Host-Microbiota Interactions Shape Local and Systemic Inflammatory Diseases John B

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Host-Microbiota Interactions Shape Local and Systemic Inflammatory Diseases John B. Grigg and Gregory F. Sonnenberg This information is current as J Immunol 2017; 198:564-571; ; of September 28, 2021. doi: 10.4049/jimmunol.1601621 http://www.jimmunol.org/content/198/2/564 Downloaded from References This article cites 122 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/198/2/564.full#ref-list-1

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Host-Microbiota Interactions Shape Local and Systemic Inflammatory Diseases John B. Grigg and Gregory F. Sonnenberg Recent advances in understanding how the mammalian with the microbiota to maintain a state of homeostasis that is immune system and intestinal microbiota functionally mutually beneficial. For example, the requirement for micro- interact have yielded novel insights for human health biota in the proper development of the immune system was first and disease. Modern technologies to quantitatively mea- demonstrated in animals reared in microorganism-free envi- sure specific members and functional characteristics ronments, known as germ-free. Germ-free animals display a of the microbiota in the gastrointestinal tract, along variety of intestinal immune defects, including impaired development of GALTs, lower amounts of secreted Ig, and re- with fundamental and emerging concepts in the field + of immunology, have revealed numerous ways in which duced intraepithelial CD8 T cells (5). Additionally, evidence Downloaded from host-microbiota interactions proceed beneficially, neu- has supported the notion of the gut microbiota having a strong influence over the development of the immune system outside trally, or detrimentally for mammalian hosts. It is clear + that the gut microbiota has a strong influence on the shape of the intestine (6). In germ-free mice, splenic CD4 Th cells are skewed toward the Th2 cell subset and promote enhanced and quality of the immune system; correspondingly, the allergic responses and type 2 immunity (6). Germ-free mice immune system guides the composition and localization of + also have decreased total numbers of peripheral CD4 Tcells, http://www.jimmunol.org/ the microbiota. In the following review, we examine the including Th17 cells (7) and regulatory T cell (Treg) com- evidence that these interactions encompass homeostasis partments (8, 9). Conversely, the intestinal immune system also and inflammation in the intestine and, in certain cases, actively shapes the composition and compartmentalization of extraintestinal tissues. Lastly, we discuss translational ther- the microbiota through various mechanisms (10–13). Overall, apies stemming from research on host-microbiota interac- these observations demonstrate that the colonizing microbiota tions that could be used for the treatment of chronic and host immune system have a complex, dynamic, and re- inflammatory diseases. The Journal of Immunology, ciprocal dialogue.

2017, 198: 564–571. Members of the microbiota are recognized by the innate im- by guest on September 28, 2021 mune system through their conserved pathogen-associated mo- he human body hosts a remarkable variety (1) and lecular patterns, referred to in this article as microbe-associated quantity (2) of microorganisms collectively referred molecular patterns (MAMPs) (14), to encompass such ligands in T to as the microbiota. The microbiota encompasses Ar- normally nonpathogenic organisms of the microbiota. MAMPs chaea, Bacteria, Eukarya, and viruses that form a complex eco- are recognized by germline-encoded pattern recognition recep- system thought to have coevolved with mammalian hosts over tors distributed spatiotemporally across various cell types and time. Commensal bacteria are the most well-defined member of tissues. Despite this ability to directly respond to microbiota- the microbiota. Among the various body surfaces where com- derived signals, several features of the immune system act in mensal bacteria reside, the gastrointestinal (GI) tract contains the cooperation with the intestinal barrier to protect the body from highest densities, which are estimated to range between 1011 and opportunistic pathogens and to limit the immune system from 1014 cells per gram of luminal content (3). This enormous overreacting to beneficial microbiota in the gut (Fig. 1A). Such cellular and genetic component of the human body is now well features include the following: a thick mucus lining the lumen recognized to provide indispensible functions in digestion, nu- of the gut epithelial cells that physically excludes most micro- trition status, and protection against invasive pathogens (4). organisms (15), secreted IgA that recognizes and binds microbe- The mammalian immune system is also significantly specific epitopes and facilitates their removal (16), and secreted enriched in the GI tract and engages in a complex dialogue antimicrobial peptides that directly neutralize microorganisms

Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Address correspondence and reprint requests to Dr. Gregory F. Sonnenberg, Weill Medicine, Weill Cornell Medicine, New York, NY 10021; Department of Microbiology Cornell Medical College, New York, NY 10021. E-mail address: gfsonnenberg@med. and Immunology, Weill Cornell Medicine, New York, NY 10065; and The Jill Roberts cornell.edu Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New Abbreviations used in this article: AhR, aryl hydrocarbon receptor; CD, Crohn’s disease; York, NY 10021 EAE, experimental autoimmune encephalitis; FMT, fecal microbiota transplant therapy; Received for publication September 19, 2016. Accepted for publication October 31, GI, gastrointestinal; IBD, inflammatory bowel disease; IEC, intestinal epithelial cell; 2016. ILC, innate lymphoid cell; ILC3, group 3 ILC; MAMP, microbe-associated molecular pattern; PSA, polysaccharide A; RA, rheumatoid arthritis; SCFA, short-chain fatty acid; This work was supported by National Institutes of Health Grants DP5OD012116, SFB, segmented filamentous bacteria; Treg, regulatory T cell; WT, wild-type. R01AI123368, R21DK110262, and U01AI095608, the National Institute of Allergy and Infectious Diseases Mucosal Immunology Studies Team, the Crohn’s and Colitis Ó Foundation of America, the Searle Scholars Program, and an American Asthma Foun- Copyright 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 dation Scholar Award.

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601621 The Journal of Immunology 565

(17, 18). In addition to their pathogen-protective effects, these phenocopy aspects of human disease when experimentally features help to maintain sequestration of the microbiota, thus induced in animal models (31). These studies support the reducing the likelihood of the mammalian immune system concept that diverse impairments of hematopoietic and non- mounting an overreactive response to commensal bacteria. hematopoietic cell signaling pathways underlie abnormal host- However, when the epithelial barrier is compromised by chem- microbiota interactions. ical, pathogenic, or inflammatory insults, the immune system Environmental and lifestyle risk factors also play a role in must deal with the resulting influx of commensal and opportu- disease development (23), as evidenced by modest disease nistic microorganisms. In most contexts, the immune system concordance between monozygotic twins who develop ulcer- responds appropriately to protect the host from invasive mi- ative colitis and CD in adulthood (32). For example, diet is crobes while maintaining long-term tolerance to the microbiota. implicated in causative and preventative roles in IBD through Not surprisingly, sustained breakdown of the intestinal barrier is various mechanisms (33). Of note, short- and long-term die- linked to several chronic inflammatory diseases, although the tary patterns can modify the composition of the gut microbiota mechanisms are still being determined (19, 20) (Fig. 1B). (34–36). Diet’s link to IBD, among other environmental risk In this review, we assess how functional interactions between factors that alter the gut microbiota, such as antibiotic use, has the mammalian immune system and the microbiota in the gut motivated investigation of associations between microbial can drive inflammatory diseases locally and systemically. dysbiosis and intestinal inflammation. Dysbiosis is defined as a Comparatively, we also examine settings in which host-microbiota microbial imbalance resulting in a shift (i.e., loss or outgrowth interactions can prevent or constrain autoimmune disease. Lastly, of a species) and overall reduction in microbial diversity. Using Downloaded from we briefly discuss the evidence advocating for the therapeutic 16S sequencing of gut fecal content, it was observed that IBD modulation of host immune factors, as well as the manipulation patients have reduced colonic microbial diversity and a detect- of microbiota or microbiota-derived biomolecules for treating able shift in bacterial enterotypes compared with healthy indi- chronic inflammatory disease. viduals (37). For example, in a cohort of CD patients, Frank et al. (38) detected a relative decrease in Firmicutes and Bac-

Aberrant host-microbiota interactions underlie intestinal teroides in the intestinal microbiota, as well as a relative increase http://www.jimmunol.org/ inflammation in the proinflammatory bacteria Enterobacteriaceae, relative to Inflammatory bowel disease (IBD) is a family of chronic in- controls(Fig.1B).Additionally,fecal metabolite analysis revealed flammatory disorders of the GI tract. In the clinic, IBD is a decrease in butyrate-producing bacterium in CD patients (39, frequently diagnosed as Crohn’s disease (CD), affecting any 40). However, no single bacterial strain or combinations of strains part of the GI tract, or ulcerative colitis, in which pathology is have been shown to directly cause or prevent IBD in humans. restricted primarily to the colon (20). As with most complex Several animal studies have demonstrated that dysbiosis can diseases, IBD is thought to occur from a combination of ge- drive inflammatory pathogenesis in the intestine. These studies netic (21, 22), environmental, and lifestyle-associated risk factors involve the demonstration that a proinflammatory consortium by guest on September 28, 2021 (23) that culminate in dysregulated host innate and adaptive of microbiota, generally resulting from immune