Modulation of alloimmune response by commensal gut microbiota and potential new avenues to influence the outcome of allogeneic transplantation by modification of the ‘gut culture’

Host defence response against microbial infections was the foundation for the Science of Immunology. Now, we know the mechanisms of such host defence which include innate immune responses that is generally nonspecific but effective in many cases and lead to more specific responses called adaptive immune response. The gene loci of class I, II and III of the major histocompatibility complex (MHC) play a major role in directing the adaptive immune responses by presenting processed antigens to T and B cells to induce appropriate antigen‐specific cellular and or humoral immune responses. In humans, these are commonly referred to as human leucocyte antigens class I/II‐HLA I/II). The class III region, the gamma region in the MHC complex, is mostly associated with regulation of immune responses along with genes associated with complement activation. The adaptive immune responses are orchestrated by T and B cells that are tuned to respond to antigens that are normally foreign to the body, because these cells are educated to avoid self‐antigens by a process of thymic education and selection of the T cells that are mostly non‐self‐reactive which also helps the B cells in eliciting specific immune responses to non‐self‐antigens. A by‐product of this is the ability of the T and B cells to elicit strong immune responses to foreign HLA/MHC (alloimmune response), which developed into the field of histocompatibility testing for allogeneic transplantation of stem cells and organs. Now, we are beginning to learn that such alloimmune responses can be influenced by the microbiota that symbiotically live in our body especially on the mucosal surfaces and on the skin. This review deals with new and emerging data on how the commensal mucosal and skin microbiota influence the immune homeostasis, and how manipulating the commensal microbiota of the mucosa and skin could influence the survival and long‐term functions of the allografts. Also, alterations of the microbiota by the inevitable immunosuppression prior to and following allogeneic transplantation could contribute towards the outcome of the allografts by alloimmune responses generated due to microbial antigen vs HLA cross‐reactivity.     

The effects of commensal microbiota on immune cell subsets and inflammatory responses

Billions of years of coevolution shaped the mutually beneficial relationships between metazoans and symbiotic commensal microorganisms. Commensal microorganisms profoundly affect the physiology of the host and provide the host with survival advantages in several ways, while they could also trigger pathogenic immune responses and threaten the well-being of the host. Recent advances in DNA sequencing technology enabled the analysis of commensal microbiota, and improvements in the techniques of culturing gut-resident microorganisms and of rearing gnotobiotic rodents have made it possible to assess the effect of individual component of microbial communities on host physiology. In this review, we discuss the current understanding of the interactions of commensal microbiota with the host immune system.     

Immunogenetic control of the intestinal microbiota

All vertebrates contain a diverse collection of commensal, symbiotic and pathogenic microorganisms, such as bacteria, viruses and fungi, on their various body surfaces, and the ecological community of these microorganisms is referred to as the microbiota. Mucosal sites, such as the intestine, harbour the majority of microorganisms, and the human intestine contains the largest community of commensal and symbiotic bacteria. This intestinal community of bacteria is diverse, and there is a significant variability among individuals with respect to the composition of the intestinal microbiome. Both genetic and environmental factors can influence the diversity and composition of the intestinal bacteria with the predominant environmental factor being diet. So far, studies have shown that diet‐dependent differences in the composition of intestinal bacteria can be classified into three groups, called enterotypes. Other environmental factors that can influence the composition include antibiotics, probiotics, smoking and drugs. Studies of monozygotic and dizygotic twins have proven that genetics plays a role. Recently, MHC II genes have been associated with specific microbial compositions in human infants and transgenic mice that express different HLA alleles. There is a growing list of genes/molecules that are involved with the sensing and monitoring of the intestinal lumen by the intestinal immune system that, when genetically altered, will significantly alter the composition of the intestinal microflora. The focus of this review will be on the genetic factors that influence the composition of the intestinal microflora.     

