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review t h e m i c r o b i o ta

Commensal bacteria at the interface of


host metabolism and the immune system
Jonathan R Brestoff1,2 & David Artis13

The mammalian gastrointestinal tract, the site of digestion and nutrient absorption, harbors trillions of beneficial commensal
microbes from all three domains of life. Commensal bacteria, in particular, are key participants in the digestion of food, and
are responsible for the extraction and synthesis of nutrients and other metabolites that are essential for the maintenance of
2013 Nature America, Inc. All rights reserved.

mammalian health. Many of these nutrients and metabolites derived from commensal bacteria have been implicated in the
development, homeostasis and function of the immune system, suggesting that commensal bacteria may influence host immunity
via nutrient- and metabolite-dependent mechanisms. Here we review the current knowledge of how commensal bacteria regulate
the production and bioavailability of immunomodulatory, diet-dependent nutrients and metabolites and discuss how these
commensal bacteriaderived products may regulate the development and function of the mammalian immune system.

The mammalian gastrointestinal tract harbors trillions of beneficial slurry is mixed with commensal bacteria, which are important for
commensal bacteria, a population composed of at least 1,0005,000 the extraction, synthesis and absorption of many nutrients and meta
species1,2. Across the animal kingdom, species as diverse as flies, fish, bolites (Box 1), including bile acids, lipids, amino acids, vitamins
mice and humans have co-opted the faculties of beneficial microbes to and short-chain fatty acids (SCFAs; Fig. 1a). These nutrients and
support normal development and homeostasis314. Recent studies have metabolites derived from commensal bacteria are directly linked to
highlighted that alterations in the composition of commensal bacterial diet and digestion and are therefore considered to be diet-dependent
populations are linked to multiple metabolic and inflammatory diseases microbial products (Box 1)14. In addition to producing diet-dependent
in humans including but not limited to inflammatory bowel disease metabolites and nutrients, commensal bacteria can produce many
(IBD), obesity, type 2 diabetes, atherosclerosis, allergy and colon different diet-independent microbial products, examples of which are
cancer915. These associations provoke fundamental questions regard- lipopolysaccharide and peptidoglycan (Box 1)1114,23,24.
ing the cellular and molecular pathways through which commensal Nutrients and metabolites derived from commensal bacteria may
bacteria regulate mammalian gene expression and influence resistance regulate immune cells via indirect and direct mechanisms. Commensal
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or susceptibility to a broad range of clinically important diseases. bacteriamediated alterations in the availability or use of energy sub-
Recent studies have identified a critical role for commensal bacteria strates (for example, by modulating oxidation of glucose and fatty acids)
and their products in regulating the development, homeostasis and func- may indirectly influence the development, homeostasis and function
tion of innate and adaptive immune cells1524. Several recent compre- of immune cells5,1114,2531, although direct experimental analyses of
hensive reviews have described how commensal bacteria are recognized these interactions are limited at present. In addition, direct effects of
by the innate immune system and how individual species or consortia of metabolites can be mediated via metabolite-specific receptors that can
commensal bacterial species can influence distinct modules of the innate activate signal-transduction pathways and transcriptional programs
and adaptive immune response1524. However, an emerging area that that control differentiation, proliferation, migration and effector
has received relatively little attention is how metabolites and nutrients function of immune cells. The roles of diet-independent microbial
derived from commensal bacteria regulate the host immune system. products in the regulation of immunity have been recently discussed
Commensal bacteria are key regulators of digestion, a process that elsewhere1524; therefore in this Review, we will discuss how commensal
begins in the mouth and continues as ingested food and its diges- bacteriaderived diet-dependent nutrients and metabolites regulate the
tive intermediates transit more than 20 feet (6 meters) to the end of host immune system (Fig. 1b). We describe how commensal bacteria
the adult human gastrointestinal tract. Along the way, the digestive can regulate the synthesis and/or availability of bile acids, SCFAs, vita-
mins, amino acids and fatty acids. In the context of each of these diet-
1Department of Microbiology, Perelman School of Medicine, University of dependent nutrients and metabolites, we discuss current knowledge
Pennsylvania, Philadelphia, Pennsylvania, USA. 2Institute for Immunology, of how these factors regulate the immune response in the context of
Perelman School of Medicine, University of Pennsylvania, Philadelphia, health and disease.
Pennsylvania, USA. 3Department of Pathobiology, School of Veterinary Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania, USA. Correspondence
should be addressed to D.A. (dartis@mail.med.upenn.edu). Regulation of bile acids by commensal bacteria
Received 19 March; accepted 10 May; published online 18 June 2013; Bile acids are a family of cholesterol-derived amphipathic mol-
doi:10.1038/ni.2640 ecules that solubilize dietary fat in the small intestine to support the