impairment, immune responses to the intestinal microbiota. Despite the can transfer disease phenotype to healthy wild-type (WT) re- complexity of IBD’s etiology, the host-microbiota interactions cipient animals. For instance, one of the first animal studies to that drive disease pathogenesis are becoming better understood implicate an IBD-causative consortium of bacteria involved the through studies in human IBD patients and animal models of horizontal transfer of microbiota from a spontaneous model of intestinal damage and inflammation. colitis (mice deficient in both T-bet and Rag2; referred to as Genetic analyses have identified loss-of-function mutations TRUC mice) into a healthy recipient mouse which resulted in and polymorphisms in key immune tolerance–related genes transfer of colitis (41). Garrett et al. (42) later identified more and immune-response elements that can lead to early-onset specifically that Klebsiella pneumoniae and Proteus mirabilis, IBD or increase disease susceptibility in adulthood (21, 22). which grow out in TRUC mice, act in conjunction with the Many primary immunodeficiencies first manifest in the GI presence of normal gut flora to drive the colitogenic effect upon tract (24). For example, individuals with loss-of-function mu- transfer. In another model, NLRP6 inflammasome–deficient tations in IL-10/IL-10R signaling present with very early–onset mice displayed spontaneous colitis that was transferrable to IBD as a result of their inability to regulate inflammatory im- WT neonates or adults via cross-fostering or cohousing (43). mune responses to commensal bacteria in the GI tract (25–27). Prevotellaceae was implicated as the primary driver of the in- Indeed, several other primary immunodeficiencies, such as com- flammatory effect in this study (43). In another study, Couturier- bined T and B cell deficiencies, are linked to early-onset GI Maillard et al. found that mice with a deficiency in NOD2 disorders (24), and many more are continually being identified had a dysbiotic consortium of microbiota that could transfer through whole exome sequencing (28). Genome-wide association colitis to healthy recipient mice (44). These studies under- studies have also identified a number of polymorphisms that are score that genetic disruption of immune pathways in the in- associated with an increased susceptibility to developing IBD in testine is sufficient to initiate colitogenic microbial dysbiosis. early life or adulthood (21, 22). The susceptibility loci include These microbial consortiums can then transfer disease even in genes and gene pathways involved in intestinal barrier function, the context of a functional immune system. innate immune recognition, adaptive immunity, and cellular Specific microbial species can be characterized by their ca- homeostasis (21). For example, genetic alterations in NOD2, pacity to provoke inflammatory responses in the intestine. an intracellular pattern recognition receptor for bacterial pep- Segmented filamentous bacteria (SFB) preferentially induce tidoglycans, confer increased susceptibility to developing CD in the differentiation of proinflammatory CD4+ Th17 cells in the adulthood (29, 30). To extend the genetic evidence, many of lamina propria of the ileum through the TLR5 innate path- the identified genetic alterations found in IBD patients can way, serum amyloid A, and direct epithelial cell adhesion 566 BRIEF REVIEWS: HOST-MICROBIOTA INTERACTIONS REGULATE INFLAMMATION Downloaded from http://www.jimmunol.org/ by guest on September 28, 2021

FIGURE 1. Host–microbiota interactions underlie homeostasis and inflammation in the intestine and extraintestinal tissues. (A) At homeostasis, gut bacteria are compartmentalized within the lumen through exclusion by the mucus, neutralization by antimicrobial peptides produced by IECs, and release of secretory IgA (sIgA) from intestinal-resident B cells. In response to various cues, ILC3s and Th17 cells in the intestine produce IL-22, which acts on IECs to promote compartmentalization of the microbiota. Tregs produce IL-10 and are induced by microbially derived SCFAs and PSA or by the bacterial species B. fragilis and Clostridium. Intestinal activation of Tregs can protect against neuroinflammation in the CNS during EAE. (B) During chronic intestinal inflammation, loss of intestinal barrier function results in bacterial translocation across the epithelium, release of commensally derived MAMPs, proinflammatory cytokine and chemokine activation, and Th17 and B cell responses. Specific bacteria exacerbate intestinal inflammation, including Prevotellaceae, Enterobacteriaceae, and the Th17-inducing SFB. Loss of tolerance to self-Ags can occur because of lowered thresholds for autoactivation (bystander effect) that can mediate autoimmunity in extraintestinal tissues. Bystander effects initiate and exacerbate Th17-mediated inflammation in mouse models of EAE and RA. In RA, Th17 and follicular helper T cell responses aid in autoantibody production in secondary lymph nodes. Licensing of cross-reactive T cell responses that recognize microbially derived peptides and react to self-peptides can also initiate autoimmunity in extraintestinal tissues, exemplified in a mouse model of experimental autoimmune uveitis (EAU).

