Vitamin A and vitamin D regulate the microbial complexity,barrier function,and the mucosal immune responses to ensure intestinal homeostasis

Diet is an important regulator of the gastrointestinal microbiota. Vitamin A and vitamin D deficiencies result in less diverse, dysbiotic microbial communities and increased susceptibility to infection or injury of the gastrointestinal tract. The vitamin A and vitamin D receptors are nuclear receptors expressed by the host, but not the microbiota. Vitamin A- and vitamin D-mediated regulation of the intestinal epithelium and mucosal immune cells underlies the effects of these nutrients on the microbiota. Vitamin A and vitamin D regulate the expression of tight junction proteins on intestinal epithelial cells that are critical for barrier function in the gut. Other shared functions of vitamin A and vitamin D include the support of innate lymphoid cells that produce IL-22, suppression of IFN-γ and IL-17 by T cells, and induction of regulatory T cells in the mucosal tissues. There are some unique functions of vitamin A and D; for example, vitamin A induces gut homing receptors on T cells, while vitamin D suppresses gut homing receptors on T cells. Together, vitamin A- and vitamin D-mediated regulation of the intestinal epithelium and mucosal immune system shape the microbial communities in the gut to maintain homeostasis.     

Epithelial cells and their neighbors. IV. Bacterial contributions to intestinal epithelial barrier integrity

Mammalian intestinal surfaces are in constant and intimate contact with a vast consortium of indigenous commensal bacteria. As a result, gut epithelia have evolved an array of strategies for limiting bacterial invasion into deeper tissues, helping to preserve the mutually beneficial nature of intestinal host-microbial relationships. In this review, we discuss a growing body of evidence indicating that commensal bacteria are actively involved in shaping the very barriers that confine them to the gut lumen. By modulating epithelial inflammatory responses, antimicrobial protein expression, and tissue repair functions, indigenous microbial populations are essential for the maintenance of healthy mucosal surfaces.     

Exosome‐mediated effects and applications in inflammatory bowel disease

Gut mucosal barriers, including chemical and physical barriers, spatially separate the gut microbiota from the host immune system to prevent unwanted immune responses that could lead to intestinal inflammation. In inflammatory bowel disease (IBD), there is mucosal barrier dysfunction coupled with immune dysregulation and dysbiosis. The discovery of exosomes as regulators of vital functions in both physiological and pathological processes has generated much research interest. Interestingly, exosomes not only serve as natural nanocarriers for the delivery of functional RNAs, proteins, and synthetic drugs or molecules, but also show potential for clinical applications in tissue repair and regeneration as well as disease diagnosis and prognosis. Biological or chemical modification of exosomes can broaden, change and enhance their therapeutic capability. We review the modulatory effects of exosomal proteins, RNAs and lipids on IBD components such as immune cells, the gut microbiota and the intestinal mucosal barrier. Mechanisms involved in regulating these factors towards attenuating IBD have been explored in several studies employing exosomes derived from different sources. We discuss the potential utility of exosomes as diagnostic markers and drug delivery systems, as well as the application of modified exosomes in IBD.     

Nonmucosal alphavirus vaccination stimulates a mucosal inductive environment in the peripheral draining lymph node

The strongest mucosal immune responses are induced following mucosal Ag delivery and processing in the mucosal lymphoid tissues, and much is known regarding the immunological parameters which regulate immune induction via this pathway. Recently, experimental systems have been identified in which mucosal immune responses are induced following nonmucosal Ag delivery. One such system, footpad delivery of Venezuelan equine encephalitis virus replicon particles (VRP), led to the local production of IgA Abs directed against both expressed and codelivered Ags at multiple mucosal surfaces in mice. In contrast to the mucosal delivery pathway, little is known regarding the lymphoid structures and immunological components that are responsible for mucosal immune induction following nonmucosal delivery. In this study, we have used footpad delivery of VRP to probe the constituents of this alternative pathway for mucosal immune induction. Following nonmucosal VRP delivery, J chain-containing, polymeric IgA Abs were detected in the peripheral draining lymph node (DLN), at a time before IgA detection at mucosal surfaces. Further analysis of the VRP DLN revealed up-regulated alpha4beta7 integrin expression on DLN B cells, expression of mucosal addressin cell adhesion molecule 1 on the DLN high endothelia venules, and production of IL-6 and CC chemokines, all characteristics of mucosal lymphoid tissues. Taken together, these results implicate the peripheral DLN as an integral component of an alternative pathway for mucosal immune induction. A further understanding of the critical immunological and viral components of this pathway may significantly improve both our knowledge of viral-induced immunity and the efficacy of viral-based vaccines.     

