Role of The Gut Microbiota in Immunity and Inflammatory Disease

The skin and mucosal surfaces of vertebrates are colo-
nized by large numbers of microorganisms, includ-

ing bacteria, fungi, parasites and viruses, commonly
referred to as the microbiota. In humans, more than
100 trillion microorganisms, mostly bacteria, colonize
the oralgastrointestinal tract, and most of these micro-
organisms reside in the distal intestine. Millions of years
of co-evolution between the host and micro organisms
have led to a mutualistic relationship in which the micro-
biota contributes to many host physiological processes
and, in turn, the host provides niches and nutrients
for microbial survival
1
. The main contributions of the
microbiota to the host include the digestion and fermen-
tation of carbohydrates, the production of vitamins, the
develop ment of gut-associated lymphoid tissues (GALTs),
the polarization of gut-specific immune responses and
the prevention of colonization by pathogens
13
. In turn,
gut immune responses that are induced by commensal
populations regulate the composition of the micro-
biota. Thus, a complex interplay between the host
immune system and the microbiota is necessary for
gut homeostasis. However, when the mutualistic rela-
tionship between the host and microbiota is disrupted,
the gut microbiota can cause or contribute to disease
4,5
.
In this Review, we provide an overview of the current
understanding of the dual role of the gut microbiota in
health and disease.
Microbiota-dependent lymphoid development
GALTs. The study of germ-free mice led to the discov-
ery that the gut microbiota is required for the normal
generation and/or maturation of GALTs. GALTs are
immune structures in which antigen can be taken up
and presented by antigen-presenting cells, and there-
fore these structures have important roles in lympho-
cyte functions that lead to inflammation or tolerance.
GALTs include the Peyers patches, crypt patches and
isolated lymphoid follicles (ILFs)
68
. In the fetus, lym-
phoid tissue inducer (LTi) cells promote the devel-
opment of Peyers patches in the absence of resident
bacteria, although Peyers patches in germ-free mice are
smaller in size than those in specific-pathogen-free mice
9
.
Unlike Peyers patches, the maturation of ILFs and crypt
patches requires stimulation by the gut microbiota
7,10
.
Specifically, incomplete maturation of ileal and colonic
ILFs is observed in mice that are deficient in various
pattern recognition receptors (PRRs) (BOX1) that are acti-
vated by bacterial stimuli, such as Toll-like receptor2
(TLR2), TLR4, and nucleotide-binding oligomerization
domain 2 (NOD2), and in their adaptor molecules, such
as myeloid differentiation primary-response protein 88
(MYD88) and TIR domain-containing adaptor protein
inducingIFN (TRIF; also known as TICAM1)
8
. The
development of ILFs is also tightly regulated by NOD1,
which is a bacterial sensor that responds to bacterial
1
Department of Pathology
and Comprehensive Cancer
Center, University of
Michigan, Ann Arbor 48109,
Michigan, USA.
2
Department of Internal
Medicine and Comprehensive
Cancer Center, University of
Michigan, Ann Arbor 48109,
Michigan, USA.
Correspondence to G.N.
e-mail:
[email protected]
doi:10.1038/nri3430
Gut-associated lymphoid
tissues
(GALTs). Lymphoid structures
and aggregates that are
associated with the intestinal
mucosa, specifically the tonsils,
Peyers patches, lymphoid
follicles, appendix or cecal
patch, and mesenteric lymph
nodes. They are enriched in
conventional and
unconventional lymphocytes,
and in specialized dendritic cell
and macrophage subsets.
Role of the gut microbiota in
immunity and inammatory disease
Nobuhiko Kamada
1
, Sang-Uk Seo
1
, Grace Y.Chen
2
and Gabriel Nez
1
Abstract | The mammalian intestine is colonized by trillions of microorganisms,
most of which are bacteria that have co-evolved with the host in a symbiotic relationship.
The collection of microbial populations that reside on and in the host is commonly
referred to as the microbiota. A principal function of the microbiota is to protect the
intestine against colonization by exogenous pathogens and potentially harmful
indigenous microorganisms via several mechanisms, which include direct competition
for limited nutrients and the modulation of host immune responses. Conversely,
pathogens have developed strategies to promote their replication in the presence of
competing microbiota. Breakdown of the normal microbial community increases the
risk of pathogen infection, the overgrowth of harmful pathobionts and inflammatory
disease. Understanding the interaction of the microbiota with pathogens and the host
might provide new insights into the pathogenesis of disease, as well as novel avenues for
preventing and treating intestinal and systemic disorders.
REVI EWS
NATURE REVIEWS | IMMUNOLOGY VOLUME 13 | MAY 2013 | 321
2013 Macmillan Publishers Limited. All rights reserved
Germ-free mice
Mice that are born and raised
in isolators, without exposure
to microorganisms.
Peyers patches
Collections of lymphoid tissue
that are located in the mucosa
of the small intestine. They
have an outer epithelial layer
consisting of specialized
epithelial cells called M cells.
Peyers patches consist of a
dome area, Bcell follicles and
interfollicular Tcell areas. High
endothelial venules are present
mainly in the interfollicular
areas.
Specific-pathogen-free mice
Mice raised in conditions
whereby an increasing number
of pathogens are excluded or
eradicated from the colony.
These animals are maintained
in the absence of most of the
known chronic and latent
persistent pathogens. Although
this enables better control of
experimental conditions related
to immunity and infection, it
also sets apart such animal
models from pathogen-exposed
humans or non-human
primates, whose immune
systems are in constant contact
with pathogens.
peptidoglycan molecules
8
. However, although it is clear
from studies using germ-free mice that GALT develop-
ment requires the presence of microbiota, the require-
ment for specific PRRs is less clear, as these studies
have been confounded by differences between mouse
strains that can result in environmental alterations in
the microbiota, which, in turn, might affect lymphoid
development independently of a specific gene defect.
T
H
17 cells. It is now well known that the resident micro-
biota regulates the development of specific lymphocyte
subsets in the gut. T helper 17 (T
H
17) cells are a specific
lineage of CD4
+
T
H
cells that are crucial for host defence
and that have a role in the development of autoimmune
disease by producing the pro-inflammatory cytokines
interleukin-17A (IL-17A), IL-17F and IL-22 (REF.11).
Unlike other subsets of CD4
+
T
H
cells, such as T
H
1 and
T
H
2 cells, T
H
17 cells preferentially accumulate in the
intestine, which indicates that the development of T
H
17
cells might be regulated by gut-intrinsic mechanisms.
Consistent with this hypothesis, the presence of intes-
tinal T
H
17 cells is greatly reduced in antibiotic-treated
or germ-free mice
1216
, which shows that the microbiota
has a crucial role in T
H
17 cell development. In fact, a
particular species of Clostridia-related bacteria, called
segmented filamentous bacteria (SFB), promotes the
generation of T
H
17 cells in mice
1315
(FIG.1a). The precise
mechanism by which SFB promote T
H
17 cell develop-
ment remains to be fully elucidated. The adhesion of
SFB to the host epithelium upregulates serum amyloid
A protein (SAA) production, which, in turn, promotes
IL-6 and IL-23 production by CD11c
+
lamina propria
dendritic cells (DCs) and the subsequent induction of
T
H
17 cell differentiation
14
(FIG.1a). Likewise, luminal
ATP, which is provided by commensal bacteria but not
by pathogenic bacteria, promotes T
H
17 cell development
through a mechanism that is distinct to that elicited by
SFB
12
. However, whether SAA and ATP are required for
T
H
17 cell development invivo remains unclear. IL-1 is
also crucial for T
H
17 cell differentiation and is specifi-
cally induced by the gut microbiota
16
(FIG.1a). Although
reconstitution of germ-free mice with the microbiota
of conventionally raised mice rescues the development of
T
H
17 cells in the gut, colonization with rat or human
microbiota does not
17
. This indicates that the microbiota
might regulate the development of T
H
17 cells in the gut
in a species-specificmanner.
T
Reg
cells. Forkhead box P3 (FOXP3)
+
regulatory T (T
Reg
)
cells comprise a subset of CD4
+
T
H
cells that accumu-
late in the intestine, where they help to maintain gut
homeostasis. The depletion of T
Reg
cells results in the
abnormal expansion of CD4
+
T
H
cells expressing com-
mensal bacteria-specific Tcell receptors (TCRs); conse-
quently, intestinal inflammation ensues
18
. Importantly,
the development of peripherally derived T
Reg
cells is partly
dependent on the gut microbiota, as the number of T
Reg