676 VOLUME 14 NUMBER 7 JULY 2013 nature immunology


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Box 1 Definitions
Metabolites: intermediates and products of metabolism. This is a broad term that usually refers to small molecules.
Nutrients: a subset of metabolites that must be acquired from the environment to support cellular processes. In mammals, the diet and commensal bacteria
provide most nutrients714.
Commensal bacteria: beneficial bacteria that reside on host barrier surfaces such as the intestine. Although the term commensal implies that bacteria benefit
and the host is unaffected, commensal bacteria and the host have a mutualistic relationship in which both derive benefit from the interaction15.
Dysbiosis: a state in which commensal bacteria populations are altered or imbalanced15. Dysbiosis is associated with several human diseases45,5868.
Diet-dependent microbial products: factors derived from commensal bacteria (for example, nutrients and metabolites) that are directly linked to diet or digestion14.
Examples of diet-dependent microbial products include but are not limited to bile acids, short-chain fatty acids, vitamins, amino acids and fatty acids. The case
of bile acids illustrates this concept. Commensal bacteria participate in the synthesis of bile acids, a family of metabolites that are stored in the gall bladder and
secreted into the intestinal lumen in response to diet-dependent signals3245. Bile salts then facilitate the digestion and absorption of lipids32. Therefore, bile acids
derived from commensal bacteria are directly linked to both diet and digestion and can be considered to be diet-dependent microbial products.
Diet-independent microbial products: factors derived from commensal bacteria that are not directly linked to diet or digestion14. Examples include but are not
limited to lipopolysaccharide and peptidoglycan.

digestion and absorption of fat and of fat-soluble vitamins. In addition regulate the function of immune cells via the G proteincoupled bile
to their roles in regulating digestion, bile acids act as signaling mol- acid receptor 1 (GPBAR1; also known as TGR5 and membrane-type
ecules that regulate metabolic homeostasis32,33 and, as we will discuss receptor for bile acids, M-BAR) and the nuclear receptor subfamily
below, immune cell homeostasis and function. Commensal bacteria 1, group H, member 4 (NR1H4; also known as farnesoid X receptor,
2013 Nature America, Inc. All rights reserved.

participate in the synthesis of bile acids in two main ways (Fig. 2a). FXR), both of which are highly expressed in monocytes and mac-
First, commensal bacteria convert primary bile acids (for example, rophages as well as other immune cell types32,33. In macrophages
cholic and chenodeoxycholic acids), which are synthesized de novo by and monocytes, bile acid signaling via these receptors is linked to
the liver, into secondary bile acids (for example, deoxycholic, litho- a common anti-inflammatory response involving the inhibition of
cholic and muricholic acids) through dehydration reactions 34. Both NF-B activity and repression of NF-Bdependent transcription
primary and secondary bile acids are subsequently reabsorbed in the (Fig.2b)4549. Treatment of macrophages with the highly selective
ileum and returned via portal circulation to the liver, where they are GPBAR1 agonist INT-777 (ref. 50) is associated with higher cellular
conjugated to glycine (in humans) or taurine (in mice)34,35. These concentrations of cAMP and activation of protein kinase A (PKA) and
covalent modifications increase the efficiency of reabsorption of bile of cAMP-responsive element-binding protein (CREB)49. The cAMP-
acids in subsequent rounds of digestion34. Second, commensal bac- PKA-CREB pathway lowers STAT1 phosphorylation and NF-B
teria deconjugate bile acids to re-derive the unconjugated forms36,37. transcriptional activity5153. Macrophages treated with INT-777
The reabsorption of unconjugated bile acids is inefficient; therefore, exhibit lower NF-B binding to the nitric oxide synthase 2 (Nos2)
deconjugation of bile acids mediated by commensal bacteria promotes promoter and attenuated induction of the proinflammatory cytokines
the excretion and elimination of bile acids32. tumor necrosis factor (TNF), interleukin 6 (IL-6) and IL-1 in
Highlighting the influence of commensal bacteria on the synthesis response to lipopolysaccharide48. These effects of INT-777 were not
of bile acids, mice and rats reared in the absence of commensal bac- observed in Gpbar1/ macrophages, indicating that GPBAR1 was
teria or treated with oral broad-spectrum antibiotics have fewer sec- required for the anti-inflammatory effects of INT-777. Consistent
ondary bile acids and more conjugated bile acids in the fecal matter, with these findings, loss-of-function studies indicate that Gpbar1/
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ileum lamina propria, liver, kidney, heart and


