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Pattern-recognition receptors (PRRs) are traditionally known to sense microbial molecules during infection to initiate inflammatory responses. However, ligands for PRRs are not exclusive to pathogens and are abundantly produced by the resident microbiota during normal colonization. Mechanism(s) that underlie this paradox have remained unclear. Recent studies reveal that gut bacterial ligands from the microbiota signal through PRRs to promote development of host tissue and the immune system, and protection from disease. Evidence from both invertebrate and vertebrate models reveals that innate immune receptors are required to promote long-term colonization by the microbiota. This emerging perspective challenges current models in immunology and suggests that PRRs may have evolved, in part, to mediate the bidirectional cross-talk between microbial symbionts and their hosts.

Although microbes have been classically viewed as pathogens, it is now well established that the majority of host-bacterial interactions are symbiotic. During development and into adulthood, gut bacteria shape the tissues, cells, and molecular profile of our gastrointestinal immune system. This partnership, forged over many millennia of coevolution, is based on a molecular exchange involving bacterial signals that are recognized by host receptors to mediate beneficial outcomes for both microbes and humans. We explore how specific aspects of the adaptive immune system are influenced by intestinal commensal bacteria. Understanding the molecular mechanisms that mediate symbiosis between commensal bacteria and humans may redefine how we view the evolution of adaptive immunity and consequently how we approach the treatment of numerous immunologic disorders.

Key Points The gut microbiota is spatially stratified along the longitudinal and cross-sectional axes of the gut. Chemical and nutrient gradients, antimicrobial peptides and physical features of the gut contribute to differences in microbial community composition in different locations. The mucosal and lumenal microbiota of the gut represent distinct microbial communities. On a smaller scale, patchiness within these communities suggests that they are highly spatially organized. Diet imparts a large effect on microbial colonization and relative abundance, but some bacteria can thrive independently of dietary changes by living on host-derived nutrients such as mucin glycans. Therefore, the mucus layer can harbour a reservoir of bacteria that is maintained regardless of food intake. The appendix and colonic crypts may also be examples of such microbial reservoirs. Only a subset of gut symbionts are able to access the epithelial surface. Mucus, antimicrobial peptides and adaptive immune activity limit tissue accessibility. Direct interfacing between the host and microbial symbionts may be important for the maintenance of homeostasis. Immunomodulation by certain symbionts allows the host to tolerate intimate relationships with potentially beneficial microorganisms. This may be a way in which commensals distinguish themselves from pathogens and prevent their elimination by the immune system. Although many diseases have been associated with dysbiosis, an understanding of the function of the microbiota in health and disease requires the biogeography of the community to be considered. Recent studies in humans have found differences specific to the mucosal community in cases of inflammatory bowel disease and hepatic encephalopathy. The gut microbiota has a strong impact on host physiology. In this Review, Mazmanian and colleagues describe the mechanisms that control the biogeography of bacteria in the gut and discuss the importance of the spatial localization of the gut microbiota during health and disease. Animals assemble and maintain a diverse but host-specific gut microbial community. In addition to characteristic microbial compositions along the longitudinal axis of the intestines, discrete bacterial communities form in microhabitats, such as the gut lumen, colonic mucus layers and colonic crypts. In this Review, we examine how the spatial distribution of symbiotic bacteria among physical niches in the gut affects the development and maintenance of a resilient microbial ecosystem. We consider novel hypotheses for how nutrient selection, immune activation and other mechanisms control the biogeography of bacteria in the gut, and we discuss the relevance of this spatial heterogeneity to health and disease.

