Nature the Immune System and the Gut

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Initially, all microorganisms were viewed aspathogens that cause and propagate infectiousdiseases and, as a field, immunology was builtaround the paradigm that the host immunesystem should recognize and eliminate theseintruders (non-self) while tolerating self-molecules to preserve homeostasis. However,the persistent association of animal and plantspecies with obligate and facultative symbionts now shows that both bacteria and theireukaryote hosts benefit from their coopera-tive relationships. These benefits suggest thatco-evolution has selected mechanisms thatpromote and maintain associations betweenbacteria and eukaryotes. In humans, trillionsof bacteria are distributed in complex andsite-specific communities on the skinand at mucosal surfaces, and the largestcommunity is found in the distal gut. As thesebacteria encode hundreds of genes that are

absent in the human genome1, the idea hasemerged that together with our microbiota,we form superorganisms in which energy andmetabolites can be exchanged2 and homeo-stasis is maintained by the immune system3.Therefore, a new paradigm proposes that theimmune system has evolved to accommodatecolonization by symbiotic bacterial commu-nities of increasing complexity while retainingthe capacity to fight pathogens.

The gastrointestinal tract is the primarysite of interactions between the host and themicrobiota. How bacterial colonization of

the gut might influence the developmentand functions of the immune system hasbecome a major focus of interest. A prevalenttheory, derived from hypotheses that werefirst postulated by Metchnikoff a centuryago, proposes that individual members ofthe microbiota might influence the balancebetween pro-inflammatory and regulatoryhost responses and that alterations in thecomposition of the microbiota (a process thatis known as dysbiosis) could jeopardize hostimmune responses and promote the devel-opment of various inflammatory disorders.Here, we discuss the principles that governthe interactions between the intestinal micro-biota and the host immune system, both inhealth and in disease. Moreover, we stresshow the complexity of the gut ecological sys-tem and the reciprocal nature of the regula-tion of the immune system and of microbial

community structures must be consideredbefore one can draw any conclusions aboutthe role of the microbiota in disease andpropose therapeutic interventions.

The host–microbiota interaction in the gut

The intestine is an open ecological systemthat is colonized immediately after birthby a microbial population that reachesan impressive density of 1012 bacteria pergram of luminal content in the distal gut.Colonization is initiated by maternallyacquired bacteria during birth; these

bacteria are then followed by hundredsof environmentally acquired species,which differ between individuals butmainly belong to two bacterial phylotypes,Firmicutes spp. and Bacteroidetes spp.2,4.A growing number of studies supportthe view that eukaryotic hosts and theirsymbionts have co-evolved towards mutu-alistic interactions that are based on thenutritional benefits that each partner gainsfrom the association5 (BOX 1). However,the huge collection of bacteria at the gutsurface is also a major threat to host integ-

rity and has driven the selection of highlyflexible defence mechanisms, which enableeukaryotic hosts to cope with their micro-bial environment and compensate for theirless rapid genetic adaptation.

The gut immune system. Recent reviewshave highlighted how the microbiota elicitsinnate and adaptive immune mechanismsthat cooperate to protect the host and main-tain intestinal homeostasis6,7. Epithelial cellsare a central component of the immunesystem of the gut. In a similar manner toimmune cells, epithelial cells express recep-tors for microbial-associated molecularpatterns (MAMPs). These receptors activatesignalling cascades that finely tune epithelialcell production of antimicrobial productsand chemokines, depending on the signalsthat are delivered by the microbiota (FIG. 1).Thus, gut epithelial cells form a potent andinducible physico-chemical barrier, whichlimits microbial growth and access to thegut surface. They can also recruit leukocytesto complement their barrier function or toparticipate in the activation of gut adap-tive immune responses. In mammals, the

development of gut-associated lymphoidtissues (GALTs) is initiated before birth bya genetic programme8. However, GALTmaturation and the recruitment of IgA-secreting plasma cells and activated T cellsto mucosal sites only occurs after birth andis strictly dependent on microbiota-derivedsignals; these signals influence the crosstalkbetween epithelial cells and gut dendriticcells (DCs), thereby modulating the natureand intensity of intestinal B and T cellresponses7,9 (FIG. 2). In immunocompetentmice, intestinal colonization stimulates

O P I N I O N

The immune system and the gutmicrobiota: friends or foes?

