models, host inflammation
suppressed the growth of Firmicutes and
Bacteroides spp., allowing proteobacteria,
which are apparently more resistant to hostderived microbicidal factors, to outcompete
these normally dominant resident bacteria27.
notably, outgrowth of proteobacteria was

also seen in Il10/ mice after, but not before,


the onset of intestinal inflammation, which
further highlights the profound influence of
the host immune response on the structure
of the microbial community 27.
Together, these observations underscore
the confounding role of host-predisposing
factors and the difficulty in assigning a
causative role for dysbiosis in IBD. However,
experimental evidence suggests that intestinal inflammation can select for bacterial
species with colitogenic properties. In T-bet/
Rag2/ ulcerative colitis (TRuC) mice, the

Healthy gut environment

Gut
lumen

Physiological microbiota
Peace-keeping
bacterium

Altered gut environment


Antibiotics, diet, hygiene,
pollutants, virus?
Dysbiosis
Decrease in peace-keeping bacteria
and increase in pathobionts

Pathobiont

Mucus
Healthy
epithelial
barrier
Damaged epithelial
barrier, increased
bacterial adherence
and penetration

TH1 cell
Lamina
propria

TH17 cell
IgA+
plasma cell TReg cell

Physiological inflammation

Pathological inflammation

Altered host immune system


Genetics
Severe monogenic
immunodeficiency
IL-10R mutations,
CVID

Immune
gene variants
NOD2, ATG16L1,
IL-23R, IRGM

Environment
Stress, diet, infections, vaccine?

Figure 4 | Schematic representation of hostmicrobiota interactions in the healthy and


inflamed gut. a | in healthy hosts, an efficient immune barrier contains the microbiota in the gut
lumen and feedback mechanisms avoid excessive activation of host immune responses. PeaceNature Reviews | Immunology
keeping bacteria that release anti-inflammatory products participate in the tuning of host responses
towards tolerance and help to prevent the pro-inflammatory effects of any pathobionts that are
present in the microbiota, thus maintaining intestinal homeostasis. b | immunodeficient patients,
who lack an important component of the gut barrier (for example, secretory immunoglobulins in
patients with common variable immunodeficiency (cviD)19) or a key regulatory pathway (for example, loss-of-function mutations that affect the interleukin-10 receptor (iL-10r)21) spontaneously
develop intestinal inflammation when exposed to the microbiota. in more common forms of inflammatory bowel disease (iBD), a complex genetic background results in more subtle alterations of gut
immune responses that may weaken the gut barrier and/or impair immunoregulation82. in these individuals, lifestyle changes or medical practices (for example, stress, diet, hygiene, smoking, antibiotics,
vaccines or appendectomy) may promote the onset of gut inflammation by affecting the immune
balance and/or the gut microbiota82. intestinal inflammation results in increased bacterial adherence,
epithelial damage and increased entry of bacteria into the intestinal lamina propria, thus sustaining
a vicious inflammatory circle. Moreover, inflammation can favour the selection of aggressive pathobionts, which are more resistant to host-derived microbicidal mediators26,27, and reduce the number
of peace-keeping species16, which results in even more severe and uncontrolled inflammation. These
pathobionts might become sufficiently aggressive to also cause disease in immunocompetent individuals43. ATG16L1, autophagy-related 16-like 1; irGM, immunity-related GTPase family M; sciD,
severe combined immunodeficient; TH cell, T helper cell; Treg cell, regulatory T cell.
740 | o CToBER 2010 | voLuME 10

