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The gut microbiota shapes intestinal


immune responses during health
and disease
June L. Round and Sarkis K. Mazmanian
Abstract | Immunological dysregulation is the cause of many non-infectious human diseases
such as autoimmunity, allergy and cancer. The gastrointestinal tract is the primary site of
interaction between the host immune system and microorganisms, both symbiotic and
pathogenic. In this Review we discuss findings indicating that developmental aspects of
the adaptive immune system are influenced by bacterial colonization of the gut. We also
highlight the molecular pathways that mediate hostsymbiont interactions that regulate
proper immune function. Finally, we present recent evidence to support that disturbances
in the bacterial microbiota result in dysregulation of adaptive immune cells, and this may
underlie disorders such as inflammatory bowel disease. This raises the possibility that
the mammalian immune system, which seems to be designed to control microorganisms,
is in fact controlled by microorganisms.

Mutualism Humans represent a scaffold on which diverse microbial disease during colonization. Surprisingly, the normal
A symbiotic association in ecosystems are established. Immediately after birth, all microbiota also contains microorganisms that have been
which both members benefit mammals are initiated into a life-long process of colo- shown to induce inflammation under particular con-
from the relationship.
nization by foreign microorganisms that inhabit most ditions. Therefore, the microbiota has the potential to
Pathogen environmentally exposed surfaces (such as the skin, exert both pro- and anti-inflammatory responses, and
An opportunistic organism mouth, gut and vagina)1,2. Shaped by millennia of evo- the composition of the bacterial communities in the gut
that rarely comes into contact lution, some hostbacterial associations have developed may be intimately linked to the proper functioning of
with the host, but causes acute into beneficial relationships, creating an environment the immune system.
or chronic disease following
infection. Derived from the
for mutualism. A key example of such an environment The immune system is responsible for recognizing,
Greek word pathos, which is provided by the vast numbers and diversity of bac- responding and adapting to countless foreign and self
means suffering. teria that are found in the lower gastrointestinal tract molecules and is therefore important during condi-
of mammals1,35. By young adulthood, both humans tions of both health and disease. Although the immune
Microbiome
and other mammals support one of the most complex system is classically thought to have evolved to protect
The collective genomes of
a microbiota. microbial ecosystems on the planet, with over 100 tril- from infection by microbial pathogens, animals peace-
lion bacteria in the distal gut 6,7. Symbiotic bacteria of fully coexist with a vast and complex microbiota, which
the mammalian gut have long been appreciated for the extensively interacts with the immune system. In this
benefits they provide to the host: they supply essential Review, we discuss recent evidence suggesting that a
nutrients, metabolize indigestible compounds, defend beneficial partnership has evolved between symbiotic
against colonization by opportunistic pathogens and bacteria and the immune system. The molecular inter-
Division of Biology,
even contribute to the development of the intestinal actions seem to direct the development of immune
California Institute of
Technology, Pasadena, architecture 8. Moreover, it seems that certain basic responses, and in turn the immune system shapes the
California 91125, USA. developmental features and functions of the mamma- composition of the microbiota. We highlight seminal
Correspondence to S.K.M. lian immune system depend on interactions with the examples of microorganisms that have a role in pre-
email: sarkis@caltech.edu human microbiome9. Unlike opportunistic pathogens, venting inflammatory bowel disease (IBD) and discuss the
doi:10.1038/nri2515
Published online 3 April 2009;
which elicit immune responses that result in tissue beneficial immune responses they elicit during protec-
corrected after print damage during infection, some symbiotic bacterial tion. Furthermore, technological advances now allow
17 July 2009 species have been shown to prevent inflammatory a more detailed understanding of the alterations of the