(45, 46) (Fig. 1B). Recently, it was found that a variety of bacte- (Fig. 1B). It is important to note that ILCs and Th17 cells also rial species exhibiting epithelial cell adhesion (such as Citrobacter mediate protection from pathogens and proper containment of rodentium, enterohemorrhagic Escherichia coli,andCandida commensal bacteria, thus promoting homeostasis in the gut albicans) could similarly induce Th17 cells in the intestine (49), which is examined later in this review. Furthermore, SFB (47). Epithelial adhesion was an indispensible bacterial char- were well characterized to significantly induce Th17 cell re- acteristic for this effect because adhesion-defective bacte- sponses but also were demonstrated to promote the develop- rial mutants failed to induce Th17 cell responses (47). Finally, ment of intestinal Tregs (8). Thus, a comprehensive analysis of Helicobacter hepaticus also was demonstrated to induce proin- microbiota-induced responses should carefully be considered, flammatory innate lymphoid cell (ILC) and Th17 cell re- and single species cannot always be defined solely as pro- or anti- sponses through the induction of cytokines IL-1b and IL-23 inflammatory. Moreover, dysbiotic blooms of bacterial species in in the colon (48). Thus, the induction of proinflammatory the gut, such as Enterobacteriaceae, can be secondary to intestinal immune cells and their subsequent effector functions under- inflammation from various insults (50), which may owe to the lie some of the pathogenic effects of these bacterial members unique ability of these bacteria to feed off the by-products of host The Journal of Immunology 567 inflammation (51). Such observations obscure cause-and-effect in germinal center formation and the production of auto- relationships between microbial dysbiosis and inflammation. antibodies that mediate disease (62). More recently, SFB col- In summary, IBD arises from a framework of genetic pre- onization in K/BxN mice was found to induce the activation of dispositions, environmental risk factors, and dysbiotic micro- follicular helper T cells in the Peyer’s patches, which sub- biota that underpins its chronic nature. Continued interrogation sequently egress to the spleen and aid in the production of of the complexity of host-microbiota interactions that promote autoantibodies (63). A unique variation of the bystander model or constrain IBD in the various contexts of human disease also was demonstrated by Campisi et al. (64): C. rodentium should yield more rationally informed preventative or therapeutic infection causes self-antigen release from apoptotic host cells, approaches. which are then processed and presented by APCs alongside bacterial peptides, resulting in the licensing of autoreactive Involvement of the gut microbiota in initiating or exacerbating Th17 cells. This reinforces the concept that severe inflam- extraintestinal inflammatory diseases mation in the intestine, arising from infection in this case, can In parallel with research on how host-microbiota interactions provide the initiating conditions for the development of local drive inflammatory diseases in the intestine, mounting evi- and systemic autoimmunity. dence suggests that these interactions also impact systemic Molecular mimicry, or an adaptive response that recognizes inflammatory disease (52–55) (Fig. 1B). Indeed, IBD patients and responds to foreign-derived non-self and self-antigens, also frequently have extraintestinal disease manifestations involving has been proposed as a general mechanism for autoimmunity the joints, skin, and eyes (56). Multi-disease cohort genome- (65, 66). Understandably, cross-reactivity of adaptive responses Downloaded from wide association studies have revealed significant overlap in has direct benefit to the host when it results in broader pro- genetic susceptibility loci for IBD with a variety of inflamma- tection against phylogenically related pathogens; in contrast, it tory diseases involving extraintestinal tissues (21, 57). Addition- can adversely result in an inappropriate response to self-antigens. ally, similar to ulcerative colitis, some autoimmune diseases, such Using mouse models, several groups have provided evidence that as rheumatoid arthritis (RA), show less disease concordance be- microbiota-derived Ags may provide the antigenic basis for tween monozygotic twins than do other autoimmune diseases the initiation of systemic autoimmune disease (55). The seminal http://www.jimmunol.org/ (58).Thissuggestsastrongrolefor environmental factors in observation that molecular mimicry