Cell Host & Microbe Minireview

Getting the Bugs out of the : Do Bacterial ‘‘Fix’’ Intestinal Responses?

Janet Chow1 and Sarkis K. Mazmanian1,* 1Division of Biology, California Institute of Technology, 1200 E. California Boulevard, Mailcode: 156-29, Pasadena, CA 91125, USA *Correspondence: [email protected] DOI 10.1016/j.chom.2008.12.006

Proinflammatory T helper 17 (Th17) cells control caused by microbial . Surprisingly, several recent reports now reveal that symbiotic gut modulate Th17 cell differentiation and function in the . As various autoimmune and allergic disorders are mediated by uncontrolled T cell responses, immune regulation by the microbiota may have direct implications for human health.

Immune Responses to Gut Bacteria -17 (IL-17) have been identified in only the The mammalian immune system is a remarkable and dynamic last few years (Bettelli et al., 2006; Weaver et al., 2007). Now, organ, responsible for many fundamental aspects of health a series of recent reports suggest that the differentiation of intes- and . Its primary task is to recognize microbial molecules tinal Th17 cells and their balance with anti-inflammatory regula- and mount appropriate and specific immune responses. It has tory T cells (Tregs) critically depends on the intestinal microbiota been historically viewed that immune reactions to bacteria occur (Figure 1). Based on the involvement of Th17 cells in various mainly during infections. However, based on more recent work inflammatory conditions, understanding how and more impor- we now know that even normal immune system development tantly why gut bacteria influence this specific T cell lineage depends on specific direction from symbiotic bacteria (Mac- may have significant implications for human health. pherson and Harris, 2004). The gastrointestinal tract provides residence to an astounding The Microbiota Shape Intestinal Th17 Cell Development number of microbial species, which have profound effects on IL-17 production is controlled by the orphan nuclear host biology and physiology (Backhed et al., 2005). Symbiotic RORgt (retinoic acid-related orphan receptor), widely consid- bacteria of the mammalian gut have long been appreciated ered the ‘‘master regulator’’ of Th17 cell differentiation (Ivanov for the benefits they provide to the host, including provision et al., 2006). Using an RORgt-GFP reporter mouse, Littman of essential nutrients, metabolism of indigestible compounds, and colleagues demonstrate that IL-17-expressing CD4+ defense against colonization by opportunistic pathogens, and T cells are preferentially enriched in the small intestinal lamina even contributions to the development of the intestinal architec- propria relative to other tissues (Ivanov et al., 2008). Though ture (Hooper and Gordon, 2001). Recent studies have shown several other sites did contain RORgt+ cells, the vast majority that symbiotic bacteria synthesize immunomodulatory mole- of nonintestinal IL-17-producing cells were not TCRab+CD4+ cules that guide maturation of the immune system (Mazmanian T cells, indicating that most ‘‘classical’’ Th17 cells are in the et al., 2005); one result of this interaction is protection from intes- gut. In order to understand the timeframe for Th17 cell develop- tinal inflammation (Mazmanian et al., 2008). Thus, it appears that ment, the authors measured IL-17 expression from various certain gut bacteria have evolved mechanisms to improve host stages during ontogeny. IL-17 production from CD4+ T cells of health by modulating intestinal immune responses. the small intestine was absent from newborn mice, but steadily As a key component of the , CD4+ increased from birth to postweaning. As mammals are born T cells are required for vital functions ranging from controlling sterile and subsequently initiated into an organized program infectious agents to the regulation of autoimmune reactions of colonization by symbiotic bacteria (Palmer et al., 2007), could and . Effector CD4+ T cells are generally divided into it be possible that the intestinal microbiota plays a role in three subtypes: T helper 1 (Th1), Th2, and Th17 (Figure 1). These Th17 cell development? three lineages are responsible for carrying out distinct and Over four decades of germ-free (GF) animal research have opposing activities that are mediated by their unique cytokine shown that genetically wild-type animals display numerous repertoires. The proper balance of immunologic responses defects in both cellular and morphologic development of the between T helper subsets has been shown to be critical to the immune system in the absence of microbiota (reviewed in Mac- overall health of humans and animals (Steinman, 2007). For pherson and Harris [2004]). Ivanov et al. explored the hypothesis example, elevated proportions of Th1/Th17 cells lead to inflam- that microbial colonization after birth induces the generation of matory bowel disease and (e.g., , intestinal Th17 cells by first examining IL-17 production by rheumatoid , ), while increased expression of CD4+ T cells in GF animals. Surprisingly, animals devoid of micro- Th2 is associated with and other allergic disor- bial (bacterial, viral, fungal, and protozoan) colonization were ders. Whereas Th1 and Th2 cells have been studied for about dramatically deficient in the production of IL-17 from TCRb+CD4+ two decades, Th17 cells that produce the potent inflammatory cells of the small intestinal (Ivanov et al., 2008).

