肠道菌群调控机体免疫功能的研究进展

人体肠道作为机体最大的免疫器官,产生全身近80%的抗体,所以肠道免疫是抵御病原的一道重要防线。肠道菌群在与宿主长期的共同进化中形成了互利共生的复杂关系,其数量、相对丰度、定植时间的早晚等多种因素均能破坏肠道菌群的相对平衡,进而对免疫系统,尤其是免疫细胞和相关炎症细胞因子造成不同程度的刺激。近年肠道菌群在免疫相关疾病的发病机制和治疗的研究中都有许多新见解,我们主要总结了肠道菌群对机体免疫功能影响的相关研究进展,旨在为寻找疾病的治疗靶点提供一些新思路。     

肠道菌群影响免疫检查点抑制剂治疗癌症的研究进展

人体肠道内寄生着约1 014 个共生菌群,这些菌群可以帮助分解人体内的食物,其代谢产物能影响人体消化能力、抗自身免疫性疾病的能力等,是人体内不可忽视的重要“器官冶。最近的研究发现,人体内的肠道菌群可以影响免疫检查点抑制剂(Immune-checkpoint blockers,ICB)治疗癌症。本文将结合近几年的研究成果,对癌症免疫治疗后出现的不良反应、肠道菌群及肠道菌群如何影响免疫检查点抑制剂(ICB)治疗癌症的研究进展进行总结,最后对肠道菌群影响癌症治疗进行展望,以期能够为研究肠道菌群与癌症治疗的关系提供理论依据。     

肠道菌群对机体抗结核免疫反应影响研究进展

结核分枝杆菌是引起结核病的病原体,常引起机体的细胞免疫应答.而肠道菌群能调节机体免疫反应,维持人体健康.近年来研究发现,患者感染MTB及使用抗结核药物治疗均可破坏宿主肠道菌群原有的平衡,而肠道菌群紊乱又会直接或间接影响患者免疫功能.本文就肠道菌群稳态对抗结核免疫反应的影响、维生素介导的肠道菌群稳态对抗结核免疫反应的影响、抗结核治疗介导的肠道菌群失调对抗结核免疫反应的影响三方面进行综述.     

肝脏疾病的肠道微生态失衡及其对机体的影响

肠道是人体重要的消化器官,也是一个由定植于肠道的大量固有菌群、肠道上皮细胞及肠道局部粘膜免疫系统组成的肠道微生态系统,它在人体的代谢、免疫系统的发育、成熟等过程中均起着非常重要的作用。肝脏与肠道的关系极为密切,肝病病人由于胆汁分泌异常等等原因导致肠道微生态的失衡,肠道菌群的数量（和）或组成结构发生变化、肠道定植抗力（B/E比值）的降低,甚至发生菌群易位,由此对机体的代谢和免疫产生一定的影响,在疾病的发生、发展中的作用不可忽视。     

肠道菌群对人体健康的作用及其应用

人类肠道菌群复杂多样,在与人类长期的共同进化过程中,具备了调节人体免疫应答、影响疾病发展的作用。 这种免疫调节作用与肠道菌群本身的多样性和关键菌种的存在与否具有紧密联系。然而肠道菌群结构和功能的特性在很大程度上受到肠道菌群宿主的饮食结构、年龄和生活环境等因素的影响。正常的肠道菌群能够调节肠上皮细胞的通透性,刺激物质代谢与免疫反应,使肠道微环境长期处于稳态;一旦肠道菌群失衡,引起肠道微环境稳态变化,则会提高许多疾病的发生风险,尤其是胃肠代谢疾病,以及免疫和神经性疾病。本文主要从肠道菌群与人体健康的关系、影响肠道菌群组成的因素、功能性食品对人体健康的影响以及如何维持肠道微生态平衡等几个方面,综述了人体肠道菌群的当前研究现状和相关产业应用,期望能够为肠道菌群与人体健康的相互关系研究及其成果转化提供新的思考。     

