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.     

99th Dahlem Conference on Infection,Inflammation and Chronic Inflammatory Disorders: The normal gut microbiota in health and disease

Mammals are metagenomic, in that they are composed not only of their own genome but also those of all of their associated microbes (microbiome). Individual variations in the microbiome influence host health and may be implicated in disease aetiology. Therefore, it is not surprising that decreased microbial diversity is associated with both obesity and inflammatory bowel disease. Studies in germ‐free mice have demonstrated that the gut microbiota is required for development of diet‐induced obesity as well as inflammatory diseases. However, the underlying molecular mechanism(s) for how the gut microbiota causes metabolic diseases is only beginning to be clarified. Furthermore, emerging data suggest that the gut microbiota may predispose or protect against other important diseases such as cardiovascular disease and diabetes.     

Etiology of Crohn’s disease: many roads lead to autophagy

Crohn's disease is a complex multifactor diseases that occur in individuals with genetic predisposition in whom environmental and microbial triggers cause a deleterious chronic immune response. Susceptibility to Crohn's disease is influenced by common variants at many loci. Genetic studies have emphasized the role of host susceptibility in inflammatory bowel disease onset with the identification of about 100 risk loci, most of which encode proteins involved in immunity, host defense against microbes, and gut homeostasis. In this review, we focus on susceptibility genes related to autophagy in the etiology of Crohn's disease (CD) and their complex interplay with the gut microbiota, as illustrated by the relationship between immunity-related GTPase family M alleles, microRNA, and xenophagy in CD predisposition.     

Inflammatory pathways in Alzheimer’s disease mediated by gut microbiota

In the past decade, numerous studies have demonstrated the close relationship between gut microbiota and the occurrence and development of Alzheimer’s disease (AD). However, the specific mechanism is still unclear. Both the neuroinflammation and systemic inflammation serve as the key hubs to accelerate the process of AD by promoting pathology and damaging neuron. What's more, the gut microbiota is also crucial for the regulation of inflammation. Therefore, this review focused on the role of gut microbiota in AD through inflammatory pathways. Firstly, this review summarized the relationship and interaction among gut microbiota, inflammation, and AD. Secondly, the direct and indirect regulatory effects of gut microbiota on AD through inflammatory pathways were described. These effects were mainly mediated by the component of the gut microbiota (lipopolysaccharides (LPS) and amyloid peptides), the metabolites of bacteria (short-chain fatty acids, branched amino acids, and neurotransmitters) and functional by-products (bile acids). In addition, potential treatments (fecal microbiota transplantation, antibiotics, probiotics, prebiotics, and dietary interventions) for AD were also discussed through these mechanisms. Finally, according to the current research status, the key problems to be solved in the future studies were proposed.     

肠道微生物群的病理生理学进展

Before the technique of advanced high-throughput sequencing comes up, less is known about the human gut microbiota. It has been understood that trillions of microbes, in which 99% are bacteria, inhabit the human gut, forming a complicated ecological community. The gut microbiota has a great impact on human physiology and susceptibility to disease through its integrative metabolic activities and interactions with the host. In physiology, gut microbiota contributes to the host acquisition of nutrition and energy from diets, promoting development and maturation of gastrointestinal tract and immune system, and protecting host from invasion of enteropathogens. In pathology, dysbiosis underlying altered gut microbiota is associated with the susceptibilities to various diseases, including inflammatory bowel disease, type 1 diabetes, asthma, obesity, metabolic syndrome, autism and cancer. Understanding of the factors that underlie alterations in the composition and function of gut microbiota will be helpful in the development of drugs and the design of therapies that target it. This goal is formidable. It is because that the compositions of gut microbiota are immensely diverse, varying between individuals in a population and fluctuating over time in an individual, especially during early development and diseases. Viewing the gut microbiota with an ecological perspective will provide new insights into how to improve our health by targeting this microbial community in clinical treatments.     

Immune homeostasis,dysbiosis and therapeutic modulation of the gut microbiota

The distal gut harbours ∼10¹³ bacteria, representing the most densely populated ecosystem known. The functional diversity expressed by these communities is enormous and relatively unexplored. The past decade of research has unveiled the profound influence that the resident microbial populations bestow to host immunity and metabolism. The evolution of these communities from birth generates a highly adapted and highly personalized microbiota that is stable in healthy individuals. Immune homeostasis is achieved and maintained due in part to the extensive interplay between the gut microbiota and host mucosal immune system. Imbalances of gut microbiota may lead to a number of pathologies such as obesity, type I and type II diabetes, inflammatory bowel disease (IBD), colorectal cancer (CRC) and inflammaging/immunosenscence in the elderly. In-depth understanding of the underlying mechanisms that control homeostasis and dysbiosis of the gut microbiota represents an important step in our ability to reliably modulate the gut microbiota with positive clinical outcomes. The potential of microbiome-based therapeutics to treat epidemic human disease is of great interest. New therapeutic paradigms, including second-generation personalized probiotics, prebiotics, narrow spectrum antibiotic treatment and faecal microbiome transplantation, may provide safer and natural alternatives to traditional clinical interventions for chronic diseases. This review discusses host–microbiota homeostasis, consequences of its perturbation and the associated challenges in therapeutic developments that lie ahead.     

