PersPecTives

bacteria are then followed by hundreds

OPINION
of environmentally acquired species,
which differ between individuals but
The immune system and the gut mainly belong to two bacterial phylotypes,
Firmicutes spp. and Bacteroidetes spp.2,4.
microbiota: friends or foes? A growing number of studies support
the view that eukaryotic hosts and their
symbionts have co-evolved towards mutu-
Nadine Cerf-Bensussan and Valrie Gaboriau-Routhiau alistic interactions that are based on the
nutritional benefits that each partner gains
Abstract | The mammalian intestine is home to a complex community of trillions of from the association5 (BOX 1). However,
bacteria that are engaged in a dynamic interaction with the host immune system. the huge collection of bacteria at the gut
Determining the principles that govern hostmicrobiota relationships is the focus surface is also a major threat to host integ-
of intense research. Here, we describe how the intestinal microbiota is able to rity and has driven the selection of highly
influence the balance between pro-inflammatory and regulatory responses and flexible defence mechanisms, which enable
eukaryotic hosts to cope with their micro-
shape the hosts immune system. We suggest that improving our understanding of
bial environment and compensate for their
the intestinal microbiota has therapeutic implications, not only for intestinal less rapid genetic adaptation.
immunopathologies but also for systemic immune diseases.
The gut immune system. Recent reviews
Initially, all microorganisms were viewed as the gut might influence the development have highlighted how the microbiota elicits
pathogens that cause and propagate infectious and functions of the immune system has innate and adaptive immune mechanisms
diseases and, as a field, immunology was built become a major focus of interest. A prevalent that cooperate to protect the host and main-
around the paradigm that the host immune theory, derived from hypotheses that were tain intestinal homeostasis6,7. Epithelial cells
system should recognize and eliminate these first postulated by Metchnikoff a century are a central component of the immune
intruders (non-self) while tolerating self- ago, proposes that individual members of system of the gut. In a similar manner to
molecules to preserve homeostasis. However, the microbiota might influence the balance immune cells, epithelial cells express recep-
the persistent association of animal and plant between pro-inflammatory and regulatory tors for microbial-associated molecular
species with obligate and facultative symbionts host responses and that alterations in the patterns (MAMPs). These receptors activate
now shows that both bacteria and their composition of the microbiota (a process that signalling cascades that finely tune epithelial
eukaryote hosts benefit from their coopera- is known as dysbiosis) could jeopardize host cell production of antimicrobial products
tive relationships. These benefits suggest that immune responses and promote the devel- and chemokines, depending on the signals
co-evolution has selected mechanisms that opment of various inflammatory disorders. that are delivered by the microbiota (FIG. 1).
promote and maintain associations between Here, we discuss the principles that govern Thus, gut epithelial cells form a potent and
bacteria and eukaryotes. In humans, trillions the interactions between the intestinal micro- inducible physico-chemical barrier, which
of bacteria are distributed in complex and biota and the host immune system, both in limits microbial growth and access to the
site-specific communities on the skin health and in disease. Moreover, we stress gut surface. They can also recruit leukocytes
and at mucosal surfaces, and the largest how the complexity of the gut ecological sys- to complement their barrier function or to
community is found in the distal gut. As these tem and the reciprocal nature of the regula- participate in the activation of gut adap-
bacteria encode hundreds of genes that are tion of the immune system and of microbial tive immune responses. In mammals, the
absent in the human genome1, the idea has community structures must be considered development of gut-associated lymphoid
emerged that together with our microbiota, before one can draw any conclusions about tissues (GALTs) is initiated before birth by
we form superorganisms in which energy and the role of the microbiota in disease and a genetic programme8. However, GALT
metabolites can be exchanged2 and homeo- propose therapeutic interventions. maturation and the recruitment of IgA-
stasis is maintained by the immune system3. secreting plasma cells and activated T cells
Therefore, a new paradigm proposes that the The hostmicrobiota interaction in the gut to mucosal sites only occurs after birth and
immune system has evolved to accommodate The intestine is an open ecological system is strictly dependent on microbiota-derived
colonization by symbiotic bacterial commu- that is colonized immediately after birth signals; these signals influence the crosstalk
nities of increasing complexity while retaining by a microbial population that reaches between epithelial cells and gut dendritic
the capacity to fight pathogens. an impressive density of 1012 bacteria per cells (DCs), thereby modulating the nature
The gastrointestinal tract is the primary gram of luminal content in the distal gut. and intensity of intestinal B and T cell
site of interactions between the host and the Colonization is initiated by maternally responses7,9 (FIG. 2). In immunocompetent
microbiota. How bacterial colonization of acquired bacteria during birth; these mice, intestinal colonization stimulates

