炎症性肠疾病的微生态调节治疗

炎症性肠病包括溃疡性结肠炎、克罗恩病等,表现为肠黏膜免疫系统对肠内共生细菌产生异常反应的一类慢性肠道疾病,有明显家族聚集性但病因不明,肠道与其共栖微生物的稳态平衡一旦破坏即可发病。不同遗传个体对有害菌、无害菌或益生菌等肠内共生菌呈现不同的反应性,而肠内共生菌对肠道卫生以及天然免疫和获得免疫间的互动具有重要作用。     

Probiotics and prebiotics in inflammatory bowel disease: microflora 'on the scope'

The intestinal microflora is a large bacterial community that colonizes the gut, with a metabolic activity equal to an organ and various functions that affect the physiology and pathology of the host's mucosal immune system. Intestinal bacteria are useful in promotion of human health, but certain components of microflora, in genetically susceptible individuals, contribute to various pathological disorders, including inflammatory bowel disease. Clinical and experimental observations indicate an imbalance in protective and harmful microflora components in these disorders. Manipulation of gut flora to enhance its protective and beneficial role represents a promising field of new therapeutic strategies of inflammatory bowel disease. In this review, we discuss the implication of gut flora in the intestinal inflammation that justifies the role of probiotics and prebiotics in the prevention and treatment of inflammatory bowel disease and we address the evidence for therapeutic benefits from their use in experimental models of colitis and clinical trials.     

Fine-tuning of the mucosal barrier and metabolic systems using the diet-microbial metabolite axis

The human intestinal microbiota has profound effects on human physiology, including the development and maintenance of the host immune and metabolic systems. Under physiological conditions, the intestinal microbiota maintains a symbiotic relationship with the host. Abnormalities in the host-microbe relationship, however, have been implicated in multiple disorders such as inflammatory bowel diseases (IBDs), metabolic syndrome, and autoimmune diseases. There is a close correlation between dietary factors and the microbial composition in the gut. Long-term dietary habits influence the composition of the gut microbial community and consequently alter microbial metabolic activity. The diet-microbiota axis plays a vital role in the regulation of the host immune system, at least partly through altering microbial metabolism. In this review, we will describe the current findings regarding how dietary factors and microbial metabolites regulate the host immune system.     

Review: Mouse models of inflammatory bowel disease--insights into the mechanisms of inflammation-associated colorectal cancer

The association between chronic inflammation and cancer has been noted for at least a century but the exact molecular mechanisms of cancer initiation and promotion by such inflammation are still poorly understood. The gastrointestinal tract is a unique organ where maintaining a balance between the colonic epithelial cells, the immune system and a fine-tuned response to the resident microflora is crucial for preserving the gut homeostasis. A breakdown of the tight interdependent regulation of the epithelium-immunity-microbiota triangle leads to inflammatory bowel disorders and may promote cancer. This review focuses on inflammation-associated colorectal cancer in mouse models of the disease and highlights emerging research trends.     

TGF-β1 Signalling, Connecting Aberrant Inflammation and Colorectal Tumorigenesis

TGF-β1 is an anti-inflammatory cytokine recognised as a key regulator of immunological homeostasis and inflammatory responses. Furthermore, TGF-β1 is important for the regulation of cell growth, differentiation and apoptosis in a wide range of tissues including the intestinal epithelium. Reduced TGF-β1 activity is thought to be responsible for the development of autoimmune disorders in several pathological conditions, including inflammatory bowel disease [IBD]. Although the cause of IBD is not yet known, research has shown that a number of factors may be involved including environment, diet and genetics, as well as cytokine exposure. Importantly, IBD is also associated with an increased lifetime risk of developing colorectal cancer, which remains the fourth most common cancer worldwide, representing a significant therapeutic challenge. As functionally implicated in both maintenance of the immune response and tissue homeostasis in the colon, TGF-β1 signalling potentially sits at the crossroads between aberrant inflammation and colorectal tumorigenesis. Hence, the purpose of this paper is to review the evidence for cross talk between TGF-β1 signalling and pathways important for colorectal tissue homeostasis, with the emphasis on understanding how deregulation of TGF-β1 signalling contributes not only to aberrant inflammatory disease but also to colorectal tumour progression.     