Nadine Cerf-Bensussan and Valérie 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 host–microbiota relationships is the focus

of intense research. Here, we describe how the intestinal microbiota is able toinfluence the balance between pro-inflammatory and regulatory responses and

shape the host’s 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.

PERSPECTIVES

NATURE REVIEWS | IMMUNOLOGY VOLUME 10 | OCTOBER 2010 | 735

© 20 Macmillan Publishers Limited. All rights reserved10


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the production of secretory IgA, the dif-ferentiation of effector T helper 1 (T

H1),

TH2 and T

H17 cells, and the development of

regulatory T (TReg

) cells10.It is increasingly clear how these adap-

tive immune elements cooperate with innateimmune cells to strengthen the gut barrierand protect the host from invading patho-gens. An outstanding issue now is to definehow individual members of the microbiotaor microbiota-derived products can affectthe balance between pro-inflammatory and

regulatory immune responses, and to establishwhether the composition of the microbiotacan influence the development of inflamma-tory diseases in and beyond the gut. Beforeconsidering the possible role of the microbiotain disease, we will first highlight how the dif-ferent colonization strategies of individualmembers of the microbiota can influence thedevelopment and function of the gut immunesystem and show that, ultimately, it is the hostimmune system that determines whether abacterium is a friend or a foe.

Anti-inflammatory roles of the microbiota. Current results indicate that a trade-off isestablished between the host immune sys-tem and the bulk of the microbiota, so thatin a healthy individual, intestinal coloniza-tion stimulates host production of micro-bicidal peptides11 and secretory IgA, whichin turn contain the microbiota within theintestinal lumen and neutralize MAMPs12.These mechanisms protect the host fromthe systemic translocation of bacteria orbacterial products and from the outburst ofpro-inflammatory cascades in intestinal epi-thelial and innate cells13. Conversely, the resi-dent bacteria also benefit from the symbioticrelationship and can thrive in the mucus,thus minimizing destruction by host-derivedinflammatory mediators. Hosts and bacteriahave evolved additional strategies to main-tain ‘friendly’ relationships. Thus, signallingcascades that occur downstream of Toll-like

receptors (TLRs) can be desensitized bycontinuous exposure to lipopolysaccharide(LPS)14 or can be attenuated by other solublemediators that are produced by the micro-biota (FIG. 1). Furthermore, some microbiota-derived soluble products can promote thefunctions of T

Reg cells15,16.

The mechanism that maintains thisfriendly relationship has been elucidatedin the case of Bacteroides fragilis, which is acommon culturable member of the micro-biota15. This bacterium possesses an unusualcapsular polysaccharide A (PSA) that is ableto drive the differentiation of interleukin-10(IL-10)-secreting T

Regcells. Colonization by

a wild-type B. fragilis, but not by a mutantstrain that lacks PSA, protected mice fromthe severe experimental colitis that is induced

Box 1 | Mutualistic relationships between hosts and their intestinal microbiota

The human intestine harbours an estimated 100 trillion bacteria, 70–80% 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 notablyClostridium 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 stressfulconditions 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 host’s 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 host–microbiota 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 profoundalterations in the microbiota structure68. Furthermore, peroxisome proliferator-activated

receptor-γ (PPARγ), which is a transcription factor that has a central role in glucidolipidicmetabolism, can control the production of microbicidal peptides by colonocytes and serves

as a feedback mechanism for the activation of nuclear factor-κB (NF-κB) in enterocytes69.

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 hostto 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.

Peyer’s 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 asSalmonella, 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.