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PersPectives

Box 1 | mutualistic relationships between hosts and their intestinal microbiota Anti-inflammatory roles of the microbiota.
Current results indicate that a trade-off is
The human intestine harbours an estimated 100 trillion bacteria, 7080% of which cannot yet be established between the host immune sys-
cultured. Each individual is thought to host several hundred species of bacteria from only 7 to 9 tem and the bulk of the microbiota, so that
phylotypes; these are mainly Gram-positive Firmicutes spp. (most notably Clostridium spp.,
in a healthy individual, intestinal coloniza-
Enterococcus spp. and Lactobacillus spp.) and Gram-negative Bacteroidetes spp. Recent
tion stimulates host production of micro-
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 bicidal peptides11 and secretory IgA, which
encodes a core of redundant bacterial genes that are likely to be needed to resist stressful in turn contain the microbiota within the
conditions in the host intestine63 and to harvest nutrients that are necessary for bacterial intestinal lumen and neutralize MAMPs12.
growth2,4. Competition between bacteria with distinct metabolic requirements might explain the These mechanisms protect the host from
massive and rapid shifts in the structure of the intestinal microbial community that are provoked the systemic translocation of bacteria or
by changes in host diet64. In addition to the genes that are necessary for microbial adaptation to bacterial products and from the outburst of
the host environment, the gut microbiome encodes multiple biosynthetic pathways that are pro-inflammatory cascades in intestinal epi-
predicted to greatly increase the hosts capacity to metabolize glycans and xenobiotics and to thelial and innate cells13. Conversely, the resi-
synthesize vitamins2,4. Moreover, studies in gnotobiotic mice have shown the broad influence of
dent bacteria also benefit from the symbiotic
the gut microbiota on host physiology. Intestinal colonizaton induces a spectrum of intestinal
relationship and can thrive in the mucus,
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 thus minimizing destruction by host-derived
signalling pathways that are involved remain largely elusive, but recent observations suggest inflammatory mediators. Hosts and bacteria
that overlapping mechanisms have been selected during hostmicrobiota co-evolution that have evolved additional strategies to main-
simultaneously control host metabolic and innate immune responses to the microbiota. In mice, tain friendly relationships. Thus, signalling
inactivation of Toll-like receptor 5 (TLR5), which is a receptor for bacterial flagellin that has an cascades that occur downstream of Toll-like
established role in host innate immune responses, results in severe obesity and profound receptors (TLRs) can be desensitized by
alterations in the microbiota structure68. Furthermore, peroxisome proliferator-activated continuous exposure to lipopolysaccharide
receptor- (PPAR), which is a transcription factor that has a central role in glucidolipidic (LPs)14 or can be attenuated by other soluble
metabolism, can control the production of microbicidal peptides by colonocytes and serves
mediators that are produced by the micro-
as a feedback mechanism for the activation of nuclear factor-B (NF-B) in enterocytes69.
biota (FIG. 1). Furthermore, some microbiota-
derived soluble products can promote the
the production of secretory IgA, the dif- regulatory immune responses, and to establish functions of TReg cells15,16.
ferentiation of effector T helper 1 (TH1), whether the composition of the microbiota The mechanism that maintains this
TH2 and TH17 cells, and the development of can influence the development of inflamma- friendly relationship has been elucidated
regulatory T (TReg) cells10. tory diseases in and beyond the gut. Before in the case of Bacteroides fragilis, which is a
It is increasingly clear how these adap- considering the possible role of the microbiota common culturable member of the micro-
tive immune elements cooperate with innate in disease, we will first highlight how the dif- biota15. This bacterium possesses an unusual
immune cells to strengthen the gut barrier ferent colonization strategies of individual capsular polysaccharide A (PsA) that is able
and protect the host from invading patho- members of the microbiota can influence the to drive the differentiation of interleukin-10
gens. An outstanding issue now is to define development and function of the gut immune (IL-10)-secreting TReg cells. Colonization by
how individual members of the microbiota system and show that, ultimately, it is the host a wild-type B. fragilis, but not by a mutant
or microbiota-derived products can affect immune system that determines whether a strain that lacks PsA, protected mice from
the balance between pro-inflammatory and bacterium is a friend or a foe. the severe experimental colitis that is induced

