Mice deficient in RA harbor reduced numbers of segmented filamentous bacteria SFB , which might contribute to the decreased number of T helper 17 T H 17 cells present in vitamin A-deficient mice Gaboriau-Routhiau et al. Accordingly, mice fed a diet deficient in vitamin A were reported to feature inhibited T H 17 cell differentiation in the lamina propria of the small intestine Cha et al.
RA was also shown to be important for the expression of gut-homing molecules on immune cells. In the absence of TLR signaling in MyDdeficient mice, intestinal DCs express low levels of retinal dehydrogenases, a critical enzyme for RA biosynthesis, and are impaired in their ability to induce gut-homing lymphocytes Iwata et al.
The impact of vitamin A even reaches beyond T-cell immunity. In the absence of vitamin A, the numbers of ILC3s are strongly diminished, while ILC2 cells and their immune program became more dominant Spencer et al. A similar phenomenon can be observed in adaptive lymphocytes, where T H 2 cells expand under vitamin A-deficient conditions on the expense of T H 1 and T H 17 immunity Pino-Lagos et al.
Together, these studies highlight the power of a diet-derived and microbiota-modulated metabolite in directing a specific type of immune response. Other vitamins can likewise participate in the post-developmental fate decisions of leukocytes. For instance, vitamin D profoundly affects T-cell activation von Essen et al.
Several studies have linked vitamin D deficiency to inflammatory bowel disease susceptibility Sun , and vitamin D receptor expression is significantly lower in IBD- and colitis-associated colon cancer patients Abreu et al. The link between the gut microbiota and vitamins is particularly apparent in the case of vitamins belonging to B and K groups, as, in their case, the host is unable to perform the biosynthetic reactions and depends on members of the commensal microbiota Roth et al. Vitamin B12 deficiency results in a decreased number of lymphocytes and suppressed NK cell activity Tamura et al.
The quintessential task of mutualistic host—microbiota interactions at mucosal surfaces is the preservation of tissue homeostasis. Over the last decade, several microbial molecules have been identified that aid in the orchestration of the tightrope walk between immunity and tolerance at the mucosal—bacterial interface Fig.
A common strategy by several such molecules is the promotion of an anti-inflammatory response. It was first demonstrated that monocolonization of germ-free mice with B. Later, it was shown that PSA of B.
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The recognition of PSA by TLR2 specifically expressed on Treg cells induces their activation, which in turn leads to suppression of the inflammatory response. This circuit is required for the colonization of B. Such metabolite-induced feedback loops might emerge as a common theme in the regulation of a stable microbial colonization by the immune system.
This is best illustrated by the epithelial innate immune sensor NLRP6, a member of the NOD-like receptor family, which is involved in viral recognition as well as inflammasome formation Levy et al. The inflammasome pathway is influenced by the microbiota-modulated metabolites taurine, histamine, and spermine, thereby regulating the level of epithelial IL production, anti-microbial peptide secretion, and intestinal community composition Levy et al.
Thus, the metabolic activity of the microbiome is sensed by the immune system, and this sensing is translated into an anti-microbial response aimed at maintaining a stable colonization. If this pathway is disturbed in genetically modified mice, dysbiosis arises, leading to the manifestation of intestinal autoinflammation Elinav et al. In addition to the amino acids that modulate NLRP6 signaling, other amino acids are involved in the maintenance of intestinal homeostasis. It was shown that protein malnutrition and specifically tryptophan depletion alters the severity of intestinal inflammation Hashimoto et al.
Angiotensin-converting enzyme 2 ACE2 controls the expression of the neutral amino acid transporter in the intestine. Transplantation of the gut microbiota to germ-free mice transfers the inflammatory phenotype and susceptibility to colitis, while a tryptophan-rich diet reverses microbial composition in this model Hashimoto et al. IDO1 activity was shown to inhibit IL, which, in a model of atherosclerosis, leads to ameliorated disease Metghalchi et al.