P E R S P E C T I V E S

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Intestinal lumen

Intestinalepithelial cellMYD88

TLR

PAMP

p50 p65

p50 p65

p65

PPAR γ

PPAR γ

NF-κB

IκB

IRAK1Expression of IRAK1decreased by LPSfrom microbiota

Nuclear translocationof NF-κB

NF-κB transcribespro-inflammatorycytokines andchemokines anddefensins

IκB ubiquitylated andtargeted to the proteasomefor degradation

ROS induced bymicrobiota inhibitubiquitin ligases

PPAR γ induced in

response to microbiotaLPS diverts NF-κBfrom nucleus

PPAR γ upregulatescolonic β-defensinsto sustain gut barrier

Pathway impairedin patients withCrohn’s disease

Bacterium

by Helicobacter hepaticus15,17. Furthermore,administration of PSA reduced the sever-ity of disease in a model of trinitrobenzenesulphonic acid (TNBS)-induced colitis17.Therefore, B. fragilis may represent a proto-type peace-keeper strain. Yet the outcomeof host–microbiota interactions cannot bepredicted from only the bacterium itself, anda bacterium that is beneficial for an immuno-competent host can become a dangerous foewhen the immune system is weakened. Thisis illustrated by the fact that B. fragilis causessevere sepsis in immunocompromised hosts.Likewise, normally harmless members of themicrobiota can initiate intestinal inflamma-tion in individuals who cannot mount effi-cient intestinal humoral responses18,19 and inindividuals with impaired intestinal immuno-regulation, most notably in those who lack afunctional IL-10 signalling pathway 20,21.

Promotion of effector immune responses. Although certain members of the microbiotahave adopted peace-keeper activities to colo-nize the intestine, others are, undoubtedly,endowed with pro-inflammatory properties.One such group, which has recently attractedmuch attention, is segmented filamentousbacteria (SFB). These unculturable speciessettle in the rodent intestine at the time ofweaning and stimulate the postnatal matu-ration of immune responses in the mousegut. Mice that are colonized by a microbiotathat lacks SFB have weaker IgA antibodyresponses22 and much poorer intestinalT cell responses compared with mice thatare colonized with SFB. Notably, mice that arecolonized by an SFB-deficient microbiotalack mucosal T

H17 cells10,23. Furthermore,

these animals cannot control colonization bythe invasive pathogen Citrobacter rodentium,which suggests that microbiota-inducedimmune responses participate in the bar-rier function of the flora23. This hypothesisis also supported by recent work that showsthat the destruction of the microbiota fol-lowing treatment with antibiotics can jeop-ardize 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 theileum and the Peyer’s patches shortly afterweaning25. This is in contrast with most othermembers of the microbiota, which remainentrapped within the mucus and have littleor no physical contact with host epithelium25.This attachment, which is perhaps necessaryto initiate the replication of SFB, is likely tofacilitate the sampling and presentation ofSFB antigens to T cells by DCs in the Peyer’spatches and to stimulate pro-inflammatory

signalling pathways in epithelial cells andDCs, resulting in robust innate and adap-tive immune responses in the intestine10,23.Such behaviour is characteristic of bona fidepathogens, which use host inflammatoryresponses to eliminate the resident flora andto colonize the remaining niches26,27. Thisattachment might enable SFB to settle in the

mouse intestine, but it also benefits the hostby strengthening the gut barrier. Strikingly,on the basis of morphological studies, SFBhave been detected in all species studied fromarthropods to mammals, including humans,and closely related 16S rRNA sequences havebeen found in chickens, trout and rodents25,28.Therefore, it is tempting to speculate that this

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

In a similar manner to immune cells, epithelial cells detect microbes through pattern-recognition recep-tors, including Toll-like receptors (TLRs). Upon TLR ligation, adaptor proteins, such as myeloid differen-

tiation primary-response protein 88 (MYD88), are recruited and activate signalling cascades, notably

the nuclear factor-κB (NF-κB) pathway, which stimulates the transcription of antimicrobial proteins,pro-inflammatory cytokines and chemokines. In resting cells, NF-κB is sequestered in the cytoplasm byits inhibitor IκB. Following TLR activation, IκB is phosphorylated, ubiquitylated and degraded by theproteasome, which allows nuclear translocation of NF-κB and transcription of NF-κB target genes. Thispathway can be modulated by microbiota-derived factors, preventing excessive and potentially delete-

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-κB cascade, is downregulated bymicrobiota-derived lipopolysaccharide (LPS)14. The polyubiquitylation and degradation of IκB can beinhibited by commensal bacteria, which inhibit a common ubiquitin ligase by inducing reactive oxygen

species (ROS)70. Peroxisome proliferator- activated receptor-γ (PPARγ), which is induced in response toTLR4 activation by LPS71, can also divert NF-κB from the nucleus72. Checkpoints that are controlled bythe microbiota are indicated by T bars. Interestingly, PPARγ positively controls the expression of the

colonic microbicidal peptide defensin 1 (REF. 69) and thus can simultaneously sustain the gut barrierand prevent excessive inflammation. This mechanism may be impaired in a subset of patients with

colonic Crohn’s disease69. PAMP, pathogen-associated molecular pattern.





