Innate immune signaling in defense against intestinal microbes

The gastrointestinal system is a common entry point for pathogenic microbes to access the inner environment of the body. Anti-microbial factors produced by the intestinal mucosa limit the translocation of both commensal and pathogenic microbes across the intestinal epithelial cell barrier. The regulation of these host defense mechanisms largely depends on the activation of innate immune receptors by microbial molecules. Under steady-state conditions, the microbiota provides constitutive signals to the innate immune system, which helps to maintain a healthy inflammatory tone within the intestinal mucosa and, thus, enhances resistance to infection with enteric pathogens. During an acute infection, the intestinal epithelial cell barrier is breached, and the detection of microbial molecules in the intestinal lamina propria rapidly stimulates innate immune signaling pathways that coordinate early defense mechanisms. Herein, we review how microbial molecules shed by both commensal and pathogenic microbes direct host defenses at the intestinal mucosa. We highlight the signaling pathways, effector molecules, and cell populations that are activated by microbial molecule recognition and, thereby, are involved in the maintenance of homeostatic levels of host defense and in the early response to acute enteric infection. Finally, we discuss how manipulation of these host defense pathways by stimulating innate immune receptors is a potential therapeutic strategy to prevent or alleviate intestinal disease.     

Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases

The gut microbiota has a critical role in the maintenance of immune homeostasis. Alterations in the intestinal microbiota and gut microbiota-derived metabolites have been recognized in many immune-related inflammatory disorders. These metabolites can be produced by gut microbiota from dietary components or by the host and can be modified by gut bacteria or synthesized de novo by gut bacteria. Gut microbiota-derived metabolites influence a plethora of immune cell responses, including T cells, B cells, dendritic cells, and macrophages. Some of these metabolites are involved in the pathogenesis of immune-related inflammatory diseases, such as inflammatory bowel diseases, diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Here, we review the role of microbiota-derived metabolites in regulating the functions of different immune cells and the pathogenesis of chronic immune-related inflammatory diseases.     

Emerging roles of host and microbial bioactive lipids in inflammatory bowel diseases

The intestinal tract harbors diverse microorganisms, host- and microbiota-derived metabolites, and potentially harmful dietary antigens. The epithelial barrier separates the mucosa, where diverse immune cells exist, from the lumen to avoid excessive immune reactions against microbes and dietary antigens. Inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease, is characterized by a chronic and relapsing disorder of the gastrointestinal tract. Although the precise etiology of IBD is still largely unknown, accumulating evidence suggests that IBD is multifactorial, involving host genetics and microbiota. Alterations in the metabolomic profiles and microbial community are features of IBD. Advances in mass spectrometry–based lipidomic technologies enable the identification of changes in the composition of intestinal lipid species in IBD. Because lipids have a wide range of functions, including signal transduction and cell membrane formation, the dysregulation of lipid metabolism drastically affects the physiology of the host and microorganisms. Therefore, a better understanding of the intimate interactions of intestinal lipids with host cells that are implicated in the pathogenesis of intestinal inflammation might aid in the identification of novel biomarkers and therapeutic targets for IBD. This review summarizes the current knowledge on the mechanisms by which host and microbial lipids control and maintain intestinal health and diseases.     

Mucosal innate immune cells regulate both gut homeostasis and intestinal inflammation

Continuous exposure of intestinal mucosal surfaces to diverse microorganisms and their metabolites reflects the biological necessity for a multifaceted, integrated epithelial and immune cell‐mediated regulatory system. The development and function of the host cells responsible for the barrier function of the intestinal surface (e.g., M cells, Paneth cells, goblet cells, and columnar epithelial cells) are strictly regulated through both positive and negative stimulation by the luminal microbiota. Stimulation by damage‐associated molecular patterns and commensal bacteria‐derived microbe‐associated molecular patterns provokes the assembly of inflammasomes, which are involved in maintaining the integrity of the intestinal epithelium. Mucosal immune cells located beneath the epithelium play critical roles in regulating both the mucosal barrier and the relative composition of the luminal microbiota. Innate lymphoid cells and mast cells, in particular, orchestrate the mucosal regulatory system to create a mutually beneficial environment for both the host and the microbiota. Disruption of mucosal homeostasis causes intestinal inflammation such as that seen in inflammatory bowel disease. Here, we review the recent research on the biological interplay among the luminal microbiota, epithelial cells, and mucosal innate immune cells in both healthy and pathological conditions.     