cells is greatly decreased in the colonic lamina propria
of germ-free mice
19,20
(FIG.1a). The induction of T
Reg
cells
is triggered by specific populations of commensal bac-
teria. The accumulation of IL-10-producing T
Reg
cells in
the colon is promoted by colonization of germ-free mice
with one of the following bacterial populations: a mix-
ture of 46 Clostridium spp. cluster IV and XIVa strains;
altered Schaedler flora (ASF), which consists of a cock-
tail of eight defined commensal bacteria; or the human
commensal bacterium Bacteroides fragilis
1921
(FIG.1a).
However, the mechanism by which specific bacterial
populations induce the development of T
Reg
cells remains
poorly understood.
IgA-producing Bcells and plasma cells. A close relation-
ship also exists between the microbiota and gut-specific
Bcell responses. IgA is a major class of immunoglobu-
lin that is produced in mucosal tissues, including in the
intestine. In the intestinal lumen, IgA is produced as pol-
ymeric IgA at high concentrations
22
(FIG.1b). Polymeric
IgA is transported via the polymeric immunoglobulin
receptor (pIgR) that is expressed on intestinal epithelial
cells and is released into the intestinal lumen as secreted
IgA (SIgA)
23
(FIG.1b). SIgA coats commensal bacteria and
soluble antigens to inhibit their binding to the host epi-
thelium and their penetration into the lamina propria
22
.
Thus, SIgA promotes intestinal barrier function and
helps to maintain hostcommensal mutualism (FIG.1b).
In addition, IgA has been shown to regulate the com-
position and the function of the gut microbiota
24
. For
example, deficiency or dysfunction of IgA as a result
of deficiency or mutation of activation-induced cytidine
deaminase (AID), respectively, leads to alterations in the
composition of the gut microbiota
25,26
. Moreover, bind-
ing of IgA to the commensal Bacteroidesthetaiotaomicron
Box 1 | Pattern recognition receptors
Pattern recognition receptors (PRRs) are receptor molecules expressed in immune
cells. PRRs recognize pathogen-associated molecular patterns (PAMPs), such as
lipopolysaccharide, flagellin, bacterial DNA and RNA, and they have crucial roles in
innate immunity and protection against pathogens. In addition to pathogens, the
gut-resident microbiota contains PAMPs that are recognized by PRRs. Most PRRs
fall into three families: the Toll-like receptors (TLRs), NOD-like receptors (NLRs) and
retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs).
TLR family members are expressed on the cell surface and in endosomes, and
stimulation of TLRs by bacterial components activates downstream adaptor molecules
such as myeloid differentiation primary response 88 protein (MYD88) and/or TIR domain-
containing adaptor protein inducing IFN (TRIF). TLR activation results in the upregulation
of pro-inflammatory mediators that facilitate host immune responses. NLRs are
cytoplasmic proteins that regulate inflammatory and apoptotic responses. The NLRs
nucleotide-binding oligomerization domain 1 (NOD1) and NOD2 share the downstream
adaptor molecule receptor-interacting serine/threonine kinase (RICK), which activates
innate immunity through nuclear factor-B (NF-B) and mitogen-activated protein
kinases (MAPKs). A specific subset of NLRs is involved in the formation of the
inflammasome, which activates caspase 1. These NLRs include NLRP3 (NOD-, LRR- and
pyrin domain-containing 3), NLRP1 and NLRC4 (NOD-, LRR- and CARD-containing4),
and they contain specific domains (a pyrin domain or a CARD) that assist in the
recruitment of the adaptor protein ASC, which forms an oligomeric complex with
caspase 1. Activation of the inflammasome and caspase 1 leads to the secretion of
mature interleukin-1 (IL-1) and IL-18, which are involved in host defence and in the
pathogenesis of multiple autoimmune diseases. RLRs are cytoplasmic proteins that
are involved in intracellular virus recognition but have been demonstrated to also
be important in gut immunity and in disease pathogenesis
166,167
. The RLRs RIG-I and
melanoma differentiation-associated protein 5 (MDA5) recognize double-stranded
RNA. Another RLR member, LGP2 (also known DHX58), lacks amino-terminal
caspase-recruitment domains and functions as a regulator of RIG-I and MDA5 signalling.
REVI EWS
322 | MAY 2013 | VOLUME 13 www.nature.com/reviews/immunol
Nature Reviews | Immunology
Epithelial
cell
a
b
FOXP3
+
T
Reg
cell
Retinoic
acid and
IL-10
SAA
ATP
SFB
Other microbiota
PSA
Other factors?
AID
Class switching
REGIII
REGIII
Lamina
propria
Gut lumen
T
H
17 cell
IL-22
IL-1,
IL-6 and
IL-23
IL-12(?)
T
H
1 cell
BAFF
and
APRIL
TSLP
TLR
BAFF,
APRIL
IL-17RB
+
DC
RORt
+
ILC3
IL-22
IgA
SIgA
APRIL, BAFF, NO,
retinoic acid
and TNF
pDC,
TIP DC and
TLR5
+
DC
CD70
+
CD11c
low
DC
and CX
3
CR1
+
CD11c
+
DC
CD103
+
DC
and TLR5
+
DC
IL-25
CD11b
+
CD11c

macrophage
CD11b
+
CD11c

macrophage
Clostridium cluster IV
and XIVa strains
PSA
+
Bacteroides fragilis
Other microbiota
B cell
IgA
+
plasma cell
IgA
+

B cell
FDC
c
TGF
Pattern recognition
receptors
(PRRs). Germline-encoded
receptors (such as the Toll-like
receptors (TLRs) and the
NOD-like receptors (NLRs))
that can sense pathogen-
associated molecular patterns
and initiate signalling
cascades that lead to an
innate immune response.
They can be membrane-bound
(such as TLRs and C-type lectin
receptors (CLRs)) or soluble
cytoplasmic receptors (such as
retinoic acid-inducible gene I
(RIG-I), melanoma differentiation-
associated protein 5 (MDA5)
and NLRs).
Peripherally derived T
Reg
cells
A subset of forkhead box P3
(FOXP3)
+
regulatory T (T
Reg
)
cells that are induced in the
periphery and mediate their
suppressive effects through
the secretion of cytokines
such as interleukin-10 and
transforming growth factor-,
which inhibit other Tcells.
Their role is to maintain
self-tolerance.
Activation-induced cytidine
deaminase
(AID). An enzyme that is
required for two crucial
events in the germinal centre:
somatic hypermutation and
class-switch recombination.
Figure 1 | The gut microbiota-mediated development of the intestinal immune system. a | Segmented filamentous
bacteria (SFB) and other commensal microorganisms activate lamina propria dendritic cells (DCs) and macrophages to
induce T helper 17 (T
H
17) cells and T
H
1 cells through the production of interleukin-1 (IL-1), IL-6 and IL-23 in the case
of T
H
17 cells, and possibly IL-12 in the case of T
H
1 cells (although the role of IL-12 in T
H
1 development in vivo in the gut
remains to be confirmed). T
H
17 cells regulate the gut microbiota community in an IL-22- and regenerating islet-derived
protein 3 (REGIII)-dependent manner. Clostridium spp. clusters IV and XIVa, polysaccharide A (PSA)
+
Bacteroides fragilis
and other microbiota stimulate intestinal epithelial cells, Tcells, and lamina propria DCs and macrophages to promote
the development and/or the activation of forkhead box P3 (FOXP3)
+
regulatory T (T
Reg
) cells. b | The microbiota stimulates
intestinal epithelial cells and DCs to promote IgA-producing Bcell and plasma cell differentiation in the lamina propria.
Toll-like receptor (TLR) activation on intestinal epithelial cells induces the secretion of Bcell-activating factor (BAFF) and
a proliferation-inducing ligand (APRIL), which promote the differentiation of IgA-producing plasma cells. Intestinal
epithelial cells also produce thymic stromal lymphoprotein (TSLP) to promote BAFF and APRIL expression by DCs. Various
types of DCs, such as plasmacytoid DCs (pDCs), TIP DCs (TNF and inducible nitric oxide synthase (iNOS)-producing DCs)
and TLR5
+
DCs secrete BAFF, APRIL, nitric oxide (NO), retinoic acid and tumour necrosis factor (TNF) to facilitate the
expression of activation-induced cytidine deaminase (AID) and IgA class-switching in Bcells. Follicular DCs (FDCs) also
induce the differentiation of IgA-producing plasma cells in Peyers patches and isolated lymphoid follicles. IgA that is
produced by lamina propria B cells is secreted into the intestinal lumen (SIgA), where it alters microbiota composition
and function. c | Innate lymphoid cells (ILCs) that express retinoic acid receptor-related orphan receptor-t (RORt) and
produce IL-22 (termed ILC3s) regulate the gut microbiome through the induction of REGIII in intestinal epithelial cells.
The microbiota positively regulates the production of IL-22 by RORt
+
ILC3s via an unknown mechanism. In addition, the
microbiota induces IL-25 secretion by endothelial cells, which acts on lamina propria IL-17 receptor B (IL-17RB)
+
DCs,
and the IL-25-activated DC subset suppresses IL-22 production by RORt
+
ILC3s. CX
3
CR1, CX
3
C-chemokine receptor 1;
SAA, serum amyloid A protein; TGF, transforming growth factor-.
REVI EWS
Follicular DCs
(FDCs). Specialized
non-haematopoietic stromal
cells that reside in the follicles
and germinal centres. These
cells possess long dendrites,
but are not related to dendritic
cells, and carry intact antigen
on their surface.
inhibits innate immune responses by affecting bacterial
gene expression
27
. The gut microbiota also regulates IgA
production, as the number of IgA-producing cells in
the intestine is markedly decreased in germ-free mice
22
.
Although the precise mechanisms by which commensal
bacteria promote the development of IgA-producing
cells remain poorly understood, bacterial recognition
through MYD88 in follicular DCs (FDCs) is known to be
important for the generation of IgA
28
(FIG.1b). Notably,
for a subset of lamina propria DCs, commensal bacteria-
derived flagellin promotes the synthesis of retinoic acid,
which is an important molecule that facilitates the differ-
entiation of IgA-producing Bcells
29,30
(FIG.1b). Likewise,
commensal bacteria promote the expression of factors
that are involved in the induction of IgA
+
Bcells, such
as tumour necrosis factor (TNF), inducible nitric oxide
synthase (iNOS; also known as NOS2), Bcell activating
factor (BAFF; also known as TNFSF13B) and a prolifer-
ation-inducing ligand (APRIL; also known as TNFSF13)
in lamina propria DCs
31,32
. In addition to TNF- and iNOS-
producing (TIP) DCs, intestinal plasma cells express TNF
and iNOS following microbial exposure, which further
promotes the IgA secretory function of intestinal B cells
33