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Intestinal epithelium

Lamina propria

Bacterium

CD103+ DC

Peyer’s patch and CD103+ DCsmigrate to MLNs and initiateadaptive immune responses

Peyer’s patch

Intestinal lumen

Microbiota-derived productsactivate TLRs

BAFF and APRILpromote T cell-dependent andT cell-independentIgA class-switching

IgA+ plasma cell

IgA molecules aretranscytosed by polymericIgA receptors and retainbacteria in the mucus

DimericsecretoryIgA

Mucus layer

TLR

M cell

Naive T cell

TCR

MHC

Peptide

Epithelialcell

BAFF,APRIL

a

cb

TSLP,TGFβ,retinoicacid

Tolerogenic DC FOXP3+

TReg cell

TH17 cell TH1 cell

ATPSAA

InflammatoryDCs

IL-1, IL-6,IL-23

IL-12

SFB

B. fragilis capsularpolysaccharide A

B. fragilis

TReg cellinduction

TReg cells maintaintolerance to foodand commensals

TH1 and TH17 cells sustain intestinal barrierby recruiting macrophages and neutrophilsand inducing antibacterial defensins

Bacterial ATP andbacteria-inducedSAA activate DCs

SFB induceIL-12-producingDCs by unknownmechansims

CX3CR1-expressingphagocyte

Direct sampling of bacteria in lumen?Antigen transfer?

CD103+ DCs acquirebacterial antigens

Transcytosed bacteria areacquired by DCs, which activateadaptive immune responses

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

microbiota. a | Intestinal adaptive immune responses can be initiated in

Peyer’s 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 Peyer’s 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-β (TGFβ) 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 promote the induction

of interleukin-10 (IL-10)-producing TReg cells through a TLR2-dependentmechanism15,17. 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-1β, 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 T

H1 cells in the lamina propria (not shown)79. T

H1

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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Intestinal colonization by SFB

Effects on intestinal compartmentEffects on peripheral compartment

Arthritis inK/BxN mice

Increasedseverity of EAE

Physiological inflammationstrengthens gut barrier inimmunocompetent hosts

Intestinal inflammationin SCID mice transferredwith effector T cells

• Stimulation of innate immuneresponses e.g. Reg IIIβ /γ production

• Stimulation of CD4+ T cell responses e.g.↑ TH1, TH2, TH17 and TReg cells

• Induction of IgA responses• Recruitment and activation of IELs

• Increased germinal centreformation in the spleen

↑ Autoantibody-secretingIgG plasma cells

↑ Circulating immunecomplexes

• Enhancedsensitizationfollowingchallenge withMOG peptide

unusual symbiont has a particularly impor-tant role in shaping the gut immune systemacross evolution. However, again, the out-come of SFB–host interactions depends onthe immune status of the host; SFB has beenassociated with the development of intestinalinflammation29 or arthritis30 in mice withimpaired immunoregulation and can alsoaggravate experimental autoimmune enceph-alomyelitis31 (FIG. 3). Interestingly, SFB alonewere not able to induce intestinal inflamma-tion in immunodeficient mice and insteadsynergized with a pathogen-free flora. Thisfinding highlights how interactions in themicrobiota community can influence hostimmune responses, thereby adding anadditional level of complexity.

The case of pathobionts. A particular sub-set of bacteria further exemplifies how thebehaviour of the microbiota is dependent on

the immune status of the host. Although thesebacteria, which are known as pathobionts,colonize the gastrointestinal tract of manyindividuals asymptomatically, they also havethe potential to cause disease. A recent studyshowed that Helicobacter hepaticus, whichis a member of the epsilon subgroup ofproteobacteria, uses its type VI secretion system (T6SS) to regulate bacterial colonization andinhibit host innate and adaptive immuneresponses, thereby actively maintainingsymbiotic relationships with immunocom-petent hosts32. However, this bacterium cancause severe typhocolitis in Il10–/– mice orin the severe combined immunodeficient(SCID) transfer model of colitis. Thesefindings highlight the central role of hostadaptive regulatory responses in main-taining symbiotic relationships with themicrobiota32.