NKT cells in mucosal immunity

The gastrointestinal tract allows the residence of an almost enumerable number of bacteria. To maintain homeostasis, the mucosal immune system must remain tolerant to the commensal microbiota and eradicate pathogenic bacteria. Aberrant interactions between the mucosal immune cells and the microbiota have been implicated in the pathogenesis of inflammatory disorders, such as inflammatory bowel disease (IBD). In this review, we discuss the role of natural killer T cells (NKT cells) in intestinal immunology. NKT cells are a subset of non-conventional T cells recognizing endogenous and/or exogenous glycolipid antigens when presented by the major histocompatibility complex (MHC) class I-like antigen-presenting molecules CD1d and MR1. Upon T-cell receptor (TCR) engagement, NKT cells can rapidly produce various cytokines that have important roles in mucosal immunity. Our understanding of NKT-cell-mediated pathways including the identification of specific antigens is expanding. This knowledge will facilitate the development of NKT cell-based interventions and immune therapies for human intestinal diseases.     

Human microbiome restoration and safety

The human gut microbiome consists of many bacteria which are in symbiotic relationship with human beings. The gut microbial metabolism, as well as the microbial-host co-metabolism, has been found to greatly influence health and disease. Factors such as diet, antibiotic use and lifestyle have been associated with alterations in the gut microbial community and may result in several pathological conditions. For this reason, several strategies including fecal microbiota transplant and probiotic administration have been applied and proven to be feasible and effective in restoring the gut microbiota in humans. Yet, safety concerns such as potential health risks that may arise from such interventions and how these strategies are regulated need to be addressed. Also, it will be important to know if these microbiome restoration strategies can have a profound impact on health. This review provides an overview of our current knowledge of the microbiome restoration strategies and safety issues on how these strategies are regulated.     

A case for antibiotic perturbation of the microbiota leading to allergy development

The use of antibiotics to treat pathogenic bacterial infections has been one of the greatest contributions to human health, yet antibiotic use also perturbs the communities of commensal and symbiotic bacteria that reside in the intestine of mammals. The microbiota are critical for normal immune development and for maintaining intestinal homeostasis, and disruption of the microbiota has been linked to the emergence of allergic disease both in humans and in animal models. The evidence and mechanisms for antibiotic-mediated disruptions leading to the onset of allergic disease at mucosal surfaces is discussed, as well as the future challenges for the field. A more complete understanding of the mechanisms by which the intestinal microbiota modulate allergic disease development will allow for interventions to counter the potentially adverse effects of antibiotic treatment on the microbiota.     

The role of innate lymphoid cells in response to microbes at mucosal surfaces

Innate lymphoid cells (ILCs) are a lymphocyte population that is mostly resident at mucosal surfaces. They help to induce an appropriate immune response to the microbiome at homeostasis. In healthy people, the mucosal immune system works symbiotically with organisms that make up the microbiota. ILCs play a critical role in orchestrating this balance, as they can both influence and in turn be influenced by the microbiome. ILCs also are important regulators of the early response to infections by diverse types of pathogenic microbes at mucosal barriers. Their rapid responses initiate inflammatory programs, production of antimicrobial products and repair processes. This review will focus on the role of ILCs in response to the microbiota and to microbial infections of the lung and intestine.     

To be or not to be a pathogen: that is the mucosally relevant question

The human interface with the microbial world has so far largely been considered through the somewhat restrictive angle of host–pathogen interactions resulting in disease. It has consequently largely ignored the daily symbiosis with the microbiota, an ensemble of symbiotic microorganisms engaged in a commensal, and for some of them mutualistic, interaction. This microbiota heavily populates essential surfaces such as the oral and intestinal cavity, the upper respiratory tract, the vagina, and the skin. Host response to the pathogens is characterized by quick recognition combined with strong innate (i.e., inflammatory) and adaptive immune responses, causing microbial eradication often at the cost of significant tissue damage. Response to the symbiotic microbiota is characterized by a process called tolerance that encompasses a complex integration of microbial recognition and tightly controlled innate (i.e., physiological inflammation) and adaptive immune responses. This dichotomy in host response is critical at the gut mucosal surface that is massively colonized by a diverse population of bacteria. The host is therefore permanently facing the challenge of discriminating among symbiotic and pathogenic bacteria in order to offer an adapted response. This asks the fundamental existential question: “to be or not to be… a pathogen.” This review has attempted to consider this question from the host angle. What do host mucosal sensing systems see in the bacteria to which they become exposed to establish proper discrimination? A new facet of medicine resides in the dysfunction of this complex balance that has likely forged the complexity of the immune system.     