Targeting mast cells in the treatment of functional gastrointestinal disorders

Enhanced knowledge of the pathophysiological basis of functional gastrointestinal disorders indicates that low-grade mucosal inflammation and mast cell hyperplasia are common findings. Mast cells are multipotent and mucosa-dwelling residents are uniquely located to communicate with host immune and nervous supersystems and with the gut microflora to provide tight microenvironmental conditions. Maintenance of homeostasis within this integrated defense system is crucial for symbiotic health, whereas breakdown of that balance might lead to uncontrolled mucosal and systemic inflammation. Numerous advances have recently emerged in the understanding of regulatory mechanisms of mast cell activation, development and homing to mucosal surfaces, as well as of the role of mast cells in key steps of mucosal inflammation. Such observations have stimulated the development of candidate drugs, such as tryptase or Syk inhibitors, that might be useful for the treatment of gastrointestinal functional disorders.     

Microecology as a target for therapeutic intervention in inflammatory bowel disease

The gastrointestinal tract is populated by several hundred grams of bacteria. Recognition of the symbiosis between bacteria and host is drawing particular attention to the implications of bacteria in human health. Probiotics are living microorganisms that upon ingestion in certain numbers exert health benefits. Prebiotics are non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth or activity of a limited number of gut bacteria. In inflammatory bowel disease (IBD), the gut flora is the key factor driving the inflammatory process that leads to intestinal lesions. Interaction of certain commensal bacteria with the gut mucosa triggers mucosal inflammation. However, certain probiotic strains are able to downregulate inflammatory pathways. Restoring the microbial balance with prebiotics and probiotics offers promise for the control of IBD.     

The biology of oral tolerance and issues related to oral vaccine design

Intestinal tissues are continuously exposed to tremendous amount of foreign material, either beneficial or harmful. Although strong protective immune responses are required to clear harmful pathogen infections, similar responses against food antigen can lead to harmful inflammation. Therefore, oral tolerance or unresponsiveness against dietary and commensal bacteria is also important to maintain tissue integrity by preventing harmful inflammatory responses in the intestine. While oral tolerance is an important phenomenon to protect unnecessary inflammatory responses, it presents an obstacle in the development of oral vaccines. Therefore an understanding of the gut immune system and the induction of oral tolerance is important. This review will focus on important aspects of the intestinal immune system and how immune responses in the intestine maintain homeostasis via oral tolerance. Also it will provide new insights in the development of oral vaccines.     

Modulation of the human gut microflora towards improved health using prebiotics--assessment of efficacy

There is increasing awareness that the human gut microflora plays a critical role in maintaining host health, both within the gastrointestinal tract and, through the absorption of metabolites, systemically. An "optimal" gut microflora establishes an efficient barrier to the invasion and colonisation of the gut by pathogenic bacteria, produces a range of metabolic substrates which in turn are utilized by the host (e.g. vitamins and short chain fatty acids) and stimulates the immune system in a non-inflammatory manner. Although little is known about the individual species of bacteria responsible for these beneficial activities, it is generally accepted that the bifidobacteria and lactobacilli constitute important components of the beneficial gut microflora. A number of diet-based microflora management tools have been developed and refined over recent decades including probiotic, prebiotic and synbiotic approaches. Each aims to stimulate numbers and/or activities of the bifidobacteria and lactobacilli within the gut microflora. The aim of this article is to examine how prebiotics are being applied to the improvement of human health and to review the scientific evidence supporting their use.     