In humans, the most classical exampleof a pathobiont is Helicobacter pylori, whichuses various mechanisms to dampen hostimmune responses and persist in the stom-ach. Gastric colonization by this bacteriumremains asymptomatic in most individu-als and has even been suggested to protect

against the development of oesophagealcarcinomas owing to downmodulation ofgastric acid secretion. Yet this bacteriumis the major cause of gastritis and gastriccancers. The circumstances that lead to thisbacterium becoming a serious health con-cern are not completely understood but arethought to include the selection of specifi-cally aggressive strains and/or host predis-posing factors, notably polymorphisms ingene promoters that increase the productionof tumour necrosis factor (TNF) or IL-1β,which is a pro-inflammatory cytokine

with potent acid-suppressive properties33.Other recently characterized pathobiontsinclude enterotoxigenic B. fragilis (ETBF),which can stimulate colonic inflammationand tumorigenesis in predisposed multipleintestinal neoplasia (MIN) mice34, and someEscherichia coli strains, which can promotegut inflammation in patients with Crohn’sdisease35,36.

Intestinal dysbiosis and IBDs

Inflammatory bowel diseases (IBDs) are

thought to arise owing to a combination ofgenetic and environmental factors that resultin dysregulated immune responses to the gutmicrobiota and the subsequent developmentof gut inflammation20. Compelling evidencefrom a variety of studies has shown dysbiosisin patients with IBD compared with healthycontrols, and this suggests a causative role fordysbiosis in gut inflammation.

Several scenarios can be considered.Pro-inflammatory bacteria, such as entero-invasive Escherichia coli strains, are morefrequently seen in the ileal mucosa of

patients with Crohn’s disease than in healthycontrols, which suggests that these bacteriacan initiate disease36. Yet to induce intestinalinflammation, the prototype E. coli LF82strain first needs to bind to an epithelialcell-expressed receptor. This receptoris absent in the normal ileal mucosa but isupregulated by interferon-γ (IFNγ) andTNF that are produced during intestinalinflammation35,37. An alternative hypo-thesis suggests that the reduced frequencyof a Firmicutes species, Faecalibacterium

prausnitzii, in the intestinal microbiota isa causative factor of Crohn’s disease16. Thisstrain releases an unidentified soluble factor,which inhibits pro-inflammatory epithelialcell responses in vitro and attenuatesinflammation in a mouse model of colitis16.

Other studies, however, suggest thatmore global changes in the compositionof the microbiota are associated with IBD,such as abnormal adherence of bacteria tothe gut mucosa, reduced bacterial diversity,decreased levels of resident Firmicutes spp.and/or Bacteroides spp. and an overgrowth

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

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 IIIβ/γ 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.





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a b

Physiological microbiota

Pathobiont

Damaged epithelialbarrier, increasedbacterial adherenceand penetration

‘Peace-keeping’bacterium

Mucus

Laminapropria

Healthyepithelial

barrier

Physiological inflammation

Pathological inflammation

TH17 cell

TReg cellTH1 cell

IgA+

plasma cell

Gutlumen

Healthy gut environmentAltered gut environmentAntibiotics, diet, hygiene,pollutants, virus?

Dysbiosis

Decrease in ‘peace-keeping’ bacteriaand increase in pathobionts

Severe monogenicimmunodeficiencyIL-10R mutations,

CVID

Immunegene variantsNOD2, ATG16L1,

IL-23R, IRGM

Genetics

Environment

Stress, diet, infections, vaccine?

Altered host immune system

of proteobacteria38–40. Strikingly, comparablechanges in the microbiota have been seenin mice in which intestinal inflammationwas induced by either an invasive pathogenor by the injection of transgenic T cellsthat attacked the gut epithelium27. In thesetwo distinct models, host inflammationsuppressed the growth of Firmicutes andBacteroides spp., allowing proteobacteria,which are apparently more resistant to host-derived microbicidal factors, to outcompetethese normally dominant resident bacteria27.Notably, outgrowth of proteobacteria was

also seen in Il10–/– mice after, but not before,the onset of intestinal inflammation, whichfurther highlights the profound influence ofthe host immune response on the structureof the microbial community 27.