(FIG.1b). Thus, the microbiota instructs lamina propria
DCs and/or FDCs to induce the differentiation of IgA-
producing Bcells, and in turn, IgA regulates the func-
tion and composition of the gut microbiota to maintain
mutualism between the host and the microbiota.
ILCs. Innate lymphoid cells (ILCs) are increasingly recog-
nized as innate immune cells that share functional charac-
teristics with Tcells (reviewed in REFS34,35). ILCs arise
from a common lymphoid precursor cell but differenti-
ate into multiple lineages on the basis of the expression
of specific transcriptional factors. Currently, ILCs have
been categorized into three main groups: T-bet
+
ILCs
(termed ILC1s) GATA-binding protein 3 (GATA3)
+

ILCs (termed ILC2s), and retinoic acid receptor-related
orphan receptor-t (RORt)
+
ILCs (termed ILC3s)
3437
.
The role of the microbiota in the development and
the function of ILCs has been controversial. Although
some studies report that the microbiota is required for
the differentiation of ILCs and for their production of
IL-22 (REFS38,39) (FIG.1c), another study suggested that
the microbiota suppressed IL-22 production by RORt
+

ILCs
40
(FIG.1c). A crucial function of IL-22 is to promote
antimicrobial peptide production by intestinal epithe-
lial cells. Specifically, IL-22 induces the expression of the
C-type lectin antimicrobial peptides regenerating islet-
derived protein 3 (REGIII) and REGIII, which can
affect the gut microbiota
41,42
. Depletion of either IL-22 or
IL-22-producing ILCs leads to overgrowth and/or dis-
semination of potentially pathogenic bacteria, such as
Alcaligenes xylosoxidans, which might increase the risk
of subsequent intestinal damage and systemic inflamma-
tion
43
. Thus, the regulation of gut-specific immune cells
by commensal bacteria has far-reaching effects that are
not limited to immune homeostasis, but also include the
regulation of the balance between beneficial and poten-
tially pathogenic commensals in the microbiota, and
resistance to intestinal pathology.
Microbiota and resistance to pathogens
It has been known for many years that germ-free mice
are more susceptible to infection than conventionally
raised mice
44,45
. Furthermore, treatment with antibiot-
ics is associated with increased colonization of patho-
gens in both mice and humans
4649
. These observations
indicate that an important function of the indigenous
microbiota might be to protect the host from infection.
The mechanisms by which commensal bacteria achieve
this remain poorly understood, but there is evidence
to indicate that both direct and indirect mechanisms
might be involved.
Direct competition for nutrients. Several studies have
shown that commensal bacteria can inhibit pathogen
colonization by successfully competing for the limited
supply of nutrients within the intestine. For example,
Escherichia coli competes with enterohaemorrhagic
E.coli (EHEC; an enteric pathogen that causes substan-
tial morbidity and mortality worldwide) for organic
acids, amino acids and other nutrients
5053
(FIG.2). As
different commensal E.coli strains have distinct meta-
bolic profiles, each strain can differentially compete
with pathogens
53
. Although our understanding of how
commensal bacteria outcompete pathogens is still
poor, studies thus far indicate that pathogen eradica-
tion might be most effective with bacteria that are meta-
bolically related to the pathogen. For example, E.coli,
but not Bacteroides spp., can effectively outcompete the
metabolically related pathogen Citrobacter rodentium,
which is a mouse bacterium that models infection by
enteropathogenic E. coli (EPEC) and EHEC
54
. The
ability of E.coli to outcompete C.rodentium is partly
mediated by competition for simple sugars that are used
by both bacteria in the intestine
54
(FIG.2).
Likewise, the enteric pathogen Salmonella enteria
subsp. enterica serovar Typhimurium is capable of colo-
nizing the intestine of mice that have been harbouring
a limited microbiota for several weeks, but it is rapidly
eradicated after co-housing with conventionally raised
mice, which indicates that not all commensal bacteria
have the ability to out-compete the pathogen
55
. The
metabolic activity of the microbiota can also affect
pathogen colonization by a mechanism that is distinct
from nutritional competition. The commensal bacterial
strain B.thetaiotaomicron produces multiple fucosidases
that generate fucose from host-derived glycans, such as
mucin, and this modulates the expression of EHEC viru-
lence genes through the activation of the fucose sensor
FusKR
56
(FIG.2).
Pathogens, in turn, have also evolved strategies to over-
come competition by commensal bacteria. One strategy
is to use nutrients that are not primarily metabolized
by commensal bacteria. Carbohydrate usage can differ
substantially between pathogenic and commensal E.coli
strains
52,57
. For example, EHEC, but not certain commen-
sal E.coli strains, can use galactose, hexuronates, man-
nose, ribose and ethanolamine, which is released into the
intestine during epithelial cell turnover, as a carbon or
nitrogen source
52,58
. Use of ethanolamine can be explained
by the presence of the ethanolamine utilization(eut)
REVI EWS
M
i
c
r
o
b
i
o
t
a

s
t
r
a
t
e
g
i
e
s
Virulence factor
expression
Nutrients
specically
used by
pathogens
Competition
for nutrients
Fucose
Pathogen Pathogen
Pathogen
colonization
Pathogen colonization
Systemic translocation
Direct
Commensal
microbiota
P
a
t
h
o
g
e
n