glossary
Ankylosing enthesopathy
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.
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.
Gnotobiotic mice
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.
IgE-associated allergies
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.
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.
Microbiome
The whole genome of all of the microorganisms that
colonize a specific environment.
Peyers patches
Collections of lymphoid follicles that are located in the
intestinal mucosa and are particularly abundant in the ileal
mucosa. Together with mesenteric lymph nodes, they form
the inductive compartment for intestinal immune responses.
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
(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.
Xenobiotics
Chemical compounds that are foreign to a living organism
and that can be toxic, even at low concentrations.

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 PersPectives

by Helicobacter hepaticus15,17. Furthermore,

administration of PsA reduced the sever- PAMP
ity of disease in a model of trinitrobenzene
sulphonic acid (TnBs)-induced colitis17.
Bacterium
Therefore, B. fragilis may represent a proto-
type 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 immuno-
TLR
competent host can become a dangerous foe Intestinal lumen
when the immune system is weakened. This
is illustrated by the fact that B. fragilis causes Intestinal
MYD88 epithelial cell
severe sepsis in immunocompromised hosts.
Expression of IRAK1
Likewise, normally harmless members of the decreased by LPS IRAK1
ROS induced by
microbiota can initiate intestinal inflamma- from microbiota microbiota inhibit
tion in individuals who cannot mount effi- ubiquitin ligases
cient intestinal humoral responses18,19 and in IB ubiquitylated and
individuals with impaired intestinal immuno- IB targeted to the proteasome
regulation, most notably in those who lack a for degradation
p50 p65
functional IL-10 signalling pathway 20,21.
NF-B PPAR induced in
Promotion of effector immune responses. Nuclear translocation response to microbiota
p65 PPAR LPS diverts NF-B
of NF-B
Although certain members of the microbiota from nucleus
have adopted peace-keeper activities to colo-
nize the intestine, others are, undoubtedly,
PPAR upregulates
endowed with pro-inflammatory properties. p50 p65 PPAR colonic -defensins
one such group, which has recently attracted to sustain gut barrier
much attention, is segmented filamentous
bacteria (sFB). These unculturable species NF-B transcribes
settle in the rodent intestine at the time of pro-inflammatory Pathway impaired
cytokines and in patients with
weaning and stimulate the postnatal matu- chemokines and Crohns disease
ration of immune responses in the mouse defensins
gut. Mice that are colonized by a microbiota
that lacks sFB have weaker IgA antibody
Figure 1 | modulation of intestinal epithelial cell pro-inflammatory responses by the microbiota.
responses22 and much poorer intestinal in a similar manner to immune cells, epithelial cells detect microbes throughNature
pattern-recognition recep-
Reviews | Immunology
T cell responses compared with mice that tors, including Toll-like receptors (TLrs). Upon TLr ligation, adaptor proteins, such as myeloid differen-