to common microbial pep- disease development. Alterations in the gut microbiota are asso- tides can induce autoimmunity came from a series of experi- ciated with several chronic inflammatory diseases outside of the ments demonstrating that structurally related microbial peptides intestine (5). Although causal relationships have not been dem- could activate MBP-specific T cells (in the Ob TCR-DR2b onstrated, these observations provoke the theory that disrupted mouse model), which then induce neurodegeneration in mice host-microbiota interactions in the gut, arising from genetic or (67). More recently, Horai et al. (68) showed that gut micro- environmental perturbations, may underlie or impact the course biota can provide the antigenic material for cross-reactivity to a of systemic autoimmune diseases. self-antigen. Using a spontaneous model of autoimmune uveitis by guest on September 28, 2021 Several research efforts in animal models have illuminated (TCR transgenic for the retinal protein IRBP), the investigators + how the gut microbiota can have a causative or protective role found that IRBP-specific CD4 T cells are first activated in the in autoimmune disease outside of the intestine. In the following gut, migrate to the eye, and drive pathogenic autoimmune sections we categorize such evidence into two, nonmutually uveitis (68). Interestingly, Kadowaki et al. (69) demonstrated exclusive groupings: bystander effects (Ag nonspecific) and that myelin protein (MOG)-specific CD4+ intraepithelial molecular mimicry (Ag specific). Although these have already lymphocytes can be activated and proliferate in response to gut been proposed and demonstrated as ways in which infectious Ags. In this context, CD4+ T cells differentiate into a regulatory pathogens, such as viruses, may lead to chronic autoimmune Th17 cell phenotype that expresses CTLA4 and TGFBR1. disease in humans (59), less research has elucidated mechanisms Upon transfer into WT mice, MOG-specific CD4+ intraepithelial in which resident or transient microbiota can have similar roles lymphocytes infiltrate the CNS and upregulate LAG3 expression, in systemic inflammatory diseases. reducing neuroinflammation (69). These experiments demon- In certain contexts, gut microbiota can exert an adjuvant strate that molecular mimicry can activate proinflammatory and effect in the priming of autoreactive adaptive immune re- immunoregulatory pathways that influence autoimmune disease sponses. Animal models support the concept that microbiota in extraintestinal sites. provide a necessary bystander role in initiating autoimmune Despite the correlative evidence that commensal bacteria can diseases in extraintestinal sites (Fig. 1B). For instance, mice directly initiate autoimmunity in extraintestinal tissues, no treated with antibiotics (60) or reared in germ-free conditions single bacterium or consortium of bacteria has been specifically (61) show reduced induction of experimental autoimmune identified in humans. Additional research and experimental encephalitis (EAE). Recolonization of germ-free mice with tools are warranted to clarify the mechanisms of bystander SFB alone induces Th17 cells in the gut and enhances neu- effects and molecular mimicry in extraintestinal autoimmune rodegeneration in the CNS upon active EAE induction (61). disease settings. Recently published articles demonstrated SFB can have a similar impact, although through a different systematic approaches to identify commensal bacteria that mechanism, to induce autoimmunity in a mouse model of incite colitis (70) or diet-dependent enteropathy (71). These spontaneous autoimmune arthritis (K/BxN) (62). Germ-free approaches consist of sequencing IgA-targeted bacterial taxa K/BxN mice are resistant to the development of arthritis, pri- from the fecal microbiota and then validating the bacterium’s marily as a result of reduced systemic germinal center formation immunological impact in gnotobiotic mice, which may prove and subsequent loss of autoantibody production. Recolonization useful for the identification of specific intestinal commensal bac- with SFB restores autoimmune arthritis through the activation of teria involved in autoimmune diseases outside of the gut. Fur- Th17 cells in the intestine, which then traffic to the spleen to aid thermore, stratification of IgA sequencing into T cell–independent 568 BRIEF REVIEWS: HOST-MICROBIOTA INTERACTIONS REGULATE INFLAMMATION and T cell–dependent IgA-production mechanisms (72) may protective and regulatory immune responses (82, 83). Of note, help to delineate bacterial