s
t
r
a
t
e
g
i
e
s
Indirect
Neutrophil
Macrophage
B cell
T
H
1 or
T
H
17 cell
ILC3
IL-1
and
IL-23
IL-1
Induce
pro-IL-1
Inamed
epithelial cell IL-22
IL-22
Plasma cell
REGIII
Mucus
SCFAs
Epithelial
cell
Killing (T6SS)
REGIII
IgA
Lamina
propria
Gut
lumen
Barrier function
TypeIV secretion system
(T6SS). An export system that
is used by Gram-negative
bacteria to deliver effector
proteins to other cells in a cell
contact-dependent manner.
operon in the genome of the EHEC strain and not in the
commensal E.coli strain
58
. Thus, pathogens have evolved
to use nutritional resources that are not consumed by
commensal bacteria to acquire a growth advantage.
Another strategy used by pathogens is the induction of
inflammation by their virulence factors. For example,
infection by S. Typhimurium results in the production
of reactive oxygen species by neutrophils, which facili-
tates the conversion of endogenous thio sulphate into
tetrathionate, thereby selectively promoting the growth
of S. Typhimurium
59,60
(FIG.2). Moreover, virulence factors
such as intimin allow C.rodentium to attach to the host
epithelium where commensal bacteria do not normally
reside
54
. Localization to epithelium-associated niches
might also allow certain pathogens such as EPEC and
EHEC to use nutrients that are available at or near the
epithelium and to escape from direct competition with
resident microorganisms (FIG.2). Furthermore, certain
Gram-negative enteric pathogens, such as Serratia marce-
scens and C.rodentium, can directly kill their commensal
competitors through the expression of the type VI secretion
system (T6SS)
61,62
(FIG.2). Thus, the outcome of infection
by pathogens is ultimately determined by both host and
commensal bacterial factors.
Figure 2 | Direct and indirect resistance of the microbiota to colonization by enteric pathogens. Direct competition
between pathogens and commensal bacteria is shown on the left-hand side. Resident microorganisms directly inhibit
the colonization and/or the proliferation of incoming enteric pathogens. Commensal microorganisms can outcompete
pathogens for shared nutrients, such as carbohydrates, amino acids and organic acids. In addition, commensal bacterial
strains such as Bacteroides thetaiotaomicron catabolize mucin to produce fucose, which inhibits virulence factor expression
by pathogenic Escherichia coli. Enteric pathogens have evolved strategies to overcome competition by commensal
bacteria. Some pathogens can directly kill their commensal competitors through their type VI secretion system (T6SS).
Pathogen-induced inflammation, which leads to increased epithelial cell turnover, provides nutrients that selectively
promote the growth of pathogens. Moreover, pathogens can localize to epithelium-associated niches that are devoid of
commensal bacteria and use nutrients near the epithelium to escape direct competition with resident microorganisms.
Indirect mechanisms of competition between commensal bacteria and pathogens are shown on the right-hand side.
Commensal bacteria catabolize polysaccharides to generate short-chain fatty acid (SCFAs), such as acetate, which
enhances intestinal epithelial cell barrier function. In addition, commensal microbiota promotes the production of mucus
and the release of antimicrobial peptides such as regenerating islet-derived protein 3 (REGIII) from epithelial cells to limit
pathogen colonization and proliferation. Innate immune cells, such as intestinal resident macrophages, neutrophils and
some group 3 innate lymphoid cells (namely ILC3s), as well as T helper 1 (T
H
1) cells, T
H
17 cells and IgA-producing Bcells
and plasma cells, are also activated by the microbiota to limit pathogen colonization. IL, interleukin.
REVI EWS
Inflammasome
A molecular complex of several
proteins, including a NOD-like
receptor (NLR), the adaptor
protein ASC and a caspase,
that, upon assembly, cleaves
pro-interleukin-1 (pro-IL-1)
and pro-IL-18, thereby
producing mature IL-1 and
IL-18.
Aryl hydrocarbon receptor
(AHR). A cytosolic,
ligand-dependent transcription
factor that translocates to the
nucleus following the binding
of specific ligands, which
include dietary and microbial
metabolites. AHR participates
in the differentiation of
regulatory Tcells, T helper 17
(T
H
17) cells and intraepithelial
intestinal Tcells, and it is
required for the secretion of
interleukin-22 by T
H
17 cells.
More recently, AHR has been
shown to have crucial roles in
the development and function
of group 3 innate lymphoid
cells, including lymphoid tissue
inducer (LTi) cells and ILC3s.
Commensal bacteria promote mucosal barrier function.
The attachment of pathogens to the surface of the intes-
tinal epithelium is a crucial initial step for infection to
occur. As a defence mechanism, the epithelium produces
mucus and antimicrobial molecules to inhibit pathogen
invasion. In the colon, the mucus layer forms a strong bar-
rier against both pathogens and commensal bacteria
63,64
.
In the small and large intestines, the inner mucus layer
near the epithelium is devoid of commensal bacteria
63,64
.
However, the mucus layer in germ-free mice is much
thinner than that in conventionally raised mice, which
indicates that the microbiota might contribute to mucus
production
65
(FIG.2). Consistent with this hypothesis, the
thickness of the mucus layer of germ-free mice can be
restored to normal by oral administration of the bacterial
products lipopolysaccharide (LPS) and peptidoglycan
65
.
The microbiota also contributes to the production of
antimicrobial molecules by epithelial cells of the small
and large intestines (FIG.2). For example, REGIII and
REGIII that are contained in Paneth cell granules
are released into the lumen to regulate hostbacte-
ria inter actions through their antimicrobial activity
66
.
Epithelium-intrinsic deletion of MYD88 impairs the
production of REGIII and REGIII; therefore, it seems
that recognition of the microbiota by TLRs medi-
ates the expression of these antimicrobial peptides
42,66
.
Importantly, the impaired production of REGIII and
REGIII increases the susceptibility of mice to infection
by enteric pathogens including Listeria mono cytogenes,
Yersinia pseudotuberculosis and S.enterica subsp. enterica
serovar Enteritidis
6769
.
The microbiota can also enhance epithelial barrier
function through the production of metabolites. For
instance, short-chain fatty acids (SCFAs), especially
acetate, produced by Bifidobacterium spp. act on the epi-
thelium to inhibit the translocation of Shiga toxin that is
produced by E.coli O157:H7 (REF.45) (FIG.2). The precise
signalling mechanism by which bacterial products and
metabolites enhance epithelial defence, and how this
mutually affects the microbiota and the host, remains
to be elucidated.
The microbiota enhances innate immunity to patho-
gens. Mononuclear phagocytes, such as macrophages
and DCs, are located in the lamina propria and promote
immunological unresponsiveness to commensal bacteria,
which is important for maintaining gut homeostasis
70,71
.
Specifically, gut-resident phagocytes are hyporespon-
sive to microbial ligands and commensal bacteria, and
they do not produce biologically significant levels of
pro-inflammatory molecules upon stimulation
7072
.
However, the microbiota is essential for upregulating
the production of pro-IL-1, the precursor to IL-1, in
resident mononuclear phagocytes
71
. Under steady-state
conditions when the epithelial barrier is intact, resident
commensal bacteria cannot also induce the processing of
pro-IL-1 into biologically active mature IL-1 and thus a
state of hyporesponsiveness is maintained
71
. By contrast,
infection by enteric pathogens such as S. Typhimurium
and Pseudomonasaeruginosa can induce the processing
of pro-IL-1 by promoting the activation of caspase 1
via the NLRC4 (NOD-, LRR- and CARD-containing 4)
inflammasome
71
. Unlike commensal bacteria, these patho-
gens are capable of activating the NLRC4 inflammasome
to produce IL-1 because they express a typeIII secretion
system, which allows the transfer of the NLRC4 agonist
flagellin into the host cytosol
71
. Consequently, BALB/c
mice that are deficient in NLRC4 or in the IL-1 receptor
(IL-1R) are highly susceptible to orogastric infection with
S. Typhimurium
71
. The protective role of IL-1 in intesti-
nal immunity is, at least partly, mediated by its ability to
induce the expression of endothelial adhesion molecules
that contribute to neutrophil recruitment and pathogen
clearance in the intestine. Thus, NLRC4-dependent IL-1
production by resident phagocytes represents a specific
response that can discriminate between pathogenic and
commensal bacteria.
The intestinal microbiota also promotes immunity
through the production of IL-22 by ILC3s
38
. Germ-free
mice show impaired intestinal production of IL-22, which
indicates that there might be a requirement for commen-
sal bacteria or their metabolites
16
. Mice with defects in
IL-22-expressing cells exhibit increased susceptibility to
C.rodentium infection, which indicates that commen-
sal bacterial-driven IL-22 that is produced by ILC3s is
important for protection against infectious pathogens
38,73,74
.
Consistent with this idea, administration of IL-22 to
aryl hydrocarbon receptor (Ahr)
/
mice, which exhibit
impaired IL-22 production, provides protection against
C.rodentium infection
74
. Taken together, these results
indicate that commensal bacteria might also promote host
defence by stimulating ILCs to produce IL-22 (FIG.2).
The microbiota promotes adaptive immunity. As men-
tioned above, specific commensal bacteria promote
the generation of different Tcell subsets in the intes-
tine
12,14,1921,75
that have unique roles during pathogen
infection (FIG.2). For instance, T
H
17 cell differentiation
that is induced by SFB colonization facilitates protec-
tion against C.rodentium infection
14
. Likewise, micro-
biota-induced T
Reg
cells attenuate intestinal damage that
is caused by exaggerated immune responses against
infectious pathogens. Specifically, B.fragilis promotes
IL-10-producing T
Reg
cells that protect against Helicobacter
hepaticus infection
21,76
, and Bifidobacterium infantis
increases the number of T
Reg
cells that attenuate intes-
tinal disease severity following S. Typhimurium infec-
tion
77
. Commensal bacteria also induce specific immune
responses, including IgA production and the generation
of CD4
+
Tcells, that are directed against their own anti-
gens
7880
. Although the precise role of commensal bacte-
ria-specific adaptive immunity against invasive pathogens
remains poorly understood, there is evidence indicating
that it is important for limiting the systemic dissemination
of commensal bacteria
81
. The induction of this firewall
function of the adaptive immune system by the micro-
biota might prevent collateral damage which could be
caused by the translocation of indigenous bacteria that
is often associated with pathogen infection and epithelial
barrier disruption. In addition, it might contribute to the
elimination of pathogens through opsonization or other
immune mechanisms.
REVI EWS
Inflammatory bowel disease
(IBD). Immune-mediated
inflammation of the bowel.
There are two main forms:
Crohns disease, which is a
granulomatous segmental
inflammation affecting any part
of the intestine; and ulcerative
colitis, which is a mucosal
inflammation involving the
rectum and extending for a
variable distance along the
colon. In developed countries,
the incidence of inflammatory
bowel disease is approximately
one in 50,000. It usually starts
in early adult life and continues
afterwards with a relapsing,
remitting course.
SAMP1/yit mice
A mutant mouse strain that
spontaneously develops a
chronic intestinal inflammation
that is mainly localized in the
terminal ileum.
Autophagy
An evolutionarily conserved
process in which acidic
double-membrane vacuoles
sequester intracellular
contents (such as damaged
organelles and
macromolecules) and target
them for degradation through
fusion to secondary lysosomes.
-defensins
One subset of defensin
proteins. Defensins and
cathelicidins are members of a
family of small antimicrobial
polypeptides that are
abundant in neutrophils and
epithelial cells. They contribute
to host defence by disrupting
the cytoplasmic membrane of
microorganisms.
Protective role of the commensal microbiota against sys-
temic infection. The mechanism by which the micro-
biota promotes systemic pathogen eradication is poorly
understood. Pretreatment of germ-free mice with LPS
induces pro-inflammatory cytokine production and
neutrophil recruitment, and can prevent systemic bac-
terial infection
82
. This observation indicates that com-
mensal bacteria might, at least partly, promote host
defence at distant sites through the release of microbial
molecules. Consistent with this hypothesis, peptido-
glycan molecules that are derived from the microbiota
are found in the periphery and can prime peripheral
blood neutrophils to facilitate their bactericidal capacity
via NOD1 signalling
83
. This neutrophil priming effect,
which is presumably induced by intestinal bacteria,
enhances host defence against systemic infection with
Streptococcus pneumoniae
83
.
The microbiota might also have an important role in
systemic antiviral immune responses. Germ-free mice
and antibiotic-treated mice show reduced innate and
adaptive immune responses to influenza virus, which
results in increased viral loads in their tissues
84,85
. The
microbiota might enhance antiviral immunity through
the inflammasome and the production of innate
cytokines that are required for optimal immune responses
against viruses
84
. For example, the microbiota promotes
type I interferon (IFN) production by macrophages
and the subsequent IFN-priming of natural killer (NK)
cells, which is important for protection against infection
with mouse cytomegalovirus and lymphocytic chorio-
meningitis virus
86
. Moreover, the gut microbiota induces
intestinal TLR-dependent DC activation and inhibits
systemic parasitic infection
87
. Recent studies also indicate
that commensal bacteria might provide tissue-specific
defence mechanisms, as has been demonstrated by the
protection provided by resident skin bacteria against
local pathogen infection
88
.
Taken together, these studies using different infection
models show a protective effect of the microbiota against
systemic infection; however, additional studies are nec-
essary to identify the underlying mechanisms as well as
the relative contributions of host defence mechanisms
that are promoted by the microbiota of specific tissues
such as the skin or the respiratory tract. It is also impor-
tant to note that commensal bacteria do not always pro-
tect against pathogenic infection and in certain contexts
they can facilitate it (as discussed below)
8991
.
The microbiota and intestinal disease
The microbiota contributes to IBD. The gut micro-
biota is essential for triggering or enhancing chronic
intestinal inflammation in various inflammatory bowel
disease (IBD)-prone mouse strains (TABLE 1). Under
germ-free conditions, Il10
/
or Tcra
/
mice, as well as
transgenic rats that have been engineered to overexpress
HLA-B27 and human 2 microglobulin, do not develop
colitis
9295
. In Il2
/
or SAMP1/yit mice, although sponta-
neous intestinal inflammation occurs even under germ-
free conditions ,symptoms are attenuated compared
with conventionally raised mutant mice
96,97
. In many
spontaneous colitis models, intestinal inflammation is
abrogated if mice also have a deficiency in individual
TLRs or in MYD88. For example, spontaneous coli-
tis that develops in Il10
/
mice, in conditional signal
transducer and activator of transcription 3 (Stat3)
/