plasma compared to conventionally reared
counterparts3845. Consistent with these a b Commensal
bacteria
observations, some human patients with IBD
have intestinal dysbiosis (Box 1) that is asso-
ciated with lower concentrations of secondary
bile acids in the feces and periphery as well as
more conjugated bile acids in the feces com- Digestion and Immune

pared to healthy subjects45. Such data suggest metabolism system

that commensal bacteria appear to be inti- Bile acid


mately involved in generating an array of bile metabolism
Figure 1 Commensal bacteria at the interface of
acids, and at least a subset of these bile acid
host metabolism and immunity. (a) Commensal
metabolites derived from commensal bacte- bacteria regulate digestion by mediating bile
ria gain access to enterohepatic and systemic Vitamin
acid synthesis, lipid absorption, amino acid
synthesis
circulation (Fig. 2a). Lipid metabolism, vitamin synthesis and SCFA
absorption SCFA production. (b) Commensal bacteria participate in
Bile acid regulation of immune cells digestion and regulate host metabolic homeostasis,
Amino acid
and commensal bacteriaderived nutrients
Marina Corral Spence

The role of commensal bacteria in the pro- metabolism


regulate the immune system. This commensal
duction of bile acids raises the question of
bacteriametaboliteimmune system axis (orange
whether bile acids derived from commensal arrows) exists in a complex network of interactions
bacteria are associated with regulation of the among commensal bacteria, host digestion and the
host immune system. Some bile acids can immune system (orange and black arrows).

nature immunology VOLUME 14 NUMBER 7 JULY 2013 677


review

Figure 2 Regulation of bile acid metabolism a


by commensal bacteria and effects of bile
acids on immune cells. (a) Roles of commensal Bile acids
bacteria in synthesis of bile acids. Bile acids are Stomach
HO
O
synthesized in the liver from cholesterol-derived OH -Taurine
Conjugated Liver
-Glycine
precursor molecules and are emptied into the HO OH -OH Unconjugated
small intestine. There, commensal bacteria
deconjugate bile acids and convert primary into
secondary bile acids. Bile acids are reabsorbed
in the ileum and transported to the liver to
complete enterohepatic circulation. Some
bile acids gain access to systemic circulation. Gall
b GPBAR1 Macrophage/
monocyte

in e
l yc ri n
bladder

e
-G au
cAMP
Molecular structure of bile acid is representative

-T
O O
PKA

H
of some but not all bile acids. (b) Bile acid

HO
Commensal

H
O
signaling in macrophages and monocytes via bacteria

HO
GPBAR1 and NR1H4. Both pathways lead
to inhibition of NF-B, albeit by different CREB

mechanisms. GPBAR1 signaling involves cAMP-


Bile acids STAT1
PKAmediated inhibition of STAT1 and NF-B,
and NR1H4 signaling leads to NR1H4-NCoR1 Ifng
NF-B
mediated repression of NF-Bresponsive Tnf
NRE Il6
elements (NRE). Bile acid stimulation of both 1. Deconjugation Il1b
2. Primary to secondary bile acids Nos2
pathways leads to less NF-Bdependent gene NCoR1
expression. (c) Bile acid signaling in NKT cells.
2013 Nature America, Inc. All rights reserved.

Return to liver and access


to systemic circulation NR1H4
This cell type expresses NR1H4, and bile acid
engagement of this nuclear receptor represses
osteopontin expression. This molecule has
many functions, including promoting neutrophil
O
OH

activation and chemotaxis as well as NKT cell Reabsorption

activation in an autocrine or paracrine manner. c NKT cell d


HO

(d) Pathogens and diseases associated with


HO

immune responses regulated by bile acids. Viral infection


Small NR1H4 IBD
NAFLD, non-alcoholic fatty liver disease. Obesity
intestine
NCoR1 NAFLD