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expression, Zaph et al. observed equivalent proportions of IL-17+ CD4+ T cells in the small intestine of GF animals (Zaph et al., 2008). The basis for the discrepancies appears enigmatic, as animal strains, housing conditions, and experimental approaches seem to be comparable between studies. However collectively, it appears that the microbiota modulates steady- state immune responses by either positively or negatively influ- encing Th17 cell development. The finding that intestinal microbes modulate IL-17 expression by intestinal CD4+ T cells represents an important aspect of biology that was previously unappreciated.

Subsets of Bacterial Populations Affect T Helper Profiles The identity of bacterial species that modulate ‘‘homeostatic’’ IL-17 production is currently unknown, but Ivanov et al. have begun to address this issue based on a very intriguing observa- tion. SPF mice from Jackson Laboratory display greatly reduced percentages of IL-17+ T cells compared to SPF mice from Taconic Farms, even though the genotypes are identical (Ivanov et al., 2008). When animals from each vendor were cohoused, the proportions of Th17 cells among small intestinal LPLs of Jackson Laboratory mice were restored. As SPF mice from each source Figure 1. T Helper Lineage Differentiation Is a Dynamic Process that contain diverse but different , this argues that partic- Is Influenced by the Intestinal Microbiota ular subsets of bacteria are specifically involved in IL-17 produc- CD4+ T helper cells can differentiate into proinflammatory (T helper 1 [Th1], Th2, or Th17) cells or anti-inflammatory regulatory T (Treg) cells. Th1 cells tion and that IL-17 production is not a result of general bacterial are characterized by their secretion of -g (IFNg), and function colonization. In support of this notion, transplantation of gut to control infections by intracellular pathogens (i.e., and bacteria). bacteria from Taconic mice into GF recipients restored their Th2 cells secrete IL-4, IL-5, and IL-13, and mediate immune responses to defect in Th17 cell numbers, whereas bacteria from Jackson extracellular pathogens (i.e., parasites and bacteria). Th17 cells secrete IL-17, IL-21, and/or IL-22, and are believed to respond following by Laboratory mice did not. The microbiome of both mice and extracellular pathogens (i.e., fungi and bacteria). However, proinflammatory man are dominated by two phyla (over 90% belong to either Bac- immune responses need to be regulated, as uncontrolled or elevated reactions teroidetes or Firmicutes) (Ley et al., 2008). Molecular analysis will result in collateral damage to host tissues. Increased and prolonged Th1/ Th17 responses are believed to drive autoimmune such as multiple indicated that Jackson mice were not colonized with Bacteroi- sclerosis, , , and psoriasis. Th2 responses, detes (formerly known as Cytophaga-Flavobacteria-Bacteroides when left unchecked, may underlie the development of asthma and several [CFB]), and treatment with that reduced Bacteroidetes allergic disorders. Proinflammatory immune reactions are controlled by regu- colonization in Taconic mice led to a reduction in IL-17 produc- latory T cells, which secrete factors such as IL-10 and TGFb, and through other + mechanisms that are still not well defined, limit T helper responses either tion by CD4 T cells. These studies suggest a profound hypoth- following clearance or during the steady state. The current view of esis: Th17 cell differentiation is directed by specific classes of T helper differentiation posits that each of these lineages is distinct, and bacteria in a dynamic and reversible manner. If true, then alter- defined by gene regulatory networks encoded by the mammalian genome during T cell development. Recent studies are now suggesting that the distinc- ations in the microbial community could alter IL-17 production tion between each lineage fate is not predetermined, and may be adaptable. in the gut, having significant implications for intestinal (and For example, the ratios between Th17 and Treg cell differentiation in the colon perhaps nonintestinal) inflammatory diseases. may be influenced by the intestinal microbiota, perhaps through modulation of their respective transcription factors, RORgt and Foxp3. Therefore, improper modulation of the balance between pro- and anti-inflammatory cell Potential Mechanisms