肠道菌群定植与B淋巴细胞免疫的研究概况

肠道菌群不仅在机体代谢方面起重要作用,而且参与了免疫系统的发育及功能调控。肠道菌群与肠道免疫系统的"平衡"在机体免疫应答、免疫耐受过程中起重要作用。其中,B淋巴细胞(简称B细胞)是体液免疫中产生抗体的重要细胞,还参与抗原提呈,在免疫系统中发挥重要作用。国内关于肠道菌群定植与B细胞免疫的关系研究较少,本文主要就肠道菌群定植与机体肠道免疫系统、免疫组织、B细胞及黏膜免疫调节之间的关系进行综述。     

双歧杆菌在肿瘤治疗中的应用

双歧杆菌作为机体肠道内数量占绝对优势的生理性菌群，对维持机体的健康发挥重要的功能。双歧杆菌能够刺激机体的免疫器官且自身具有抗肿瘤活性。此外，双歧杆菌专性厌氧的特性使其在肿瘤的基因治疗中起重要的作用。     

MDR1基因多态性在自身免疫性疾病精准诊疗中的应用

自身免疫性疾病 (Autoimmune Disease,AID) 是因机体对自身抗原发生反应,免疫稳态失衡而引起自身组织损伤的疾病状态,与自身抗原、免疫调节异常、交叉抗原、遗传因素有关。AID 精准诊疗是目前 AID 临床管理的新方向。 多药耐药-1 (Multi-drug Resistance-1,MDR1) 基因多态性在 AID 的诊断和鉴别诊断,确定疾病活动、严重程度和并发症, 治疗方案选择及疗效预测等方面有良好的应用前景,并将有助于实现临床AID患者个体化管理。本文就MDR1基因多态性在常见AID精准诊疗中应用的研究进展做一综述。     

饮食、肠道菌群与炎症性肠病

炎症性肠病 (Inflammatory Bowel Disease,IBD) 是一种胃肠道的慢性免疫相关性炎症性疾病,目前发病机制尚不十分明确,与遗传因素、机体免疫失调、环境因素 (如饮食) 和肠道菌群等因素均密切相关。目前普遍认为饮食因素和肠道菌群均是IBD发病机制的重要环节,而饮食可以通过改变肠道菌群及其代谢产物调节肠道微生态环境,肠道菌群的改变也能影响饮食的作用效果。本文主要讨论饮食、肠道菌群以及饮食与肠道菌群的相互作用对IBD的影响。     

肠道菌群或许能改变人的精神状态

正人体肠道内寄生着超过10万亿个细菌,跟人类共同经过漫长的进化过程,与人类密不可分,相互依赖。它们不但能影响体重和消化能力、抵御感染和自体免疫疾病的患病风险,甚至能影响人的脑功能和行为,在各种心理疾病中发挥着不容忽视的作用。肠道菌群与精神疾病有的科学家提出将肠道菌群看作一个重要的"器官"。肠道菌群可通过自身或其代谢产物影响大脑,大脑也可以反过来通过神经、     

Microbiota regulate the development and function of the immune cells

Microbiota is a group of microbes coexisting and co-evolving with the immune system in the host body for millions of years. There are mutual interaction between microbiota and the immune system. Immune cells can shape the populations of microbiota in the gut of animals and humans, and the presence of microbiota and the microbial products can regulate the development and function of the immune cells in the host. Although microbiota resides mainly at the mucosa, the effect of microbiota on the immune system can be both local at the mucosa and systemic through the whole body. At the mucosal sites, the presences of microbiota and microbial products have a direct effect on the immune cells. Microbiota induces production of effectors from immune cells, such as cytokines and inflammatory factors, influencing the further development and function of the immune cells. Experimental data have shown that microbial products can influence the activity of some key factors in signaling pathways. At the nonmucosal sites, such as the bone marrow, peripheral lymph nodes, and spleen, microbiota can also regulate the development and function of the immune cells via several mechanisms in mice, such as introduction of chromatin-level changes through histone acetylation and DNA methylation. Given the important effect of microbiota on the immune system, many immunotherapies that are mediated by immune system rely on gut microbiota. Thus, the study of how microbiota influences immune system bring a potential therapy prospect in preventing and treating diseases.     