members that have the strongest ca- group 3 ILCs (ILC3s) can modify the composition and ana- pacity to invoke autoreactive T cell responses. tomical localization of the microbiota. ILC3s respond to a variety of inflammatory cytokines (i.e., IL-1b, IL-23, IL-6) and Protective host-microbiota interactions can prevent or diminish local microbiota-derived metabolites (i.e., aryl hydrocarbon receptor and systemic inflammatory responses [AhR] ligands) (83). Following activation, ILC3s produce In addition to the detrimental outcomes of host-microbiota multiple effector molecules, including the cytokine IL-22, interactions, attention has focused on interactions that lead which acts directly on IECs to produce antimicrobial pep- to beneficial physiological states associated with mammalian tides, increase mucus production from goblet cells, and increase health. Recently identified mechanisms including microbiota- fucosylation of the mucus (84–86). During steady-state, the derived metabolites, regulatory immune cell types, systemic Ig, physiological outcome of this response is to maintain proper and intrinsic immune functions that coordinate to enforce localization and composition of commensal bacteria (87, 88). peripheral tolerance have been elucidated from experimental In response to breakdown of the intestinal barrier from various models of inflammatory diseases. insults, such as infection with C. rodentium, this pathway re- The presence of microbiota in the gut of conventionalized inforces compartmentalization of the pathogen to prevent its mice was shown to have an essential role in generating the systemic dissemination from the intestine (89, 90). CD4+ Foxp3+ Treg compartment (73), a key cellular medi- Recently, it was demonstrated that microbiota-derived in- ator of regulatory immune responses. Several research groups dole metabolites of tryptophan in the diet can target AhR in Downloaded from have identified specific species of commensal bacteria, or Th17 cells and ILC3s to promote production of IL-22 (91). consortia of commensal bacteria, that regulate the number, Mice deficient for the adaptor protein CARD9 develop quality, and TCR repertoire of intestinal Tregs. As reviewed spontaneous colitis and display a loss of bacterial species able recently (74), it is clear that many members of the commensal to convert tryptophan into ligands for AhR. Supplementation microbiota have a Treg-inducing capacity; well-documented of three Lactobacillus strains capable of metabolizing trypto- 2/2 examples include Bacteroides fragilis (75) and Clostridium (9) phan into AhR ligands protected CARD9 mice against in- http://www.jimmunol.org/ (Fig. 1A). Recently, Faith et al. (76) devised a systematic flammation in the colon (91). These results expand the evidence approach to elucidate combinations of human-associated mi- that particular metabolites in the gut microenvironment are key crobial species that can promote intestinal Treg responses in to the proper regulation of gut homeostasis. Notably, ILC3s can gnotobiotic mice. This method may permit the identification also directly limit microbiota-specific T cell responses to main- of new immunoregulatory phenotypes that are associated with tain intestinal homeostasis through Ag presentation on MHC particular members of the human microbiota. class II (92, 93). Future investigation of ILC3s and other regu- In parallel with the identification of groups or specific latory pathways that influence host-microbiota interactions in members of the microbiota, more reductionist approaches have the GI tract could provoke the development of novel treatment by guest on September 28, 2021 identified microbiota-derived molecules and metabolites that options for inflammatory disease. stimulate Treg responses. The best-characterized molecules Systemic Ig responses to commensal microbiota also were by which the microbiota promote Treg differentiation are found to be essential for the maintenance of beneficial host- bacterial-derived polysaccharide A (PSA) and short-chain microbiota interactions. For example, maternally acquired fatty acids (SCFAs) (Fig. 1A). PSA was the first documented IgA and IgG in neonatal mice leads to dampened T cell– microbiota-derived molecule that directs the development of a dependent immune responses against commensal bacteria balanced T cell compartment in mice (6). Later, it was found (94). Additionally, systemic IgG responses to Gram-negative that colonization of mice with PSA-sufficient strains of the bacterial commensals, acquired early and over the course of commensal B. fragilis