Key Points Germ-free mice have many immunological defects in the intestine, including smaller mesenteric lymph nodes and Peyer's patches, decreased numbers of interleukin-17 (IL-17)-producing T helper 17 (T H 17) cells and defects in regulatory T (T Reg ) cells. In addition, germ-free mice have impaired immune responses to certain pathogens, including Shigella and Listeria species. These findings indicate that the intestinal microbiota might influence both pro- and anti-inflammatory responses. Intestinal homeostasis depends on maintaining a proper balance between pro- and anti-inflammatory pathways that are mediated by T H 17 and T Reg cells, respectively. Improper regulation of inflammatory pathways can lead to diseases such as inflammatory bowel disease (IBD). IBD results from the breakdown in immune tolerance to gut bacteria. Indeed, spontaneous disease does not occur in many mouse models of experimental colitis, including IL-2- and IL-10-deficient mice, when raised under germ-free conditions. Susceptibility to IBD is influenced by many factors, including genetic and dietary factors. However, recent studies have shown that the intestinal microbiota could be an important factor in driving disease. Similar to observations made in animal models, changes in the microbiota of humans have been implicated in disease. Numerous studies have revealed a significant alteration in the microbiota of patients with IBD compared with healthy individuals, although whether changes in the intestinal microbiota are the cause or effect of disease still needs to be determined. Several species of bacteria that peacefully reside in the intestine have been shown to have a protective role during IBD. These bacteria are referred to as probiotic bacteria and include species such as Lactobacillus casei and Bifidobacteria longum . The mechanisms by which these bacteria protect from disease are thought to involve modulation of T Reg cell responses. A product of B. fragilis , polysaccharide A, elicits IL-10 production by CD4 + T cells and mediates protection from IBD, demonstrating that symbiotic intestinal bacteria have developed strategies to influence the host immune system. Does harbouring certain strains of bacteria predispose an individual to disease or protect from it? As symbiotic bacteria seem to have evolved mechanisms to promote protection from potentially pathogenic bacteria in the microbiota, disease may result from the absence of these symbiotic organisms and their beneficial molecules. Therefore, dysbiosis (a shift in the composition of the intestinal microbiota) could be an underlying factor in the development of IBD. Disturbances in the balance between 'good' and 'bad' bacteria that reside in the gut could underlie the development of inflammatory bowel diseases, according to the authors of this Review. They describe how a 'normal' microbiota is required for proper functioning of the immune system. Immunological dysregulation is the cause of many non-infectious human diseases such as autoimmunity, allergy and cancer. The gastrointestinal tract is the primary site of interaction between the host immune system and microorganisms, both symbiotic and pathogenic. In this Review we discuss findings indicating that developmental aspects of the adaptive immune system are influenced by bacterial colonization of the gut. We also highlight the molecular pathways that mediate host–symbiont interactions that regulate proper immune function. Finally, we present recent evidence to support that disturbances in the bacterial microbiota result in dysregulation of adaptive immune cells, and this may underlie disorders such as inflammatory bowel disease. This raises the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms.

To maintain intestinal health, the immune system must faithfully respond to antigens from pathogenic microbes while limiting reactions to self-molecules. The gastrointestinal tract represents a unique challenge to the immune system, as it is permanently colonized by a diverse amalgam of bacterial phylotypes producing multitudes of foreign microbial products. Evidence from human and animal studies indicates that inflammatory bowel disease results from uncontrolled inflammation to the intestinal microbiota. However, molecular mechanisms that actively promote mucosal tolerance to the microbiota remain unknown. We report herein that a prominent human commensal, Bacteroides fragilis, directs the development of Foxp3⁺ regulatory T cells (Tregs) with a unique \"inducible\" genetic signature. Monocolonization of germ-free animals with B. fragilis increases the suppressive capacity of Tregs and induces anti-inflammatory cytokine production exclusively from Foxp3⁺ T cells in the gut. We show that the immunomodulatory molecule, polysaccharide A (PSA), of B. fragilis mediates the conversion of CD4⁺ T cells into Foxp3⁺ Treg cells that produce IL-10 during commensal colonization. Functional Foxp3⁺ Treg cells are also produced by PSA during intestinal inflammation, and Toll-like receptor 2 signaling is required for both Treg induction and IL-10 expression. Most significantly, we show that PSA is not only able to prevent, but also cure experimental colitis in animals. Our results therefore demonstrate that B. fragilis co-opts the Treg lineage differentiation pathway in the gut to actively induce mucosal tolerance.