The role of the intestinal microbiota in the development of atopic disorders

The prevalence of atopic diseases, including eczema, allergic rhinoconjunctivitis and asthma, has increased worldwide, predominantly in westernized countries. Recent epidemiological studies and experimental research suggest that microbial stimulation of the immune system influences the development of tolerance to innocuous allergens. The gastrointestinal microbiota composition may be of particular interest, as it provides an early and major source of immune stimulation and seems to be a prerequisite for the development of oral tolerance. In this review the observational studies of the association between the gut microbiota and atopic diseases are discussed. Although most studies indicated an association between the gut microbiota composition and atopic sensitization or symptoms, no specific harmful or protective microbes can be identified yet. Some important methodological issues that have to be considered are the microbiological methods used (traditional culture vs molecular techniques), the timing of examining the gut microbiota, the definition of atopic outcomes, confounding and reverse causation. In conclusion, the microbiota hypothesis in atopic diseases is promising and deserves further attention. To gain more insight into the role of the gut microbiota in the etiology of atopy, large-scale prospective birth cohort studies using molecular methods to study the gut microbiota are needed.     

Adaptive immune education by gut microbiota antigens

Host–microbiota mutualism has been established during long‐term co‐evolution. A diverse and rich gut microbiota plays an essential role in the development and maturation of the host immune system. Education of the adaptive immune compartment by gut microbiota antigens is important in establishing immune balance. In particular, a critical time frame immediately after birth provides a ‘window of opportunity’ for the development of lymphoid structures, differentiation and maturation of T and B cells and, most importantly, establishment of immune tolerance to gut commensals. Depending on the colonization niche, antigen type and metabolic property of different gut microbes, CD4 T‐cell responses vary greatly, which results in differentiation into distinct subsets. As a consequence, certain bacteria elicit effector‐like immune responses by promoting the production of pro‐inflammatory cytokines such as interferon‐γ and interleukin‐17A, whereas other bacteria favour the generation of regulatory CD4 T cells and provide help with gut homeostasis. The microbiota have profound effects on B cells also. Gut microbial exposure leads to a continuous diversification of B‐cell repertoire and the production of T‐dependent and ‐independent antibodies, especially IgA. These combined effects of the gut microbes provide an elegant educational process to the adaptive immune network. Contrariwise, failure of this process results in a reduced homeostasis with the gut microbiota, and an increased susceptibility to various immune disorders, both inside and outside the gut. With more definitive microbial–immune relations waiting to be discovered, modulation of the host gut microbiota has a promising future for disease intervention.     

Interaction between gut microbiota and toll-like receptor: from immunity to metabolism

The human gut contains trillions of commensal bacteria, and similar to pathogenic bacteria, the gut microbes and their products can be recognized by toll-like receptors (TLRs). It is well acknowledged that the interaction between gut microbiota and the local TLRs help to maintain the homeostasis of intestinal immunity. High-fat intake or obesity can weaken gut integrity leading to the penetration of gut microbiota or their bacterial products into the circulation, leading to the activation of TLRs on immune cells and subsequently low-grade systemic inflammation in host. Metabolic cells including hepatocytes and adipocytes also express TLRs. Although they are able to produce and secrete inflammatory molecules, the effectiveness remains low compared with the immune cells embedded in the liver and adipose tissue. The interaction of TLRs in these metabolic cells or organs with gut microbiota remains unclear, but a few studies have suggested that the functions of these TLRs are related to metabolism. Alteration of the gut microbiota is associated with body weight change and adiposity in human, and the interaction between the commensal gut microbiota and TLRs may possibly involve both metabolic and immunological regulation. In this review, we will summarize the current findings on the relationship between TLRs and gut microbiota with a focus on metabolic regulation and discuss how such interaction participates in host metabolism.     