are colonized with sFB. notably, mice that are tiation primary-response protein 88 (MYD88), are recruited and activate signalling cascades, notably
colonized by an sFB-deficient microbiota the nuclear factor-B (NF-B) pathway, which stimulates the transcription of antimicrobial proteins,
lack mucosal TH17 cells10,23. Furthermore, pro-inflammatory cytokines and chemokines. in resting cells, NF-B is sequestered in the cytoplasm by
these animals cannot control colonization by its inhibitor iB. Following TLr activation, iB is phosphorylated, ubiquitylated and degraded by the
the invasive pathogen Citrobacter rodentium, proteasome, which allows nuclear translocation of NF-B and transcription of NF-B target genes. This
which suggests that microbiota-induced pathway can be modulated by microbiota-derived factors, preventing excessive and potentially delete-
immune responses participate in the bar- rious host pro-inflammatory responses. immediately after birth, expression of the interleukin-1 receptor-
associated kinase 1 (irAK1), which is the proximal activator of the NF-B cascade, is downregulated by
rier function of the flora23. This hypothesis
microbiota-derived lipopolysaccharide (LPs)14. The polyubiquitylation and degradation of iB can be
is also supported by recent work that shows inhibited by commensal bacteria, which inhibit a common ubiquitin ligase by inducing reactive oxygen
that the destruction of the microbiota fol- species (rOs)70. Peroxisome proliferator- activated receptor- (PPAr), which is induced in response to
lowing treatment with antibiotics can jeop- TLr4 activation by LPs71, can also divert NF-B from the nucleus72. checkpoints that are controlled by
ardize innate immune responses in the gut the microbiota are indicated by T bars. interestingly, PPAr positively controls the expression of the
and promote colonization by pathogens24. colonic microbicidal peptide defensin 1 (rEF. 69) and thus can simultaneously sustain the gut barrier
A striking feature of sFB is their strong and prevent excessive inflammation. This mechanism may be impaired in a subset of patients with
adherence to the surface epithelium of the colonic crohns disease69. PAMP, pathogen-associated molecular pattern.
ileum and the Peyers patches shortly after
weaning 25. This is in contrast with most other
members of the microbiota, which remain signalling pathways in epithelial cells and mouse intestine, but it also benefits the host
entrapped within the mucus and have little DCs, resulting in robust innate and adap- by strengthening the gut barrier. strikingly,
or no physical contact with host epithelium25. tive immune responses in the intestine10,23. on the basis of morphological studies, sFB
This attachment, which is perhaps necessary such behaviour is characteristic of bona fide have been detected in all species studied from
to initiate the replication of sFB, is likely to pathogens, which use host inflammatory arthropods to mammals, including humans,
facilitate the sampling and presentation of responses to eliminate the resident flora and and closely related 16s rRnA sequences have
sFB antigens to T cells by DCs in the Peyers to colonize the remaining niches26,27. This been found in chickens, trout and rodents25,28.
patches and to stimulate pro-inflammatory attachment might enable sFB to settle in the Therefore, it is tempting to speculate that this