Marina Corral Spence


Elimination Type 2 diabetes
mice exhibited exaggerated colitis in response NF-B Atherosclerosis
Colon cancer
Opn
to treatment of dextran sodium sulfate (DSS) NRE

and trinitrobenzene sulfonate (TNBS),


two mouse models of intestinal damage
and inflammation54.
Similarly, treatment of intestinal lamina propria CD11b+ cells with by the spontaneous intestinal inflammation observed at steady state in
the NR1H4-selective agonist INT-747 was associated with a decrease Nr1h4/ mice with functional GPBAR1 but not Gpbar1/ mice with
in the expression of NF-Bdependent genes Tnf, Il6, Il1b, Ifng and functional NR1H4 (refs. 46,54), the above-mentioned studies indicate
Nos2 in response to treatment with lipopolysaccharide46. Treatment of that bile-acid signaling pathways have a common anti-inflammatory
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wild-type mice exposed to DSS or TNBS with INT-747 was also associ- function involving inhibition of NF-B.
ated with lower expression of IL-1, IL-6 and monocyte chemotractant
protein 1 (MCP-1) as well as lower colonic inflammation55. However, Bile acids in health and disease
unlike bile acidGPBAR1 pathwaydependent inhibition of NF-B The role of commensal bacteria in the production of bile acids and
activity, NR1H4-mediated repression of NF-Bdependent transcrip- the anti-inflammatory effects of bile acids in some cell types raise
tion appears to be regulated through stabilization of the nuclear recep- questions about whether bile acids derived from commensal bacteria
tor corepressor 1 (NCoR1) on NF-Bresponsive elements, thereby might influence the functions of the immune system in diseases asso-
blocking access to NF-B46. Although future studies are required, ciated with dysbiosis. Such diseases include IBD45,58,59, obesity6,6063,
the anti-inflammatory properties of the bile acidNR1H4 pathway non-alcoholic fatty liver disease64, type 2 diabetes62,63,65, atherosclero-
are likely not specific to monocytes and macrophages, as NR1H4 is sis66,67, colon cancer68, viral infection69,70 and others (Fig. 2d). Here
expressed in other immune cell types, including liver natural killer T we will briefly discuss IBD and viral infection.
(NKT) cells (Fig. 2c). For example, in liver NKT cells NR1H4 regulates As reviewed above, bile acids appear to regulate the function of at
the expression of osteopontin56,57, a pleiotropic protein that regulates least some immune cell types through GPBAR1 and NR1H4, both
many cell types, an example of which is neutrophils. Compared to of which lead to the inhibition of NF-Bdependent expression of
wild-type mice, NR1H4-deficient mice have more liver NKT cell proinflammatory genes. Mice lacking GPBAR1 or NR1H4 exhibit
derived osteopontin and increased liver neutrophils in concanavalin exaggerated colitis in models of intestinal inflammation, and stimulat-
Ainduced hepatitis56. Moreover, natural secondary bile acids, which ing these receptors appears to be associated with protection against
can bind both GPBAR1 and NR1H4 (ref. 33), also appear to have colon tissue damage46,54,55,71. Patients with IBD, at least two diseases
anti-inflammatory effects in nonimmune cells, as treatment of intes- (Crohns disease and ulcerative colitis) with diverse phenotypes, are
tinal epithelial cell lines such as Caco-2 cells with deoxycholic acid or reported to have alterations in commensal bacteria as well as dimin-
lithocholic acid abrogates IL-1induced expression of IL-8 (ref. 45). ished concentrations of bile acids45,58,59 and, in the case of Crohns
Although GPBAR1 and NR1H4 are not fully redundant, as evidenced disease, diminished NR1H4 activity in the ileum72. These correlative

678 VOLUME 14 NUMBER 7 JULY 2013 nature immunology


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studies provoke speculation about whether loss of bile acids derived neutrophils, macrophages and monocytes92,100. A similar recep-
from commensal bacteria might contribute to the development of at tor, GPR41 (FFA3), also recognizes SCFA ligands with a different
least some subsets of IBD and whether the use of analogs of bile acids rank-order of ligand potency9193,99, but GPR41 expression is low or
might be a novel therapeutic strategy to treat this complex set of dis- undetectable in neutrophils and monocytes92,100, and at present there
eases. However, the conjugated bile acid taurocholic acid supports the is limited evidence to suggest a direct role for GPR41 in the regulation
growth of pathogenic bacteria that promote colitis in IL-10deficient of the immune system.
mice73, indicating that a better understanding of the commensal bac- SCFAs propionate and acetate, derived from commensal bacte-
teriabile acidimmune system axis is necessary to fully understand ria, promote neutrophil chemotaxis 85,89,90,92. The SCFA-induced
the role of bile acids in IBD. In this context, additional research will chemotactic response in neutrophils is associated with an increase
be necessary to investigate the possible roles of bile acid metabolites in intracellular calcium levels, a decrease in cAMP concentration and
in clinically stratified IBD patients. activation of ERK1/2 (ref. 92). Unlike bone marrowderived neu-
The bile acidmediated decrease in NF-B activity in macrophages trophils (BMDNs) from wild-type mice, Gpr43/ BMDNs do not
and monocytes may also be associated with the impaired antiviral exhibit calcium influx in response to acetate treatment and do not
immunity observed in germ-free mice or mice with experimentally undergo acetate-induced chemotaxis85. Furthermore, production
altered composition of commensal bacteria69,70. Macrophages from of reactive oxygen species and the phagocytic activity of wild-type
germ-free and antibiotic-treated mice have lower NF-Bdependent BMDNs but not of Gpr43/ BMDNs is increased with acetate treat-
gene expression and interferon responses in association with dimin- ment85, indicating that SCFAs promote not only neutrophil chemo-
ished CD8+ T cell and NKT cell function, diminished capacity to limit taxis but also neutrophil function. Consistent with the role of SCFAs
viral replication and greater susceptibility to viral infection69,70. These in promoting neutrophil chemotaxis, Gpr43/ mice treated with DSS
studies suggest that commensal microbiota provide instructive tonic to induce colitis had lower neutrophil content in the colon compared
signals that support the proper functioning of innate immune cells and to wild-type mice treated with DSS89. However, other studies report
2013 Nature America, Inc. All rights reserved.