The gut as a lymphoepithelial organ: The role of intestinal epithelial cells in mucosal immunity

Mucosal surfaces covered by a layer of epithelial cells represent the largest and most critical interface between the organism and its environment. The barrier function of mucosal surfaces is performed by the epithelial layer and immune cells present in the mucosal compartment. As recently found, epithelial cells, apart from their participation in absorptive, digestive and secretory processes perform more than a passive barrier function and are directly involved in immune processes. Besides the well known role of epithelial cells in the transfer of polymeric immunoglobulins produced by lamina propria B lymphocytes to the luminal content of mucosals (secretory Igs), these cells were found to perform various other immunological functions, to interact with other cells of the immune system and to induce an efficient inflammatory response to microbial invasion: enzymic processing of dietary antigens, expression of class I and II MHC antigens, presentation of antigens to lymphocytes, expression of adhesive molecules mediating interaction with intraepithelial lymphocytes and components of extracellular matrix, production of cytokines and probable participation in extrathymic T cell development of intraepithelial lymphocytes. All these functions were suggested to influence substantially the mucosal immune system and its response. Under immunopathological conditions,e.g. during infections and inflammatory bowel and celiac diseases, both epithelial cells and intraepithelial lymphocytes participate substantially in inflammatory reactions. Moreover, enterocytes could become a target of mucosal immune factors. Mucosal immunosurveillance function is of crucial importance in various pathological conditions but especially in the case of the most frequent malignity occurring in the intestinal compartment,i.e. colorectal carcinoma. Proper understanding of the differentiation processes and functions of epithelial cells in interaction with other components of the mucosal immune system is therefore highly desirable. Dedicated to Professor J. Šterzl on the occasion of his 70th birthday     

Proteinase-activated receptors (PARs) in infection and inflammation in the gut

Proteinases have been shown to act as signaling molecules that are able to send specific signals to cells through the activation of proteinase-activated receptors (PARs). Those receptors which are expressed in a wide variety of cells in the gastrointestinal tract are considered as "emergency" mechanisms, particularly involved in inflammatory responses of the gut. Depending on the cell types of the gut in which PARs are activated, their activation interacts with all aspects of the gut physiology: motility, barrier function, transports, innate immune response, sensory functions, and even proliferation. A growing body of evidences discussed here suggests that these receptors, and the proteinases that activate them, are important mediators of the innate immune response of the gut and could play a major role in chronic inflammatory states of the gut (inflammatory bowel diseases), or infectious diseases.     

Temporal and anatomic relationship between virus replication and cytokine gene expression after vaginal simian immunodeficiency virus infection

The current knowledge about early innate immune responses at mucosal sites of human immunodeficiency virus (HIV) entry is limited but likely to be important in the design of effective HIV vaccines against heterosexual transmission. This study examined the temporal and anatomic relationship between virus replication, lymphocyte depletion, and cytokine gene expression levels in mucosal and lymphoid tissues in a vaginal-transmission model of HIV in rhesus macaques. The results of the study show that the kinetics of cytokine gene expression levels in the acute phase of infection are positively correlated with virus replication in a tissue. Thus, cytokine responses after vaginal simian immunodeficiency virus (SIV) inoculation are earliest and strongest in mucosal tissues of the genital tract and lowest in systemic lymphoid tissues. Importantly, the early cytokine response was dominated by the induction of proinflammatory cytokines, while the induction of cytokines with antiviral activity, alpha/beta interferon, occurred too late to prevent virus replication and dissemination. Thus, the early cytokine response favors immune activation, resulting in the recruitment of potential target cells for SIV. Further, unique cytokine gene expression patterns were observed in distinct anatomic locations with a rapid and persistent inflammatory response in the gut that is consistent with the gut being the major site of early CD4 T-cell depletion in SIV infection.     