Germ-free mice mono-associated with a single species of Bacteroides are found to be resistant to further colonization by the same, but not different, species; a unique class of polysaccharide utilization loci that is required for the penetration of the colonic mucus and colonization of the crypt channel niche is discovered that explains this observed species-specific saturable colonization. Stabilizing the gut microbiota The molecular processes used by bacteria to successfully colonize the gastrointestinal tract are poorly understood. Here Sarkis Mazmanian and colleagues report the surprising finding that germ-free mice mono-associated with a single species of Bacteroides are resistant to further colonization by the same, but not different, species. The authors go on to identify a unique class of polysaccharide utilization proteins — named commensal colonization factors (CCFs) — that is conserved among intestinal Bacteroides. The ccf genes of Bacteroides fragilis are required for penetration of the colonic mucus and colonization of the crypt channel niche, providing a mechanistic understanding for the observed species-specific saturable colonization. Mammals harbour a complex gut microbiome, comprising bacteria that confer immunological, metabolic and neurological benefits 1 . Despite advances in sequence-based microbial profiling and myriad studies defining microbiome composition during health and disease, little is known about the molecular processes used by symbiotic bacteria to stably colonize the gastrointestinal tract. We sought to define how mammals assemble and maintain the Bacteroides , one of the most numerically prominent genera of the human microbiome. Here we find that, whereas the gut normally contains hundreds of bacterial species 2 , 3 , germ-free mice mono-associated with a single Bacteroides species are resistant to colonization by the same, but not different, species. To identify bacterial mechanisms for species-specific saturable colonization, we devised an in vivo genetic screen and discovered a unique class of polysaccharide utilization loci that is conserved among intestinal Bacteroides . We named this genetic locus the commensal colonization factors ( ccf ). Deletion of the ccf genes in the model symbiont, Bacteroides fragilis , results in colonization defects in mice and reduced horizontal transmission. The ccf genes of B. fragilis are upregulated during gut colonization, preferentially at the colonic surface. When we visualize microbial biogeography within the colon, B. fragilis penetrates the colonic mucus and resides deep within crypt channels, whereas ccf mutants are defective in crypt association. Notably, the CCF system is required for B. fragilis colonization following microbiome disruption with Citrobacter rodentium infection or antibiotic treatment, suggesting that the niche within colonic crypts represents a reservoir for bacteria to maintain long-term colonization. These findings reveal that intestinal Bacteroides have evolved species-specific physical interactions with the host that mediate stable and resilient gut colonization, and the CCF system represents a novel molecular mechanism for symbiosis.

The gut commensal Bacteroides fragilis or its capsular polysaccharide A (PSA) can prevent various peripheral and CNS sterile inflammatory disorders. Fatal herpes simplex encephalitis (HSE) results from immune pathology caused by uncontrolled invasion of the brainstem by inflammatory monocytes and neutrophils. Here we assess the immunomodulatory potential of PSA in HSE by infecting PSA or PBS treated 129S6 mice with HSV1, followed by delayed Acyclovir (ACV) treatment as often occurs in the clinical setting. Only PSA-treated mice survived, with dramatically reduced brainstem inflammation and altered cytokine and chemokine profiles. Importantly, PSA binding by B cells is essential for induction of regulatory CD4 + and CD8 + T cells secreting IL-10 to control innate inflammatory responses, consistent with the lack of PSA mediated protection in Rag −/− , B cell- and IL-10-deficient mice. Our data reveal the translational potential of PSA as an immunomodulatory symbiosis factor to orchestrate robust protective anti-inflammatory responses during viral infections. The capsular polysaccharide A (PSA) of Bacteroides fragilis is known to have immunomodulatory capability during sterile inflammatory disorders. Here Ramakrishna and colleagues show that PSA administration in a murine model of herpes simplex encephalitis induces IL-10 producing B and T cell populations that confer protection against lethal challenge and brain pathology.