the coordination of adaptive immune responses69,70. It is also possible, fewer colonic neutrophils in wild-type mice treated with DSS and
however, that germ-free and antibiotic-treated mice have impaired acetate85 or DSS and butyrate101 compared to mice treated with DSS
macrophage and NKT function because of elevated bile acid concen- alone. It is not known why treatment with SCFAs and genetic deletion
trations, which would be expected to inhibit NF-Bdependent gene of the SCFA receptor GPR43 led to similar anti-inflammatory phe-
expression, such as the interferon response programs in macrophages notypes in DSS-induced colitis, and further research will be required
and monocytes. Consistent with this idea are studies demonstrating to investigate this issue.
that cells treated with bile acids have an impaired capacity to limit Other cell types have also emerged as targets of SCFAs, includ-
replication of hepatitis C virus and of porcine enteric calicivirus74,75. ing monocytes, dendritic cells, T cells and intestinal epithelial cells
In addition, treatment of hepatocytes with the NR1H4 antagonist (Fig.3c). Human peripheral blood mononuclear cells (PBMCs)
Z-guggulsterone improves the ability of hepatocytes treated with express GPR43, and treatment of this cell type with SCFAs dimin-
bile acids to limit replication of hepatitis C virus75. This bile acid ished expression of monocyte chemotactic protein-1 and production
mediated effect is associated with activation of the PKA pathway of TNF, IFN- and IL-10 in response to treatment with lipopolysac-
and less STAT1 phosphorylation as well as impaired interferon charide100. In dendritic cells, treatment with butyrate is associ-
responses74. Collectively, these studies suggest that an increase in ated with decreased expression of the pro-inflammatory cytokines
bile acid signaling via GPBAR1 and NR1H4 may be associated with IL-12 and IFN-, and increased expression of IL-10 and IL-23
lower antiviral immunity in germ-free and antibiotic-treated mice. (refs. 102,103). There is also some evidence to suggest that butyrate may
More studies will be required to investigate further whether bile acids regulate the ability of dendritic cells to present antigen and to prime
regulate the functions of innate and adaptive immune cells in mice Tcells. For example, butyrate treatment of dendritic cells is associated
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with experimentally altered composition of commensal bacteria. with downregulation of antigen-presentation machinery, including
CD40, CD80, CD86 and major histocompatibility complex class II
Commensal bacteriaderived short-chain fatty acids (refs.102,103). In a dendritic cell and T cell co-culture system, how-
SCFAs are 16 carbons in length and are produced in the colon by ever, butyrate-treated dendritic cells elicit increased T cellderived
bacterial fermentation of plant-derived nondigestible polysaccharides, production of IL-17 and IL-10 (ref. 102). In addition to regulating
such as cellulose (Fig. 3a)7679. The most abundant SCFAs are butyrate dendritic cellT cell interactions, SCFAs might also directly regu-
(C4), propionate (C3) and acetate (C2) in the intestinal lumen80,81. late responses of T cells, as SCFAs may inhibit proliferation and
Compared to the case in conventionally reared mice, the contents promote apoptosis in CD4+ T cells104107. Furthermore, SCFAs
of colons of germ-free mice include more of the nondigestible plant appear to regulate production of proinflammatory cytokines in
oligosaccharide raffinose40, a bacterial fermentation substrate82, and nonimmune cells, as Caco-2 cells treated with butyrate and IL-1
markedly diminished concentrations of SCFAs8385, indicating that produce less IL-8 than do Caco-2 cells treated with IL-1 alone, indi-
commensal microbiota are essential for synthesis of SCFAs. cating that a colonic epithelial cell line is also responsive to butyrate108.
In primary colonic epithelial cells, SCFA deficiency establishes
SCFA regulation of immune cells an energy-deprived state and leads to activation of autophagy 84,
Several roles have been described for SCFAs, including the regu- a process that is linked to many aspects of innate and adaptive immu-
lation of host metabolism8688 and function of the immune sys- nity98 and the maintenance of intestinal barrier integrity109. The
tem85,89,90. SCFAs might regulate the immune system in multiple molecular mechanisms by which SCFAs regulate all of these cell types
ways, for example, through the activation GPR43 (free fatty acid are not well understood, although treating cells with butyrate has
receptor 2, FFA2)9193, the inhibition of histone deacetylases84,9497 been linked to the inhibition of histone deacetylases84,86,97,105,110 and
or the regulation of autophagy84,98 (Fig. 3b). GPR43 is a G protein alterations in histone acetylation that depend on the metabolic state
coupled receptor that recognizes endogenous SCFA ligands, including of the cell95. Future studies will be required to define the full spec-
acetate, propionate and butyrate9193,99, and is highly expressed in trum of cellular targets and molecular mechanisms through which