inability of DCs to properly regulate TnF


production results in a severe and highly
penetrating colitis. Intestinal inflammation
spontaneously progresses to colonic dysplasia and rectal adenocarcinoma; therefore,
disease progression in this model is similar
to that seen in human IBD41,42. TRuC colitis
can be prevented by eradicating the microbiota with broad-spectrum antibiotics.
Moreover, in a situation that recalls rare
reports of intrafamilial transmission of IBD
in humans, colitis can be transmitted from
TRuC mice to wild-type mice in both crossfostering and co-housing experiments41.
Furthermore, the microbiota in TRuC
mice exhibits complex changes, including
selective enrichment of two proteobacteria,
Proteus mirabilis and Klebsiella pneumonia.
These two bacteria are not sufficient to
induce colitis in gnotobiotic TRuC mice;
however, they can colonize the intestine
of wild-type mice and, in concert with a
pathogen-free microbiota, induce colonic
inflammation43. These data highlight how
the host immune response can shape the
microbiota and eventually lead to the selection of aggressive bacteria, which not only
survive in the inflamed gut but also promote
inflammation.
what are the therapeutic implications
of these findings? At the very least, they
explain the difficulties in establishing and
maintaining remission in patients with IBD
using drugs that target host inflammatory
components or the microbiota without also
correcting host-predisposing factors. They
highlight the importance of identifying
such predisposing factors and designing
more specific therapies for IBD. They also
suggest the need for combined approaches
that can restore local ecological conditions
and correct dysbiosis to reinstate balanced
hostmicrobiota interactions in the long
term (FIG. 4).
Microbiota and systemic immunity
so far we have focused on the roles of the
microbiota in intestinal immunity, both
in health and disease; however, growing
evidence suggests that the intestinal microbiota can also have an important impact on
the development of the peripheral immune
system. Moreover, dysbiosis has been
implicated in the development of extraintestinal immune-mediated diseases. It will
be crucial to determine the extent to which
the impact of the microbiota depends
on the host immune status, whether individual bacterial species can exert distinctive
roles and, ultimately, whether the observed
dysbiosis has a causative role in disease.
www.nature.com/reviews/immunol

2010 Macmillan Publishers Limited. All rights reserved

PersPectives
Effects on the peripheral immune system.
The exact impact of the gut microbiota on
the hosts peripheral immune system is controversial. Two groups have convincingly
shown that specific immune responses to
the intestinal microbiota are largely confined
to the intestinal lymphoid compartment in
immunocompetent mice with an efficient
gut barrier 13,44,45. However, studies comparing mice that were raised in conventional
or germ-free conditions highlight the
importance of the intestinal microbiota for
the development of the peripheral immune
system in immunocompetent hosts. notably,
the spleens of germ-free mice contain fewer
and smaller germinal centres46 and decreased
numbers of memory CD4+ T cells, and
cytokine production by these T cells shows a
TH2-type profile47.
The mechanisms that underlie the
stimulatory effects of the microbiota on the
peripheral immune system of immunocompetent hosts are not well understood.
Recent work suggests that soluble factors
that are produced by the microbiota can
translocate from the gut to the bloodstream
and activate innate immune cells. For
example, the opsonophagocytic activity of
neutrophils is primed by microbiota-derived
peptidoglycan, which results in enhanced
protection against pneumococcal sepsis48.
Moreover, monocolonization with B. fragilis
corrects systemic T cell deficiencies and
the TH1/TH2 imbalance of germ-free mice
due to the stimulation of DC IL-12 production by the bacteriums unusual capsular
polysaccharide47.
Allergy and dysbiosis. The hygiene
hypothesis, which has been revised
several times since its initial formulation by strachan in 1989, stipulates that
decreased exposure to infectious agents,
as well as changes in the intestinal microbiota during infancy, might alter immune
regulatory networks and account for the
dramatic increase in the incidence of
allergic diseases that has been observed in
developed countries49. several studies have
reported differences in the composition
of the faecal microbiota of infants who
develop an allergic disease and those who
do not. notably, a decreased frequency
of Lactobacillus and Bifidobacterium spp.
has been suggested to precede the onset
of allergy 50, and prophylactic approaches,
which are based on the administration of
probiotics to mothers and newborns at
high risk for IgE-associated allergies, have
been initiated. A recent study reports
that 1 month of prenatal and 6 months of

postnatal pre- and probiotic supplementation can reduce the incidence of eczema
and food-specific IgE in a subset of highrisk children who are born by caesarean
section51. This protective effect was not
seen in vaginally delivered children and
was transient, as it was significant at
2 years of age but not by 5 years of age.
The results of such interventions remain
conflicting and a causative link between dysbiosis, which is induced by changes in lifestyle or recent medical practices, and allergy
remains difficult to establish51,52. Moreover,
experimental studies that support the role
of the microbiota in the development of
allergic diseases are still scarce (TABLE 1). one
study has reported increased development
of allergic airway disease in mice that were
treated with a short course of oral antibiotics53. Another interesting study showed that
TLR4 activation by microbiota-derived
LPs was necessary to prevent anaphylaxis
after oral immunization with the peanutderived allergen Arah 1. TLR4-deficient or
antibiotic-treated mice showed an increased
TH2-type skewing of cytokine responses
compared with control mice. Conversely,
activation of TLR9 by oral administration of
CpG oligodeoxynucleotides could abrogate
allergic symptoms and correct the TH1/TH2
imbalance54. However, additional work is
needed to delineate whether and how the
composition of the microbiota might
influence the onset of allergy.
Autoimmunity and the microbiota. The
possibility that the intestinal microbiota is
involved in the development of systemic
autoimmunity has recently attracted growing attention. Changes in the composition of
the gut flora have been reported in patients
in the early phases of rheumatoid arthritis55
when compared with a control group with
fibromyalgia. However, such studies cannot
establish a link between dysbiosis and the
development of disease. Therefore, the role
of the microbiota has been more directly
addressed by comparing the onset and/or
severity of experimental autoimmune diseases in germ-free mice with disease onset
and/or severity in mice that have been
colonized by a diverse microbiota.
In several models of autoimmunity,
the progression of disease was comparable between both sets of mice5658. In
other models, contradictory roles for the
microbiota have been reported (TABLE 1).
The microbiota was shown to trigger
disease in several mouse models of autoimmune arthritis. For example, in a mouse
strain that is prone to the spontaneous