B cells as a critical node in the microbiota–host immune system network

Mutualism with our intestinal microbiota is a prerequisite for healthy existence. This requires physical separation of the majority of the microbiota from the host (by secreted antimicrobials, mucus, and the intestinal epithelium) and active immune control of the low numbers of microbes that overcome these physical and chemical barriers, even in healthy individuals. In this review, we address how B-cell responses to members of the intestinal microbiota form a robust network with mucus, epithelial integrity, follicular helper T cells, innate immunity, and gut-associated lymphoid tissues to maintain host–microbiota mutualism.     

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

The intestinal epithelium forms a barrier between the microbiota and the rest of the body. In addition, beyond acting as a physical barrier, the function of intestinal epithelial cells (IECs) in sensing and responding to microbial signals is increasingly appreciated and likely has numerous implications for the vast network of immune cells within and below the intestinal epithelium. IECs also respond to factors produced by immune cells, and these can regulate IEC barrier function, proliferation and differentiation, as well as influence the composition of the microbiota. The mechanisms involved in IEC–microbe–immune interactions, however, are not fully characterized. In this review, we explore the ability of IECs to direct intestinal homeostasis by orchestrating communication between intestinal microbes and mucosal innate and adaptive immune cells during physiological and inflammatory conditions. We focus primarily on the most recent findings and call attention to the numerous remaining unknowns regarding the complex crosstalk between IECs, the microbiota and intestinal immune cells.     

Crossing the barriers: Revisiting the gut feeling in rheumatoid arthritis

To avoid autoimmunity, it is essential to keep the balance between the defence against pathogens and the maintenance of tolerance to self-antigens. Mucosal inflammation may lead to breakdown of tolerance and activation of autoreactive cells. Growing evidence suggests a major contribution of gut microbiota to the onset of chronic, autoimmune inflammatory diseases including rheumatoid arthritis (RA). RA patients show significant differences in the composition of gut microbiota compared to healthy controls, and in murine arthritis models certain bacteria can induce inflammatory Th17 responses or autoantibody production. The gut microbiota plays an important role in regulating the balance between immunogenic and tolerogenic immune responses. The intestinal barrier is the site of the body where most host–microbiota interaction takes place. Certain microbiota or their metabolites can cause a break in homeostasis by affecting the intestinal barrier integrity and permeability. However, an intact intestinal barrier is essential to separate the intestinal epithelium from toxins, microorganisms, and antigens in the gut lumen. This review will focus on the correlation between a leaky gut and the onset of arthritis. Furthermore, it will be discussed how targeting the intestinal barrier function by dietary changes might provide an opportunity to modulate the development of RA.     

Microbial metabolites,short‐chain fatty acids,restrain tissue bacterial load,chronic inflammation,and associated cancer in the colon of mice

The intestinal immune system is regulated by microbes and their metabolites. The roles of gut microbial metabolites in regulating intestinal inflammation and tumorigenesis are incompletely understood. We systematically studied the roles of short‐chain fatty acids (SCFAs) and their receptors (GPR43 or GPR41) in regulating tissue bacterial load, acute versus chronic inflammatory responses, and intestinal cancer development. SCFA receptor‐, particularly GPR43‐, deficient mice were defective in mounting appropriate acute immune responses to promote barrier immunity, and developed uncontrolled chronic inflammatory responses following epithelial damage. Further, intestinal carcinogenesis was increased in GPR43‐deficient mice. Dietary fiber and SCFA administration suppressed intestinal inflammation and cancer in both GPR43‐dependent and independent manners. The beneficial effect of GPR43 was not mediated by altered microbiota but by host tissue cells and hematopoietic cells to a lesser degree. We found that inability to suppress commensal bacterial invasion into the colonic tissue is associated with the increased chronic Th17‐driven inflammation and carcinogenesis in the intestine of GPR43‐deficient mice. In sum, our results reveal the beneficial function of the SCFA‐GPR43 axis in suppressing bacterial invasion and associated chronic inflammation and carcinogenesis in the colon.     