nature immunology VOLUME 14 NUMBER 7 JULY 2013 679


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Figure 3 Synthesis of SCFAs by commensal a


bacteria, and regulation of immunity by SCFAs.

(a) Commensal bacteria ferment nondigestible COO C1 Formate
Nondigestible
polysaccharides ingested in the diet (for polysaccharides COO

C2 Acetate
example, cellulose) to produce SCFAs. Various Commensal bacterial COO

C3 Propionate
SCFAs and their molecular structures are fermentation

COO C4 Butyrate
shown. C1C6 refers to the number of carbons. Cellulose
n
Isoforms of these SCFAs are not shown. COO C5 Valerate
CO2
(b) Known molecular pathways through which COO

C6 Hexanoate
SCFA regulate populations of immune cells.
Intestinal lumen
SCFAs bind the G proteincoupled receptor
GPR43, which leads to a decrease in cAMP
levels, calcium influx and ERK1/2 activation.
SCFAs also inhibit histone deacetylases b
(HDACs), which are transcriptional repressor SCFA
Plasma GPR43
proteins. (c) SCFA regulation of neutrophils, membrane HDACs
macrophages/monocytes (M), dendritic cells
(DCs), CD4+ T cells and intestinal epithelial
cells (IEC). ROS, reactive oxygen species; Cytoplasm

MHCII, major histocompatibility class II.


++
Ca
cAMP influx

SCFAs regulate development and function of


immune cells.
2013 Nature America, Inc. All rights reserved.

ERK1/2 Nucleus

+
SCFAs in health and disease PMN CD4 T cell

As discussed above, commensal bacteria are


c
Chemotaxis Apoptosis
essential for the production of SCFAs, which ROS production Proliferation
Phagocytic activity
appear to have anti-inflammatory properties
in multiple types of immune cells. This raises M DC
fundamental questions about whether SCFAs
might contribute to responses of immune TNF, IFN-, IL-1
MCP-1
CD80, CD86, CD40, MHCII
IL-12, IFN-

Marina Corral Spence


cells in diseases associated with alterations IL-10, IL-23

in populations of commensal bacteria. Germ-


free mice, which are deficient in SCFAs in the IL-8
IEC
gastrointestinal tract8385, exhibit an exagger- Autophagy