Microbiota-immune system interaction: an uneasy alliance

An estimated 100 trillion microbes colonize human beings, with the majority of organisms residing in the intestines. This microbiota impacts host nutrition, protection, and gut development. Alterations in microbiota composition are associated with susceptibility to various infectious and inflammatory gut diseases. The mucosal surface is not a static barrier that simply prevents microbial invasion but a critical interface for microbiota-immune system interactions. Recent work suggests that dynamic interactions between microbes and the host immune system at the mucosal surface inform immune responses both locally and systemically. This review focuses on intestinal microbiota-immune interactions leading to intestinal homeostasis, and show that these interactions at the GI mucosal surface are critical for driving both protective and pathological immune responses systemically.     

Epithelial antimicrobial peptides in host defense against infection

One component of host defense at mucosal surfaces seems to be epithelium-derived antimicrobial peptides. Antimicrobial peptides are classified on the basis of their structure and amino acid motifs. Peptides of the defensin, cathelicidin, and histatin classes are found in humans. In the airways, α-defensins and the cathelicidin LL-37/hCAP-18 originate from neutrophils. β-Defensins and LL-37/hCAP-18 are produced by the respiratory epithelium and the alveolar macrophage and secreted into the airway surface fluid. Beside their direct antimicrobial function, antimicrobial peptides have multiple roles as mediators of inflammation with effects on epithelial and inflammatory cells, influencing such diverse processes as proliferation, immune induction, wound healing, cytokine release, chemotaxis, protease-antiprotease balance, and redox homeostasis. Further, antimicrobial peptides qualify as prototypes of innovative drugs that might be used as antibiotics, anti-lipopolysaccharide drugs, or modifiers of inflammation.     

Interactions of bacterial pathogens with dendritic cells during invasion of mucosal surfaces

Recent studies of mucosal immunity suggest a key role for dendritic cells in the regulation of gut immune responses, in both physiological and pathological conditions. Dendritic cells are widely distributed in the lamina propria of the gut and are involved in direct bacterial uptake across mucosal surfaces, which questions the role of dendritic cells in innate mucosal responses. Approximately 400 commensal microbial species are present in the gut lumen. So how do dendritic cells distinguish pathogens from luminal microflora? Are the cytokines and chemokines induced in dendritic cells tailored to the class of microbes being recognized? Several very important questions still need to be addressed.     

Role of epithelial nitric oxide in airway viral infection

The airway mucosal epithelium is the first site of virus contact with the host, and the main site of infection and inflammation. Nitric oxide (NO) produced by the airway epithelium is vital to antiviral inflammatory and immune defense in the lung. Multiple mechanisms function coordinately to support high-level basal NO synthesis in healthy airway epithelium and further induction of NO synthesis in the infected airway of normal hosts. Hosts deficient in NO synthesis, such as those patients with cystic fibrosis, have impaired antiviral defense and may benefit from therapies to augment NO levels in the airways.     

Importance of probiotics in the prevention and treatment of colorectal cancer

Colorectal cancer (CRC) remains one of the most common and deadly cancers. Intestinal gut microflora is important to maintain and contributes to several intestinal functions, including the development of the mucosal immune system, absorption of complex macromolecules, synthesis of amino acids/vitamins and the protection against pathogenic microorganisms. It is well known that the gut microbiota changes or dysbiosis may have an essential impact in the initiation and promotion of chronic inflammatory pathways and also have a profound different genetic and epigenetic alterations leading to dysplasia, clonal expansion, and malignant transformation. Probiotic bacteria has antitumor activity with various mechanisms such as nonspecific physiological and immunological mechanisms. This review evaluates the effects of microbiota and probiotics in clinical trials, in vitro and animal model studies that have explored how probiotic against cancer development and also discusses the possible immunomodulatory mechanisms. Several mechanisms alteration of the intestinal microflora; inactivation of cancerogenic compounds; competition with putrefactive and pathogenic microbiota; improvement of the host's immune response; antiproliferative effects via regulation of apoptosis and cell differentiation; fermentation of undigested food; inhibition of tyrosine kinase; reduces the enteropathogenic complications before and after colon cancer surgery and improve diarrhea and it's have been able to create the integrity of gut mucosal and have stimulatory effects on the systemic immune system and prevent the CRC metastasis. Research in clinical trials encouraging findings that support a role of probiotics in CRC prevention and improve the safety and effectiveness of cancer therapy even though additional clinical research is still necessary.     