by which Bacteria Modulate Gut responses can lead to immune disorders, potentially linking the microbiota Immune Profiles to noninfectious diseases. The mechanism of microbiota-mediated Th17 cell differentiation was recently addressed by Takeda and colleagues, who reported Only a minor defect in IL-17 production was noted for gd T cells, that 50-triphosphate (ATP) is sufficient to increase suggesting that the lack of Th17 cells was not due to an overall IL-17 production from CD4+ T cells (Atarashi et al., 2008). Inves- deficiency in immune activation, and that specific features of tigating T helper cell among LPLs of the colon, Atar- the immune response are sensitive to the microbiota. Moreover, ashi et al. revealed that GF animals display a reduction in colonic TCRb+ Th17 cells from lamina propria (LPLs) appear IL-17 levels and fecal ATP concentrations. They also show that to represent the major source of IL-17, as levels of the Il17 tran- intestinal bacteria secrete copious amounts of ATP. Signaling script are greatly reduced in GF intestines compared to those through ATP sensors, long known to be involved in enteric of colonized animals. When GF animals were reconstituted with nervous system function, has recently been shown to induce the microbiota of SPF (specific pathogen-free) animals, the expression of IL-23 from dendritic cells (Schnurr et al., IL-17 production in the small intestine returned as the proportions 2005). As IL-23 is involved in the expansion and maintenance of of Th17 cells increased gradually over several weeks. In contrast the Th17 cell lineage, the authors speculated that ATP produced to the finding that GF animals are deficient in intestinal IL-17 by the microbiota may be critical for IL-17 expression by intestinal

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CD4+ T cells. Indeed, either rectal or intraperitoneal administra- mediating ‘‘communication’’ between the microbiota and the tion of ATP to GF mice resulted in an increase in Th17 proportions, innate and adaptive immune system is an emerging and exciting and treatment of SPF mice with apyrase (which cleaves ATP) led field of research. to a decrease in the percentages of IL-17-producing CD4+ T cells in colonic LPLs. It is intriguing that intraperitoneal injection of ATP led to an increase in colonic IL-17 levels and raises questions Regulatory T Cells Respond to Microbial Products regarding tissue specificity (Were other anatomical locations to Balance T Helper Responses also affected by systemic ATP treatment? Does ATP influence A healthy immune system is designed to balance inflammatory homing to the gut?). However, cytokine responses responses with suppressive mechanisms to limit collateral seem to be specific. Although GF animals are reduced in inter- damage to tissues. Many studies have identified a reciprocal feron-g (IFNg) production, ATP did not affect the expression of relationship between inflammation mediated by T helper cells IFNg, which is the canonical cytokine produced by Th1 cells. and anti-inflammatory (Treg) responses (Bettelli These observations suggest that different molecular signals et al., 2006). Foxp3 (forkhead box P3) is a Treg lineage specific (possibly produced by distinct members of the microbiota) transcription factor that can induce regulatory phenotypes and mediate differential T helper cell phenotypes during intestinal immunosuppressive functions by CD4+ T cells (Fontenot et al., colonization. A recent study similarly reported that gut bacteria 2005). Defects in Foxp3 Treg activity (such as by in mediate IL-17 and IFNg production in the colon, though the role the gene) severe multiorgan lymphoproliferative of ATP was not investigated (Niess et al., 2008). Consistent with disease in both humans and animals (Foussat et al., 2003). the notion that ATP may be acting on intestinal dendritic cells Previous studies have identified a critical role for Foxp3+ Tregs (DCs), conditioned media from cultures of intestinal bacteria in controlling intestinal inflammation, and Ivanov et al. report (but not ) was able to induce IL-17 production that Tregs are proportionally increased in LPLs of GF animals by CD4+ T cells during in vitro CD11c+ DC-T cell cocultures. (simultaneous with a decrease in Th17 cells) (Ivanov et al., Treatment of the conditioned media with apyrase abolished this 2008). Accordingly, Belkaid and colleagues investigated