Although the effects of commensal bacteria on intestinal immune development seem to be profound, it remains speculative whether the gut microbiota influences extraintestinal biological functions. Multiple sclerosis (MS) is a devastating autoimmune disease leading to progressive deterioration of neurological function. Although the cause of MS is unknown, microorganisms seem to be important for the onset and/or progression of disease. However, it is unclear how microbial colonization, either symbiotic or infectious, affects autoimmunity. Herein, we investigate a role for the microbiota during the induction of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice maintained under germ-free conditions develop significantly attenuated EAE compared with conventionally colonized mice. Germ-free animals, induced for EAE, produce lower levels of the proinflammatory cytokines IFN-γ and IL-17A in both the intestine and spinal cord but display a reciprocal increase in CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs). Mechanistically, we show that gut dendritic cells from germ-free animals are reduced in the ability to stimulate proinflammatory T cell responses. Intestinal colonization with segmented filamentous bacteria (SFB) is known to promote IL-17 production in the gut; here, we show that SFBs also induced IL-17A-producing CD4⁺ T cells (Th17) in the CNS. Remarkably, germ-free animals harboring SFBs alone developed EAE, showing that gut bacteria can affect neurologic inflammation. These findings reveal that the intestinal microbiota profoundly impacts the balance between pro- and antiinflammatory immune responses during EAE and suggest that modulation of gut bacteria may provide therapeutic targets for extraintestinal inflammatory diseases such as MS.

Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells and also inhibits in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin-10-producing CD4 + T cells. These results show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles. A gut issue: Bacterial symbiosis shapes a healthy immune response (Nature Cover 29 May 2008) Microbiologists are beginning to understand how and why mammals are colonized by multitudes of symbiotic bacteria. But what differentiates 'good' from benign or harmful bacteria remains largely unknown. The intestinal microbe Bacteroides fragilis was shown in 2005 to have profound effect on the mammalian immune system, an effect ascribed to a single molecule, capsular polysaccharide A (PSA). Now B. fragilis PSA is shown to protect animals against both bacterial and chemical colitis in a process involving interleukin-10-producing T cells. This suggests that B. fragilis helps maintain human health by suppressing the intestinal inflammatory response, and that symbiosis factors may provide a route to new therapies. In the cover graphic (by Tom DiCesere, Sarkis Mazmanian & Dennis Kasper), In the cover graphic, PSA (yellow) surrounds B. fragilis (green) in the intestine and is taken up by a dendritic cell and processed within the endosomal pathway to a reduced molecular size. The depolymerized PSA is presented by the major histocompatibility complex class II molecule to the CD4 + T cell (green, white, yellow), which becomes activated. Work in this field is being promoted by several major efforts to characterize the human microbiota and determine its role in health and disease, including the Human Microbiome Project. In News Features, Asher Mullard examines the various approaches, and Apoorva Mandavilli reports on a rare opportunity to watch the gut being colonized from scratch after intestinal transplants. Bacteroides fragilis is a member of the human intestinal microbiota. It is reported that a single molecule produced by this bacterium, polysaccharide A, can suppress the intestinal inflammatory response and thus protect from experimental colitis.

Amyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated with neurodegenerative diseases. While genetic and environmental factors can influence amyloid formation, molecular triggers and/or facilitators are not well defined. Growing evidence suggests that non-identical amyloid proteins may accelerate reciprocal amyloid aggregation in a prion-like fashion. While humans encode ~30 amyloidogenic proteins, the gut microbiome also produces functional amyloids. For example, curli are cell surface amyloid proteins abundantly expressed by certain gut bacteria. In mice overexpressing the human amyloid α-synuclein (αSyn), we reveal that colonization with curli-producing Escherichia coli promotes αSyn pathology in the gut and the brain. Curli expression is required for E. coli to exacerbate αSyn-induced behavioral deficits, including intestinal and motor impairments. Purified curli subunits accelerate αSyn aggregation in biochemical assays, while oral treatment of mice with a gut-restricted amyloid inhibitor prevents curli-mediated acceleration of pathology and behavioral abnormalities. We propose that exposure to microbial amyloids in the gastrointestinal tract can accelerate αSyn aggregation and disease in the gut and the brain.