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Microbiota microbial population of the gut during IBD. If some Together with various morphological tissue defects
The amalgam of bacteria are actively shaping a healthy immune system, that are observed in the intestines of germ-free animals,
microorganisms that make does the absence of these organisms lead to disease? It it seems that the entire ultrastructural development of
up a complex and diverse has recently been proposed that the total information the gut is intimately connected to intestinal bacteria.
community living within a given
anatomical niche (usually an
encoded by the mammalian genome is not sufficient For example, intestinal epithelial cells (IeCs), which line
environmentally exposed to carry out all functions that are required to maintain the gut and form a physical barrier between lumenal
surface of the body). health and that products of our microbiome are crucial contents (including the microbiota) and the under-
for protection from various diseases10. It is possible that lying cells of the immune system, have altered patterns
Inflammatory bowel disease
alterations in the development or composition of the of microvilli formation and decreased rates of cell turn-
A chronic condition of the
intestine that is characterized
microbiota (known as dysbiosis) disturb the partnership over in germ-free animals compared with wild-type
by severe inflammation and between the microbiota and the human immune system, animals13. Furthermore, gut bacteria have been shown
mucosal destruction. The most ultimately leading to altered immune responses that may to direct the glycosylation of lumenally exposed surface
common forms in humans are underlie various human inflammatory disorders. proteins of IeCs14.
ulcerative colitis and Crohns
disease.
IeCs have many immunological functions (TABLE 1):
Insights gained from germ-free mice they secrete and respond to various cytokines and express
Gut-associated Developmental defects in germ-free mice. Several impor- molecules that directly interact with lymphocytes (such as
lymphoid tissue tant effects of the microbiota on the host immune sys- MHC molecules). expression and localization of pattern
Lymphoid structures and
tem have been determined by studies of gnotobiology, recognition receptors (such as Toll-like receptors; TlRs)
aggregates associated with the
intestinal mucosa, specifically
which is the selective colonization of germ-free (sterile) by the epithelium is influenced by bacterial coloniza-
the tonsils, Peyers patches, animals, the immune responses of which have not been tion of the gut, and the expression of defensins and other
lymphoid follicles, appendix or influenced by interactions with molecules of pathogenic antimicrobial proteins is defective in germ-free animals
caecal patch and mesenteric and beneficial microorganisms. Germ-free animals show (TABLE 1). Consistent with this notion, the Gram-negative
lymph nodes. They are
extensive defects in the development of gut-associated commensal organism Bacteroides thetaiotaomicron, but
enriched in conventional and
unconventional lymphocytes lymphoid tissues9,11 and in antibody production (BOX 1), not the Gram-positive microorganism Bifidobacterium
and specialized dendritic cell and have fewer and smaller Peyers patches and mesenteric longum, induces the expression of the antimicrobial
and macrophage subsets. They lymph nodes (Mlns) compared with animals housed peptide ReG3 (regenerating islet-derived 3) by spe-
provide the first line of defence
under specific pathogen free (SPF) conditions (TABLE 1). cialized IeCs known as Paneth cells15,16. Intriguingly, the
against entry of pathogens
across the mucosal barrier.
A recent report has also shown that germ-free animals specificity of ReG3 is directed towards certain Gram-
show impaired development and maturation of isolated positive bacteria. It is therefore tempting to speculate that
lymphoid follicles (IlFs)12. These inducible structures symbiotic bacteria direct innate immune responses of the
seem to form normally following the introduction of gut gut in an effort to protect their environment. Collectively,
bacteria, suggesting a dynamic relationship between the the observations of developmental defects in germ-free
immune system and the microbiota. mice at the tissue, cellular and molecular levels suggest
that normal immune function may be impaired in the
absence of the gut microbiota.
Box 1 | Antibody responses in germ-free animals
One of the first immunological defects observed in germ-free mice was a marked Defects in immune responses in germ-free mice. Germ-
reduction in the levels of secretory IgA found in the intestine94. Association of mice free animals are more susceptible to infection by certain
with a specific bacterial species leads to increased IgA expression. As numerous bacteria, viruses and parasites. When challenged with
studies have shown that secretory IgA coats commensal (and pathogenic) bacteria,
the Gram-negative enteric pathogen Shigella flexneri,
some have speculated that IgA is involved in limiting the penetration of bacteria into
host tissues. Studies from activation-induced cytosine deaminase (AID)-deficient
germ-free animals showed decreased immune resist-
animals (which cannot undergo class switching to IgA), have shown that these mice ance to infection and increased mortality compared
display lymphoid hyperplasia of the gut and an altered microbiota, thereby favouring with conventionally colonized animals17. Prior coloni-
the outgrowth of specific classes of bacteria95. Although some studies have shown zation with specific commensal bacteria antagonized
that IgA is involved in protection from infection by some enteric bacteria and viruses96, S. flexneri infection, whereas colonization with con-
other studies suggest that IgA deficiency does not cause increased prevalence of trol species such as Escherichia coli did not, implying
disease in animals and that IgA-deficient individuals are generally healthy. However, a that some members of the microbiota provide protec-
role for symbiotic bacteria in actively shaping the production of secretory IgA is now tion against intestinal bacterial pathogens18. Infection
emerging. Dendritic cells (DCs) that have acquired gut commensal bacteria migrate to by the Gram-positive intracellular pathogen Listeria
mesenteric lymph nodes, where they induce the production of IgA from naive B cells97.
monocytogenes results in decreased bacterial clearance
This process is required to control the penetration of commensal bacteria through the
gut epithelial cell barrier98. Recently, it has been shown that sensing of symbiotic
in germ-free animals compared with colonized ani-
bacterial products by Toll-like receptors on intestinal epithelial cells results in mals19. The mechanism for this increased susceptibility
localized class switching to IgA2 (rEf. 99), a process that potentially affects has been attributed to a T cell trafficking defect to the
interactions between the immune system and the microbiota100. The discovery that site of L. monocytogenes infection in germ-free animals.
symbiotic bacteria direct the function of a specialized mucosal DC population Specifically, germ-free mice that have been infected
that induces IgA class switching also implicates a role for the microbiota in shaping with L. monocytogenes have decreased accumulation of
intestinal immune responses101. Furthermore, IgA responses were recently shown CD44+CD62l+ T cells (CD44 and CD62l (also known
to be involved in maintaining hostbacterial mutualism by limiting innate immune as l-selectin) are known to be involved in the homing
responses to a specific gut symbiont102. The renewed interest in the biological of lymphocytes to sites of inflammation), resulting in
functions of intestinal secretory IgA promises to provide important clues on the
increased bacterial burden compared with SPF ani-
molecular communication between the immune system and the microbiota.
mals20. Finally, Salmonella enterica subspecies enterica

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Table 1 | Intestinal immunological defects in germ-free mice


