Gut dysbiosis promotes the breakdown of oral tolerance mediated through dysfunction of mucosal dendritic cells

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肠道菌群参与宿主免疫应答的作用及机制研究进展

肠道菌群作为动物体内重要的组成部分,能够直接参与机体的免疫调控作用,促进机体免疫系统发育,维持正常免疫功能。同时,免疫系统对肠道菌群又有调控和制约作用。本文主要综述了肠道菌群的组成以及影响肠道菌群变化的因素,系统阐述了肠道菌群与疾病相互作用的机制,总结了肠道菌群在宿主感染与免疫应答中的作用,为开展肠道菌群参与机体免疫应答的机制方面的研究提供新的思路。     

肠道菌群失衡诱发肠易激综合征的机制

肠易激综合征（irritable bowel syndrome,IBS）是一种常见的功能性胃肠道疾病,严重地威胁着人类的健康与生存质量。最近的研究发现IBS的发病机制是复杂多样的,尽管其确切的发病原因尚不完全清楚,但有证据显示IBS可能与肠道菌群失衡有关。本文就有关肠道菌群的功能、IBS患者肠道菌群的特点、肠道菌群失衡导致IBS发病的可能机制的研究进展作一综述,旨在为IBS的早期诊断与有效治疗提供有价值的理论依据。     

Gut feelings of safety: tolerance to the microbiota mediated by innate immune receptors

To enable microbial colonization of the gut mucosa, the intestinal immune system must not only react to danger signals but also recognize cues that indicate safety. Recognition of safety, paradoxically, is mediated by the same environmental sensors that are involved in signaling danger. Indeed, in addition to their well‐established role in inducing inflammation in response to stress signals, pattern recognition receptors and a variety of metabolic sensors also promote gut‐microbiota symbiosis by responding to “microbial symbiosis factors”, “resolution‐associated molecular patterns”, markers of energy extraction and other signals indicating the absence of pathogenic infection and tissue damage. Here we focus on how the paradoxical roles of immune receptors and other environmental sensors define the microbiota signature of an individual.     

肠道微生物群与脱发的相关性研究进展

随着年轻人群脱发比例的逐年增加,头发健康问题日益受到关注。脱发会影响人们的生活质量,并对心理和社交生活产生巨大影响。近年来,对肠道微生物群的生理功能性研究已不再仅仅局限于胃肠道。研究表明肠道和肠道微生物群与皮肤有密切关系,提示“肠-皮肤轴”的存在。本文在已有的“肠-皮肤轴”研究现状基础上,总结近年来文献资料,探讨肠道微生物群与脱发之间可能的联系和潜在机制,为脱发的发病机制和治疗靶点提供新的认识和观点。     

Diet leaves a genetic signature in a keystone member of the gut microbiota

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Balancing reactive oxygen species generation by rebooting gut microbiota

Reactive oxygen species (ROS; free radical form O₂^•−, superoxide radical; OH^•, hydroxyl radical; ROO^•, peroxyl; RO^•, alkoxyl and non-radical form ¹O₂, singlet oxygen; H₂O₂, hydrogen peroxide) are inevitable companions of aerobic life with crucial role in gut health. But, overwhelming production of ROS can cause serious damage to biomolecules. In this review, we have discussed several sources of ROS production that can be beneficial or dangerous to the human gut. Micro-organisms, organelles and enzymes play crucial role in ROS generation, where NOX1 is the main intestinal enzyme, which produce ROS in the intestine epithelial cells. Previous studies have reported that probiotics play significant role in gut homeostasis by checking the ROS generation, maintaining the antioxidant level, immune system and barrier protection. With current knowledge, we have critically analysed the available literature and presented the outcome in the form of bubble maps to suggest that the probiotics help in controlling the ROS-specific intestinal diseases, such as inflammatory bowel disease (IBD) and colon cancer. Finally, it has been concluded that rebooting of the gut microbiota with probiotics, postbiotics or faecal microbiota transplantation (FMT) can have crucial implications in the structuring of gut communities for the personalized management of the gastrointestinal (GI) diseases.     

Age‐related changes in the marmoset gut microbiome

The gut microbiome is known to play a significant role in human health but its role in aging remains unclear. The objective of this study was to compare the gut microbiome composition between young adult and geriatric non‐human primates (marmosets) as a model of human health and disease. Stool samples were collected from geriatric (8+ years) and young adult males (2–5 years). Stool 16S ribosomal RNA V4 sequences were amplified and sequenced on the Illumina MiSeq platform. Sequences were clustered into operational taxonomic units and classified via Mothur's Bayesian classifier referenced against the Greengenes database. A total of 10 young adult and 10 geriatric marmosets were included. Geriatric marmosets had a lower mean Shannon diversity compared with young marmosets (3.15 vs. 3.46; p = 0.0191). Geriatric marmosets had a significantly higher mean abundance of Proteobacteria (0.22 vs. 0.09; p = 0.0233) and lower abundance of Firmicutes (0.15 vs. 0.19; p = 0.0032) compared with young marmosets. Geriatric marmosets had a significantly higher abundance of Succinivibrionaceae (0.16 vs. 0.01; p = 0.0191) and lower abundance of Porphyromonadaceae (0.07 vs. 0.11; p = 0.0494). In summary, geriatric marmosets had significantly altered microbiome diversity and composition compared with young adult marmosets. Further studies are needed to test microbiome‐targeted therapies to improve healthspan and lifespan.     