In addition to tryptophan, the microbiota is pivotal for the regulation of intestinal levels of the amino acid arginine, which in turn exerts a modulatory effect on the immune system. Germ-free mice feature elevated levels of arginine, indicating that commensal bacteria are involved in the metabolism of arginine to downstream derivatives, including polyamines Matsumoto et al. Correspondingly, polyamine levels are strongly diminished in the absence of the microbiome Matsumoto et al. Polyamines in turn exert their immunomodulatory effect on various cell types, including macrophages and epithelial cells, where they contribute to suppressed inflammation Kibe et al.
Although arginine is primarily metabolized in the liver, immune cells can also serve as an extrahepatic source for arginase-1 Arg1 activity during infection and inflammation Raber et al. Myeloid cell Arg1 has immunosuppressive capacities Rodriguez et al. A further example of an anti-inflammatory molecule produced by the microbiota is provided by SCFAs, which have been briefly discussed above in the context of their impact on hematopoiesis, indicating that certain metabolites may perform a multitude of functions at several layers of immune regulation.
The anti-inflammatory effect of SCFAs has been well characterized in both immune cells and epithelial cells. The intestinal microbiota, through the production of SCFAs, can suppress inflammation through several distinct mechanisms. Germ-free mice as well as colonized mice treated with acetate show ameliorated severity of DSS-induced colitis, and this beneficial effect is dependent on the receptor GPR As in the case of immune system development, SFCAs exert their symbiosis-promoting effects both locally at the tissue level and systemically.
A low-fiber diet increased the severity of allergic airway inflammation, while propionate administration protected from airway inflammation with reduced amounts of IL-4, IL-5, IL, and IL in the lung Trompette et al. Another major function of SCFAs in dampening the inflammatory response is the regulation of colonic Treg homeostasis Atarashi et al. SCFAs were shown to selectively expand Tregs in the large intestine. Interestingly, a mixture of Clostridia species, which are a prominent source of SCFA production, induced the development of Tregs and the production of the anti-inflammatory cytokine IL Atarashi et al.
SCFAs also facilitate peripheral extrathymic generation of Tregs through a different mechanism Furusawa et al. Butyrate epigenetically regulates gene expression through inhibition of histone deacetylases HDACs , resulting in enhanced histone acetylation in the noncoding sequences of the FoxP3 locus Arpaia et al. The role of butyrate as a HDAC inhibitor was also shown to contribute to the suppression of inflammatory response by intestinal macrophages Chang et al. Taken together, these results highlight the central importance of SCFAs in the communication between the microbiome and the host immune system.
The study of metabolites as messengers between the microbiota and the immune system has initiated a paradigm change in our understanding of host—microbial interactions. The increasing mechanistic knowledge about how microbiota metabolism shapes the physiology of its host impacts at least three areas of fundamental importance to both the conceptualization of host—microbiota interactions and its translation to clinical applications.
First, the discoveries made in the field of microbiome research over the last decade have challenged our model of how the immune system recognizes and eliminates micro-organisms upon contact with the host. The notion that microbial recognition by pattern recognition receptors of the innate immune system inevitably leads to the initiation of an immune and inflammatory response that aims at achieving eradication of the microbial trigger cannot possibly apply to the situation of colonization by commensal microbes.
As such, the mechanisms of an immune response to pathogenic infection, studied in detail for almost a century, might represent the exception rather than the rule with regard to microbial handling by the immune system. The conceptual difficulty in the distinction between commensal colonization and pathogenic infection by the immune system lies in the fact that the ligands of all known pattern recognition receptors are conserved molecular structures that are essential for microbial existence and therefore shared across the spectrum of pathogenic and nonpathogenic micro-organisms.
To reconcile these apparently opposing concepts, microbial viability, localization, and virulence factor expression have been suggested as hallmarks of pathogen-induced immune responses Sander et al. The discovery of bacterial metabolites as modulators of immune responses adds an important facet to our understanding of the distinction between mutualism and pathogenicity at the host—microbial interface. By sensing microbial metabolites, the immune system may evaluate microbial activity rather than the mere presence or absence of micro-organisms at a given location.