The role of the adaptive immune system in regulation of gut microbiota

The gut nourishes rich bacterial communities that affect profoundly the functions of the immune system. The relationship between gut microbiota and the immune system is one of reciprocity. The microbiota contributes to nutrient processing and the development, maturation, and function of the immune system. Conversely, the immune system, particularly the adaptive immune system, plays a key role in shaping the repertoire of gut microbiota. The fitness of host immune system is reflected in the gut microbiota, and deficiencies in either innate or adaptive immunity impact on diversity and structures of bacterial communities in the gut. Here, we discuss the mechanisms that underlie this reciprocity and emphasize how the adaptive immune system via immunoglobulins (i.e. IgA) contributes to diversification and balance of gut microbiota required for immune homeostasis.     

Long-distance relationships - regulation of systemic host defense against infections by the gut microbiota

Despite compartmentalization within the lumen of the gastrointestinal tract, the gut microbiota has a far-reaching influence on immune cell development and function throughout the body. This long-distance relationship is crucial for immune homeostasis, including effective host defense against invading pathogens that cause systemic infections. Herein, we review new insights into how commensal microbes that are spatially restricted to the gut lumen can engage in long-distance relationships with innate and adaptive immune cells at systemic sites to fortify host defenses against infections. In addition, we explore the consequences of intestinal dysbiosis on impaired host defense and immune-mediated pathology during infections, including emerging evidence linking dysbiosis with aberrant systemic inflammation and immune-mediated organ damage in sepsis. As such, therapeutic modification of the gut microbiota is an emerging target for interventions to prevent and/or treat systemic infections and sepsis by harnessing the long-distance relationships between gut microbes and systemic immunity.     

Gut microbiota, probiotics, and vitamin D: interrelated exposures influencing allergy, asthma, and obesity?

Current evidence supports a role for gut colonization in promoting and maintaining a balanced immune response in early life. An altered or less diverse gut microbiota composition has been associated with atopic diseases, obesity, or both. Moreover, certain gut microbial strains have been shown to inhibit or attenuate immune responses associated with chronic inflammation in experimental models. However, there has been no fully adequate longitudinal study of the relation between the neonatal gut microbiota and the development of allergic diseases (eg, atopic asthma) and obesity. The emergence of promising experimental studies has led to several clinical trials of probiotics (live bacteria given orally that allow for intestinal colonization) in human subjects. Probiotic trials thus far have failed to show a consistent preventive or therapeutic effect on asthma or obesity. Previous trials of probiotics have been limited by small sample size, short duration of follow-up, or lack of state-of-the art analyses of the gut microbiota. Finally, there is emerging evidence that the vitamin D pathway might be important in gut homeostasis and in signaling between the microbiota and the host. Given the complexity of the gut micriobiota, additional research is needed before we can confidently establish whether its manipulation in early life can prevent or treat asthma, obesity, or both.     

Metabolism at the centre of the host–microbe relationship

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

Influence of gastrointestinal commensal bacteria on the immune responses that mediate allergy and asthma

The human intestine contains more than 100 trillion microorganisms that maintain a symbiotic relationship with the host. Under normal conditions, these bacteria are not pathogenic and in fact confer health benefits to the host. The microbiota interacts with the innate and adaptive arms of the host's intestinal?mucosal immune system and through these mechanisms drives regulatory cell differentiation in the gut that is?critically involved in maintaining immune tolerance. Specifically, the microbiota can activate distinct tolerogenic dendritic cells in the gut and through this interaction can drive regulatory T-cell differentiation. In addition, the microbiota is important in driving T(H)1 cell differentiation, which corrects the T(H)2 immune skewing that is thought to occur at birth. If appropriate immune tolerance is not established in early life and maintained throughout life, this represents a risk factor for the development of inflammatory, autoimmune, and allergic diseases.?Early-life events are instrumental in establishing the microbiota, the composition of which throughout life is influenced?by various environmental and lifestyle pressures. Significant efforts are now being made to establish interventional approaches that can create a healthy microbiota that confers maximum tolerogenic immunomodulatory effects in the gut and that will protect against systemic inflammatory disease pathologies.