Host sialoglycans and bacterial sialidases: a mucosal perspective

Sialic acids are nine-carbon-backbone sugars that occupy outermost positions on vertebrate cells and secreted sialoglycoproteins. These negatively charged hydrophilic carbohydrates have a variety of biological, biophysical and immunological functions. Mucosal surfaces and secretions of the mouth, airway, gut and vagina are especially sialoglycan-rich. Given their prominent positions and important functions, a variety of microbial strategies have targeted host sialic acids for adherence, mimicry and/or degradation. Here we review the roles of bacterial sialidases (neuraminidases) during colonization and pathogenesis of mammalian mucosal surfaces. Evidence is presented to support the myriad roles of mucosal sialoglycans in protecting the host from bacterial infection. In opposition, many bacteria hydrolyse sialic acids during associations with the gastrointestinal, oral, respiratory and reproductive tracts. Sialidases promote bacterial survival in mucosal niche environments in several ways, including: (i) nutritional benefits of sialic acid catabolism, (ii) unmasking of cryptic host ligands used for adherence, (iii) participation in biofilm formation and (iv) modulation of immune function. Bacterial sialidases are among the best-studied enzymes involved in pathogenesis and may also drive commensal and/or symbiotic host associations. Future studies should continue to define host substrates of bacterial sialidases and the mechanisms of their pathologic, commensal and symbiotic interactions with the mammalian host.     

The role of IL-15 in gastrointestinal diseases: A bridge between innate and adaptive immune response

IL-15 is a member of the IL-2 family of cytokines whose signaling pathways are a bridge between innate and adaptive immune response. IL-15 is part of the intestinal mucosal barrier, and functions to modulate gut homeostasis. IL-15 has pivotal roles in the control of development, proliferation and survival of both innate and adaptive immune cells.IL-15 becomes up-regulated in the inflamed tissue of intestinal inflammatory disease, such as IBD, Celiac Disease and related complications. Indeed, several studies have reported that IL-15 may participate to the pathogenesis of these diseases. Furthermore, although IL-15 seems to be responsible for inflammation and autoimmunity, it also may increase the immune response against cancer. For these reasons, we decided to study the intestinal mucosa as an ‘immunological niche’, in which immune response, inflammation and local homeostasis are modulated.Understanding the role of the IL-15/IL-15R system will provide a scientific basis for the development of new approaches that use IL-15 for immunotherapy of autoimmune diseases and malignancies. Indeed, a better understanding of the complexity of the mucosal immune system will contribute to the general understanding of immuno-pathology, which could lead to new therapeutical tools for widespread immuno-mediated diseases.     

Mucosal immunity and vaccination.

The gut mucosal immune system is a critical component of the body's defense against pathogenic organisms, especially those responsible for enteric infections associated with diarrhoeal disease. Attempts to vaccinate against infections of mucosal tissues have been less successful than vaccination against systemic infections, to a large extent reflecting a still incomplete knowledge about the most efficient means for inducing protective local immune responses at these sites. Secretory IgA (SIgA) is the predominating immunoglobulin along mucosal surfaces, and SIgA antibodies generated in gastrointestinal, respiratory or genito-urinary mucosal tissues can confer protection against infections affecting or originating in these sites. An efficacious intestinal SIgA immunity-inducing oral vaccine against cholera has been developed recently, and development of oral vaccines against other enteric infections such as those caused by enterotoxigenic Escherichia coli, Shigella and rotaviruses is in progress as well. Based on the concept of a common mucosal immune system through which activated lymphocytes from the gut can disseminate immunity to other mucosal and glandular tissues, there is currently also much interest in the possibility of developing oral vaccines against infections in the respiratory and urogenital tracts. However, the large and repeated antigen doses often required to achieve a protective immune response still makes this vaccination approach impractical for many purified antigens. There is, therefore, a great need to develop strategies for enhancing delivery of antigen to the mucosal immune system as well as to identify mucosa-active immunostimulating agents (adjuvants). These and other aspects of mucosal immunity in relation to immunization and vaccine development are discussed in this short review article.     