Inflammatory bowel disease and immunonutrition: novel therapeutic approaches through modulation of diet and the gut microbiome

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract, thought to at least in part reflect an aberrant immune response to gut bacteria. IBD is increasing in incidence, particularly in populations that have recently immigrated to western countries. This suggests that environmental factors are involved in its pathogenesis. We hypothesize that the increase in IBD rates might reflect the consumption of an unhealthy Western diet, containing excess calories and lacking in key nutritional factors, such as fibre and vitamin D. Several recent studies have determined that dietary factors can dramatically influence the activation of immune cells and the mediators they release through a process called immunonutrition. Moreover, dietary changes can profoundly affect the balance of beneficial versus pathogenic bacteria in the gut. This microbial imbalance can alter levels of microbiota‐derived metabolites that in turn can influence innate and adaptive intestinal immune responses. If the diet–gut microbiome disease axis does indeed underpin much of the ‘western’ influence on the onset and progression of IBD, then tremendous opportunity exists for therapeutic changes in lifestyle, to modulate the gut microbiome and to correct immune imbalances in individuals with IBD. This review highlights four such therapeutic strategies – probiotics, prebiotics, vitamin D and caloric restriction – that have the potential to improve and add to current IBD treatment regimens.     

Microbiome and colorectal cancer: Unraveling host-microbiota interactions in colitis-associated colorectal cancer development

Dysbiosis of gut microbiota occurs in many human chronic immune-mediated diseases, such as inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). Reciprocally, uncontrolled immune responses, that may or may not be induced by dysbiosis, are central to the development of IBD and CAC. There has been a surge of interest in investigating the relationship between microbiota, inflammation and CAC. In this review, we discuss recent findings related to gut microbiota and chronic immune-mediated diseases, such as IBD and CAC. Moreover, the molecular mechanisms underlying the roles of chronic inflammation in CAC are examined. Finally, we discuss the development of novel microbiota-based therapeutics for IBD and colorectal cancer.     

肠道微生态与肠道疾病

人类肠道微生态是一个包含大量肠道微生物的复杂生态系统,近年来研究发现肠道细菌过度繁殖可导致胃肠道动力失调及内脏神经敏感性改变,最终导致肠易激综合征的发生,而肠道菌群引起的肠粘膜异常免疫应答损伤被认为是炎症性肠病发病机制的关键所在,另外,肠道微生态还可过参与炎症性肠病的病理生理过程或直接代谢产生致癌物质影响肠道肿瘤的发生发展。由此我们发现,肠道微生态不仅参与了消化吸收、物质代谢等胃肠道基本生理过程,还直接关系到肠道疾病的发生。本文将就目前肠道微生态与肠道疾病的研究进展进行简单综述。     

99th Dahlem Conference on Infection,Inflammation and Chronic Inflammatory Disorders: Host–microbe interactions in the gut: target for drug therapy,opportunity for drug discovery

The commensal microbiota, most of which resides in the gut, is an environmental regulator of mucosal and systemic immune maturation. Epidemiological studies suggest that changes in the microbiota may represent a link between a modern lifestyle and risk of certain immuno-allergic diseases. This suggests that the microbiota is an appropriate target for therapy or prophylaxis, the rationale for which is addressed here using inflammatory bowel disease as an example. It is also evident from comparative studies of germ-free and conventionally colonized animals that the microbiota is a source of regulatory signals for full development of the host. In some instances these signals have been defined molecularly, and may be suitable for exploitation in novel drug discovery. Most of the versatile drugs in common usage today were derived originally from living matter in the wider environment; could it be time to mine new drugs from microbial-derived signalling molecules in the inner environment of the gut? Several examples illustrate the potential of the gut microbiota as a rich repository from which bioactives with immunological impact can be mined, and translated to human health care or to animal husbandry.     

Impact of diet and the bacterial microbiome on the mucous barrier and immune disorders

The prevalence of chronic immune and metabolic disorders is increasing rapidly. In particular, inflammatory bowel diseases, obesity, diabetes, asthma and chronic obstructive pulmonary disease have become major healthcare and economic burdens worldwide. Recent advances in microbiome research have led to significant discoveries of associative links between alterations in the microbiome and health, as well as these chronic supposedly noncommunicable, immune/metabolic disorders. Importantly, the interplay between diet, microbiome and the mucous barrier in these diseases has gained significant attention. Diet modulates the mucous barrier via alterations in gut microbiota, resulting in either disease onset/exacerbation due to a “poor” diet or protection against disease with a “healthy” diet. In addition, many mucosa-associated disorders possess a specific gut microbiome fingerprint associated with the composition of the mucous barrier, which is further influenced by host-microbiome and inter-microbial interactions, dietary choices, microbe immigration and antimicrobials. Our review focuses on the interactions of diet (macronutrients and micronutrients), gut microbiota and mucous barriers (gastrointestinal and respiratory tract) and their importance in the onset and/or progression of major immune/metabolic disorders. We also highlight the key mechanisms that could be targeted therapeutically to prevent and/or treat these disorders.     