Regulation of innate and adaptive immunity by the commensal microbiota

The microbial communities that inhabit the intestinal tract are essential for mammalian health. Communication between the microbiota and the host establishes and maintains immune homeostasis, enabling protective immune responses against pathogens while preventing adverse inflammatory responses to harmless commensal microbes. Specific bacteria, such as segmented filamentous bacteria, Clostridium species, and Bacteroides fragilis, are key contributors to immune homeostasis in the gut. The cellular and molecular interactions between intestinal microbes and the immune system are rapidly being elucidated. Here, we review advances in our understanding of the microbial populations that shape the mucosal immune system and create a protective defense that prevents infection while tolerating friendly commensals.     

Insights into the role of vaginal microbiome in women's health

The vaginal microbiome is a complex and dynamic microecosystem that fluctuates continually throughout a woman's life. Lactobacillus, a bacterium that possesses antibacterial properties dominates a healthy vaginal microbiome. Bacterial vaginosis is the most common vaginal disorder that has been linked with the dysbiosis of normal vaginal microbiota. Despite the importance of vaginal microbiome, little is known about functions it performs especially, how it helps in protecting the female reproductive tract. This knowledge gap is a significant impediment to the development of effective and feasible clinical treatments that might be required to improve women's health. Thus, a deeper understanding of the functional aspects and not just the composition of vaginal microbiome may aid in improving the diagnostics and treatment strategies. Recent advancement in molecular methods and computational biology have allowed researchers to acquire more knowledge about the vaginal microbiome. The use of metagenomics (culture-independent high-throughput technology) and bioinformatics tools have improved our understanding of the vaginal microbiome. In this review, we have attempted to explore the factors that may alter normal vaginal microbiota homeostasis such as age, sexual behavior, ethnicity, and hygiene, and so forth. We also discuss the role of probiotics in restoring healthy vaginal microbiome.     

AllergoOncology: Microbiota in allergy and cancer—A European Academy for Allergy and Clinical Immunology position paper

The microbiota can play important roles in the development of human immunity and the establishment of immune homeostasis. Lifestyle factors including diet, hygiene, and exposure to viruses or bacteria, and medical interventions with antibiotics or anti‐ulcer medications, regulate phylogenetic variability and the quality of cross talk between innate and adaptive immune cells via mucosal and skin epithelia. More recently, microbiota and their composition have been linked to protective effects for health. Imbalance, however, has been linked to immune‐related diseases such as allergy and cancer, characterized by impaired, or exaggerated immune tolerance, respectively. In this AllergoOncology position paper, we focus on the increasing evidence defining the microbiota composition as a key determinant of immunity and immune tolerance, linked to the risk for the development of allergic and malignant diseases. We discuss novel insights into the role of microbiota in disease and patient responses to treatments in cancer and in allergy. These may highlight opportunities to improve patient outcomes with medical interventions supported through a restored microbiome.     

Key questions to guide a better understanding of host-commensal microbiota interactions in intestinal inflammation

Co-evolution with an extremely complex commensal enteric microbiota has helped shape mammalian mucosal immune responses. A yet incompletely defined subset of intestinal bacteria is required to stimulate chronic, immune-mediated intestinal inflammation, including human Crohn's disease, and intestinal microbiota composition is altered in a characteristic manner by the inflammatory response to create a dysbiotic relationship of protective vs. aggressive bacteria. We pose a number of questions regarding host interactions with the enteric microbiota, including influences of inflammation, host genetics, early environmental exposure, and diet on microbial composition and function, and conversely, the effect of bacterial metabolism, enteric fungi and viruses, and endogenous protective bacterial species on host immune and inflammatory responses. These questions are designed to stimulate research that will promote a better understanding of host-microbial interactions in the intestine and promote targeted novel therapeutic interventions.     

Regulation of the polymeric immunoglobulin receptor and IgA transport: new advances in environmental factors that stimulate pIgR expression and its role in mucosal immunity

Secretory IgA (SIgA) antibodies represent the first line of antigen-specific immune defense protecting the mucosal surfaces against environmental pathogens and antigens, and maintaining homeostasis with the commensal microbiota. The polymeric immunoglobulin receptor (pIgR) has the dual role of transporting locally produced dimeric IgA across mucosal epithelia, and serving as the precursor of secretory component, a glycoprotein that enhances the immune functions of SIgA. The complex regulation of pIgR expression and transcytosis by host and microbial factors is finely tuned to optimize the role of SIgA in mucosal immunity. Disruption of this regulatory network in disease states similar to inflammatory bowel disease can result in profound consequences for mucosal homeostasis and systemic sequelae. Future research into the function and regulation of pIgR and SIgA may offer new insights into the prevention and treatment of infectious and inflammatory diseases that originate at mucosal surfaces.     