ated response of the immune system to DSS-


induced colitis in some studies85. Consistent
with these findings, treatment of germ-free mice with the SCFA ace- source of these vitamins113. The influence of vitamins on develop-
tate is sufficient to ameliorate the intestinal inflammation in response ment and function of immune cells has been discussed in detail
to treatment with DSS85. This effect is not observed in Gpr43/ mice, elsewhere114122, and we will therefore briefly discuss this here only
indicating that GPR43 is required for the anti-inflammatory effects of in the context of a recently discovered link between commensal
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SCFA in this model of intestinal inflammation in germ-free mice85. In bacteriaderived vitamin biosynthetic intermediates and immune cells
contrast, another study showed that conventionally reared Gpr43/ that directly recognize these intermediates. In particular, the mono-
mice exhibit less intestinal inflammation in response to treatment with morphic major histocompatibility complex class Irelated protein
DSS than wild-type mice but develop systemic bacterial dissemina- (also known as MR1) presents vitamin from the riboflavin (vitamin
tion and die of complications resulting from sepsis89, suggesting that B2) biosynthetic pathway to mucosa-associated invariant T cells122,
SCFAs might regulate intestinal barrier function, a topic that warrants a population of T cells that produces IL-17 and IFN- and that is
further investigation. Notably, treatment of IBD patients with butyrate activated in response to microbe-derived products of the riboflavin
enemas diminishes intestinal inflammation111, and in vitro treatment biosynthetic pathway122126. These data suggest that commensal
of IBD lesional biopsies with butyrate is associated with lower pro- bacteriaderived metabolites in vitamin biosynthetic pathways,
duction of pro-inflammatory cytokines112. Collectively, these studies not just the vitamin end product, may be previously unappreciated
suggest that SCFAs might influence responses of immune cells in at groups of molecules that regulate immune cells or that immune cells
least some forms of IBD. Despite these advances, future work will use to sense commensal bacteria. Whether immune cells recognize
be required to define how SCFAs regulate responses of the immune intermediates of other vitamin biosynthetic pathways has yet to
system in the context of IBD. be determined. In addition, it is currently unknown whether or
how vitamin biosynthetic intermediates influence development,
Commensal bacteriaderived vitamins and immunity homeostasis or function of immune cellstopics that should be
Vitamins are organic nutrients that are necessary for normal cel- the subject of future inquiries.
lular function. For humans, there are 13 essential vitamins: the
fat-soluble vitamins A, D, E and K and the water-soluble vitamins Commensal bacteriaderived amino acids and immunity
B1, B2, B3, B5, B6, B7, B9, B12 and C. Some commensal bacterial spe- There are 20 essential amino acids that must be acquired through the
cies have the capacity to synthesize essential vitamins, especially of diet and absorbed via amino acid transport proteins in the intestine.
the B and K groups, and this has been proposed to be an important Several studies suggest that commensal bacteria are important for the

680 VOLUME 14 NUMBER 7 JULY 2013 nature immunology


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extraction, synthesis or absorption of some amino acids, including profile5,40,41,44,147. Commensal bacterial regulation of lipid homeo
alanine, aspartate, glutamate, glycine and tryptophan, although many stasis has also been reported in other species, as zebrafish raised in
of the reported differences in these amino acids appear to be tissue- an axenic environment exhibit impaired lipid absorption and altered
specific40,44,127132. Amino acids serve as building blocks for protein lipid profiles3. It therefore seems that commensal bacteria are neces-
synthesis, substrates that feed directly into metabolic pathways (for sary for the maintenance of lipid homeostasis.
example, glutamine into the citric acid cycle) and cell-to-cell signaling This association raises the question of whether commensal bacteria
molecules (for example, the neurotransmitter glycine). Some amino regulate the immune system via modulation of systemic lipid home-
acids, such as arginine, leucine, glutamine and tryptophan, are also ostasis. Such a phenomenon could be mediated in at least two ways:
associated with regulation of the immune system119,130,133140. It is the direct sensing of lipid moieties or the establishment of a metabolic
not yet known whether amino acids that are regulated by commen- program that favors some immune functions or the development of
sal bacteria influence the development, homeostasis or function of some cell types over others. The first mechanism is supported by
immune cells, but emerging research suggests that this might be the data showing that invariant natural killer T (iNKT) cells, which rec-
case. For example, tryptophan concentrations in the lumen of the colon ognize and respond to glycolipid antigens presented on the major
are lower in germ-free mice compared to conventionally reared mice, histocompatibility complex class Irelated molecule CD1d148 are
suggesting that production or absorption of this amino acid is altered altered in mice lacking commensal bacteria149,150. Germ-free mice
in the absence of commensal bacteria131. Tryptophan influences pro- and a wild-type strain with less Sphingomonas, a glycolipid-producing
liferation of T cells by regulating passage through the G1 phase of the commensal bacteria taxa, have fewer iNKT cells compared to wild-
cell cycle137 and regulates immune responses in models of skin allo- type mice harboring more Sphingomonas150. Others have shown that
graft rejection, tumor growth and autoimmune encephalomyelitis 138 there are more iNKT cells in the small intestine of germ-free mice, a
as well as in TNBS-induced colitis119. Additional research is required tissue-specific effect associated with signals derived from commensal
to investigate the emerging link between amino acids that are regulated bacteria early in mouse development that regulate the ontogeny of
2013 Nature America, Inc. All rights reserved.

by commensal bacteria and the immune system. iNKT cells150.