The gut as communicator between environment and host: immunological consequences

During human evolution, the mucosal immune system developed two anti-inflammatory mechanisms: immune exclusion by secretory antibodies (SIgA and SIgM) to control epithelial colonization of microorganisms and inhibit penetration of harmful substances; and immunosuppression to counteract local and peripheral hypersensitivity against innocuous antigens such as food proteins. The latter function is referred to as oral tolerance when induced via the gut. Similar mechanisms also control immunity to commensal bacteria. The development of immune homeostasis depends on "windows of opportunity" where adaptive and innate immunities are coordinated by antigen-presenting cells; their function is not only influenced by microbial products but also by dietary constituents, including vitamin A and lipids like polyunsaturated omega-3 fatty acids. These factors can in several ways exert beneficial effects on the immunophenotype of the infant. Also breast milk provides immune-modulating factors and SIgA antibodies - reinforcing the gut barrier. Mucosal immunity is most abundantly expressed in the gut, and the intestinal mucosa of an adult contains at least 80% of the body's activated B cells - terminally differentiated to plasmablasts and plasma cells (PCs). Most mucosal PCs produce dimeric IgA which is exported by secretory epithelia expressing the polymeric Ig receptor (pIgR), also called membrane secretory component (SC). Immune exclusion is therefore performed mainly by SIgA. Notably, pIgR knockout mice which lack SIgs show increased uptake of food and microbial antigens and they have a hyper-reactive immune system with disposition for anaphylaxis; but this untoward development is counteracted by cognate oral tolerance induction as a homeostatic back-up mechanism.     

Autophagy and Digestive Disorders: Advances in Understanding and Therapeutic Approaches

The gastrointestinal (GI) tract is a series of hollow organs that is responsible for the digestion and absorption of ingested foods and the excretion of waste. Any changes in the GI tract can lead to GI disorders. GI disorders are highly prevalent in the population and account for substantial morbidity, mortality, and healthcare utilization. GI disorders can be functional, or organic with structural changes. Functional GI disorders include functional dyspepsia and irritable bowel syndrome. Organic GI disorders include inflammation of the GI tract due to chronic infection, drugs, trauma, and other causes. Recent studies have highlighted a new explanatory mechanism for GI disorders. It has been suggested that autophagy, an intracellular homeostatic mechanism, also plays an important role in the pathogenesis of GI disorders. Autophagy has three primary forms: macroautophagy, microautophagy, and chaperone-mediated autophagy. It may affect intestinal homeostasis, host defense against intestinal pathogens, regulation of the gut microbiota, and innate and adaptive immunity. Drugs targeting autophagy could, therefore, have therapeutic potential for treating GI disorders. In this review, we provide an overview of current understanding regarding the evidence for autophagy in GI diseases and updates on potential treatments, including drugs and complementary and alternative medicines.     

Development and persistence of multi-resistance to antibiotics in bacteria; an analysis and a new approach to this urgent problem

The intestinal microflora may have more influence on infectious diseases, than the mere control of growth of opportunistic micro-organisms by colonisation resistance (CR) and unspecific stimulation of the immune system. In compromised patients the CR may become decreased for several reasons but mostly because antibiotics reach the intestine during treatment. The consequence of a CR-decrease is that antibiotic-resistant opportunistic micro-organisms may increase in numbers in the gut. In this context, it is hypothesised that if the CR could be maintained at a normal level, the risk for maintenance and spread of resistant strains could be mitigated. Such maintenance requires absence of active antibiotic substance in the gut. This might be brought by the inactivation of antimicrobial agents by intestinal contents. Intra-intestinal inactivation has been described to occur along two possible routes: (1) inactivation by chemical binding or absorption and (2) by enzymatic destruction. Secondly, the composition of the intestinal microflora should be maintained at a normal level in case of other reasons for CR-decrease than antibiotic activity. Comprehensive study of the composition of normal microflora and the strains of species which play a role in CR with techniques which have become available during last decade, is recommended as well as the application of certain pre- and probiotics. It is concluded that antibiotic inactivation may be an ancient strategy of nature which should become incorporated in antibiotic treatment. Antibiotic use and development of resistance may have occurred when ecosystems formed several billions of years ago. Protection against antibiotics produced by newcomers into the ecosystem may have developed as it was necessary to maintain locally available nutrients for the inhabitants of the ecosystem. Should this hypothesis be correct, it is plausible that antimicrobial inactivation by antibiotic inactivating molecules is ubiquitous. In the ecosystem of the digestive tract, molecules involved in inactivation may predominantly be formed by microorganisms.     