The microbiota and immune-mediated diseases: Opportunities for therapeutic intervention

A multitude of diverse microorganisms, termed the microbiota, reside in the gut, respiratory tract, skin, and genital tract of humans and other animals. Recent advances in metagenomic sequencing and bioinformatics have enabled detailed characterization of these vital microbial communities. Studies in animal models have uncovered vital previously unrecognized roles for the microbiota in normal function of the immune responses, and when perturbed, in the pathogenesis of diseases of the gastrointestinal tract and lungs, but also at distant sites in the body including the brain. The composition of gut and respiratory microbiota can influence systemic inflammatory responses that mediate asthma, allergy, inflammatory bowel disease, obesity-related diseases, and neurodevelopmental or neurodegenerative conditions. Experiments in mouse models as well as emerging clinical studies have revealed that therapeutic manipulation of the microbiota, using fecal microbiota transplantation, probiotics, or engineered probiotics represent effective nontoxic approaches for the treatment or prevention of Clostridium difficile infection, allergy, and autoimmune diseases and may enhance the efficacy of certain cancer immunotherapeutics. This review discusses how commensal bacteria can influence immune responses that mediate a range of human diseases and how the microbiota are being targeted to treat these diseases, especially those resistant to pharmacological therapies.     

Opioid-induced gut microbial disruption and bile dysregulation leads to gut barrier compromise and sustained systemic inflammation

Morphine and its pharmacological derivatives are the most prescribed analgesics for moderate to severe pain management. However, chronic use of morphine reduces pathogen clearance and induces bacterial translocation across the gut barrier. The enteric microbiome has been shown to have a critical role in the preservation of the mucosal barrier function and metabolic homeostasis. Here, we show for the first time, using bacterial 16s rDNA sequencing, that chronic morphine treatment significantly alters the gut microbial composition and induces preferential expansion of Gram-positive pathogenic and reduction in bile-deconjugating bacterial strains. A significant reduction in both primary and secondary bile acid levels was seen in the gut, but not in the liver with morphine treatment. Morphine-induced microbial dysbiosis and gut barrier disruption was rescued by transplanting placebo-treated microbiota into morphine-treated animals, indicating that microbiome modulation could be exploited as a therapeutic strategy for patients using morphine for pain management.     

Control of antiviral immunity by pattern recognition and the microbiome

Human skin and mucosal surfaces are in constant contact with resident and invasive microbes. Recognition of microbial products by receptors of the innate immune system triggers rapid innate defense and transduces signals necessary for initiating and maintaining the adaptive immune responses. Microbial sensing by innate pattern-recognition receptors is not restricted to pathogens. Rather, proper development, function, and maintenance of innate and adaptive immunity rely on continuous recognition of products derived from the microorganisms indigenous to the internal and external surfaces of mammalian host. Tonic immune activation by the resident microbiota governs host susceptibility to intestinal and extra-intestinal infections, including those caused by viruses. This review highlights recent developments in innate viral recognition leading to adaptive immunity, and discusses potential links between viruses, microbiota, and the host immune system. Furthermore, we discuss the possible roles of microbiome in chronic viral infection and pathogenesis of autoimmune disease and speculate on the benefit for probiotic therapies against such diseases.     

女性生殖道黏膜免疫进展

黏膜免疫是抵御细菌、病毒等病原体侵入机体的第一道防线。女性生殖道黏膜免疫通过固有免疫和适应性免疫不仅可抵抗致病菌的入侵,还有助于成功受精及妊娠,从而维持女性生殖健康。女性生殖道固有免疫系统包括黏膜上皮的机械屏障、共生菌的微生物屏障、固有免疫细胞及其受体的免疫屏障,适应性免疫包括B细胞介导的体液免疫及T细胞介导的细胞免疫。女性生殖道黏膜免疫不仅参与局部炎症,还可能具有抗肿瘤免疫应答的作用。此外,女性生殖道黏膜免疫受性激素的调节,从而有利于维持局部微环境的稳态。本文就近年有关女性生殖道黏膜免疫的研究进展进行总结。