if micro- activity, strongly suggesting that ATP, and not another bacterially biota influence the equilibrium between effector T cells and regu- produced factor, is required for Th17 cell differentiation. The latory T cells in the gut. Toll-like receptors (TLRs) are well known same conditioned media that induced IL-17 expression did not to modulate intestinal inflammation, and TLR9 signaling can limit increase IFNg levels in the coculture system, demonstrating Treg suppression. The authors observed that Tlr9/ animals that ATP does not affect the differentiation of TH1 cells. Using (reared under SPF conditions) contained increased proportions an treatment regimen to target specific classes of of Foxp3+ T cells in various gut tissues, most notably in the bacteria, Atarashi et al. also show that fecal ATP concentrations lamina propria of the small intestine (Hall et al., 2008). Concom- are lowered along with Th17 cell proportions. Collectively, these itantly, the levels of IFNg and IL-17 were markedly decreased findings imply that specific members of the microbiota may among CD4+ T cells of Tlr9/ animals in multiple intestinal preferentially produce ATP, which ultimately promotes IL-17 tissues. Thus, signaling through TLR9 appears to reciprocally expression in the colon of experimental animals. modulate the equilibrium between effector T cells and regulatory The intestinal symbiotic bacteria are separated from the gut- T cells. Hall et al. go on to show that engagement of TLR9 with associated lymphoid tissues (GALT) by a single layer of intestinal the model ligand CpG (a microbial DNA mimic) inhibits naive epithelial cells. Correspondingly, epithelial cell responses to T cell differentiation into Tregs, and the same effect is observed nonpathogenic gut bacteria may impact the and develop- with DNA extracted from intestinal microbes. Furthermore, cells ment of intestinal immune responses. Artis and colleagues from Tlr9/ animals did not respond to gut bacterial DNA. The recently investigated the contributions of the microbiota on authors suggest that intestinal bacteria may be involved in intestinal epithelial cell (IEC) regulation of Th17 development suppressing Treg cell conversion, and that the absence of (Zaph et al., 2008). Their studies indicate that the proportions TLR9 limits inflammatory responses due to a defect in ‘‘sensing’’ of colonic (and cecal patch) Th17 cells were elevated in GF the microbiota. A role for the microbiota in mediating this animals compared to SPF animals, which displayed nominal process was demonstrated when administration of antibiotics levels of IL-17. This finding was consistent in at least two strains resulted in reduced Th1 and Th17 cytokine responses, similar of mice (C57BL/6 and BALB/c). Zaph et al. further show that to that observed in Tlr9/ animals. Gut bacterial DNA given to levels of IL-23, in addition to those of IL-17, are increased in antibiotic-treated mice restored the levels of IFNg and IL-17, colonic tissues of GF mice. As IL-23 is known to be required suggesting that DNA from the microbiota functions as an adju- for maintenance of the Th17 , the authors speculate vant to increase homeostatic levels of inflammatory cytokines. that inhibition of IL-23 expression by the microbiota reduces The findings that gut bacteria induce controlled, homeostatic IL-17 production. Accordingly, the IECs of GF animals are defi- inflammation may have important consequences, as a mucosal cient in the expression of IL-25, a known inhibitor of IL-23. Treat- immune system that is ‘‘primed’’ by the microbiota may be ment of GF mice with IL-25 reduced IL-17 and IL-23 expression able to respond more quickly to pathogenic infections. Though in the colon, whereas IL-25/ animals displayed increased the specificity of the DNA is still uncertain (for example, will IL-17 and IL-23 levels. Although we do not know the identity of DNA from microbial communities outside the gut have the the IL-25-inducing microorganism(s), these data suggest that same effect?), and the mechanism by which DNA inhibits Treg the microbiota may signal through IECs to regulate the develop- conversion is not fully known, Hall et al. provide interesting ment of colonic TH17 cells. Though an extensive analysis is potential functions for gut bacteria in modulating intestinal beyond the scope of this review, the role of epithelial cells in immune responses.