Does the microbiota regulate immune responses outside the gut?

Perturbations in the gastrointestinal (GI) microbiota composition that occur as a result of antibiotics and diet in "westernized" countries are strongly associated with allergies and asthma ("hygiene hypothesis"). The microbiota ("microflora") plays a crucial role in the development of mucosal tolerance, including the airways. Significant attention has been focused on the role of the microbiota in GI development, immune adaptation and initiation of GI inflammatory diseases. This review covers the post-developmental functions that the microbiota plays in regulating immunological tolerance to allergen exposure outside the GI tract and proposes the question: is the microbiota a major regulator of the immune system?     

Mucosal immunity and vaccination

Abstract The gut mucosal immune system is a critical component of the body's defense against pathogenic organisms, especially those responsible for enteric infections associated with diarrhoeal disease. Attempts to vaccinate against infections of mucosal tissues have been less successful than vaccination against systematic infections, to a large extent reflecting a still incomplete knowledge about the most efficient means for inducing protective local immune responses at these sites. Secretory IgA (SIgA) is the predominating immunoglobulin along mucosal surfaces, and SIgA antibodies generated in gastrointestinal, respiratory or genito-urinary mucosal tissues can confer protection against infections affecting or originating in these sites. An efficacious intestinal SIgA immunity-inducing oral vaccine against cholera has been developed recently, and development of oral vaccines against other enteric infections such as those caused by enterotoxigenic Escherichia coli, Shigella and rotaviruses is in progress as well. Based on the concept of a common mucosal immune system through which activated lymphocytes from the gut can disseminate immunity to other mucosal and glandular tissues, there is currently also much interest in the possibility of developing oral vaccines against infections in the respiratory and urogenital tracts. However, the large and repeated antigen doses often required to achieve a protective immune response still makes this vaccination approach impractical for many purified antigens. There is, therefore, a great need to develop strategies for enhancing delivery of antigen to the mucosal immune system as well as to identify mucosa-active immunostimulating agents (adjuvants). These and other aspects of mucosal immunity in relation to immunization and vaccine development are discussed in this short review article.     

Cytokine-mediated regulation of antimicrobial proteins

Antimicrobial proteins constitute a phylogenetically ancient form of innate immunity that provides host defence at skin and mucosal surfaces. Although some components of this system are constitutively expressed, new evidence reviewed in this Progress article shows that the production of certain antimicrobial proteins by epithelial cells can also be regulated by cytokines of the innate and adaptive immune systems. In particular, the effector cytokines interleukin-17 and interleukin-22, which are produced by the T-helper-17-cell subset, are emerging as crucial regulators of antimicrobial-peptide production in the gut and the lungs. This suggests that this T-cell lineage and its cytokines have important roles in skin and mucosal immunity.     

WAP domain proteins as modulators of mucosal immunity

WAP (whey acidic protein) is an important whey protein present in milk of mammals. This protein has characteristic domains, rich in cysteine residues, called 4-DSC (four-disulfide core domain). Other proteins, mainly present at mucosal surfaces, have been shown to also possess these characteristic WAP-4-DSC domains. The present review will focus on two WAP-4-DSC containing proteins, namely SLPI (secretory leucocyte protease inhibitor) and trappin-2/elafin. Although first described as antiproteases able to inhibit in particular host neutrophil proteases [NE (neutrophil elastase), cathepsin-G and proteinase-3] and as such, able to limit maladaptive tissue damage during inflammation, it has become apparent that these molecules have a variety of other functions (direct antimicrobial activity, bacterial opsonization, induction of adaptive immune responses, promotion of tissue repair, etc.). After providing information about the 'classical' antiproteasic role of these molecules, we will discuss the evidence pertaining to their pleiotropic functions in inflammation and immunity.