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PersPectives

a
M cell
Intestinal lumen
Bacterium

Intestinal epithelium
Lamina propria
MHC
Peptide
TCR
CX3CR1- Naive T cell
expressing Transcytosed bacteria are
phagocyte CD103+ DCs acquire Peyers patch
bacterial antigens acquired by DCs, which activate
Direct sampling of adaptive immune responses
bacteria in lumen?
Antigen transfer?
Peyers patch and CD103+ DCs
CD103+ DC migrate to MLNs and initiate
adaptive immune responses

b c
IgA molecules are B. fragilis
transcytosed by polymeric SFB
IgA receptors and retain
bacteria in the mucus Microbiota-
derived products
activate TLRs

TSLP, B. fragilis capsular ATP Bacterial ATP and

TLR bacteria-induced
TGF, polysaccharide A SAA
Mucus layer retinoic SAA activate DCs
acid
SFB induce
TReg cell IL-12-producing
induction DCs by unknown
Dimeric Epithelial Inflammatory mechansims
BAFF,
secretory cell DCs
APRIL
IgA FOXP3 +
Tolerogenic DC IL-1, IL-6, IL-12
BAFF and APRIL TReg cell
promote T cell- IL-23
TReg cells maintain
dependent and tolerance to food
T cell-independent and commensals
IgA class-switching
IgA+ plasma cell
TH17 cell 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 Dc-
and 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 epithe-
lial 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), transform-
ing growth factor- (TGF) and retinoic acid, to acquire a tolerogenic pheno-
type; 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
Naturepromote
Reviews the induction
| Immunology
of interleukin-10 (iL-10)-producing Treg cells through a TLr2-dependent
mechanism15,17. However, some commensal bacteria can stimulate the dif-
ferentiation of inflammatory mucosal T cells. T helper 17 (TH17) cell differen-
tiation 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 pro-
tein (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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unusual symbiont has a particularly impor-
tant role in shaping the gut immune system
across evolution. However, again, the out-
come 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 enceph-
alomyelitis31 (FIG. 3). Interestingly, sFB alone
were not able to induce intestinal inflamma-
tion 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 sub-
set 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 immunocom-
petent 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 main-
taining 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 stom-
ach. Gastric colonization by this bacterium
remains asymptomatic in most individu-
als 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 con-
cern are not completely understood but are
thought to include the selection of specifi-
cally aggressive strains and/or host predis-
posing factors, notably polymorphisms in
gene promoters that increase the production
of tumour necrosis factor (TnF) or IL-1,
which is a pro-inflammatory cytokine
nATuRE REvIEws | Immunology
PersPectives
Intestinal colonization by SFB
Effects on intestinal compartment Effects on peripheral compartment
Stimulation of innate immune Increased germinal centre Enhanced
responses e.g. Reg III/ production formation in the spleen sensitization
Stimulation of CD4+ T cell responses e.g. Autoantibody-secreting following
TH1, TH2, TH17 and TReg cells IgG plasma cells challenge with
Induction of IgA responses Circulating immune MOG peptide
Recruitment and activation of IELs complexes
Physiological inflammation Intestinal inflammation
strengthens gut barrier in in SCID mice transferred Arthritis in Increased
immunocompetent hosts with effector T cells K/BxN mice 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 immunocompe-
tent 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/ micro-
bicidal peptides10,23,80, which protect against colonizing pathogens24. Additionally, sFB simultane-
ously 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 com-
bined 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 trans-
genic 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. patients with Crohns disease than in healthy
other recently characterized pathobionts controls, which suggests that these bacteria
include enterotoxigenic B. fragilis (ETBF), can initiate disease36. Yet to induce intestinal
which can stimulate colonic inflammation inflammation, the prototype E. coli LF82
and tumorigenesis in predisposed multiple strain first needs to bind to an epithelial
intestinal neoplasia (MIn) mice34, and some cell-expressed receptor. This receptor
Escherichia coli strains, which can promote is absent in the normal ileal mucosa but is
gut inflammation in patients with Crohns upregulated by interferon- (IFn) and
disease35,36. TnF that are produced during intestinal
inflammation35,37. An alternative hypo-
Intestinal dysbiosis and IBDs thesis suggests that the reduced frequency
Inflammatory bowel diseases (IBDs) are of a Firmicutes species, Faecalibacterium
thought to arise owing to a combination of prausnitzii, in the intestinal microbiota is
genetic and environmental factors that result a causative factor of Crohns disease16. This
in dysregulated immune responses to the gut strain releases an unidentified soluble factor,
microbiota and the subsequent development which inhibits pro-inflammatory epithelial
of gut inflammation20. Compelling evidence cell responses in vitro and attenuates
from a variety of studies has shown dysbiosis inflammation in a mouse model of colitis16.
in patients with IBD compared with healthy other studies, however, suggest that
controls, and this suggests a causative role for more global changes in the composition
dysbiosis in gut inflammation. of the microbiota are associated with IBD,
several scenarios can be considered. such as abnormal adherence of bacteria to
Pro-inflammatory bacteria, such as entero- the gut mucosa, reduced bacterial diversity,
invasive Escherichia coli strains, are more decreased levels of resident Firmicutes spp.
frequently seen in the ileal mucosa of and/or Bacteroides spp. and an overgrowth
voLuME 10 | o CToBER 2010 | 739
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PersPectives