or purified PSA protect against experi- life, were shown to provide cross-protection against Gram- mentally induced colitis and that the protective effect required negative pathogens, such as E. coli and Salmonella, in mice the presence of a functional IL-10–producing CD4+ Tcell (95). These observations reinforce the concept that microbial compartment (6). Furthermore, prophylactic or therapeutic composition and the timing of host-commensal interactions administration of PSA could protect mice from the induction provide the foundation for balanced immunity in the intes- of EAE, which was dependent on an IL-10–producing Treg tine. Lastly, the microbiota was observed to promote its own population (77). This suggests that the effects of PSA-mediated compartmentalization within the intestinal lumen, as well as Treg induction can have a systemic influence over peripheral provide protection to the host from pathogens (96, 97). Re- tolerance in tissues outside of the intestine. SCFAs are another cent identification of the gut–vascular barrier system in the group of immunoregulatory molecules that are primarily de- small intestine (98), which restricts dissemination of gut bac- rived from the microbiota-mediated digestion of dietary fiber teria, should provide a new therapeutic framework for con- and promote the differentiation of peripheral Tregs (78–80). straining disease manifestations that are due to bacterial Interestingly, SCFAs, such as acetate, can be detected in the translocation across the intestinal epithelium. blood circulation (81), suggesting that microbiota-derived SCFAs can have far-ranging effects outside of the intestine. Manipulation of intestinal microbiota and host-microbiota Along with the well-documented role of Tregs, other re- interactions to treat inflammatory diseases cently identified cell types and cytokine–cytokine receptor Established immunosuppressive medicines, such as glucocor- pathways that connect hematopoietic and nonhematopoietic ticoids, still represent effective front-line therapies to treat cells mediate tolerance at the intestinal barrier. For example, inflammatory disease (99), but they have clear disadvantages ILCs maintain dialogue with intestinal epithelial cells (IECs), as a long-term treatment option. Not surprisingly, the medical intestinal dendritic cells, and other cell types to coordinate and biotechnology sectors have taken an interest in translating The Journal of Immunology 569 knowledge of host-microbiota interactions into better standards many inflammatory diseases. Furthermore, rationally designed of care and medicines to treat autoimmune diseases. For ex- therapies that modulate or re-establish beneficial interactions are a ample, therapies aiming to adoptively transfer Tregs or promote promising approach for the treatment of intestinal and extra- their in vivo induction in patients are being explored as thera- intestinal inflammatory diseases. Emergent technologies aim to peutic approaches for IBD (100). Additionally, mAbs have been focus research efforts on identifying the scope and relevance of developed to block cytokine pathways implicated in chronic these interactions more systematically and unambiguously. inflammation. For instance, blockade of the Th1 and Th17 cell pathways by targeting the shared anti-p40 subunit of IL-12/IL- Acknowledgments 23 with the mAb ustekinumab is rapidly advancing through We thank members of the Sonnenberg Laboratory for discussions and critical clinical trials as a novel treatment for moderate-to-severe CD reading of the manuscript. (101, 102). ILCs have received increasing attention as novel targets for the treatment of inflammatory diseases given some of Disclosures their analogous signaling pathways with T cells (103). Clinical The authors have no financial conflicts of interest. investigation on how specific subsets of ILCs respond to approved mAb therapies that target cytokine/cytokine receptor pathways, or novel small molecules targeting transcriptional References regulators, will extend and refine the paradigm of ILC involve- 1. Human Microbiome Project Consortium. 2012. Structure, function and diversity of the healthy human microbiome. Nature 486: 207–214. ment in provoking and resolving inflammatory disease in the 2. Sender, R., S. Fuchs, and R. Milo. 2016. Are we really vastly outnumbered? Downloaded from intestine and in extraintestinal tissues (104–106). revisiting the ratio of bacterial to host cells in humans. Cell 164: 337–340. 3. Hill, D. A., and D. Artis. 2010. 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