Together, these observations underscorethe confounding role of host-predisposingfactors and the difficulty in assigning acausative role for dysbiosis in IBD. However,experimental evidence suggests that intes-tinal inflammation can select for bacterialspecies with colitogenic properties. In T -bet –/– Rag2–/– ulcerative colitis (TRUC) mice, the

inability of DCs to properly regulate TNFproduction results in a severe and highlypenetrating colitis. Intestinal inflammationspontaneously progresses to colonic dyspla-sia and rectal adenocarcinoma; therefore,disease progression in this model is similarto that seen in human IBD41,42. TRUC colitiscan be prevented by eradicating the micro-biota with broad-spectrum antibiotics.Moreover, in a situation that recalls rarereports of intrafamilial transmission of IBDin humans, colitis can be transmitted fromTRUC mice to wild-type mice in both cross-fostering and co-housing experiments41.Furthermore, the microbiota in TRUCmice exhibits complex changes, includingselective enrichment of two proteobacteria,Proteus mirabilis and Klebsiella pneumonia.These two bacteria are not sufficient toinduce colitis in gnotobiotic TRUC mice;however, they can colonize the intestine

of wild-type mice and, in concert with apathogen-free microbiota, induce colonicinflammation43. These data highlight howthe host immune response can shape themicrobiota and eventually lead to the selec-tion of aggressive bacteria, which not onlysurvive in the inf lamed gut but also promoteinflammation.

What are the therapeutic implicationsof these findings? At the very least, theyexplain the difficulties in establishing andmaintaining remission in patients with IBDusing drugs that target host inflammatorycomponents or the microbiota without alsocorrecting host-predisposing factors. Theyhighlight the importance of identifyingsuch predisposing factors and designingmore specific therapies for IBD. They alsosuggest the need for combined approachesthat can restore local ecological conditionsand correct dysbiosis to reinstate balancedhost–microbiota interactions in the longterm (FIG. 4).

Microbiota and systemic immunity

So far we have focused on the roles of themicrobiota in intestinal immunity, both

in health and disease; however, growingevidence suggests that the intestinal micro-biota can also have an important impact onthe development of the peripheral immunesystem. Moreover, dysbiosis has beenimplicated in the development of extra-intestinal immune-mediated diseases. It willbe crucial to determine the extent to whichthe impact of the microbiota dependson the host immune status, whether indi-

vidual bacterial species can exert distinctiveroles and, ultimately, whether the observeddysbiosis has a causative role in disease.

Figure 4 | Schematic representation of host–microbiota 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. ‘Peace-

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 exam-

ple, loss-of-function mutations that affect the interleukin-10 receptor (IL-10R)21) spontaneouslydevelop intestinal inflammation when exposed to the microbiota. In more common forms of inflam-

matory 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 indi-

viduals, 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 patho-

bionts, 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 indi-

viduals43. ATG16L1, autophagy-related 16-like 1; IRGM, immunity-related GTPase family M; SCID,

severe combined immunodeficient; TH cell, T helper cell; T

Reg cell, regulatory T cell.





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Effects on the peripheral immune system. The exact impact of the gut microbiota onthe host’s peripheral immune system is con-troversial. Two groups have convincinglyshown that specific immune responses tothe intestinal microbiota are largely confinedto the intestinal lymphoid compartment inimmunocompetent mice with an efficientgut barrier13,44,45. However, studies compar-ing mice that were raised in conventionalor germ-free conditions highlight theimportance of the intestinal microbiota forthe development of the peripheral immunesystem in immunocompetent hosts. Notably,the spleens of germ-free mice contain fewerand smaller germinal centres46 and decreasednumbers of memory CD4+ T cells, andcytokine production by these T cells shows aT

H2-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 factorsthat are produced by the microbiota cantranslocate from the gut to the bloodstreamand activate innate immune cells. Forexample, the opsonophagocytic activity ofneutrophils is primed by microbiota-derivedpeptidoglycan, which results in enhancedprotection against pneumococcal sepsis48.Moreover, monocolonization with B. fragilis corrects systemic T cell deficiencies andthe T

H1/T

H2 imbalance of germ-free mice

due to the stimulation of DC IL-12 produc-tion by the bacterium’s unusual capsularpolysaccharide47.