Metabolic endotoxemia and cardiovascular disease: A systematic review about potential roles of prebiotics and probiotics

Translocation of microbiome-derived lipopolysaccharide (LPS) to the bloodstream (metabolic endotoxaemia) is associated with a significantly increased risk of cardiovascular diseases (CVD); however, the direction of this association is not fully understood. It has been revealed by some studies that alterations in the intestinal microbiota (dysbiosis) lead to increased intestinal permeability and translocation of LPS to the blood circulation. LPS may trigger toll-like receptor 4- (TLR-4) mediated inflammatory responses; this could lead to a chronic low-grade pro-inflammatory condition named metabolic endotoxaemia (ME), which is typically observed in CVD patients. ME is promoted by increased intestinal permeability. Moreover, dysbiosis leads to production of trimethylamine-N-oxide (TMAO), a gut bacterial metabolite suggested as a new risk factor in CVD development. Probiotics, extensively reviewed for decades, are live microorganisms which, when taken in adequate amounts, have beneficial effects on the host metabolism. Prebiotics are a type of dietary fibre that act as nourishment for the good bacteria in the gut and decrease the population of pathogen bacteria that produce greater amounts of endotoxins. Although an association has been postulated between ME and CVD, the results of studies investigating the role of antibiotic therapy in preventing the disease have been inconsistent. In this review, we discuss how prebiotics and probiotics modulate gut microbiota and consequently might help with prevention and/or treatment of CVD associated with ME.     

Neuroimmunology of the gut: physiology, pathology, and pharmacology

It has been increasingly appreciated that an intimate interaction between cells of the nervous and immune systems takes place in the gut, and may have a role in diverse inflammatory disorders. Thus, for instance, activation of the enteric nervous system may reduce intestinal epithelial permeability, via several mediators including S-nitrosoglutathione and vasoactive intestinal peptide (VIP). Moreover, ablation of glial cells instigated enterocolitis in murine models. These neuronal effects are particularly intriguing given our current understanding of the immunopathogenesis of Crohn's disease, in which intestinal barrier defect is suspected to at least partly drive the immune hyper-reactivity and ensuing inflammation. Parasympathetic nicotinic signaling, primarily via nicotinic acetylcholine receptor alpha7 (alpha7 nACHr), also exerts immunomodulatory effects, possibly underlaying the detrimental effects of smoking on Crohn's disease, and its beneficial impact on ulcerative colitis. These, and others, neuro-immune interactions may pave the way to the design of novel therapeutic agents for the treatment of chronic inflammatory bowel disorders.     

Toll-like receptors and NOD/CARD proteins: pattern recognition receptors are key elements in the regulation of immune response

The magnitude of the response to a specific immunogen such as an infectious agent is the result of a complex interaction between genetic and environmental factors. For example, in intestinal inflammation, the inflammatory response appears to be regulated by the indigenous microflora of the gut, by receptors in epithelial cells and antigen-presenting cells in the intestinal mucosa, and by immunologic factors. Recent evidence suggests that genetic variants of human immunomodulating genes influence the susceptibility to and severity of infectious diseases and the subsequent clinical outcome of disease. This review will focus on recently identified pattern recognition receptors which are located on innate immune and epithelial cells, and recognize pathogen-associated molecular patterns. The binding of specific pathogen-associated molecular patterns to these receptors results in the activation of a signal transduction pathway through nuclear factor (NF)-kappaB which leads to either enhanced or inhibited immune responses that modify the production of inflammatory effectors, such as cytokines. This article reports on the identification and functional characterization including the discovery of mutants which completely abolish NF-kappaB signal transduction of pattern recognition receptors, such as the extracellular Toll-like receptors and the intracellular nucleotide oligomerization domain/caspase recruitment domain (NOD/CARD) receptors, as well as their role in clinical disease. Knowledge of pattern recognition receptors such as Toll-like receptors and NOD/CARD intracytoplasmic proteins, including their functions and their downstream signaling pathways, may provide a new molecular basis for preventing or blocking inflammation associated with pathogenic microorganisms. This could direct a new focus for better and more specific therapeutic treatments based on immuno-intervention that can promise a better quality of life for those suffering from chronic disturbances of the immune response.     