The metabolite profile characteristic of a pathogenic invasion likely differs from the one characteristic of homeostasis, and thus this change in metabolite composition and concentrations may be sensed by the immune system as a deviation from homeostatic set points to initiate an appropriate inflammatory response.
Second, despite the rapid progress over the last decade in the identification of bacterial drivers of human diseases, the selective eradication of disease-associated micro-organisms from the intestinal microbial community remains a major challenge. Currently, antibiotics and fecal microbiota transplantation are the only clinically approved approaches to targeting a disease-causing microbiota.
The use of antibiotics in the treatment of aberrant host—microbial interactions resembles the use of chemotherapy in cancer treatment in that it removes the causative agent of a disease at the cost of major disruptions in the endogenous cellular organization. Similarly, the effectiveness of fecal microbiota transplantation is based on the replacement of the entire intestinal community—a radical intervention resulting in an often unpredictable outcome.
The identification of specific microbiota-derived metabolites and their effect on the host immune system has provided mechanistic insights that are much more tangible than the association of disease phenotypes with microbial taxa in large data set collections. On the one hand, metabolites are ideally suited as biomarkers for disease development, as their detection is usually affordable and scalable and may precede the onset of clinically manifest disease symptoms.
On the other hand, the causal involvement of microbiota-derived metabolites in the molecular etiology of human disease presents direct opportunities for the rational development of new patient-tailored therapies. Beneficial metabolites can be administered with typically easy-to-control pharmacokinetics and without the danger of inadvertent immune responses to the drug. In addition, disease-associated metabolites can be targeted by pharmacological or nutritional intervention, potentially without strong interference from the homeostatic metabolism.
The first proof of principal studies have included microbial targeting of the TMAO metabolism in the treatment of atherosclerosis Wang et al. Third, the microbiome harbors a sheer endless reservoir of metabolic capabilities, which has led to the suggestion that, while the cataloging of microbial taxa that colonize mammalian mucosal surfaces may reach saturation within the next decade of microbiome research, the assessment of the entirety of the chemical complexity encoded by the microbiome is still in its infancy. This is interesting with regard to the pharmacologic opportunities mentioned above but may also help to better define a fundamental aspect of host—microbiota interactions; namely, the evolutionary teleology of microbial niche construction through modulation of the host immune system.
The initial goal at early stages of the Human Microbiome Project had been to define a core microbiome shared by all individuals, motivated by the assumption that coevolution between the microbiota and its host has yielded an indispensable canon of bacteria characteristic of the intestinal community in the human gut Turnbaugh et al.
With the study of metabolites as common outputs of bacterial metabolic function, the notion of a functional core can be revisited. It is conceivable that different taxonomic groups of bacteria have evolved to perform similar metabolic functions and are thus classifiable by the type of metabolites that they produce and, consequently, the type of physiologic response that they elicit in the host.
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One may speculate that, despite the vast taxonomic diversity and variability that has been documented in cataloging studies of various human microbiomes to date, the members of the commensal microbiota can be classified into a limited variety of functional subsets with respect to their metabolite profile Thaiss and Elinav Therefore, distinct groups of bacteria with niche-specific immunomodulatory activity might have evolved, employing similar metabolic pathways and metabolite signatures for the maintenance of homeostatic colonization.
Such a level of understanding regarding the molecular details of colonization mechanisms and immune cell—microbiota cross-talk would open up a new area in this young field of study, resulting in numerous possibilities for the therapeutic exploitation of basic discoveries.
We thank the members of the Elinav laboratory for fruitful discussions. We apologize to investigators whose relevant work was not included in this review owing to space constraints. Weber; Mr. Donald L. View all Metabolites: messengers between the microbiota and the immune system Maayan Levy 1 , Christoph A.
[The role of gut microbiota in the regulation of the immune response].