Allerg y and dysbiosis. The ‘hygienehypothesis’, which has been revisedseveral times since its initial formula-tion by Strachan in 1989, stipulates thatdecreased exposure to infectious agents,as well as changes in the intestinal micro-biota during infancy, might alter immuneregulatory networks and account for thedramatic increase in the incidence ofallergic diseases that has been observed in

developed countries49. Several studies havereported differences in the compositionof the faecal microbiota of infants whodevelop an allergic disease and those whodo not. Notably, a decreased frequencyof Lactobacillus and Bifidobacterium spp.has been suggested to precede the onsetof allergy 50, and prophylactic approaches,which are based on the administration ofprobiotics to mothers and newborns athigh risk for IgE-associated allergies, havebeen initiated. A recent study reportsthat 1 month of prenatal and 6 months of

postnatal pre- and probiotic supplementa-tion can reduce the incidence of eczemaand food-specific IgE in a subset of high-risk children who are born by caesareansection51. This protective effect was notseen in vaginally delivered children andwas transient, as it was significant at2 years of age but not by 5 years of age.

The results of such interventions remainconflicting and a causative link between dys-biosis, which is induced by changes in life-style or recent medical practices, and allergyremains difficult to establish51,52. Moreover,experimental studies that support the roleof the microbiota in the development ofallergic diseases are still scarce (TABLE 1). Onestudy has reported increased developmentof allergic airway disease in mice that weretreated with a short course of oral antibiot-ics53. Another interesting study showed thatTLR4 activation by microbiota-derived

LPS was necessary to prevent anaphylaxisafter oral immunization with the peanut-derived allergen Arah 1. TLR4-deficient orantibiotic-treated mice showed an increasedT

H2-type skewing of cytokine responses

compared with control mice. Conversely,activation of TLR9 by oral administration ofCpG oligodeoxynucleotides could abrogateallergic symptoms and correct the T

H1/T

H2

imbalance54. However, additional work isneeded to delineate whether and how thecomposition of the microbiota mightinfluence the onset of allergy.

Autoimmunity and the microbiota. Thepossibility that the intestinal microbiota isinvolved in the development of systemicautoimmunity has recently attracted grow-ing attention. Changes in the composition ofthe gut flora have been reported in patientsin the early phases of rheumatoid arthritis55 when compared with a control group withfibromyalgia. However, such studies cannotestablish a link between dysbiosis and thedevelopment of disease. Therefore, the roleof the microbiota has been more directlyaddressed by comparing the onset and/or

severity of experimental autoimmune dis-eases in germ-free mice with disease onsetand/or severity in mice that have beencolonized by a diverse microbiota.

In several models of autoimmunity,the progression of disease was compa-rable between both sets of mice56–58. Inother models, contradictory roles for themicrobiota have been reported (TABLE 1).The microbiota was shown to triggerdisease in several mouse models of auto-immune arthritis. For example, in a mousestrain that is prone to the spontaneous

development of an autoimmune ankylosingenthesopathy , disease does not developunder germ-free conditions. Furthermore,disease develops in mice that are colonizedwith a mixture of culturable anaerobesbut not in mice that are colonized withLactobacillus or Staphylococcus spp.59. Thisfinding suggests a role for a specific com-ponent (or components) of the microbiotain disease progression. A triggering rolefor the microbiota, specifically for SFB, wasalso seen in the autoimmune arthritis thatdevelops in K/BxN mice30. In this model,an uncontrolled T

H17 cell response that is

induced by SFB stimulated the productionof autoantibodies and led to the deposi-tion of immune complexes in the joints(FIG. 3). The microbiota also promoteddisease in another IL-17-dependent modelof arthritis, which develops in mice thatlack the IL-1 receptor antagonist60. Finally,

the microbiota and, to a lesser degree, SFBenhanced the severity of experimentalautoimmune encephalomyelitis31. Theaggravating role of the microbiota in thesemodels is consistent with its central role inthe induction of T

H17 cell responses.

By contrast, the microbiota was shownto have a protective role in collagen-induced arthritis61 and to prevent diabetesdevelopment in myeloid differentiationprimary-response protein 88 (MYD88)-deficient non-obese diabetic (NOD) mice62,as in both models disease was more severeif animals were housed in germ-free condi-tions. It remains unclear why a protectiverole for the microbiota during the develop-ment of diabetes is seen in the presenceof impaired TLR signalling. The completelack of TLR signalling in Myd88–/– Trif(TIR-domain-containing adaptor proteininducing IFNβ)–/– mice has been associ-ated with abnormal bacterial translocationinto the spleen and activation of systemicadaptive responses. It will be interesting toevaluate whether comparable mechanismsoperate in Myd88–/– NOD mice and par-ticipate in the protection against diabetes.