mice or in mice with a deletion in inhibitor of nuclear
factor-B kinase- (IKK; also known as NEMO) spe-
cifically in intestinal epithelial cells (NEMO
IEC
mice)
is reversed when these mice also lack TLRs or MYD88
(REFS98101). However, Il2
/
mice that are deficient in
MYD88 still develop spontaneous colitis
99
. In this model,
the microbiota might drive colitis through the promo-
tion of inflammatory T
H
17 cell responses
12
that occur
independently ofMYD88.
Similar to mice, human intestinal mononuclear
phagocytes show hyporesponsiveness to microbial stim-
ulation under steady-state conditions
102,103
. However, in
patients with IBD, intestinal mononuclear phagocytes
robustly respond to microbial products and to the resi-
dent bacteria, which results in the production of large
amounts of pro-inflammatory cytokines such as TNF
and IL-23, as occurs in IBD-prone mice
103
. Thus, the
abnormal activation of resident intestinal mononuclear
phagocytes by commensal bacteria might facilitate the
development or persistence of intestinal inflammation in
IBD. Consistent with this idea, intestinal macrophages
isolated from Il10
/
mice robustly respond to gut bac-
teria, whereas wild-type intestinal macrophages are
hyporesponsive
7072
. However, the increased production
of pro-inflammatory molecules by intestinal phagocytes
might also reflect the activity of recruited monocytes
in areas of infection or inflammation.
There is genetic evidence showing that the impaired
recognition and killing of commensal bacteria also con-
tributes to IBD development, as has been suggested by
the fact that many of the identified IBD-susceptibility
genes regulate hostmicrobial interactions
104
. NOD2,
which is an intracellular sensor of bacterial peptidog-
lycan, was identified as a susceptibility gene for Crohns
disease, and Crohns disease-associated NOD2 muta-
tions are associated with a loss of function of the pro-
tein
105107
. Mutations in the autophagy regulatory genes
autophagy related gene 16-like 1 (ATG16L1) and immu-
nity-related GTPase family M (IRGM) are also linked
to Crohns disease
108,109
, and autophagy dysfunction is
associated with defects in bacterial killing
110112
. In addi-
tion, NOD2 and autophagy proteins regulate the func-
tion of Paneth cells, which release granules containing
antimicrobial peptides in response to bacteria
113
. NOD2
is highly expressed in Paneth cells, and some studies
report diminished expression of Paneth cell -defensins
in individuals with Crohns disease-associated NOD2
mutations
114,115
. Nod2
/
mice have impaired antimicro-
bial functions in Paneth cells, resulting in the accumu-
lation of ileal bacteria, which might contribute to IBD
pathogenesis
116
. Atg16l1-mutant (Atg16l1
HM
) mice show
abnormal granule formation in Paneth cells, which is
also observed in patients with Crohns disease who
have homozygous mutations in ATG16L1 (REF.117). In
Atg16l1
HM
mice this abnormality can be triggered by
enteric viral infection (for example, by murine noro-
virus) and is associated with increased susceptibility
REVI EWS
to chemically induced colitis
118
. Thus, defects in host
mechanisms that recognize and clear bacteria are
associated with the development of human IBD. How
genetic defects lead to chronic colitis in patients with
IBD remains unknown, but it is possible that impaired
NOD2 or autophagy function might result in the accu-
mulation of intestinal commensal bacteria that have the
capacity to locally invade the intestinal mucosa and to
trigger an abnormal inflammatory response.
The role of the pathobiont in IBD. As non-pathogenic
symbionts, the gut microbiota derives nutritional ben-
efits from the host and help to maintain gut homeostasis.
However, under certain conditions, particular bacterial
populations that are typically found in very low abun-
dance can acquire pathogenic properties. These condi-
tions include inherent immune defects as well as changes
in diet and/or acute inflammation, and can result in
the disruption of the normal balanced state of the gut
Table 1 | Role of the gut microbiota in the protection or induction of IBD
Commensal bacterium Host Genotype Disease Receptors Possible mechanism Refs
Commensal microbiota that protect against IBD
Clostridium spp. clusters
IV and XIVa
Mouse Wild-type DSS colitis Unknown Induction of T
Reg
cells 19
Altered Schaedler flora Mouse Wild-type DSS colitis MYD88 and
TRIF
Induction of T
Reg
cells 20
Bacteroides fragilis Mouse Wild-type TNBS colitis TLR2, MYD88 Induction of T
Reg
cells via
polysaccharide A
21
Bacteroides vulgatus Mouse Il2
/
Spontaneous colitis Unknown Suppression of Escherichia coli-
triggered colitis in Il2
/
mice
120
Faecalibacterium
prausnitzii
Human NA IBD Unknown Induction of IL-10 by PBMCs 148
Commensal microbiota that promote the development of IBD
E. coli Mouse Il10
/
Spontaneous colitis Unknown Monocolonization of germ-free
mice induces colitis
119
E.coli Mouse Il2
/
96, 120
Enterococcus faecalis Mouse Il10
/
119
B.vulgatus Rat HLA-B27B2m
transgenic
rats induces colitis
96
B.vulgatus Mouse Il10r2
/
Tgfbr2
/
Spontaneous colitis Unknown Colonization of antibiotic-
treated mice triggers colitis
122
Bacteroides
thetaiotaomicron
Mouse Il10r2
/
Tgfbr2
/
Spontaneous colitis Unknown Colonization of antibiotic-treated
mice triggers colitis
122
B.thetaiotaomicron Rat HLA-B27B2m
transgenic
rats induces colitis
95
Bacteroides unifirmatis Mouse Il10r2
/
Tgfbr2
/
Spontaneous colitis Unknown Colonization of antibiotic-treated
mice triggers colitis
122
Klebsiella pneumoniae*
Mouse Tbx21
/
Rag2
/
Spontaneous colitis Unknown Other commensal bacteria are
required for the induction of colitis
123,124
Proteus mirabilis*
Mouse Tbx21
/
Rag2
/
Spontaneous colitis Unknown Other commensal bacteria are
required for the induction of colitis
123,124
Helicobacter typhlonius* Mouse Tbx21
/
Rag2
/
Spontaneous colitis Unknown Transmissible to non-colitogenic
TRUC mice
125
Prevotellaceae*
Mouse Nlrp6
/
, Asc
/
or
Casp1
/
DSS colitis Unknown Impaired IL-18 signalling promotes
pathobiont expansion
126
TM7*
Mouse Nlrp6
/
, Asc
/
or
Casp1
/
DSS colitis Unknown Impaired IL-18 signalling promotes
126
Bilophila wadsworthia Mouse Il10
/
Spontaneous colitis Unknown Consumption of a diet composed
of milk-derived fat induces
128
B2m, gene encoding 2-microglobulin; Casp1, caspase 1; DSS, dextran-sulphate sodium; IBD, inflammatory bowel disease; IL, interleukin; MYD88, myeloid
differentiation primary-response protein 88; NA, not applicable; Nlrp6, NOD-, LRR- and pyrin domain-containing 6; PBMCs, peripheral blood mononuclear cells;
Rag2, recombination-activating gene 2; Tbx21, T-box 21 (encodes T-bet); Tgfbr2, transforming growth factor- receptor 2; TLR, Toll-like receptor; TNBS,
2,4,6-trinitrobenzene sulphonic acid; T
Reg
cell, regulatory Tcell; TRIF, TIR domain-containing adaptor protein inducing IFN; TRUC, Tbx21
/
Rag2
/
mice.
*Transmissable to mutant hosts.
Transmissable to wild-type hosts.