Immunological defect Site Phenotype in germ-free mice compared with
conventionally housed mice
Development of small Peyers patches Fewer and less cellular
intestine
Lamina propria Thinner and less cellular
Germinal centres Fewer plasma cells
Isolated lymphoid follicles Smaller and less cellular
Development of mesenteric Germinal centres Smaller, less cellular and with fewer plasma cells
lymph nodes
CD8+ T cells Intestinal epithelial Fewer cells and with reduced cytotoxicity
lymphocytes
Peyers patches
CD4+ T cells Lamina propria Fewer cells; decreased Th17 cells in the small intestine
Groups of lymphoid nodules
but increased Th17 cells in the colon
that are present in the small
intestine (usually the ileum). CD4+CD25+ T cells Mesenteric lymph nodes Reduced expression of FoxP3 and reduced suppressive
They occur massed together capacity
on the intestinal wall, opposite
the line of attachment of the
Expression of angiogenin 4 Paneth cells Reduced
mesentery. Peyers patches Expression of REG3 Paneth cells Reduced
consist of a dome area, B cell
follicles and interfollicular T cell Production of secretory IgA B cells Reduced
areas. High endothelial venules Levels of ATP Intestine Reduced
are present mainly in the
interfollicular areas. Expression of MhC class II Intestinal epithelial cells Reduced
molecules
Mesenteric lymph node Expression of TLR9 Intestinal epithelial cells Reduced
(MLN). A lymph node that is
located at the base of the Levels of IL-25 Intestinal epithelial cells Reduced
mesentery. MLNs collect FoxP3, forkhead box P3; IL-25, interleukin 25; REG3; regenerating islet-derived 3; Th17, T helper 17; TLR9, Toll-like receptor 9.
lymph (including cells and
antigens) draining from the
intestinal mucosa. serovar Typhimurium is known to cause a more severe The microbiota and IBD
acute gastroenteritis in germ-free animals21; however, Immune system regulation during IBD. The impact
Specific pathogen free
Conditions in which animals are
the reasons for this remain unclear. of the microbiota on human health is best exempli-
reared and maintained in an establishing an infection requires the initial task of fied by studies on IBD, such as Crohns disease and
environment with an unknown colonizing the host. For intestinal pathogens, this can ulcerative colitis2426. Both are serious medical disorders
complex microbiota that is free be a challenge as all mammals are stably colonized by that are characterized by aberrant inflammation in the
from specific known pathogens.
communities of bacteria that can act as a barrier to gastrointestinal tract, resulting in severe clinical out-
Isolated lymphoid follicles infection (known as colonization resistance). Recent comes in affected patients. The causes of these diseases
Small lymphoid aggregates studies suggest that inflammation induced in response are complex and include contributions from genetic,
located in the anti-mesenteric to S. Typhimurium infection changes the composi- geographic and habitual factors27. IBD (particularly
wall of the small intestine, tion of the microbiota and suppresses its regrowth. Crohns disease) is generally believed to be driven by
which contain B cells, dendritic
cells, stromal cells and some
S. Typhimurium exploits this deficiency in colonization T cells and has classically been thought to be associated
T cells. They may contain resistance to establish infection and cause disease22. with increases in pro-inflammatory cytokines such as
germinal centres. They are In addition to maintaining a barrier to the coloniza- tumour necrosis factor (TnF) and interferon- (IFn).
thought to have a role in tion of potentially pathogenic organisms, the microbiota However, recently a new population of inflammatory
maintaining equilibrium
might also provide immunological benefits to the host. T cells, termed T helper 17 (TH17) cells, which produce
between the immune system
and the microbiota. In support of this idea is the finding that germ-free ani- the pro-inflammatory cytokine interleukin-17 (Il-17)
mals show reduced antigen-specific systemic immune and require Il-23 for their maintenance and function,
Pattern recognition receptor responses to S. Typhimurium23. This suggests that have been implicated in the pathogenesis of human
A host receptor (such as enteric pathogens such as S. Typhimurium might have and experimental colitis2833. These pro-inflammatory
Toll-like receptors) that can
sense pathogen-associated
developed strategies to counter both the immune system responses are counterbalanced by specialized T cells
molecular patterns and initiate and the microbiota during the infectious process. known as regulatory T (Treg) cells. The development and
signalling cascades (which Although a lot of work is still required to determine function of TReg cells is thought to be controlled by
involve the activation of the beneficial immune responses that are induced by the transcription factor forkhead box P3 (FoXP3), the
nuclear factor-B) that lead to
the microbiota, it is exciting to consider the teleological absence of which results in massive multiorgan lympho-
an innate immune response.
notion that indigenous bacteria actively prevent enteric proliferative disease34. The mechanisms by which TReg
Commensal disease by infectious microorganisms to fortify their cells suppress inflammation are diverse and include
A microorganism that benefits niche. If this is true, then an evolutionary alliance has the following: expression of inhibitory cytokines such
from an association with no been forged between mammals and beneficial bacteria as Il-10, transforming growth factor- (TGF) and
known effects on the host.
Derived from the Latin phrase
that is crucial for maintaining the long-term survival of Il-35; disruption of cellular metabolism through the
com mensa, meaning to share both. In other words, is our well-being dependent on the expression of Il-2 receptor (Il-2R; which comprises
a table. microorganisms we harbour? Il-2R -chain (CD25), Il-2R -chain and common

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cytokine receptor -chain); cytolysis; and targeting the parasite burden. Previous work has suggested that TlR
maturation of dendritic cells (DCs) through cell surface signalling is important for maintaining gut homeo-
expression of molecules such as cytotoxic T lymphocyte stasis42, and these recent findings extend this obser-
antigen 4 and lymphocyte activation gene 3 (rEf. 35). A vation to suggest that a molecular dialogue between
population of intestinal DCs expressing the cell surface immune receptors and microbial molecules confers
antigen CD103 has recently been shown to be instru- resistance to enteric infection.
mental in the development and function of intestinal The contribution of the microbiota to the develop-
FoXP3+ TReg cells. CD103+ DCs, but not CD103 DCs, ment of TReg cells remains unclear, as conflicting obser-
can promote the conversion of CD4+FoXP3 T cells vations have been reported. An initial study43 observed
into CD4+FoXP3+ TReg cells in a TGF- and retinoic a reduction in the percentage of FoXP3+ cells within
acid-dependent manner 36, which indicates that special- the CD4+CD25+ T cell subset in the Mlns of germ-free
ized mechanisms exist in the intestine to promote the mice compared with conventionally colonized animals.
induction and maintenance of TReg cells. Foxp3 mRnA levels were also lower in CD4+CD25+
The importance of TReg cells in the regulation of intes- cells isolated from the lymph nodes of germ-free mice.
tinal homeostasis is best illustrated by the finding that Consistent with these findings, another study 45 observed
these cells can prevent the induction of experimental lower levels of Foxp3 mRnA in CD4+CD62l T cells
colitis following transfer into diseased hosts37. The ability from germ-free mice. In addition, it has been reported
of TReg cells to secrete Il-10 and Il-35 has been reported that TReg cells from germ-free animals are not as effective
to be important during protection. Indeed, TReg cells as TReg cells from conventionally colonized animals at
that are deficient in either of the two subunits of Il-35 suppressing CD4+ T cell proliferation in vitro44. Indeed,
(epsteinBarr virus-induced protein 3 and Il-12) can- populations of TReg cells from germ-free animals pro-
not provide protection from induction of experimental duced less Il-10 and could not prevent disease in a trans-
colitis38. In addition, animals in which Il-10 has been fer model of experimental colitis45. In contrast to these
specifically ablated from CD4+FoXP3+ T cells succumb observations, recent studies have reported no change
to inflammatory disease of the intestine (as well as of the in the percentage of CD4+FoXP3+ T cells in the colon
skin and lungs), but show no signs of autoimmunity. So, lamina propria of germ-free mice46, and in fact another
it seems that cytokine production by TReg cells might be study 39 reported increased percentages of CD4+FoXP3+
Crohns disease an important protective mechanism that limits uncon- in the small intestine39.
A form of chronic inflammatory trolled immune responses at environmentally exposed These conflicting observations might be due to the
bowel disease that can affect surfaces such as the gut. particular subsets of TReg cells that were analysed, dif-
the entire gastrointestinal tract, Recent studies have begun to reveal the mechanisms ferences in experimental methodologies and/or the
but is most common in the
colon and terminal ileum. It is
of intestinal immune modulation by the microbiota. tissues from which TReg cells were harvested. Alternatively,
characterized by transmural A recent study 39 has shown that germ-free animals the particular diet given to the animal might influence
inflammation, strictures and have defective T H17 cell development in the small TReg cell subsets in the intestine, as most animal food
granuloma formation, and is intestine and that the reduction in Il-17 production might have varying amounts of microbial molecules
believed to result from an
is associated with a reciprocal increase in the number (such as TlR ligands), even if autoclaved. However,
abnormal T cell-mediated
immune response to of CD4+FoXP3+ TReg cells in the colon of these mice. these data collectively suggest that intestinal bacteria
commensal bacteria. Reconstitution of these animals with a complex and interact with the mammalian immune system to direct
diverse microbiota that does not contain the promi- the differentiation of both pro- and anti-inflammatory
Ulcerative colitis nent phyla Bacteroidetes does not restore proper T cell populations. Therefore, induction of effector T cell
A chronic disease that
is characterized by
immune balance, suggesting that distinct organisms responses and modulation of TReg cell function by the
inflammation of the mucosa might have the capacity to modulate pro- and anti- microbiota may be a crucial component of diseases such
and sub-mucosa of the large inflammatory responses in the gut. The identity of spe- as IBD. It is possible that different classes (or even spe-
intestine. cific bacterial species and bacterial molecules that are cies) of bacteria induce distinct immunological functions.
involved in regulating the balance between TH cell and Therefore, the equilibrium between inflammation and
Regulatory T (TReg) cell
A specialized type of CD4+ TReg cell subsets in the gut remain unknown. However, homeostasis in the gut could be due to the composition
T cell that can suppress the several common bacterial products are known to have of the microbiota.
responses of other T cells. immunomodulatory effects. For example, ATP gen-
These cells provide a crucial erated by intestinal bacteria specifically increases the IBD and a breakdown in tolerance to gut bacteria. IBD
mechanism for the
maintenance of peripheral
production of Il-17 (but not IFn) in the colon40; con- involves a shift from a regulated intestinal immune
self tolerance and are sistent with this, germ-free animals have reduced Il-17 response to one that is driven by unrestrained immune
characterized by expression and ATP levels in the colon. In addition, DnA from cell activation and pro-inflammatory cytokine produc-
of CD25 (the -chain of the commensal bacteria triggers TlR9 signalling and con- tion4749. The cause of this increase in immune stimulation
interleukin-2 receptor) and the
fers resistance to the enteric parasite Encephalitozoon is of great interest, and several lines of evidence indicate a
transcription factor forkhead
box P3 (fOXP3). cuniculi 41. Accordingly, antibiotic treatment of ani- fundamental role for commensal bacteria in the progres-
mals to eliminate gut bacteria results in increased sion of disease50. Patients with IBD respond favourably
Parasite susceptibility to infection by this parasite. Treatment to antibiotic treatment and faecal diversion and have
An opportunistic organism that of parasite-infected mice with DnA isolated from the higher antibody titres against indigenous bacteria than
maintains a prolonged and
close association with the host,
intestinal microbiota led to the upregulation of T H1 unaffected individuals5153. In addition, inflammatory
which benefits the parasite at and TH17 cell responses, which coincided with sup- lesions are more pronounced in areas of the intestine
the expense of the host. pression of TReg cell activity; this resulted in decreased that contain the highest number of bacteria.