Interestingly, the caecal microbiota of Myd88–/– NOD mice differed significantlyfrom that of NOD mice and could attenuatethe development of type 1 diabetes whentransferred to the newborn progeny ofgerm-free NOD mice62; this suggests thatone or more species that confer protectionagainst disease might have been selectedfor in the NOD mice with impairedTLR signalling.

Taken together, these data providenovel examples of the complex interplaythat exists between the host immune





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also indicates the possible contribution ofthe intestinal microbiota to immunologicaldiseases outside the gut. However, from themicrobial perspective, the host is simply acomplex environment and the distinctionbetween health and disease is importantonly as far as it affects microbial fitness.The challenge that lies ahead is to determinewhen changes in our microbiota are theprimary cause of a disease and when thesechanges merely reflect the enormous capacityof bacteria for rapid and continuous genetic

system and the microbiota, and the dif-ficulties in attempting to delineate therespective roles of host predisposingfactors and specific bacterial species. Todetermine the therapeutic implicationsof these observations, further research isneeded to elucidate how the microbiotais able to influence peripheral immuneresponses and how such microbiota-driven responses can interfere with theimmunological mechanisms that underliea given autoimmune disease.

Conclusion

An increasing number of studies are pro-gressively unravelling the fascinating inter-actions that occur between eukaryotes andtheir bacterial symbionts. It is now clearthat the intestinal microbiota profoundlyinfluences host metabolic and immunepathways and participates in human healthand disease. Compelling evidence shows apivotal role for the microbiota in the devel-opment of many gastrointestinal diseases,from inflammation to cancer. Recent work

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 allergyto peanut allergen

Weanling C3H mice orC57BL/6 mice

Oral cocktail of antibiotics for 3 weeks Induction of anaphylacticsymptoms, increased production ofIgE and IL-13

54

Tlr4 mutant or Tlr4–/– mice None

IgE-mediated allergicairway disease inducedby Aspergillus fumigatus spores or ovalbumin

BALB/c and C57BL/6 mice Oral cefoperazone (Cefobid, Pfizer;Cefazone, Pharco B International)for 5 days and a single oral gavage ofCandida albicans

Increase in pulmonary eosinophilsand enhanced synthesis of IgE, IL-5and IL-13

49,53

Autoimmunity

Systemic lupuserythematosus

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

Type 1 diabetes NOD mice§ x Myd88 –/–mice Germ-free mice Increased incidence and severity 62

NOD Myd88–/–mice Colonization with specificpathogen-free flora

No disease

Spontaneous ankylosingenthesopathy

Male B10.BR mice Germ-free mice No disease 59

Colonization with probioticLactobacillus spp.

No disease

Colonization with a mixture ofBacteroides, Enterococcus, Veillonella and Staphylococcus spp.

Disease restored

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 segmentedfilamentous bacteria

Disease restored

Experimentalautoimmuneencephalomyelitis

C57BL/6J mice Germ-free mice Weak severity 31

Specific pathogen-free flora Maximal severity

Colonization with segmentedfilamentous bacteria

Intermediate severity

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. *AIREregulates the transcription of peripheral autoantigens in medullary thymic epithelial cells and is necessary for thymic negative selection; ‡AID is central forclass-switch recombination and somatic hypermutation in B cells; §NOD mice provide a polygenic model of type 1 diabetes; ||Mice with a transgenic T cell receptoragainst a self peptide that is derived from glucose-6-phosphate isomerase.





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Nadine Cerf-Bensussan and Valérie Gaboriau-Routhiau

are at the Institut National de la Santé et de la

Recherche Médicale (INSERM) U989, Université 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: [email protected]

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AcknowledgementsThe authors thank W. Garrett for sharing unpublished data.

Their work is supported by grants from the Institut National

de la Santé et de la Recherche Médicale (INSERM), theInstitut 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 statementThe authors declare no competing financial interests.

FURTHER INFORMATIONNadine Cerf-Bensussan’s homepage: http://www.

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