Manipulation of epithelial integrity and mucosal immunity by host and microbiota-derived metabolites

The human intestinal tract contains a large number of microbes, their metabolites, and potentially harmful food antigens. The intestinal epithelium separates the mucosa where immune cells are located from luminal microbes by expressing various factors that assemble into physical and chemical barriers. In addition to epithelial cells, immune cells are essential for enforcing mucosal barriers through production of inflammatory and anti-inflammatory mediators. Intestinal microbiota, represented by gut ecological communities of living microorganisms, influences maturation and homeostasis of host immune system and contributes to the maintenance of the epithelial integrity with small molecules derived from their metabolism, termed metabolites. In turn, immune cells receive signals from microbiota, and may play key role in maintenance of a healthy bacterial composition and reinforcement of epithelial barrier functions, leading to the establishment of a host-bacterial mutualism. Alterations in the microbiota community and metabolome profiles are observed in patients with various disorders including inflammatory bowel disease. In this review, we will discuss physiological functions of the microbiota and its metabolites in regulating host immune system and reinforcing epithelial barrier functions. Further understanding of these processes will aid in identification of novel therapeutic targets and subsequent development of therapeutic interventions in a range of chronic inflammatory diseases.     

Development of gut microbiota in infants not exposed to medical interventions

Knowledge of the composition of a normal healthy gut microbiota during infancy is important for understanding the role of gut microbiota in disease. A limitation of previous studies is that they are based on infants who have been subject to factors, which can have a profound disruptive effect on the natural colonization process. We describe the colonization process, during the first 4 months after birth, in 85 infants who have experienced no major medical or dietary interventions. They were all vaginally delivered, healthy, term infants, who were not exposed to antibiotics, exclusively breastfed during their first month of life and at least partially breastfed up to 4 months. Selected microbial groups were identified by targeting small subunit microbial ribosomal RNA genes. In contrast to more recent studies, but in agreement with older studies, almost all our infants harbored γ-Proteobacteria and Bifidobacterium. Yet undefined non-cultivable species belonging to Bacteroides, as well as microbes identified as Lachnospiraceae 2, were common. Strong associations were observed between some specific constituents of microbiota at day 4 and the concentration of specific microbial groups at day 120, indicating that early gut microbiota may influence later microbiota. Novel information of the undisturbed composition of early gut microbiota in babies is presented.     

Blastocystis in Health and Disease: Are We Moving from a Clinical to a Public Health Perspective?

Blastocystis is a genus of common single-celled intestinal parasitic protists with an unsettled role in human health and disease. Being a stable component of intestinal microbiota, once established, the Blastocystis parasite appears more common in healthy individuals than in patients with infectious, functional, or inflammatory bowel disease. Recent data suggest that the parasite is associated with certain gut microbiota profiles and health indices. Convincing data and tools differentiating asymptomatic colonization from infection are yet to be demonstrated. Although the parasite may elicit disease under certain circumstances, the focus on Blastocystis may be shifting from a clinical to a public health perspective.     

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.     

Interrelatedness between dysbiosis in the gut microbiota due to immunodeficiency and disease penetrance of colitis

The composition of the microbiome in health and disease has only recently become a major research focus. Although it is clear that an imbalance or dysbiosis in the microbiota is associated with disease, its interrelatedness to disease penetrance is largely unknown. Inflammatory bowel disease (IBD) is an excellent disease in which to explore these questions because of the extensive genetic studies identifying disease susceptibility loci and the ability to easily sample the intestinal microbiota in IBD patients due to the accessibility of stool samples. In addition, mouse models of IBD have contributed to our understanding of the interrelatedness of the gut microbiota and genes associated with IBD. The power of the mouse studies is that multiple colitis models exist that can be used in combination with genetically modified mice that harbour deficiencies in IBD susceptibility genes. Collectively, these studies revealed that bacterial dysbiosis does occur in human IBD and in mouse colitis models. In addition, with an emphasis on immune genes, the mouse studies provided evidence that specific immune regulatory proteins associated with IBD influence the gut microbiota in a manner consistent with disease penetrance. In this review, we will discuss studies in both humans and mice that demonstrate the impact of immunodeficiences in interleukin‐10, interleukin‐17, nucleotide‐binding oligomerization domain (NOD) 2, NOD‐like receptor proteins 3 and 6, Toll‐like receptor or IgA have on the interrelatedness between the composition of the gut microbiota and disease penetrance of IBD and its mouse models.     

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.     

S100 proteins in the pathogenesis and diagnosis of inflammatory bowel disease

Crohn’s disease and ulcerative colitis (the inflammatory bowel diseases) are two well characterized conditions featuring inflammation of the gastrointestinal tract. Gut inflammation may be detected, assessed and measured by a variety of methods but their utility varies extensively. Over the past decade, calprotectin, belonging to a family of S100 proteins, has been shown to be a reliable marker of gut inflammation that corresponds to neutrophil migration. In addition, other members of the S100 family have important roles in inflammation and may also be useful markers of gut inflammation. Furthermore, these proteins may have functional roles in gut defense or in the pathogenesis of inflammatory bowel disease.