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Further evidence for the involvement of gut bacteria a Immunological equilibrium


in IBD is provided by studies of animal models. Pre- Symbionts Commensals Pathobionts
treatment of mice with antibiotics has been shown to
alleviate subsequent intestinal inflammation in several
animal models54,55. HlA-B27-transgenic rats, Il-10- and
Il-2-deficient mice raised in conventional conditions
spontaneously develop chronic colitis, whereas they do
not develop intestinal inflammation if raised in germ- Regulation Inflammation
free conditions5658. In a model of colitis induced by the
adoptive transfer of pathogenic T cells into immuno-
deficient (Scid/ (severe combined immunodeficient) or b Immunological dysequilibrium Pathogens
Rag/ (recombination-activating gene)) recipient mice,
colonization of animals with intestinal pathogens such as
Helicobacter hepaticus was found to exacerbate inflam-
mation59. Moreover, colitis can be induced in healthy
animals through the adoptive transfer of T cells that are
reactive against specific commensal organisms50,60.
Inflammation
The only microorganism reported to be strongly Regulation
associated with Crohns disease is adherent-invasive
E. coli 61. However, it seems that inflammatory responses Figure 1 | Immunological dysregulation associated with
in human and experimental IBD are directed towards dysbiosis of the microbiota. a | A healthy microbiota
Nature Reviews | Immunology
certain subsets of commensal organisms that have contains a balanced composition of many classes of
pathogenic potential, such as Helicobacter, Clostridium bacteria. Symbionts are organisms with known health-
and Enterococcus species. Curiously, these organisms are promoting functions. Commensals are permanent
residents of this complex ecosystem and provide no benefit
abundant in the microbiota and are not typically patho-
or detriment to the host (at least to our knowledge).
genic. As the microbiota of all mammals contains these
Pathobionts are also permanent residents of the microbiota
potentially harmful species, known as pathobionts (fIG. 1), and have the potential to induce pathology. b | In conditions
it is not entirely clear why inflammation ensues only in of dysbiosis there is an unnatural shift in the composition of
subjects affected by IBD. the microbiota, which results in either a reduction in the
It is well known that genetic factors have an important numbers of symbionts and/or an increase in the numbers
role in the pathogenesis of IBD, as shown by the familial of pathobionts. The causes for this are not entirely clear,
aggregation of IBD and the increased concordance for but are likely to include recent societal advances in
IBD in monozygotic twins. Genome-wide association developed countries. The result is non-specific inflammation,
studies have identified genetic variants that are highly which may predispose certain genetically susceptible
people to inflammatory disease and may be caused by
linked to disease. These include disease-associated muta-
pathogens, which are opportunistic organisms that cause
tions in genes that are involved in bacterial sensing (such
acute inflammation.
as NOD2 (nucleotide-binding oligomerization domain 2;
also known as CARD15))62 and T cell immunity (such
as IL23R)30, which highlights the connection between (encoded by Tbx21) is a T-box family transcription fac-
microorganisms and inflammation in IBD. In addition, tor that controls type 1 pro-inflammatory responses67.
studies in animal models provide further evidence to loss of T-bet in mice lacking an adaptive immune sys-
support the importance of host genetics in susceptibil- tem (such as Rag/ mice) resulted in the development
ity to IBD. Indeed, microorganisms that do not initiate of spontaneous intestinal inflammation that resembled
disease in immunocompetent mice, such as E. coli and ulcerative colitis68. Treatment of these mice with broad
Enterococcus faecalis, cause disease when introduced into spectrum antibiotics cured the intestinal disease, which
genetically susceptible mouse strains63. indicates that inflammation was driven by the micro-
In addition to the crucial role of genetic factors in biota. Furthermore, when wild-type animals were co-
determining susceptibility to IBD, some investigators housed with Tbx21/Rag/ mice that had colitis, they
have suggested that IBD results, at least in part, from developed a comparable colitis-like disease68, suggest-
dysbiosis of the microbiota and not because of the ing that the transfer of colitogenic microorganisms alone
acquisition of an infectious agent 64. It remains unclear (the identity of which is still unclear) was sufficient to
whether dysbiosis directly causes disease or is a result of induce experimental ulcerative colitis.
the altered intestinal environment. Future studies using A second study 69 addressing the involvement of dys-
animal models in which the microbiota can be selec- biosis in disease provided metagenomic analysis (culture-
Pathobiont
A symbiont that does not tively manipulated during the course of experimental independent analysis of microbial community structure)
normally elicit an inflammatory disease may begin to address this important issue. of microbiota in a mouse model of obesity using leptin-
response but under particular Recently, the notion that dysbiosis influences intes- deficient (ob/ob) mice. Remarkably, transfer of the micro-
conditions (environmentally tinal disease has gained increasing attention5,65,66, with biota from ob/ob mice into germ-free wild-type mice
induced) has the potential
to cause dysregulated
studies showing evidence that the composition of the resulted in an increase in the mean body fat of the recipi-
inflammation and lead microbiota alone (and not genetics or environment) ent animals69,70. Consistent with this observation, the
to disease. may be important for the induction of disease. T-bet proportion of Bacteroidetes spp. in the microbiota of