肠道菌群改变与结核分枝杆菌感染相互作用的研究进展

人体内肠道菌群数量庞大,参与机体物质代谢以及免疫应答反应,成为目前众多研究的热点.肠道菌群对于维持呼吸系统稳态,特别是肺部的稳态发挥着重要作用.目前越来越多的结果证明肠道菌群对机体免疫系统具有诱导和调节作用,这种免疫反应的改变对于结核病的发病和治疗有着深远意义.本文梳理了近年来国内外发表的肠道菌群与结核病相关的文献,讨...     

Feasibility of fecal microbiota transplantation via oral gavage to safely alter gut microbiome composition in marmosets

Disruption of microbial communities within human hosts has been associated with infection, obesity, cognitive decline, cancer risk and frailty, suggesting that microbiome-targeted therapies may be an option for improving healthspan and lifespan. The objectives of this study were to determine the feasibility of delivering fecal microbiota transplants (FMTs) to marmosets via oral gavage and to evaluate if alteration of the gut microbiome post-FMT could be achieved. This was a prospective study of marmosets housed at the Barshop Institute for Longevity and Aging Studies in San Antonio, Texas. Eligible animals included healthy young adult males (age 2–5 years) with no recent medication use. Stool from two donors was combined and administered in 0.5 ml doses to five young recipients once weekly for 3 weeks. Safety outcomes and alterations in the gut microbiome composition via 16S ribosomal RNA sequencing were compared at baseline and monthly up to 6 months post-FMT. Overall, significant differences in the percent relative abundance was seen in FMT recipients at the phylum and family levels from baseline to 1 month and baseline to 6 months post-FMT. In permutational multivariate analysis of variance analyses, treatment status (donor vs. recipient) (p = .056) and time course (p = .019) predicted β diversity (p = .056). The FMT recipients did not experience any negative health outcomes over the course of the treatment. FMT via oral gavage was safe to administer to young adult marmosets. The marmoset microbiome may be altered by FMT; however, progressive changes in the microbiome are strongly driven by the host and its baseline microbiome composition.     

Sinomenine promotes differentiation of induced pluripotent stem cells into immature dendritic cells with high induction of immune tolerance

BACKGROUNDImmature dendritic cells (imDCs) play an important role in the induction of donor-specific transplant immunotolerance. However, these cells have limitations, such as rapid maturation and a short lifespan in vivo. In previous studies, induced pluripotent stem cells (iPSCs) differentiated into imDCs, and sinomenine (SN) was used to inhibit the maturation of imDCs. AIMTo study the capacity of SN to maintain iPSC-derived imDCs (SN-iPSCs-imDCs) in an immature state and the mechanism by which SN-iPSCs-imDCs induce immunotolerance.METHODSIn this study, mouse iPSCs were induced to differentiate into imDCs in culture medium without or with SN (iPSCs-imDCs and SN-iPSCs-imDCs). The imDC-related surface markers, endocytotic capacity of fluorescein isothiocyanate-Dextran and apoptosis were analyzed by flow cytometry. The effects of iPSCs-imDCs and SN-iPSCs-imDCs on T-cell stimulatory function, and regulatory T (Treg) cell proliferative function in vitro were analyzed by mixed lymphocyte reaction. Cytokine expression was detected by ELISA. The apoptosis-related proteins of iPSCs-DCs and SN-iPSCs-DCs were analyzed by western blotting. The induced immunotolerance of SN-iPSCs-DCs was evaluated by treating recipient Balb/c skin graft mice. Statistical evaluation of graft survival was performed using Kaplan–Meier curves.RESULTSBoth iPSCs-imDCs and SN-iPSCs-imDCs were successfully obtained, and their biological characteristics and ability to induce immunotolerance were compared. SN-iPSCs-imDCs exhibited higher CD11c levels and lower CD80 and CD86 levels compared with iPSCs-imDCs. Reduced major histocompatibility complex II expression, worse T-cell stimulatory function, higher Treg cell proliferative function and stronger endocytotic capacity were observed with SN-iPSCs-imDCs (P < 0.05). The levels of interleukin (IL)-2, IL-12, interferon-γ in SN-iPSCs-imDCs were lower than those in iPSCs-imDCs, whereas IL-10 and transforming growth factor-β levels were higher (P < 0.05). The apoptosis rate of these cells was significantly higher (P < 0.05), and the expression levels of cleaved caspase3, Bax and cleaved poly(ADP-ribose) polymerase were higher after treatment with lipopolysaccharides, but Bcl-2 was reduced. In Balb/c mice recipients immunized with iPSCs-imDCs or SN-iPSCs-imDCs 7 d before skin grafting, the SN-iPSCs-imDCs group showed lower ability to inhibit donor-specific CD4⁺ T-cell proliferation (P < 0.05) and a higher capacity to induce CD4⁺CD25⁺FoxP3⁺ Treg cell proliferation in the spleen (P < 0.05). The survival span of C57bl/6 skin grafts was significantly prolonged in immunized Balb/c recipients with a donor-specific pattern. CONCLUSIONThis study demonstrated that SN-iPSCs-imDCs have potential applications in vitro and in vivo for induction of immunotolerance following organ transplantation.     