of proteobacteria3840. strikingly, comparable also seen in Il10/ mice after, but not before, inability of DCs to properly regulate TnF
changes in the microbiota have been seen the onset of intestinal inflammation, which production results in a severe and highly
in mice in which intestinal inflammation further highlights the profound influence of penetrating colitis. Intestinal inflammation
was induced by either an invasive pathogen the host immune response on the structure spontaneously progresses to colonic dyspla-
or by the injection of transgenic T cells of the microbial community 27. sia and rectal adenocarcinoma; therefore,
that attacked the gut epithelium27. In these Together, these observations underscore disease progression in this model is similar
two distinct models, host inflammation the confounding role of host-predisposing to that seen in human IBD41,42. TRuC colitis
suppressed the growth of Firmicutes and factors and the difficulty in assigning a can be prevented by eradicating the micro-
Bacteroides spp., allowing proteobacteria, causative role for dysbiosis in IBD. However, biota with broad-spectrum antibiotics.
which are apparently more resistant to host- experimental evidence suggests that intes- Moreover, in a situation that recalls rare
derived microbicidal factors, to outcompete tinal inflammation can select for bacterial reports of intrafamilial transmission of IBD
these normally dominant resident bacteria27. species with colitogenic properties. In T-bet/ in humans, colitis can be transmitted from
notably, outgrowth of proteobacteria was Rag2/ ulcerative colitis (TRuC) mice, the TRuC mice to wild-type mice in both cross-
fostering and co-housing experiments41.
Furthermore, the microbiota in TRuC
a b Altered gut environment mice exhibits complex changes, including
Healthy gut environment
Antibiotics, diet, hygiene,
pollutants, virus? selective enrichment of two proteobacteria,
Proteus mirabilis and Klebsiella pneumonia.
These two bacteria are not sufficient to
Dysbiosis
Gut
Physiological microbiota induce colitis in gnotobiotic TRuC mice;
lumen Decrease in peace-keeping bacteria however, they can colonize the intestine
Peace-keeping and increase in pathobionts
of wild-type mice and, in concert with a
bacterium Pathobiont pathogen-free microbiota, induce colonic
Mucus inflammation43. These data highlight how
the host immune response can shape the
Healthy
epithelial microbiota and eventually lead to the selec-
barrier tion of aggressive bacteria, which not only
Damaged epithelial survive in the inflamed gut but also promote
barrier, increased inflammation.
bacterial adherence
and penetration what are the therapeutic implications
Pathological inflammation of these findings? At the very least, they
IgA+ TH17 cell explain the difficulties in establishing and
TH1 cell plasma cell TReg cell Altered host immune system maintaining remission in patients with IBD
Lamina Genetics using drugs that target host inflammatory
propria Physiological inflammation components or the microbiota without also
Severe monogenic Immune
immunodeficiency gene variants correcting host-predisposing factors. They
IL-10R mutations, NOD2, ATG16L1, highlight the importance of identifying
CVID IL-23R, IRGM
such predisposing factors and designing
Environment more specific therapies for IBD. They also
suggest the need for combined approaches
Stress, diet, infections, vaccine?
that can restore local ecological conditions
Figure 4 | Schematic representation of hostmicrobiota interactions in the healthy and and correct dysbiosis to reinstate balanced
inflamed gut. a | in healthy hosts, an efficient immune barrier contains the microbiota in the gut hostmicrobiota interactions in the long
lumen and feedback mechanisms avoid excessive activation of host immune responses. Peace- term (FIG. 4).
Nature 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
Microbiota and systemic immunity
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 so far we have focused on the roles of the
patients with common variable immunodeficiency (cviD)19) or a key regulatory pathway (for exam- microbiota in intestinal immunity, both
ple, loss-of-function mutations that affect the interleukin-10 receptor (iL-10r)21) spontaneously in health and disease; however, growing
develop intestinal inflammation when exposed to the microbiota. in more common forms of inflam- evidence suggests that the intestinal micro-
matory bowel disease (iBD), a complex genetic background results in more subtle alterations of gut biota can also have an important impact on
immune responses that may weaken the gut barrier and/or impair immunoregulation82. in these indi- the development of the peripheral immune
viduals, lifestyle changes or medical practices (for example, stress, diet, hygiene, smoking, antibiotics, system. Moreover, dysbiosis has been
vaccines or appendectomy) may promote the onset of gut inflammation by affecting the immune implicated in the development of extra-
balance and/or the gut microbiota82. intestinal inflammation results in increased bacterial adherence, intestinal immune-mediated diseases. It will
epithelial damage and increased entry of bacteria into the intestinal lamina propria, thus sustaining
be crucial to determine the extent to which
a vicious inflammatory circle. Moreover, inflammation can favour the selection of aggressive patho-
bionts, which are more resistant to host-derived microbicidal mediators26,27, and reduce the number the impact of the microbiota depends
of peace-keeping species16, which results in even more severe and uncontrolled inflammation. These on the host immune status, whether indi-
pathobionts might become sufficiently aggressive to also cause disease in immunocompetent indi- vidual bacterial species can exert distinctive
viduals43. ATG16L1, autophagy-related 16-like 1; irGM, immunity-related GTPase family M; sciD, roles and, ultimately, whether the observed
severe combined immunodeficient; TH cell, T helper cell; Treg cell, regulatory T cell. dysbiosis has a causative role in disease.