REVI EWS
Unclassied
bacteria
GALT development
T
H
17 and T
H
1 cells
Barrier function
REGIII
Chronic inammation
Homeostasis
Benecial
bacteria
Pathobionts
Gut
lumen
Lamina
propria
Symbiont
Homeostasis Inammatory bowel disease
Dysbiosis
Transmissable
to healthy host
Unknown
contribution
Genetic factors (for
example, mutations in
Nod2, Atg16I1 and Il23r)
Environmental factors
(diet, stress and infection)
T
Reg
cell
IL-10
REGIII
T
Reg
cells
IL-10
REGIII
T
H
17 cells
T
H
1 cells
Rag
Recombinase activating genes;
Rag1and Rag2 are expressed
in developing lymphocytes.
Mice that are deficient in either
of these genes fail to produce
B or Tcells owing to a
developmental block in the
gene rearrangement that is
necessary for receptor
expression.
microbiota, which is referred to as dysbiosis
5
. Dysbiosis
involves the abnormal accumulation or increased viru-
lence of certain commensal populations of bacteria,
thereby transforming former symbionts into patho-
bionts (FIG.3). Pathobionts are typically colitogenic in
that they can trigger intestinal inflammation; therefore,
there has been considerable interest in the identification
of pathobionts to understand the pathogenesis ofIBD.
Colitogenic pathobionts have been identified using
rodent models of spontaneous colitis (TABLE1). For exam-
ple, colonization of germ-free Il10
/
or Il2
/
mice with one
of several particular E.coli or Enterococcus faecalis strains,
but not with Bacteroides vulgatus, induces colitis
119121
.
By contrast, B.vulgatus, but not E.coli, triggers colitis in
HLA-B27-transgenic rats
94,95
. The differential colitogenic
capacity of these bacteria cannot be merely explained
by differences in the host species (mouse versus rat), as
B.vulgatus, but not E.coli, induces intestinal inflamma-
tion in mice that are deficient in both IL-10R2 and TGF
receptor 2 (REF.122). These findings indicate that specific
immune defects in the host might determine the ability
of individual commensal bacteria to trigger colitis (FIG.3).
However, the physiological relevance of these findings
remains unclear because monocolonization of germ-free
mice does not mimic the normal complex gut ecosystem.
Mice that have only innate immune cells with a defi-
ciency in T-bet (Tbx21
/
(gene encoding T-bet) Rag
/

mice; also known as TRUC mice) develop spontaneous
ulcerative colitis-like inflammation
123
. This colitis is trans-
missible to T-bet-sufficient Rag
/
mice and even to
wild-type mice through co-housing, which indicates that
impaired T-bet signalling in innate immune cells leads to
the overgrowth of pathobionts that cause disease
123
. Indeed,
the analysis of gut microbial communities in TRUC mice
showed that Klebsiella pneumoniae and Proteus mirabilis,
both of which are found in very low abundance in healthy
mice, accumulate in the guts of TRUC mice
124
. These bac-
teria can trigger colitis in T-bet-sufficient Rag
/
mice and
in wild-type mice, which indicates that they can function
as pathobionts. Interestingly, although K.pneumoniae or
P.mirabilis can induce colitis in healthy mice, mono-
or dual-colonization of germ-free TRUC mice with these
bacteria does not, which indicates that interactions with
additional commensal bacteria are required to actually
trigger inflammation
124
. The proteobacterium Helicobacter
typhlonius also accumulates in colitic TRUC mice, and
oral administration of the bacterium is sufficient to
induce colitis in non-colitic TRUC mice, but not in T-bet-
sufficient Rag
/
mice
125
. Similarly, the colitis induced
by H.typhlonius is not transmissible to wild-type mice
125
.
Figure 3 | Protective and pathogenic role of the gut microbiota in IBD. During homeostasis (left-hand side), the gut
microbiota has important roles in the development of intestinal immunity. Beneficial subsets of commensal bacteria tend
to have anti-inflammatory activities. Pathobionts that are colitogenic are directly suppressed by beneficial commensal
bacteria partly through the induction of regulatory immune responses, involving regulatory T (T
Reg
) cells, interleukin-10
(IL-10) and regenerating islet-derived protein 3 (REGIII). In inflammatory bowel disease (IBD) (right-hand side), a
combination of genetic factors (for example, mutations in nucleotide-binding oligomerization domain 2 (Nod2),
autophagy-related gene 16-like 1 (Atg16l1) and interleukin-23 receptor (Il23r)) and environmental factors (such as
infection, stress and diet) result in disruption of the microbial community structure, a process termed dysbiosis. Dysbiosis
results in a loss of protective bacteria and/or in the accumulation of colitogenic pathobionts, which leads to chronic
inflammation involving hyperactivation of T helper 1 (T
H
1) and T
H
17 cells. Dashed line shows that that the suppression of
pathobionts by beneficial bacteria is diminished. In certain contexts, pathobionts can be transferred to the host and can
cause disease without the host having a predisposing genetic susceptibility. It is unknown whether unclassified bacteria
have a role in the pathogenesis of IBD. GALT, gut-associated lymphoid tissue.
REVI EWS
iNKT cells
Invariant natural killer (iNKT)
cells; a population of cells that
are thought to be particularly
important in bridging the
innate and adaptive immune
responses. iNKT cells are
typified by a capacity for
self-recognition and rapid
release of cytokines such as
interferon-.
There is increasing evidence that defects in the NOD-
like receptor (NLR) family of proteins are associated with
dysbiosis. For example, Nlrp6
/
mice have impaired IL-18
production, which is associated with an abnormal expan-
sion of the commensal bacterial species Prevotellaceae and
the candidate division TM7 (REF.126). Although Nlrp6
/