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VSL#3 obese people is lower than that of lean people, suggest- Beneficial gut bacteria promote homeostasis
A mixture of bacteria ing that alterations in the normal human microbiota may The evidence described above implicates the microbiota
consisting of four strains of affect disease. Similarly to IBD, obesity seems to have a in shaping immune responses during health and disease,
Lactobacillus (L. casei, strong genetic component 71. The complex interplay but it is still not known which particular organisms are
L. plantarum, L. acidophilus
and L. delbrueckii subspecies
between host genotype and its effects on the microbiota mediating these beneficial responses and, more impor-
bulgaricus), three strains of is an area worthy of investigation, and such studies may tantly, how this is achieved. Here we review the mecha-
Bifidobacterium (B. longum, provide further support for an important role for dysbiosis nisms by which the microbiota affects the mammalian
B. breve and B. infantis) and in metabolic disorders. immune system and the implications for the prevention
Streptococcus salivarius
Similar to the findings in animal studies, dysbiosis has or treatment of IBD.
subspecies thermophilus.
been implicated in IBD in humans, with several stud- In the early 1900s, Ilya Mechnikov was the first to
ies showing a significant alteration in the microbiota of propose the use of live microorganisms to maintain
patients with IBD7274. A recent metagenomic study 74 bowel health and prolong life. now, the term probi-
compared the microbiota of patients with IBD with that otic is used to describe dietary microorganisms that
of non-IBD controls and revealed a statistically signifi- are beneficial to the health of the host 76. As shown in
cant difference in their composition. Specifically, the TABLE 2 , many individual or combinations of bacte-
microbiota of IBD patients showed abnormal microbial rial species have been shown to ameliorate the symp-
composition that was characterized by depletion of two toms of IBD in humans and mouse models. Although
phyla of bacteria, the Firmicutes and Bacteriodetes, which many of these probiotic strains decrease toxic micro-
are both prominently represented in non-IBD controls. bial metabolic activities, more recent evidence shows
longitudinal studies are required to determine whether that these organisms can modulate intestinal immune
this particular profile (that is, the loss of certain classes of responses. The common feature of almost all bacte-
bacteria) can be used as a diagnostic tool to identify people rial species that are used as probiotics is their ability
with a greater likelihood of developing IBD. Although our to control inflammation. Bacterial species can act on
understanding of how dysbiosis might affect IBD is still several cell types (epithelial cells, DCs and T cells), but
at its infancy, new sequencing technologies provide the recent evidence suggests that the induction of TReg cells
means to analyse the microbiomes of numerous healthy by these microorganisms is crucial to their ability to
and diseased individuals75. With increased knowledge of limit inflammation and disease. Treatment of mice
species-specific alterations during disease, the molecular with colitis with the probiotic cocktail VSL#3 increased
mechanisms that link dysbiosis of the microbiota to intes- the production of Il-10 and the percentage of TGF-
tinal inflammation can systematically be explored in both expressing T cells 77. More importantly, transfer of
animal and human studies. lamina propria mononuclear cells from vSl#3-treated

Table 2 | Bacteria shown to be protective in inflammatory bowel disease


Bacterial strain model system Disease type or model mechanism of disease suppression
VSL#3* human and Pouchitis, ulcerative colitis and Induction of IL-10- and TGF-expressing T cells
mouse TNBS-induced colitis
Bifidobacteria lactis Rat TNBS-induced colitis Decreased levels of colonic TNF and iNoS
Bifidobacteria infantis Mouse Salmonella enterica-induced enteritis Induction of TReg cells and inhibition of NF-B activation
Escherichia coli Nissle 1917 human and Ulcerative colitis and DSS-induced Decreased colonic inflammation induced by TLR2 and
mouse colitis TLR4 activation
Lactobacillus rhamnosus GG Mouse and rat TNBS-induced colitis and Induction of TReg cells
hLA-B27-associated colitis
Lactobacillus salivarius Mouse TNBS-induced colitis Decreased colonic inflammation
Lactobacillus reuteri Mouse IL-10-deficient mice Upregulation of NGF and decreased levels of IL-8 and
TNF in cell lines
Lactobacillus plantarum 299v Mouse IL-10-deficient mice Decreased levels of IFN and IL-12p40
Lactobacillus fermentum Rat TNBS-induced colitis Decreased levels of colonic TNF and iNoS
Lactobacillus casei Rat TNBS-induced colitis Decreased levels of colonic cyclooxygenase 2
Bacteriodes thetaiotaomicron Rat S. enterica-induced enteritis Decreased levels of IL-8 and TNF in colorectal
adenocarcinoma cell line
Bacteriodes fragilis Mouse T cell transfer and TNBS-induced colitis Production of CD4+ T cell-derived IL-10
Yo-MIx Y109 FRo 1000
Mouse TNBS-induced colitis ND
Faecalibacterium prausnitzii Mouse TNBS-induced colitis Decreased levels of NF-B, IL-8 and TNF and increased
IL-10 production
*A mixture of Lactobacillus spp. (Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus and Lactobacillus delbrueckii subspecies bulgaricus), Bifidobacterium spp.
(Bifidobacterium longum, Bifidobacterium breve and Bifidobacterium infantis) and Streptococcus salivarius subspecies thermophilus. A mixture of S. thermophilus, L. acidophilus
and B. longum. DSS, dextran sulphate sodium; IFN, interferon-; IL, interleukin; iNoS, inducible nitric oxide synthase; ND, not determined; NF-B, nuclear factor-B;
NGF, nerve growth factor; TGF, transforming growth factor-; TLR, Toll-like receptor; TNBS, trinitrobenzene sulphonic acid; TNF, tumour necrosis factor; TReg, regulatory T.