nATuRE REvIEws | Immunology

development of an autoimmune ankylosing


enthesopathy, disease does not develop
under germ-free conditions. Furthermore,
disease develops in mice that are colonized
with a mixture of culturable anaerobes
but not in mice that are colonized with
Lactobacillus or Staphylococcus spp.59. This
finding suggests a role for a specific component (or components) of the microbiota
in disease progression. A triggering role
for the microbiota, specifically for sFB, was
also seen in the autoimmune arthritis that
develops in K/Bxn mice30. In this model,
an uncontrolled TH17 cell response that is
induced by sFB stimulated the production
of autoantibodies and led to the deposition of immune complexes in the joints
(FIG. 3). The microbiota also promoted
disease in another IL-17-dependent model
of arthritis, which develops in mice that
lack the IL-1 receptor antagonist 60. Finally,
the microbiota and, to a lesser degree, sFB
enhanced the severity of experimental
autoimmune encephalomyelitis31. The
aggravating role of the microbiota in these
models is consistent with its central role in
the induction of TH17 cell responses.
By contrast, the microbiota was shown
to have a protective role in collageninduced arthritis61 and to prevent diabetes
development in myeloid differentiation
primary-response protein 88 (MYD88)deficient non-obese diabetic (noD) mice62,
as in both models disease was more severe
if animals were housed in germ-free conditions. It remains unclear why a protective
role for the microbiota during the development of diabetes is seen in the presence
of impaired TLR signalling. The complete
lack of TLR signalling in Myd88/ Trif
(TIR-domain-containing adaptor protein
inducing IFn)/ mice has been associated with abnormal bacterial translocation
into the spleen and activation of systemic
adaptive responses. It will be interesting to
evaluate whether comparable mechanisms
operate in Myd88/ noD mice and participate in the protection against diabetes.
Interestingly, the caecal microbiota of
Myd88/ noD mice differed significantly
from that of noD mice and could attenuate
the development of type 1 diabetes when
transferred to the newborn progeny of
germ-free noD mice62; this suggests that
one or more species that confer protection
against disease might have been selected
for in the noD mice with impaired
TLR signalling.
Taken together, these data provide
novel examples of the complex interplay
that exists between the host immune
voLuME 10 | o CToBER 2010 | 741

2010 Macmillan Publishers Limited. All rights reserved

PersPectives
Table 1 | Effect of the microbiota on systemic immune-mediated diseases
model

Animal strain

Protocol to alter microbiota

observed effects

Refs

Oral cocktail of antibiotics for 3 weeks

induction of anaphylactic
symptoms, increased production of
ige and iL-13

54

49,53

Allergy
ige-mediated food allergy Weanling c3H mice or
to peanut allergen
c57BL/6 mice
Tlr4 mutant or Tlr4/ mice

None

BALB/c and c57BL/6 mice

Oral cefoperazone (cefobid, Pfizer;


cefazone, Pharco B international)
for 5 days and a single oral gavage of
Candida albicans

increase in pulmonary eosinophils


and enhanced synthesis of ige, iL-5
and iL-13

systemic lupus
erythematosus

MrL/lpr mice

Germ-free mice

No change in autoimmunity

58

APeceD

Aire/ mice*

Germ-free mice

No change in autoimmunity

56

spontaneous gastritis

Aid/ mice

Germ-free mice

No change in autoimmunity

57

collagenous arthritis

Fischer rats (resistant)

Germ-free rats

enhanced humoral responses

61

Dark Agouti rats (sensitive)

Germ-free rats

increased severity

NOD mice x Myd88/ mice

Germ-free mice

increased incidence and severity

NOD Myd88/ mice

colonization with specific


pathogen-free flora

No disease

Male B10.Br mice

Germ-free mice

No disease

colonization with probiotic


Lactobacillus spp.