Figure 1. Previous Section Next Section. Short chain fatty acids SCFAs Among the most abundant molecules produced by gut bacteria are SCFAs, which have been found recently to control multiple aspects of human immunity and metabolism Morrison and Preston Tryptophan metabolites One prominent example of how the microbiota impacts tissue-level immune maturation is the microbial metabolism of tryptophan.
Retinoic acid RA In addition to the orchestration of immune system maturation, metabolites fine-tune immune responses at the level of post-developmental differentiation. Previous Section.
Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn's disease patients with elevated 1,dihydroxyvitamin D and low bone mineral density. Gut 53 : — Mol Cell Biol 33 : — Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature : — Induction of colonic regulatory T cells by indigenous Clostridium species. Science : — T reg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Mucosal Immunol 8 : — Bacteria live on the skin, in the nose and ears, and, most of all, in the gut.
Until recently, if most people thought about those bacteria at all, we tended to think of them as fairly separate from us. They help with digestion, but otherwise they stay on their side of the intestinal lining, and we stay on our side. For example, certain cells in the lining of the gut spend their lives excreting massive quantities of antibodies into the gut. Cynthia Sears , a professor of medicine at Johns Hopkins and member of its Kimmel Cancer Center, studies the role of the microbiome in causing colon cancer in mice and humans.
Colon cancer seems to stem from an interaction among the microbiome, the immune system and epithelial cells that line the colon. The protein sets off a huge array of actions in the epithelial cells that line the colon. In certain mice, it can cause inflammation and cancer of the colon.
This is largely thought to be useful for fighting off bacteria and fungi, but it can also turn against the body and cause cancer in the colon. No one species has been found to always cause colon cancer in humans. Instead, carcinogenesis may have to do with a shift in the ecology of the gut—that is, in the makeup of the bacterial community.
Scientists have suspected since the s that bacteria contribute to colon cancer. She has studied the role of the gut microbiome in another disease: tuberculosis. Winglee and Bishai thought the microbiome might provide a faster way to diagnose TB than the current gold-standard test, which takes weeks. Winglee infected five mice with TB.
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Then, she collected stool samples once a month until the mice died and analyzed the genetic material they contained. She found that TB changed the bacterial communities significantly. Soon after infection, the diversity of the gut microbiota dropped off. As time went on, the samples became more diverse, but with different bacteria than were there before the mice got TB.
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Metabolites as drivers of immune system development and differentiation
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Expansion of intestinal prevotella copri correlates with enhanced susceptibility to arthritis. Intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol. Download references. NS and NL performed the literature search and wrote the main body of the manuscript. XD provided critical writing in the revised manuscript. HN designed and instructed the writing of the manuscript. All authors read and approved the final manuscript. Correspondence to Haitao Niu. Reprints and Permissions.
Search all BMC articles Search. Abstract The gut microbiota, the largest symbiotic ecosystem with the host, has been shown to play important roles in maintaining intestinal homeostasis. Background The mammalian gut contains a microbial community, defined as the microbiome, which includes bacteria, viruses, fungi, etc. The intestinal mucosal immune system The immune system is regulated by immune organs, immune cells, soluble cytokines and cell receptors.
Gut microbiome and mucosal immunity Over the course of evolution, the microbiome maintains symbiosis with the gut environment. The dysbiosis of the gut microbiome induces intestinal diseases The intestinal microbiota and mucosal immunity constantly interact to achieve intestinal homeostasis. Effects of gut microbiome and mucosal immunity in autoimmune diseases The pathogenetic mechanism of systemic autoimmune diseases remains unclear; genetic and environmental factors may have certain effects.
Conclusions In summary, intestinal microbiota coordinates to shape host immunity and contribute to maintaining intestinal homeostasis and inhibiting inflammation. References 1. Article PubMed Google Scholar 5. Article Google Scholar 7. Article Google Scholar Article PubMed Google Scholar CAS Google Scholar Availability of data and materials Not applicable. Competing interests The authors declare that they have no competing interests.