Maturation of function in dendritic cells for tolerance and immunity

The capacity of antigen presenting dendritic cells (DC) to function in both tolerance and immunity is now well documented. The function and characteristics of different DC subsets are reviewed here and their capacity to activate T cells under different conditions of maturation and activation is discussed. The immunogenic potential of exosomes produced by DC is also considered in light of evidence that the capacity of exosomes to activate T cells for tolerance or immunity appears to mirror that of the parent DC. A model is proposed whereby exosomes produced by immature DC can function to maintain peripheral tolerance, while exosomes produced by more mature DC can stimulate effector T cells.     

肠道微生物群在人类健康衰老中的作用机制研究进展北大核心

衰老的特征是组织器官的功能衰退以及衰老相关疾病风险的增加,这给维护和促进健康长寿带来一系列新的挑战。尽管进行了广泛的衰老相关研究,但进展有限。人们越来越意识到肠道微生物群的结构和功能积极参与了衰老过程。肠道微生物群紊乱表现为许多与年龄相关的肠外器官轴的衰老。肠道微生物群可以被调节,这暗示了通过肠道微生物群抗衰老是一个可以实现的重要目标。本综述总结了肠道微生物群在不同年龄段中的动态演替,这种动态的肠道微生物群从胎儿到出生和婴儿期开始迅速发展,从断奶期到幼儿期迅速变化,然后建立稳定的成年人菌群,直到随着年龄增长最后发生衰退;肠道微生物群与肠外器官轴(大脑、心脏、肝脏、胰腺、肌肉、皮肤和骨骼)衰老相关疾病,以及通过饮食、粪菌移植和微生态制剂调节肠道微生物群靶向抗衰老的研究进展,以期为调控肠道微生物群抗衰老研究提供参考。     

Age-dependent changes in the gut microbiota and serum metabolome correlate with renal function and human aging

Human aging is invariably accompanied by a decline in renal function, a process potentially exacerbated by uremic toxins originating from gut microbes. Based on a registered household Chinese Guangxi longevity cohort (n = 151), we conducted comprehensive profiling of the gut microbiota and serum metabolome of individuals from 22 to 111 years of age and validated the findings in two independent East Asian aging cohorts (Japan aging cohort n = 330, Yunnan aging cohort n = 80), identifying unique age-dependent differences in the microbiota and serum metabolome. We discovered that the influence of the gut microbiota on serum metabolites intensifies with advancing age. Furthermore, mediation analyses unveiled putative causal relationships between the gut microbiota (Escherichia coli, Odoribacter splanchnicus, and Desulfovibrio piger) and serum metabolite markers related to impaired renal function (p-cresol, N-phenylacetylglutamine, 2-oxindole, and 4-aminohippuric acid) and aging. The fecal microbiota transplantation experiment demonstrated that the feces of elderly individuals could influence markers related to impaired renal function in the serum. Our findings reveal novel links between age-dependent alterations in the gut microbiota and serum metabolite markers of impaired renal function, providing novel insights into the effects of microbiota-metabolite interplay on renal function and healthy aging.     

A preliminary study of gut dysbiosis in children with food allergy

Gut microbiota of food allergic children was analyzed by high throughput 16S rRNA gene sequencing. Signs of gut dysbiosis, which is likely associated with gut inflammation, was observed in children with food allergies. For example, decreased abundance of genus Akkermansia but increased abundance of Veillonella was found in children with food allergy in comparison with healthy control children.     