No disease

colonization with a mixture of


Bacteroides, Enterococcus, Veillonella
and Staphylococcus spp.

Disease restored

Germ-free mice

No disease

ige-mediated allergic
airway disease induced
by Aspergillus fumigatus
spores or ovalbumin

Autoimmunity

Type 1 diabetes

spontaneous ankylosing
enthesopathy

spontaneous arthritis

Autoimmune arthritis

experimental
autoimmune
encephalomyelitis

Il1Ra/ BALB/c mice

colonization with Lactobacillus bifidus

Disease restored

Il1Ra/ Tlr4/ mice

None

same disease incidence,


decreased severity

Il1Ra/ Tlr2/ mice

None

increased severity

KrN-c57BL/6|| NOD mice

Germ-free mice

No disease

colonization with segmented


filamentous bacteria

Disease restored

Germ-free mice

Weak severity

specific pathogen-free flora

Maximal severity

colonization with segmented


filamentous bacteria

intermediate severity

c57BL/6J mice

62

59

60

30

31

Aid, activation-induced cytidine deaminase; Aire, autoimmune regulator; APeceD, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; iL,
interleukin; Il1Ra, iL-1 receptor antagonist; Myd88, myeloid differentiation primary-response protein 88; NOD, non-obese diabetic; Tlr, Toll-like receptor. *Aire
regulates the transcription of peripheral autoantigens in medullary thymic epithelial cells and is necessary for thymic negative selection; AiD is central for
class-switch recombination and somatic hypermutation in B cells; NOD mice provide a polygenic model of type 1 diabetes; ||Mice with a transgenic T cell receptor
against a self peptide that is derived from glucose-6-phosphate isomerase.

system and the microbiota, and the difficulties in attempting to delineate the
respective roles of host predisposing
factors and specific bacterial species. To
determine the therapeutic implications
of these observations, further research is
needed to elucidate how the microbiota
is able to influence peripheral immune
responses and how such microbiotadriven responses can interfere with the
immunological mechanisms that underlie
a given autoimmune disease.

Conclusion
An increasing number of studies are progressively unravelling the fascinating interactions that occur between eukaryotes and
their bacterial symbionts. It is now clear
that the intestinal microbiota profoundly
influences host metabolic and immune
pathways and participates in human health
and disease. Compelling evidence shows a
pivotal role for the microbiota in the development of many gastrointestinal diseases,
from inflammation to cancer. Recent work

742 | o CToBER 2010 | voLuME 10

also indicates the possible contribution of


the intestinal microbiota to immunological
diseases outside the gut. However, from the
microbial perspective, the host is simply a
complex environment and the distinction
between health and disease is important
only as far as it affects microbial fitness.
The challenge that lies ahead is to determine
when changes in our microbiota are the
primary cause of a disease and when these
changes merely reflect the enormous capacity
of bacteria for rapid and continuous genetic
www.nature.com/reviews/immunol

2010 Macmillan Publishers Limited. All rights reserved

PersPectives
adaptation to new ecological conditions. An
in-depth understanding of the principles
and mechanisms that underlie microbial
community structures and hostsymbiont
relationships will be pivotal for the development of therapeutic approaches that manipulate the intestinal microbiota to maintain
human health.
Nadine Cerf-Bensussan and Valrie Gaboriau-Routhiau
are at the Institut National de la Sant et de la
Recherche Mdicale (INSERM) U989, Universit Paris
Descartes, 156 rue de Vaugirard, 75730 Paris
Cedex 15, France; and the Institut National de la
Recherche Agronomique (INRA) UM1319, Domaine de
Vilvert, 78350 Jouy-en-Josas, France.
Correspondence to N.C.-B.
e-mail: nadine.cerf-bensussan@inserm.fr
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Acknowledgements

The authors thank W. Garrett for sharing unpublished data.


Their work is supported by grants from the Institut National
de la Sant et de la Recherche Mdicale (INSERM), the
Institut National de la Recherche Agronomique (INRA) and
the Agence Nationale de la Recherche and Fondation
Princesse Grace. The authors are partners of the European
Community networks Cross-Talk (contract number
PITN-GA-2008-215553) and Tornado (FP7 222720).

Competing interests statement

The authors declare no competing financial interests.

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