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Symbiont mice prevented colitis in recipient mice, indicating that subset abolished the ability of the treated DCs to protect
An organism that lives in the vSl#3 cocktail can initiate the generation of a pro- against disease, suggesting that L. rhamnosus-treated
association with a host (usually tective population of cells. Depletion of TGF-bearing DCs can initiate TReg cell activity 79. It has recently been
for a lifetime) without obvious CD4+ T cells from mice treated with probiotic bacteria shown that some patients with Crohns disease have a
benefit or harm to either
member.
before the transfer of lamina propria cells abolished specific reduction in a prominent gut microorganism,
the protective capacity of these cells77. More recently, Faecalibacterium prausnitzii 80. Intriguingly, oral adminis-
in a model of pathogen-induced inflammation, treat- tration of F. prausnitzii or supernatant from F. prausnitzii
ment of mice with Bifidobacteria infantis led to a reduc- cultures increased the production of Il-10 by periph-
tion in intestinal inflammation and an increase in the eral blood mononuclear cells, reduced the production of
number of CD4+CD25+ TReg cells78. Adoptive transfer of TnF in the colon and ameliorated intestinal disease in
the CD4+CD25+ TReg cell population from mice fed with mice80. This seminal study therefore provides evidence
B. infantis inhibited inflammation-induced activation of for a direct link between a decrease in a particular spe-
nuclear factor-B (nF-B) in recipient mice. cies from the human microbiota and the development of
naive CD4+ T cells can adopt a regulatory pheno- intestinal disease, suggesting that symbiotic microorgan-
type by interacting with intestinal DCs36. Foligne et al.79 isms might have a direct role in maintaining a healthy
show that bone-marrow-derived DCs (BMDCs) internal- gut. The specific molecules produced by these bacterial
ize Lactobacillus rhamnosus, but maintain an immature species remain unknown.
phenotype. Transfer of BMDCs incubated with L. rham- The first demonstration that a single molecule made
nosus could protect against the induction of intestinal by a commensal microorganism could promote ben-
disease79. Moreover, depletion of the CD4+CD25+ T cell eficial immune responses was provided by the identi-
fication of polysaccharide A (PSA), which is produced
by the human symbiont Bacteroides fragilis (fIG. 2) .
Intestinal lumen H. hepaticus
Colonization of germ-free mice with B. fragilis or treat-
B. fragilis Pro-inflammatory ment with purified PSA directs the development of
signals the immune system, including the expansion and dif-
+++++
PSA - - - - - Epithelial cell ferentiation of splenic CD4+ T cells81. PSA has several
immunomodulatory activities in germ-free mice that
are colonized by B. fragilis, and these include correcting
systemic T cell deficiencies, restoring balance between
TH cell subsets and directing lymphoid organogenesis.
The importance of B. fragilis in maintaining a healthy
immune response was recently illustrated by the find-
+++
- -
ing that colonization of germ-free mice by B. fragilis
DC or treatment with purified PSA can protect against the
TH17 cell
IL-10 induction of experimental IBD66. Moreover, mice that
MHC class II
IL-17, IL-23 are colonized by a mutant form of this microorganism
and TNF that lacks expression of PSA (B. fragilis PSA) are no
TCR TH1 cell
longer protected from the disease. Furthermore, oral
treatment of mice with purified PSA protects recipi-
++
- -

- -
++

ent animals from weight loss, decreases levels of the


CD4+ TReg cell
T cell pro-inflammatory cytokines TnF, Il-17 and Il-23,
TReg cell and inhibits epithelial cell hyperplasia and neutrophil
TReg cell infiltration to the gut, which are associated with disease
TH cell
TH cell TReg cell induction in these models66.
To provide insight into the mechanistic basis for
PSA-mediated protection, it was shown that increases
in the local production of Il-10 were required for the
Mesenteric lymph node
anti-inflammatory properties of PSA. Accordingly, PSA
Figure 2 | model for Bacteroides fragilis-mediated protection from disease does not protect against the induction of colitis in Il-10-
induced by Helicobacter hepaticus. Bacteroides fragilis produces polysaccharide A deficient mice, indicating that PSA functions by inducing
(PSA), which induces an immunoregulatory programme thatNature provides protection
Reviews from
| Immunology the production of Il-10. Indeed, CD4+ T cells purified
inflammation induced by Helicobacter hepaticus. PSA is taken up by intestinal dendritic from Mlns during PSA-mediated protection of colitis
cells (DCs), which presumably migrate to the local mesenteric lymph nodes, where produced increased levels of Il-10 compared with control
they initiate T cell responses by presenting PSA on MhC class II molecules to CD4+ mice. In addition, transfer of Il-10-deficient CD4+ T cells
T cells. Recognition of PSA by naive CD4+ T helper (Th) cells promotes the induction
into Rag/ recipient mice abolished the ability of PSA to
of anti-inflammatory or regulatory characteristics that include the production of
interleukin-10 (IL-10). IL-10 then suppresses the production of pro-inflammatory
protect against experimental colitis66. These findings indi-
cytokines (such as IL-17, IL-23 and tumour necrosis factor (TNF)) induced by cate that a single bacterial product can stimulate CD4+
H. hepaticus and protects against the induction of experimental colitis. The balance T cells to produce Il-10 and lead to the suppression of
between the pro-inflammatory Th17 cell responses to H. hepaticus and the regulatory the inflammatory process during colitis. This suggests that
T (TReg) cell responses to B. fragilis supports the control of intestinal inflammation. other beneficial bacteria may also produce factors that can
TCR, T cell receptor. positively shape the host immune response in IBD.