An epithelial armamentarium to sense the microbiota

Intestinal epithelial cells were once thought to be inert, non-responsive cells that simply acted as a physical barrier that prevents the contents of the intestinal lumen from accessing the underlying tissue. However, it is now clear that these cells express a full repertoire of Toll- and Nod-like receptors, and that their activation by components of the microbiota is vital for the development of a functional epithelium, maintenance of barrier integrity, and defense against pathogenic organisms. Additionally, mounting evidence suggests that epithelial sensing of bacteria plays a significant role in the management of the numbers and types of microbes present in the gut microbiota via the production of antimicrobial peptides and other microbe-modulatory products. This is a critical process, as it is now becoming apparent that alterations in the composition of the microbiota can predispose an individual to a wide variety of chronic diseases. In this review, we will discuss the bacterial pattern recognition receptors that are known to be expressed by the intestinal epithelium, and how each of them individually contributes to these vital protective functions. Moreover, we will review what is known about the communication between epithelial cells and various classes of underlying leukocytes, and discuss how they interact with the microbiota to form a three-part relationship that maintains homeostasis in the gut.     

The mammalian intestinal epithelium as integral player in the establishment and maintenance of host-microbial homeostasis

Only one single layer of epithelial cells separates the densely colonized and environmentally exposed intestinal lumen from the largely sterile subepithelial tissue. Together with the overlaying mucus and the subepithelial mucosal immune system the epithelium has evolved to maintain homeostasis in the presence of the enteric microbiota. It also contributes to rapid and efficient antimicrobial host defence in the event of infection with pathogenic microorganisms. Both, epithelial antimicrobial host defence and homeostasis rely on signalling pathways induced by innate immune receptors demonstrating the active role of epithelial cells in the host-microbial interplay. The interaction of epithelial cells with professional immune cells illustrates the integrated function within the mucosal tissue. In the present review we focus on structural and functional changes of the intestinal epithelium during the fetal-neonatal transition and infancy and try to delineate its role in the induction and maintenance of host-microbial homeostasis. We also address factors that impair epithelial functions and may lead to disruption of the mucosal barrier, tissue damage and the development of symptomatic disease.     

Metabolism at the centre of the host–microbe relationship

Maintaining homoeostatic host–microbe interactions is vital for host immune function. The gut microbiota shapes the host immune system and the immune system reciprocally shapes and modifies the gut microbiota. However, our understanding of how these microbes are tolerated and how individual, or communities of, gut microbes influence host function is limited. This review will focus on metabolites as key mediators of this complex host–microbe relationship. It will look at the central role of epithelial metabolism in shaping the gut microbiota, how microbial metabolites influence the epithelium and the mucosal and peripheral immune system, and how the immune system shapes microbial composition and metabolism. Finally, this review will look at how metabolites are involved in cross-talk between different members of the microbiota and their role during infections.     

Paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa

Mucosal surfaces are colonized by a diverse and dynamic microbiota. Much investigation has focused on bacterial colonization of the intestine, home to the vast majority of this microbiota. Experimental evidence has highlighted that these colonizing microbes are essential to host development and homeostasis, but less is known about host factors that may regulate the composition of this ecosystem. While evidence shows that IgA has a role in shaping this microbiota, it is likely that effector molecules of the innate immune system are also involved. One hypothesis is that gene-encoded antimicrobial peptides, key elements of innate immunity throughout nature, have an essential role in this regulation. These effector molecules characteristically have activity against a broad spectrum of bacteria and other microbes. At mucosal surfaces, antimicrobial peptides may affect the numbers and/or composition of the colonizing microbiota. In humans and other mammals, defensins are a predominant class of antimicrobial peptides. In the small intestine, Paneth cells (specialized secretory epithelial cells) produce high quantities of defensins and several other antibiotic peptides and proteins. Data from murine models indicate that Paneth cell defensins play a pivotal role in defense from food and water-borne pathogens in the intestinal lumen. Recent studies in humans provide evidence that reduced Paneth cell defensin expression may be a key pathogenic factor in ileal Crohn's disease, a subgroup of inflammatory bowel disease (IBD), and changes in the colonizing microbiota may mediate this pathogenic mechanism. It is also possible that low levels of Paneth cell defensins, characteristic of normal intestinal development, may predispose premature neonates to necrotizing enterocolitis (NEC) through similar close links with the composition of the intestinal microbiota. Future studies to further define mechanisms by which defensins and other host factors regulate the composition of the intestinal microbiota will likely provide new insights into intestinal homeostasis and new therapeutic strategies for inflammatory and infectious diseases of the bowel.     

The interaction of intestinal microbiota and innate lymphoid cells in health and disease throughout life

Immunity is shaped by commensal microbiota. From early life onwards, microbes colonize mucosal surfaces of the body and thereby trigger the establishment of immune homeostasis and defense mechanisms. Recent evidence reveals that the family of innate lymphoid cells (ILCs), which are mainly located in mucosal tissues, are essential in the maintenance of barrier functions as well as in the initiation of an appropriate immune response upon pathogenic infection. In this review, we summarize recent insights on the functional interaction of microbiota and ILCs at steady-state and throughout life. Furthermore, we will discuss the interplay of ILCs and the microbiota in mucosal infections focusing on intestinal immunity.     

Microbiota and host immune responses: a love–hate relationship

A complex relationship between the microbiota and the host emerges early at birth and continues throughout life. The microbiota includes the prokaryotes, viruses and eukaryotes living among us, all of which interact to different extents with various organs and tissues in the body, including the immune system. Although the microbiota is most dense in the lower intestine, its influence on host immunity extends beyond the gastrointestinal tract. These interactions with the immune system operate through the actions of various microbial structures and metabolites, with outcomes ranging from beneficial to deleterious for the host. These differential outcomes are dictated by host factors, environment, and the type of microbes or products present in a specific ecosystem. It is also becoming clear that the microbes are in turn affected and respond to the host immune system. Disruption of this complex dialogue between host and microbiota can lead to immune pathologies such as inflammatory bowel diseases, diabetes and obesity. This review will discuss recent advances regarding the ways in which the host immune system and microbiota interact and communicate with one another.     

The gut mucus network: A dynamic liaison between microbes and the immune system

A complex mucus network made up of large polymers of the mucin-family glycoprotein MUC2 exists between the large intestinal microbial mass and epithelial and immune cells. This has long been understood as an innate immune defense barrier against the microbiota and other luminal threats that reinforces the barrier function of the epithelium and limits microbiota contact with the tissues. However, past and recent studies have provided new evidence of how critical the mucus network is to act as a ‘liaison’ between host and microbe to mediate anti-inflammatory, mutualistic interactions with the microbiota and protection from pathogens. This review summarizes historical and recent insights into the formation of the gut mucus network, how the microbes and immune system influence mucus, and in turn, how the mucus influences immune responses to the microbiota.     

The intestinal neuro-immune axis: crosstalk between neurons,immune cells,and microbes

The gastrointestinal tract is densely innervated by a complex network of neurons that coordinate critical physiological functions. Here, we summarize recent studies investigating the crosstalk between gut-innervating neurons, resident immune cells, and epithelial cells at homeostasis and during infection, food allergy, and inflammatory bowel disease. We introduce the neuroanatomy of the gastrointestinal tract, detailing gut-extrinsic neuron populations from the spinal cord and brain stem, and neurons of the intrinsic enteric nervous system. We highlight the roles these neurons play in regulating the functions of innate immune cells, adaptive immune cells, and intestinal epithelial cells. We discuss the consequences of such signaling for mucosal immunity. Finally, we discuss how the intestinal microbiota is integrated into the neuro-immune axis by tuning neuronal and immune interactions. Understanding the molecular events governing the intestinal neuro-immune signaling axes will enhance our knowledge of physiology and may provide novel therapeutic targets to treat inflammatory diseases.     