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Regulation of Intestinal Th17 Responses Conclusion by the Microbiota during Experimental Disease The human gastrointestinal tract is home to a complex micro- A ‘‘balanced’’ equilibrium among T helper cell responses is bial ecosystem that contains 10-fold more cells than the required for many aspects of immunologic health. Imbalances , encodes for 100 times the number of genes in in the composition of the bacterial microbiota, known as dysbio- the human genome, and possesses the metabolic capacity of sis, are postulated to be a major factor in human disorders such the human . Though millions of years of coevolution have as inflammatory bowel disease (IBD). To address the impact of forged the potential for host-bacterial symbiosis, the influence IL-17 production by the microbiota for health, Takeda and of this ‘‘forgotten organ’’ on our biology and health is only now colleagues show that the administration of ATP during the induc- being truly appreciated. Based on clinical, epidemiologic, and tion of intestinal inflammation results in increased and immunologic evidence, it appears that changes in the intestinal severity of disease (Atarashi et al., 2008). Using an experimental microbiota may be an essential factor in numerous inflamma- model of whereby T cells are transferred into severe tory disorders. Accordingly, a recent series of articles is begin- combined immunodeficient (SCID) mice, it was shown that ning to highlight the importance of balancing both the effector ATP injections led to a specific increase in Th17 cells. This and regulatory arms of the intestinal immune response. These increase coincided with exacerbation of disease symptoms, studies show that the microbiota influences proinflammatory including increases in inflammatory cell infiltration into colonic Th17 cell differentiation through molecular pathways that tissues, epithelial , and weight loss. However, it may include bacterial DNA, ATP, and signaling through IECs. must be considered that the T cell transfer model was performed Several reports, not described here, have recently revealed in SPF animals, which are known to develop disease as a conse- that intestinal bacteria also induce Treg development and func- quence of uncontrolled immune reactions directed toward the tion (though the molecular mechanisms remain a mystery). resident microbiota. Thus, as expected, ATP administration Collectively, emerging evidence indicates that a healthy micro- augmented the disease process by elevating Th17 responses. biota mediates overall ‘‘balance’’ in the immune system, as As noted by the authors, this experimental approach does not opposed to strictly driving pro- or anti-inflammatory responses. test the homeostatic function of microbiota-mediated IL-17 How the microbiota does so is most likely a function of the production. GF recipient animals do not develop disease when community structure—i.e., the microbiota is not a single entity, the same T cells are transferred, and so the biological role for but an amalgam of diverse microorganisms with distinct roles. ATP during Th17 differentiation may be better revealed in the Some organisms may drive Treg development specifically, absence of inflammation induced toward SPF bacteria. As while others only promote Th17 development. Though Th17 IL-17 is known to be involved in protection from extracellular cells are required for clearance of extracellular pathogens, pathogens, challenge of GF mice with enteric pathogens in the excessive levels of IL-17 are implicated in diseases such as presence or absence of ATP may help assign a possible function multiple sclerosis, IBD, psoriasis, , and rheumatoid to Th17 cell differentiation in the gastrointestinal tract. arthritis. Therefore, depletion of Treg promoting organisms Though not working in a GF system, Hall et al. explored the and/or overgrowth of microbes that drive Th17 development potential that signals from the microbiota may help protect may result in a proinflammatory immune profile. Factors that animals from microbial infections. After showing that antibiotic change the composition of the microbiota (pervasive antibiotic treatment of mice led to a decrease in intestinal IL-17 production use, hygiene, high-calorie diets, , etc.) could alter (similar to Tlr9/ animals), and that DNA from intestinal bacteria healthy microbial balances resulting in inflammatory disorders. was sufficient to correct this defect, the authors speculated that As Aristotle wrote, ‘‘True virtue lies in moderation.’’ Perhaps a reduction in IL-17 may impair immune responses that control immunologic virtue is lost during dysbiosis, adversely tipping intestinal infections (Hall et al., 2008). Infection of antibiotic the balance toward exacerbated inflammation that results in treated animals with Encephalitozoon cuniculi, a microsporidial disease. As the mammalian immune system evolved in the pathogen that causes severe diarrhea in immunocompromised presence of symbiotic microbes (i.e., mammals were never people, resulted in an increase in parasite infectivity. Therefore, germ free), it is very conceivable that some microbes actively similar to studies done in GF mice (Macpherson and Harris, network with the immune system to regulate specific host 2004), the microbiota appears to limit enteric infections. More responses. If true, then we may have to contemplate the possi- importantly, administration of DNA to animals bility that the human genome does not encode all functions with antibiotics provided protection from E. cuniculi infections, required for health, and that we depend on crucial interactions suggesting that homeostatic restoration of IL-17 levels provides with the human microbiome for our wellbeing. a health benefit to the host. A control TLR ligand (lipopolysac- charide; LPS) did not reduce parasite burden, indicating the REFERENCES specificity of DNA for this process. Therefore, it appears that a reduction in IL-17 levels (either in GF or antibiotic-treated Atarashi, K., Nishimura, J., Shima, T., Umesaki, Y., Yamamoto, M., Onoue, M., Yagita, H., Ishii, N., Evans, R., Honda, K., and Takeda, K. (2008). ATP drives animals) may cause immunologic deficiencies and increased lamina propria T(H)17 cell differentiation. Nature 455, 808–812. susceptibility to pathogenic infections. 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