mice do not develop spontaneous colitis, these mice have
an increased susceptibility to dextran sulphate sodium
(DSS)-induced colitis, and this phenotype is transmis-
sible to wild-type mice by co-housing
126
. This study
demonstrates a correlation between the accumulation of
Prevotellaceae and TM7, as well as DSS-induced colitis
susceptibility, but whether these bacteria are the direct
cause of this susceptibility and whether their accumu-
lation is indeed NLRP6-dependent remain to be deter-
mined. Similarly, bacterial genomic sequencing shows
that Nod2
/
mice, which have an increased susceptibility
to DSS-induced colitis, have an altered microbiota that
can be transferred to wild-type mice to increase dis-
ease susceptibility
127
. However, the specific pathobionts
involved have not yet been identified.
Diet has a considerable effect on the composition of
microbial communities and can lead to the expansion
of pathobionts. For instance, a diet rich in saturated milk
fats, but not in polyunsaturated vegetable oil fats, induces
dysbiosis and expansion of Bilophila wadsworthia, which
is a hydrogen-consuming, sulphite-reducing commen-
sal bacterium. This intestinal bacterium promotes pro-
inflammatory T
H
1 immunity and exacerbates colitis
in IBD-prone Il10
/
mice but not in wild-type mice
128
.
Although further studies are necessary, the increase in
taurine conjugation of hepatic bile acids might stimulate
the growth of sulphite-reducing microorganisms such as
B.wadsworthia, which promote harmful inflammation
via mechanisms that remain to be elucidated
128
.
Taken together, these observations indicate that
defects in the immune system and/or changes in diet
can trigger dysbiosis, which results in the accumulation
of pathobionts that promote transmissible or non-trans-
missible colitis (FIG.3). There is increasing evidence that
dysbiosis affects susceptibility to developing not only
IBD but also colitis-associated colon cancer in mouse
models, as well as colon cancer in humans
127,129133
. The
role of commensal bacteria in intestinal cancer has been
recently reviewed
134
and is not discussedhere.
Protective effect of the microbiota in IBD. Although
colitogenic pathobionts promote the development
of IBD, commensal bacteria are also crucial for reducing
IBD susceptibility, and this has generated considerable
interest in the development of probiotic approaches to
prevent IBD (TABLE 1). The protective effect of com-
mensal bacteria is evident from studies using germ-free
mice, which are more susceptible to DSS-induced colitis
than conventionally housed mice
135137
. Consistent with
these observations, deficiency in TLR2, TLR4, TLR9 or
MYD88 are all associated with increased susceptibility to
DSS-induced colitis
138140
. Tlr5
/
mice also develop spon-
taneous colitis in certain mouse housing facilities, which
strongly indicates that the microbiota might affect disease
susceptibility
141,142
. However, the precise mechanisms by
which the microbiota mediates resistance against the
development of colitis through TLR signalling remain
unclear. Administration of LPS (a TLR4 ligand) or CpG
(a TLR9 ligand) protects mice from colitis by promoting
epithelial barrier function following the upregulation of
cytoprotective heat shock proteins or by the induction
of typeI IFN production, respectively
138,139,143
. In addi-
tion, the production of protective IgA and IgM suppresses
the harmful dissemination of commensal bacteria after
colonic damage through MYD88 signalling in Bcells
140
.
The human commensal bacterium B.fragilis also pro-
tects mice from colitis by promoting the accumulation of
IL-10-producing T
Reg
cells in the colon
76,144
. This protective
effect is mediated by the outer membrane polysaccharideA
(PSA) of B.fragilis
76,144
. TLR2-mediated internalization
of PSA into DCs, followed by its surface presentation,
activates IL-10-producing T
Reg
cells
145,146
. Commensal
bacterial stimulation through MYD88 also limits the
trafficking of CX
3
CR1
+
mononuclear phagocytes that
capture luminal non-invasive bacteria to the mesenteric
lymph nodes (MLNs)
147
. Consequently, disruption of the
commensal microbiota and/or MYD88 signalling results
in excessive B and Tcell stimulation in the MLNs, which
might contribute to the development ofIBD.
It has also been reported that the microbiota protects
against colitis through TLR-independent mechanisms.
For example, the colonization of neonatal germ-free
mice with whole microbiota results in decreased hyper-
methylation of the CXC-chemokine ligand 16 (Cxcl16)
gene
75
. This epigenetic modification of the Cxcl16 gene
reduces CXCL16 expression and CXCL16-mediated
accumulation of iNKT cells that can contribute to colitis
development
75
. Clostridium spp. (clusters IV and XIVa)
and ASF also promote the development of FOXP3
+

T
Reg
cells, which can protect against chemically induced
colitis
19,20
(FIG.3). Differentiation of T
Reg
cells that are
induced by Clostridium spp. (clusters IV and XIV) is
independent of NOD1, NOD2, caspase-recruitment
domain-containing protein 9 (CARD9; a signalling
molecule downstream of Dectin-1) and MYD88 sig-
nalling
19
; however, the induction of T
Reg
cells by ASF
requires MYD88TRIF signalling
20
. Intestinal commen-
sal bacteria can also exert protective anti-inflammatory
effects through their production of metabolites, such as
SCFAs
136
. Likewise, numbers of Faecalibacterium praus-
nitzii, a principal member of the phylum Firmicutes, are
reduced in patients with Crohns disease. Culture super-
natants of F.prausnitzii containing secreted metabolites
exhibit anti-inflammatory effects on human epithelial
cell lines invitro, and they decrease the susceptibility of
mice to chemically induced colitis in vivo, although it is
unclear whether these effects are TLR-independent
148
.
Thus, commensal bacteria and their products have activ-
ities that can protect the host against inflammation by
different mechanisms (FIG.3).
Microbiota and extra-intestinal diseases
Multiple sclerosis. The gut microbiota has the capacity
to affect the development of autoimmune central nerv-
ous system (CNS) disorders. Broad-spectrum antibi-
otics are given orally to mice reduce the symptoms of
REVI EWS
Basophil B cell
iNKT cell
Gut
lumen
Lamina
propria
IgE
Pancreas Lungs
Firmicutes
Bacteroidetes
T
Reg
cell
IL-1
CNS
Joint
T
H
17
cell
IL-1R
antagonist
T
H
17 cell
T
H
17 cell
Peripheral blood
Multiple sclerosis
EAE
Type 1 diabetes
Pancreatitis
Allergic
inammation
Arthritis
Benecial
commensal bacteria
SFB
Experimental autoimmune
encephalomyelitis
(EAE). An experimental model
of multiple sclerosis that is
induced by immunization
of susceptible animals with
myelin-derived antigens,
such as myelin basic protein,
proteolipid protein or myelin
oligodendrocyte glycoprotein.
K/BxN transgenic mice
Mice formed by crossing
non-obese diabetic (NOD)/Lt
mice with KRN Tcell receptor-
transgenic mice on the C57BL/6
background. As the KRN
receptor on Tcells recognizes a
peptide from the autoantigen
glucose-6-phosphate
isomerase, these mice develop
an arthritis that is mediated,
and transferable, by circulating
antibodies against glucose-6-
phosphate isomerase.
experimental autoimmune encephalomyelitis (EAE)
149
. In
one model of multiple sclerosis, mice are immunized
with the self antigen myelin oligodendrocyte glyco-
protein (MOG) in complete Freunds adjuvant (CFA).
Disease symptoms in either MOGCFA-induced EAE or
in a spontaneous EAE mouse model are reduced when
the mice are housed under germ-free conditions
150,151
.
Monocolonization of germ-free mice with SFB results
in an increase in the number of T
H
17 cells in both the
intestinal lamina propria and the CNS, which results in
severe EAE
150
(FIG.4). Thus, SFB-enhanced T
H
17 cell-
mediated inflammation might contribute to EAE exac-
erbation. However, it is unclear whether the disease is
caused by the migration of SFB-specific T
H
17 cells into
the CNS or by the expansion of pathogenic autoantigen-
specific Tcells that are promoted by intestinal T
H
17
cell responses (FIG.4). By contrast, certain populations
of commensal bacteria are capable of attenuating CNS
inflammation. For example, PSA
+
B. fragilis, which
induces FOXP3
+
T
Reg
cell differentiation, can prevent
EAE symptoms
152
(FIG.4). Thus, the pathogenesis of CNS
disorders might ultimately depend on the balance of
different community members in the gut microbiota.
Arthritis. Autoimmune arthritis, such as rheumatoid
arthritis, is a systemic inflammatory disease that pri-
marily affects the joints but can also affect other parts
of the body. The events that trigger the development of
autoimmune arthritis remains unknown. However, in
mouse models, the gut microbiota contributes to disease
symptoms. Arthritis symptoms in K/BxN transgenic mice
are reduced in a germ-free environment
136,153
. As in EAE,
T
H
17 cell responses are implicated in promoting disease,
and SFB-mediated enhancement of T
H
17 cell immunity
stimulates autoantibody production by Bcells, which
leads to arthritic symptoms
153
(FIG.4). T
H
17 cell immunity
is also a key factor in spontaneous rheumatoid arthri-
tis in IL-1R antagonist (Il1rn)
/
mice, which exhibit
Figure 4 | Gut microbiota affects extra-intestinal autoimmune diseases. Segmented filamentous bacteria (SFB)
colonization induces T helper 17 (T
H
17) cell development in the intestine. These T
H
17 cells might migrate to the periphery
to affect systemic and central nervous system (CNS) immunity; increased intestinal T
H
17 cells enhance the expansion
of pathogenic autoantigen-specific Tcells in the intestine and cause inflammation in the CNS. By contrast, beneficial
commensal bacteria can attenuate CNS inflammation through the induction of forkhead box P3 (FOXP3)
+
regulatory T (T
Reg
)
cells. Induced T
H
17 cells can also promote autoimmune arthritis by facilitating autoantibody production by Bcells (not
shown). In addition, microbiota-induced interleukin-1 (IL-1) signalling participates in the development of rheumatoid
arthritis through the induction of T
H
17 cells. The IL-1 receptor (IL-1R) antagonist blocks IL-1 signalling and abrogates
joint inflammation. Balance in the microbial community also determines susceptibility to type1 diabetes. A decreased
Firmicutes/Bacteroidetes ratio as a result of a deficiency in myeloid differentiation primary-response protein 88 (MYD88)
in non-obese diabetic mice is associated with an attenuated risk of type 1 diabetes. SFB-induced T
H
17 cells protect the host
against type 1 diabetes development by an unknown mechanism. Finally, exposure to microorganisms in neonatal, but not
adult, life decreases the accumulation of invariant natural killer T (iNKT) cells in the gut, which results in protection against
allergic inflammation in the lungs. In addition, microbial compounds stimulate peripheral Bcells through Bcell-intrinsic
MYD88 signalling and inhibit IgE production. Decreased levels of peripheral IgE result in decreased numbers of basophils,
and attenuate the risk of allergic airway inflammation. EAE, experimental autoimmune encephalomyelitis.
REVI EWS
excessive IL-1 signalling, enhanced IL-17 expression
and increased arthritic symptoms
154
. Similar to K/BxN
mice, arthritic symptoms in Il1rn
/
mice are diminished
when the mice are housed in germ-free conditions, which
indicates that the microbiota might be essential for the
progression of arthritis in this model, although whether
SFB are involved is unclear
155
(FIG.4). Together with the
observation that IL-1 signalling is essential for T
H
17 cell
differentiation
16
, these results indicate that the microbiota
is involved in the pathogenesis of rheumatoid arthritis
partly through the promotion of T
H
17 cell responses.
T1D. Type1 diabetes (T1D) is an autoimmune disorder
that results in the destruction of insulin-producing cells
in the pancreas. Recent studies with NOD mice, which
have been used to model this disease, have provided some
insights into how the gut microbiota can affect the devel-
opment of T1D. Diabetes in NOD mice is ameliorated in
the absence of MYD88 (REF.156). However, protection
against diabetes in Myd88
/
NOD mice is abrogated by
antibiotic treatment and in germ-free conditions
156
. These
data indicate that commensal bacteria might be impor-
tant for reducing disease susceptibility in this model.
Indeed, 16S ribosomal RNA sequencing showed altera-
tions in the composition of the microbiota in Myd88
/