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Effects on the peripheral immune system.
The exact impact of the gut microbiota on
the hosts peripheral immune system is con-
troversial. 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 compar-
ing 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 immuno-
competent 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 produc-
tion by the bacteriums unusual capsular
polysaccharide47.
Allergy and dysbiosis. The hygiene
hypothesis, which has been revised
several times since its initial formula-
tion by strachan in 1989, stipulates that
decreased exposure to infectious agents,
as well as changes in the intestinal micro-
biota 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
nATuRE REvIEws | Immunology
postnatal pre- and probiotic supplementa-
tion can reduce the incidence of eczema
and food-specific IgE in a subset of high-
risk 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 dys-
biosis, which is induced by changes in life-
style 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 antibiot-
ics53. Another interesting study showed that
TLR4 activation by microbiota-derived
LPs was necessary to prevent anaphylaxis
after oral immunization with the peanut-
derived 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 grow-
ing 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 dis-
eases 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 compa-
rable 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 auto-
immune arthritis. For example, in a mouse
strain that is prone to the spontaneous
2010 Macmillan Publishers Limited. All rights reserved
PersPectives
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 com-
ponent (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 deposi-
tion 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 collagen-
induced 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 condi-
tions. It remains unclear why a protective
role for the microbiota during the develop-
ment 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 associ-
ated 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 par-
ticipate 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
PersPectives

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

model Animal strain Protocol to alter microbiota observed effects Refs
Allergy
ige-mediated food allergy Weanling c3H mice or Oral cocktail of antibiotics for 3 weeks induction of anaphylactic 54
to peanut allergen c57BL/6 mice symptoms, increased production of
ige and iL-13
Tlr4 mutant or Tlr4/ mice None
ige-mediated allergic BALB/c and c57BL/6 mice Oral cefoperazone (cefobid, Pfizer; increase in pulmonary eosinophils 49,53
airway disease induced cefazone, Pharco B international) and enhanced synthesis of ige, iL-5
by Aspergillus fumigatus for 5 days and a single oral gavage of and iL-13
spores or ovalbumin Candida albicans
Autoimmunity
systemic lupus MrL/lpr mice Germ-free mice No change in autoimmunity 58
erythematosus
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
Type 1 diabetes NOD mice x Myd88/ mice Germ-free mice increased incidence and severity 62
NOD Myd88/ mice colonization with specific No disease
pathogen-free flora
spontaneous ankylosing Male B10.Br mice Germ-free mice No disease 59
enthesopathy
colonization with probiotic No disease
Lactobacillus spp.
colonization with a mixture of Disease restored
Bacteroides, Enterococcus, Veillonella
and Staphylococcus spp.
spontaneous arthritis Il1Ra/ BALB/c mice Germ-free mice No disease 60
colonization with Lactobacillus bifidus Disease restored
Il1Ra/ Tlr4/ mice None same disease incidence,
decreased severity
Il1Ra/ Tlr2/ mice None increased severity
Autoimmune arthritis KrN-c57BL/6|| NOD mice Germ-free mice No disease 30
colonization with segmented Disease restored
filamentous bacteria
experimental c57BL/6J mice Germ-free mice Weak severity 31
autoimmune
encephalomyelitis specific pathogen-free flora Maximal severity
colonization with segmented intermediate severity
filamentous bacteria
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 dif-
ficulties 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 microbiota-
driven responses can interfere with the
immunological mechanisms that underlie
a given autoimmune disease.
Conclusion
An increasing number of studies are pro-
gressively unravelling the fascinating inter-
actions 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 devel-
opment of many gastrointestinal diseases,
from inflammation to cancer. Recent work
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

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2010 Macmillan Publishers Limited. All rights reserved


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 develop-
ment of therapeutic approaches that manip-
ulate 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
doi:10.1038/nri2850
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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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