nATURe RevIeWS | Immunology volUMe 9 | MAy 2009 | 319

2009 Macmillan Publishers Limited. All rights reserved


REVIEWS

Symbiosis For many years, Il-10-producing regulatory T cells absence of these symbiotic organisms and their ben-
A constant and intimate (known as TR1 cells) were considered to be distinct from eficial molecules? In other words, if symbiosis factors
relationship that occurs naturally occurring, thymic-derived CD4+CD25+FoXP3+ actively maintain health, can dysbiosis compromise
between dissimilar species, TReg cells82. It is now apparent that there is overlap bacterium-mediated immune regulation and lead to
which was originally defined
as living together. Although
between these two populations and that Il-10-producing inflammation? Recent epidemiological and clinical
it is often used to describe a TR1 cells can be found in the FoXP3+ TReg cell subset reports have described marked increases in the inci-
beneficial relationship, and are crucial for the control of experimental colitis. dence of several immune-mediated disorders, such
symbiosis does not necessarily Although TR1 cell clones that are specific for caecal as IBD, asthma, atopy (affecting the skin, respiratory
imply that either partner gains
bacterial contents have been generated83, the ability of tract and gut), rheumatoid arthritis, type 1 diabetes and
an advantage.
a molecule from symbiotic bacteria to regulate FoXP3+ multiple sclerosis, in Western populations, including
TReg cell differentiation and function awaits further vali- those of western european nations, the United States
dation. nevertheless, current evidence supports that idea and Japan. The rapidity of the increase in disease
that certain beneficial bacteria have evolved molecules rates does not support a solely genetic basis for these
(known as symbiosis factors) that induce protective intes- observations84. Instead, this could be due to changes
tinal immune responses. Knowledge of which beneficial in hostmicroorganism interactions caused by the
species of bacteria can prevent or cure disease, and har- implementation of antimicrobial strategies (including
nessing the potent immunosuppressive potential of sym- vaccination, sanitation, Western diets and antibacterial
biosis factors will be important steps towards designing therapeutics) that do not discriminate between infec-
new and natural therapeutics for IBD. tious and non-infectious microorganisms (fIG. 3).
If improvements in hygiene and health care have
The microbiota hypothesis and human disease altered the process by which a healthy microbiota is
Does harbouring certain strains of bacteria predispose assembled and maintained, then patients with these
an individual to disease or protect from it? B. fragilis has diseases in developed countries should display signs
been shown to protect its host from inflammatory dis- of dysbiosis. This indeed seems to be the case, at least
ease caused by subsequent infection with H. hepaticus in according to a growing number of studies that are now
an animal model of experimental colitis66. As symbiotic linking these diseases (which are mostly prevalent in
bacteria seem to have evolved mechanisms to provide Western populations) to alterations in the microbiota.
protection from colonization by pathobionts that are The bacterial composition of the intestines of patients
present in the microbiota, does disease result from the with IBD is known to differ from that of healthy con-
trols74. However, studies that aimed to identify the spe-
cific pathogenic organism (or organisms) that triggers
Host genetics Lifestyle Early colonization Medical practices inflammation have repeatedly identified reactions only
Mutations in Diet Birth in hospitals Vaccination use to intestinal bacteria that are shared by all humans
NOD2, IL23R, Stress Altered exposure Antibiotic
ATG16L and IGRM to microbes Hygiene healthy and ill. So far, no infectious organisms have been
conclusively shown to be the causative agents of IBD.
This raises the possibility that the targets of inflamma-
tion in IBD are not pathogens and instead are pathobi-
Dysbiosis onts that are overrepresented during dysbiosis (fIG. 1).
Indeed, in 1999 an investigation of the role of intestinal
bacteria in the development of asthma concluded that
Disease Health allergic children from Sweden and estonia had lower
TH1, TH2 and TH17 cells TReg cells levels of colonization by Bacteroides spp. and higher lev-
els of colonization by aerobic microorganisms than non-
Figure 3 | Proposed causes of dysbiosis of the microbiota. We propose that the allergic children from either region85. epidemiological
composition of the microbiota can shape a healthy immune Nature Reviews
response | Immunology
or predispose studies have provided evidence for a link between altered
to disease. Many factors can contribute to dysbiosis, including host genetics, lifestyle,
intestinal microbiota to other allergic disorders, such as
exposure to microorganisms and medical practices. host genetics can potentially
influence dysbiosis in many ways. An individual with mutations in genes involved atopic eczema and rheumatoid arthritis8688. Although it
in immune regulatory mechanisms or pro-inflammatory pathways could lead to is not clear whether dysbiosis is the cause or an effect of
unrestrained inflammation in the intestine. It is possible that inflammation alone disease, it seems that deviations in the composition of
influences the composition of the microbiota, skewing it in favour of pathobionts. the gut microbiota may be one factor underlying the
Alternatively, a host could select or exclude the colonization of particular organisms. development of disease in genetically predisposed
This selection can be either active (as would be the case of an organism recognizing a individuals.
particular receptor on the host) or passive (the host environment is more conducive to on these basis of these recent studies, investiga-
fostering the growth of select organisms). Selection of pathobionts by the host could tors are now turning their attention to understanding
tip the balance in favour of inflammation. Diet and stress also have the potential to how (and, more importantly, why) mammals harbour
influence the microbiota103. Birth in the sterile environment of hospitals can protect
multitudes of symbiotic bacteria. As discussed above,
from exposure to dangerous pathogens, but can also prevent early exposure to
health-promoting bacteria. overuse of vaccination and antibiotics, which do not the effects of the microbiota on the immune system
distinguish between pathogenic or symbiotic microorganisms, could adversely alter are becoming increasingly evident. It is therefore of
the microbiota. ATG16L, autophagy-related gene 16-like; IGRM, immunity-related great interest that the immune-mediated disorders,
GTPase family, M; IL23R, interleukin-23 receptor; NOD2, nucleotide-binding the incidence of which has increased in Western coun-
oligomerization domain 2; Th, T helper; TReg, regulatory T. tries, seem to involve reduced TReg cell activity. Indeed,