Alterations in the composition of commensal bacteria could Commensal bacteria might also regulate immune cell function
be an important etiologic factor in protein energy malnutrition through the fatty acidy sensor proteins in the peroxisome proliferator-
(PEM)127,128, a set of diseases characterized by immunodeficiency. activated receptor (PPAR) family of nuclear receptors that recognize
For example, children with various forms of PEM have greater rates endogenous and exogenous lipid moieties and initiate transcrip-
of infection141143, higher infection-associated mortality143,144 and tional changes linked to metabolic reprogramming and immune
diminished vaccine efficacy145,146. Although insufficient dietary pro- function151155. Commensal bacteria promote PPAR-dependent
tein intake is considered to be a causal factor in the development of export of NF-B from the nucleus and decrease expression of the
PEM, recent data suggest that commensal bacteria also have a role in NF-Bdependent gene Il8 in a PPAR-dependent manner156.
PEM127,128, perhaps because of their ability to synthesize, extract or Moreover, treatment of human intestinal epithelial cells from new-
regulate the absorption of amino acids. Supporting this hypothesis, it borns with Enterococcus fecalis is associated with the activation of
has been demonstrated that twins discordant for kwashiorkor, a PEM PPAR-1 and increased production of IL-10 (ref. 157). Therefore,
disease, have distinct gut microbiomes127. In addition, colonization of commensal bacteria appear capable of producing or stimulating
germ-free mice with fecal matter from the kwashiorkor-affected twin the production of PPAR-activating molecules. However, additional
leads to rapid weight loss as well as impaired weight gain when given research is needed to investigate the molecular mechanisms by which
ready-to-use therapeutic food, a clinical intervention used in areas of metabolites derived from commensal bacteria regulate PPAR family
widespread undernutrition127. Moreover, treatment of kwashiorkor members and to explore how commensal bacteria regulate the
patients with ready-to-use therapeutic food plus an oral antibiotic immune system via PPARs.
npg

cocktail resulted in increased weight gain and decreased mortality An alternative mechanism by which alterations in lipid homeosta-
compared to kwashiorkor patients treated with ready-to-use ther- sis can alter immune system function is by establishing a metabolic
apeutic food that did not receive antibiotics128. This suggests that state that favors some immune processes over others. For example,
commensal bacteria contribute to the etiology of this PEM disease, T cells rely on fatty-acid oxidation at steady state and proceed through
a notion supported by studies of germ-free mice that suggest that multiple metabolic checkpoints as they become activated, expand,
commensal bacteria regulate bioavailability and/or uptake of amino contract and differentiate into effector or memory T cells25,26,158.
acids40,44,129,131,132. The mechanisms through which commensal bac- T helper cells, including TH1, TH2 and TH17 cells, tend to rely on
teria regulate host amino acid metabolism in various compartments glucose metabolism, whereas regulatory T cells and memory CD8+
are unclear, and understanding how commensal bacteria-dependent T cells exhibit increased fatty acid oxidation27,28,159. Blocking gly-
amino acid abnormalities affect the immune system will require colysis inhibits development of TH17 cells and promotes generation
additional functional analyses. of T regulatory cells28. Treating mice with the anti-diabetes drug
metformin or the immunosuppressant drug rapamycin, two pleio-
Commensal bacteria, fatty acids and immunity tropic molecules that promote oxidation of fatty acids via distinct
Fatty acids are a large family of nutrients that serve as energy sub- pathways, is associated with increased CD8+ memory T cell formation
strates and that regulate or support the function of many immune and function159. Oxidation of fatty acids also regulates hematopoi-
cells. Germ-free fish, mice and rats exhibit altered lipid meta etic stem cell maintenance and immune cell hematopoiesis160. Thus,
bolism3,5,40,41,44,147, and lipid homeostasis abnormalities in germ- the metabolic characteristics of immune cells may dictate their
free mice can be partially rescued by colonization with human fecal development and function, and alterations in lipid homeostasis that
contents39. Furthermore, mice reared in a germ-free environment are dependent on commensal bacteria may represent an unappre-
have lower fat mass compared to their conventionally reared coun- ciated mechanism through which commensal bacteria influence
terparts5, a phenotype that is associated with a diminished capacity the immune system. Additional functional studies will be required
for harvesting energy from ingested food61 and a broadly altered lipid to understand how lipids derived from commensal bacteria and

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684 VOLUME 14 NUMBER 7 JULY 2013 nature immunology