NOD mice compared with their Myd88-sufficient NOD
littermates. These alterations were characterized by a
lower Firmicutes/Bacteroides ratio on a phylum level
and indicate that certain bacterial populations might
contribute to protection against T1D (FIG.4). As it has
been recently demonstrated that deficiencies in MYD88
or individual TLRs alone do not affect the composition
of the gut microbiota
157
, it is possible that the genetic
background of the NOD mice contributes to the effect of
MYD88 deficiency on microbiota composition.
Interestingly, SFB has also been implicated in pro-
tection against T1D, which indicates that intestinal
T
H
17cells in certain contexts might be protective, despite
their link to autoimmunity
158
(FIG.4). SFB-mediated pro-
tection against T1D seems to be gender-specific: male
NOD mice with SFB have a lower incidence of T1D than
their female counterparts
158
. Furthermore, the microbiota
in male NOD mice is distinct from that in females and
it contributes to increased testosterone levels, which are
associated with protection against T1D
159
. Indeed, trans-
ferring the microbiota from male into female NOD mice
results in increased levels of testosterone and reduced
susceptibility to T1D in female NOD mice
159
. Much
work remains to be done to understand the complexities
of T
H
17 cell responses and the mechanisms by which the
gut microbiota contributes to the development ofT1D.
Allergic inflammation. Under germ-free conditions,
host immune responses are T
H
2-biased
17
. Restoration
of the gut microbiota in germ-free mice results in
an increase in T
H
1 and T
H
17 cells and a reduction of
T
H
2-type responses to levels that are observed in conven-
tionally housed mice
17
. This indicates that the microbi-
ota might be important in maintaining balance in T
H
cell
responses. The mechanism by which the microbiota
achieves this is still unclear. Germ-free mice or mice
treated with antibiotics have an expansion of basophils
in the peripheral blood as well as increased serum IgE
levels
160
(FIG.4). The expansion of basophils as a result
of microbiota depletion exacerbates the allergic airway
inflammation that is triggered by exposure to house
dust mite allergen
160
. The microbiota is directly sensed
by Bcells and activates MYD88 signalling to limit IgE
class-switching in Bcells. As CpG stimulation alone can
prevent IgE production by Bcells, the TLR9MYD88
axis might have a crucial role in IgE responses that can
lead to allergic inflammation
160
.
Consistent with this idea, allergic responses to food
antigens are aggravated in antibiotic-treated mice or in
Tlr4
/
mice, but are ameliorated by CpG treatment
161
.
Thus, exposure to microorganisms that stimulate TLR
signalling might be important in reducing the develop-
ment of allergic inflammation by the promotion of T
H
1
rather than T
H
2 cell polarization. A recent study dem-
onstrated that neonatal colonization of the gut micro-
biota is essential for reducing numbers of iNKT cells in
the intestine, and iNKT cells have been implicated in
mediating allergic responses in the lungs
75
(FIG.4). Taken
together, the essential role of the gut microbiota in regu-
lating immune balance in the intestine might explain its
ability to influence susceptibility to allergies. These find-
ings support the hygiene hypothesis, which arose from
the observation that early exposure to bacteria during
infancy is associated with a reduced incidence of allergic
diseases.
Other extra-intestinal diseases. Systemic dissemination
of the gut microbiota has a crucial role in thedevelop-
ment of severe acute pancreatitis
162
. Cerulein-induced
pancreatitis is dramatically reduced in Nod1
/
mice,
which indicates that there might be an important role
for commensal bacteria-mediated NOD1 activation in
the development of pancreatitis
163
. NOD1 stimulation
induces CC-chemokine ligand 2 (CCL2) production,
thereby promoting the recruitment of CCR2
+
monocytes
that facilitate pancreatitis
163
.
Intestinal dysbiosis might also be linked to the
pathogenesis of cystic fibrosis, as mice with cystic
fibrosis-like disease exhibit an increased abundance
of Mycobacteriaceae spp., Enterobacteriaceae spp.,
Clostridaceae spp., and B.fragilis
164
. However, the pre-
cise mechanisms by which a dysbiotic microbiota affects
the pathophysiology of cystic fibrosis still remains to be
elucidated.
Perspectives
The gut microbiota has been studied for more than a
century; however, recent studies have shown ever-
expanding roles for these microscopic organisms in
health and disease. Despite the complexity of the gut
microbiota, there is a delicate balance in bacterial popu-
lations such that any disruption in this balance leads to
dysbiosis and, consequently, to decreased resistance to
pathogen colonization, to the favoured growth of patho-
bionts and to pathological immune responses. Although
the association of dysbiosis with disease pathogenesis
has become evident, it is still largely unknown which
NOD mice
Non-obese diabetic (NOD)
mice spontaneously develop
type1 diabetes as a result of
autoreactive Tcell-mediated
destruction of pancreatic
-islet cells.
Hygiene hypothesis
This hypothesis originally
stated that the increased
incidence of atopic diseases in
westernized countries was a
consequence of living in an
overly clean environment,
which resulted in an
understimulated immune
system that responded
inappropriately to harmless
antigens. More recently it has
been proposed that an
absence of exposure to
pathogens, in particular
helminths, might predispose
individuals to both increased
allergy and autoimmune
disease.
REVI EWS
factors are important in triggering dysbiosis. Obviously,
both genetic and environmental factors are important in
shaping the microbiota; however, the relative contribu-
tions of these two groups of factors, and the mechanism
by which they interact to lead to dysbiosis, remain areas
of active investigation.
Other questions that need to be further addressed are
whether dysbiosis is disease-specific and whether the
timing with which dysbiosis occurs during the lifetime
of the host is important for disease pathogenesis, espe-
cially as microbiota colonization early in life is crucial for
the optimal development and function of the immune
system. Given the importance of the gut microbiota and
dysbiosis in disease pathogenesis, targeting the micro-
biota is an attractive therapeutic approach. In fact, faecal
microbiota transplantation (FMT) has been highly effec-
tive in the treatment of Clostridiumdifficile infection
165
,
which indicates that the correction of dysbiosis might
be a valid approach for reducing susceptibility to other
diseases, including IBD. Clearly, much work remains to
be done not only to achieve a deeper understanding of
hostmicrobial relationships but also to establish the
best way to use that relationship to prevent or to treat
diseases within and outside the intestine.
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Acknowledgements
This work is supported by grants from the US National
Institutes of Health and the Bill & Melinda Gates Foundation,
USA. N.K. is supported by a Research Fellowship from the
Crohns and Colitis Foundation of America.
Competing interests statement
The authors declare no competing financial interests.
FURTHER INFORMATION
Gabriel Nezs homepage: http://www.med.umich.edu/
immprog/faculty/nunezg.htm
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The skin and mucosal surfaces of vertebrates are colo-

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