Gut matters: microbe-host interactions in allergic diseases

The human body can be considered a metaorganism made up of its own eukaryotic cells and trillions of microbes that colonize superficial body sites, such as the skin, airways, and gastrointestinal tract. The coevolution of host and microbes brought about a variety of molecular mechanisms, which ensure a peaceful relationship. The mammalian barrier and immune functions warrant simultaneous protection of the host against deleterious infections, as well as tolerance toward harmless commensals. Because these pivotal host functions evolved under high microbial pressure, they obviously depend on a complex network of microbe-host interactions. The rapid spread of immune-mediated disorders, such as autoimmune diseases, inflammatory bowel diseases, and allergies, in westernized countries is thus thought to be due to environmentally mediated disturbances of this microbe-host interaction network. The aim of the present review is to highlight the importance of the intestinal microbiota in shaping host immune mechanisms, with particular emphasis on allergic diseases and possible intervention strategies.     

Adaptive immunity in the host-microbiota dialog

The intestinal tract represents the largest mucosal surface and is a major site of multifaceted interactions between the host mucosal immune system and components of the intestinal microbiota. Host immune responses to the commensal microbiota are tightly controlled and, meanwhile, the microbiota actively shapes intestinal immune responses to itself. Appreciation of these interactions during health and disease may direct therapeutic approaches to a broad range of autoimmune and inflammatory disorders in humans. In this review, we will discuss findings on how the intestinal immune system, especially adaptive immune cells, helps accommodate the large number of resident bacteria, and in turn how the microbiota shapes intestinal immune responses to achieve mutualism.     

The front line of enteric host defense against unwelcome intrusion of harmful microorganisms: mucins, antimicrobial peptides, and microbiota

The intestinal tract is a complex ecosystem that combines resident microbiota and the cells of various phenotypes with complex metabolic activities that line the epithelial wall. The intestinal cells that make up the epithelium provide physical and chemical barriers that protect the host against the unwanted intrusion of microorganisms that hijack the cellular molecules and signaling pathways of the host and become pathogenic. Some of the organisms making up the intestinal microbiota also have microbicidal effects that contribute to the barrier against enteric pathogens. This review describes the two cell lineages present in the intestinal epithelium: the goblet cells and the Paneth cells, both of which play a pivotal role in the first line of enteric defense by producing mucus and antimicrobial peptides, respectively. We also analyze recent insights into the intestinal microbiota and the mechanisms by which some resident species act as a barrier to enteric pathogens. Moreover, this review examines whether the cells producing mucins or antimicrobial peptides and the resident microbiota act in partnership and whether they function individually and/or synergistically to provide the host with an effective front line of defense against harmful enteric pathogens.     

Microbiota and metabolites in rheumatic diseases

As a gigantic community in the human body, the microbiota exerts pleiotropic roles in human health and disease ranging from digestion and absorption of nutrients from food, defense against infection of pathogens, to regulation of immune system development and immune homeostasis. Recent advances in “omics” studies and bioinformatics analyses have broadened our insights of the microbiota composition of the inner and other surfaces of the body and their interactions with the host. Apart from the direct contact of microbes at the mucosal barrier, metabolites produced or metabolized by the gut microbes can serve as important immune regulators or initiators in a wide variety of diseases, including gastrointestinal diseases, metabolic disorders and systemic rheumatic diseases. This review focuses on the most recent understanding of how the microbiota and metabolites shape rheumatic diseases. Studies that explore the mechanistic interplay between microbes, metabolites and the host could thereby provide clues for novel methods in the diagnosis, therapy, and prevention of rheumatic diseases.