320 | MAy 2009 | volUMe 9 www.nature.com/reviews/immunol

2009 Macmillan Publishers Limited. All rights reserved


REVIEWS

studies in animal models and humans indicate that alter the outcome of immune development and poten-
deficiencies in TReg cell populations or function underlie tially predispose individuals to various inflammatory
asthma, IBD, rheumatoid arthritis, type 1 diabetes and diseases later in life (fIG. 3).
multiple sclerosis89 and that CD4+CD25+FoXP3+ TReg on the basis of clinical, epidemiological and immuno-
cells can prevent, and in some cases treat, these disor- logical evidence, it seems possible that changes in the intes-
ders in laboratory animals. In addition, the observed tinal microbiota may be an essential factor in the incidence
reduction in the numbers and function of certain TReg of numerous inflammatory disorders. It is conceivable
cell populations 45,43, together with numerous other that the absence of beneficial microorganisms (owing to
immunological defects that may precipitate disease in dysbiosis) that promote the appropriate development of
germ-free animals, implicates a role for the microbiota the immune system leads to the induction of inflamma-
in actively supporting health. After millions of years of tory responses and immune-mediated disease. Recent
co-evolution, have societal advances paradoxically and studies have shown that at least for experimental IBD,
adversely affected human health by reducing our exposure spontaneous disease occurs when immune suppression
to health-promoting bacteria? is defective; thus, inflammation seems to be a default
immunological state in the absence of regulation 93.
Concluding remarks Pathogenic bacteria clearly induce local inflammation
Although it has been known for decades that we har- during acute infections, but have symbiotic bacteria
bour millions of commensal bacteria, recent studies evolved to regulate the inflammatory processes that
have only just begun to reveal the extraordinary com- are harmful to the host (and therefore, harmful to the
plexity and diversity of the human microbiota. This con- existence of the symbiont)? Research has implicated
sortium of bacteria contains tenfold more cells than the innate and adaptive immune suppression during the
human body, 100 times the number of genes than control of disorders such as IBD, autoimmunity, asthma
the human genome and has the metabolic capacity of the and allergy, cancer and infectious diseases. According
human liver 90,91. How is such a complex microbial net- to numerous recent studies, we propose that there is a
work assembled after birth? A recent study 92 on devel- vast, intricate and unexpected level of interdependence
opment of the intestinal microbiota in infants revealed between beneficial bacteria and the immune system.
that in the first few days to weeks of life, the microbiota It is possible that genetic and habitual factors shape the
of newborns is highly variable and subject to waves of composition of the microbiota, which in turn shapes
temporal fluctuations (possibly representing a time the immune system of individuals that are predisposed to
of sampling or trial and error) to coordinately assem- inflammatory disease (fIG. 3). The recent identification of
ble a stable microbiota. The first years of life are also symbiotic bacteria with potent anti-inflammatory prop-
a time of great post-natal development of the immune erties, and their correlative absence during disease,
system. As the microbiota has marked influences on the suggests that certain aspects of human health may
immune system, deviations from the normal develop- depend on the status of the microbiota. The medi-
ment of the microbiota (through modern strategies cal and social reconsideration of the microbial world
such a caesarean section, formula-based diet, hygiene, may have profound consequences for the health of our
vaccination and use of antimicrobials in infants) may future generations.

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ERRATUM

The gut microbiota shapes intestinal immune responses during health


and disease
June L. Round & Sarkis K. Mazmanian
Nature Reviews Immunology 9, 313323 (2009); published online 30 April 2009; corrected after print 17 July 2009
In the version of this article initially published, references for table 2 were missing. A referenced version is provided below.

Table 2 | Bacteria shown to be protective in inflammatory bowel disease


Bacterial strain model system Disease type or model mechanism of disease suppression refs
VSL#3* human and Pouchitis, ulcerative colitis and Induction of IL-10- and TGF-expressing T cells 13
mouse TNBS-induced colitis
Bifidobacteria lactis Rat TNBS-induced colitis Decreased levels of colonic TNF and iNoS 4
Bifidobacteria infantis Mouse Salmonella enterica-induced Induction of TReg cells and inhibition of NF-B 5
enteritis activation
Escherichia coli Nissle 1917 human and Ulcerative colitis and Decreased colonic inflammation induced by TLR2 and 6,7
mouse DSS-induced colitis TLR4 activation
Lactobacillus rhamnosus GG Mouse and rat TNBS-induced colitis and Induction of TReg cells 8,9
hLA-B27-associated colitis
Lactobacillus salivarius Mouse TNBS-induced colitis Decreased colonic inflammation 8
Lactobacillus reuteri Mouse IL-10-deficient mice Upregulation of NGF and decreased levels of IL-8 and 10,11
TNF in cell lines
Lactobacillus plantarum 299v Mouse IL-10-deficient mice Decreased levels of IFN and IL-12p40 12
Lactobacillus fermentum Rat TNBS-induced colitis Decreased levels of colonic TNF and iNoS 13
Lactobacillus casei Rat TNBS-induced colitis Decreased levels of colonic cyclooxygenase 2 4
Bacteriodes thetaiotaomicron Rat S. enterica-induced enteritis Decreased levels of IL-8 and TNF in colorectal 14
adenocarcinoma cell line
Bacteriodes fragilis Mouse T cell transfer and Production of CD4+ T cell-derived IL-10 15
TNBS-induced colitis
Yo-MIx Y109 FRo 1000 Mouse TNBS-induced colitis ND 9
Faecalibacterium prausnitzii Mouse TNBS-induced colitis Decreased levels of NF-B, IL-8 and TNF and increased 16
IL-10 production
*A mixture of Lactobacillus spp. (Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus and Lactobacillus delbrueckii subspecies bulgaricus), Bifidobacterium spp.
(Bifidobacterium longum, Bifidobacterium breve and Bifidobacterium infantis) and Streptococcus salivarius subspecies thermophilus. A mixture of S. thermophilus, L. acidophilus
and B. longum. DSS, dextran sulphate sodium; IFN, interferon-; IL, interleukin; iNoS, inducible nitric oxide synthase; ND, not determined; NF-B, nuclear factor-B;
NGF, nerve growth factor; TGF, transforming growth factor-; TLR, Toll-like receptor; TNBS, trinitrobenzene sulphonic acid; TNF, tumour necrosis factor; TReg, regulatory T.

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