Gut microflora: a new target for therapeutic approaches in inflammatory bowel disease

Background: Intestinal microflora contribute to the pathogenesis of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. Objective: This review summarizes current clinical knowledge about the role of intestinal microflora in inflammatory bowel disease and their importance as targets for new forms of therapy. Methods: Recent knowledge on gut microbial ecology, role of microflora, and pattern recognition receptors is summarized in relation to inflammatory bowel disease. The results of in vitro experiments, in vivo animal studies and human clinical trials with the use of agents targeting microflora, including prebiotics, probiotics and synbiotics, are described briefly. Conclusion: Altering the composition of intestinal microflora through prebiotics, probiotics and synbiotics may improve the clinical outcome of patients with inflammatory bowel disease.     

Bifidobacteria and lactobacilli in human health

The gastrointestinal microflora is a complex ecological system, normally characterized by a flexible equilibrium. The most important role of the microflora, from the point of view of the host, is probably to act in colonization resistance against exogenous, potentially pathogenic, microorganisms. Bifidobacteria and lactobacilli are Gram-positive lactic acid-producing bacteria constituting a major part of the intestinal microflora in humans and other mammals. Administration of antimicrobial agents may cause disturbances in the ecological balance of the gastrointestinal microflora with several unwanted effects such as colonization by potential pathogens. To maintain or reestablish the balance in the flora, supplements of intestinal microorganisms, mainly bifidobacteria and lactobacilli, sometimes called probiotics, have been successfully used. This article reviews the role of bifidobacteria and lactobacilli in human health.     

抗生素对肠道定植抗力的影响研究进展

哺乳动物的胃肠道寄居着复杂的微生物种群,这些微生物种群被称为肠道微生物群,其与宿主的健康和疾病状态息息相关。肠道菌群可以防止外源病原体在胃肠道中定植,这种现象被称为“定植抗力”。对肠道微生态的干扰,譬如抗生素的使用,可能会改变微生物的组成,影响宿主免疫功能,并导致定植抗性的丧失,从而使宿主易于被病原体定植。本文对肠道定植抗力的形成机制以及抗生素对定植抗力影响的研究进展进行综述,旨在为人们合理使用抗生素、研发抗生素替代疗法提供理论参考。     

岩藻糖及岩藻聚糖硫酸酯对肠道微生物的影响研究进展

岩藻糖作为动物体内常见的单糖之一,是动物肠道上皮细胞及肠道微生物表面糖蛋白的重要糖基组成成分。岩藻糖及海洋生物中富含岩藻糖的岩藻聚糖硫酸酯,既可作为肠道微生物的碳源和能量物质,也与肠道微生物的黏附、定植以及肠道细胞免疫调节息息相关,对肠道微生物与宿主的共生及维持人类肠道健康有重要作用。本文对岩藻糖及岩藻聚糖硫酸酯对肠道微生物的营养调控、肠道微生物与宿主共生及肠炎等疾病的影响进行综述,为肠炎等相关疾病的防治提供有用参考。     

Probiotics in inflammatory bowel disease--therapeutic rationale and role

The intestinal flora has a conditioning effect on intestinal homeostasis, delivering regulatory signals to the epithelium, the mucosal immune system and to the neuromuscular activity of the gut. Beneficial metabolic activities of the enteric flora include nutrient production, metabolism of dietary carcinogens, conversion of prodrugs to active drugs. However, increasing evidence suggests that some components of the enteric flora are essential ingredients in the pathogenesis of inflammatory bowel disease (IBD); this has prompted interest in therapeutic manipulation of the flora with probiotics. Probiotics are biologic control agents-described as live microbial food supplements which confer a health benefit beyond inherent basic nutrition. Multiple potential beneficial effects have been attributed to the probiotic use of lactic acid bacteria, bifidobacteria and other non-pathogenic commensals. At present, much of the promise of probiotics remains outside the realm of evidence-based medicine and awaits the results of prospective trials, now underway. No reliable in vitro predictors of in vivo efficacy of putative probiotics have been identified. Rigorous comparisons of probiotic performance have not been performed and the suitability of a given probiotic for different individuals is largely unexplored. Notwithstanding, an improved understanding of the normal commensal flora and host-flora interactions has the potential to open up new therapeutic strategies for inflammatory disorders of the gut.