胞质型肽聚糖识别蛋白RfPGRP-L2在维持红棕象甲肠道菌群稳态中的作用

【目的】明确入侵害虫红棕象甲Rhynchophorus ferrugineus胞质型肽聚糖识别蛋白RfPGRP-L2在肠道菌群稳态的维持和调控过程中的作用,将为靶向破坏肠道菌群稳态的害虫控制新策略研发提供新的科学依据和作用靶标。【方法】利用生物信息学方法分析RfPGRP-L2的序列特征。利用RT-qPCR分析RfPGRP-L2在健康红棕象甲4龄幼虫不同组织(头、脂肪体、表皮、前肠、中-/后肠、血淋巴)以及大肠杆菌Escherichia coli DH5α和金黄色葡萄球菌Staphylococcus aureus经注射（注射1 μL OD₆₀₀=1.6的菌液）和喂食（取食涂抹1 mL OD₆₀₀=1.6的菌液的甘蔗薄片）两种不同方式分别感染后红棕象甲4龄幼虫肠道和脂肪体中的表达量;进行RfPGRP-L2原核表达,利用体外孵育方法检测重组蛋白RfPGRP-L2对大肠杆菌DH5α和金黄色葡萄球菌的凝集和抑菌活性;RNAi干扰RfPGRP-L2后,检测红棕象甲4龄幼虫血淋巴和肠道中大肠杆菌菌落数的变化;利用RT-qPCR分析RNAi干扰RfPGRP-L2后红棕象甲4龄幼虫脂肪体和肠道中抗菌肽基因表达量的变化;利用基于细菌16S rRNA的高通量测序分析RNAi干扰RfPGRP-L2对健康红棕象甲4龄幼虫肠道菌群结构组成的影响。【结果】SMART预测发现红棕象甲RfPGRP-L2基因编码的蛋白中无跨膜结构域也无信号肽,这表明RfPGRP-L2是一种胞质型肽聚糖识别蛋白。RT-qPCR检测发现,RfPGRP-L2主要在健康红棕象甲4龄幼虫血淋巴、肠道和脂肪体等免疫组织中表达;被注射感染大肠杆菌和金黄色葡萄球菌6 h和12 h后,红棕象甲4龄幼虫脂肪体中RfPGRP-L2的表达量分别显著上调;被喂食感染大肠杆菌6 h后,红棕象甲4龄幼虫肠道中RfPGRP-L2的表达量显著增加。重组表达蛋白RfPGRP-L2能引起大肠杆菌和金黄色葡萄球菌发生凝集反应,这说明RfPGRP-L2能够识别这两种细菌。当RfPGRP-L2被干扰后,红棕象甲4龄幼虫对肠道和血淋巴中感染EGFP标记的大肠杆菌的清除能力显著弱于对照组;肠道中抗菌肽基因RfCecropin的表达量显著降低;健康红棕象甲4龄幼虫肠道中细菌的菌落数量显著高于对照组,而且肠道菌群结构组成也发生了明显的变化。【结论】红棕象甲体内胞质型肽聚糖识别蛋白RfPGRP-L2能够通过识别细菌并激活肠上皮细胞中相应的免疫信号通路促进抗菌肽基因的表达,从而介导对肠道菌群稳态的调控。     

肠道真菌研究进展

真菌菌群是肠道菌群的重要组成部分,在肠道微生态稳态的维持和宿主的免疫调节中发挥重要作用。肠道真菌失调通常和肠道疾病甚至肠道外疾病有关。本文就肠道真菌的定殖与组成、真菌菌群对肠道微生态的调控、菌群失调促进疾病的发展机制、基于肠道真菌的治疗策略和肠道真菌的鉴定分析方法等方面的进展进行了综述和展望,旨在系统认识肠道真菌调节宿主健康和促进疾病发生的机制,为相关疾病的诊断和治疗提供重要参考。     

肠道微生物对肥胖影响

肠道微生物是哺乳动物最密集的微生物群落,也是最多样化的微生物群落之一。随着宏基因组学的不断发展,肠道微生物成为热门的研究领域。肠道微生物具有保护和代谢等功能,在胰岛素抵抗和肥胖等疾病中发挥重要作用。本文介绍了肠道微生物及其代谢物通过调节食欲、神经递质合成分泌、炎性反应进而调节肥胖,探讨了肠道微生物的影响因素,展望了肠道微生物对治疗人类肥胖的应用前景。     

Alterations in the gut microbiota of patients with acquired immune deficiency syndrome

Acquired immune deficiency syndrome (AIDS), caused by infection with human immunodeficiency virus (HIV), is associated with gastrointestinal disease, systemic immune activation and changes in the gut microbiota. Here, we aim to investigate the gut microbiota patterns of HIV‐infected individuals and HIV‐uninfected individuals in populations from South China. We enrolled 33 patients with HIV (14 participants treated with highly active antiretroviral therapy [HAART] for more than 3 months; the remaining 19 individuals had not received treatment) and 35 healthy controls (HC) for a cross‐sectional comparison of gut microbiota using stool samples. Gut microbial communities were profiled by sequencing the bacterial 16S rRNA genes. Dysbiosis was more common among patients with AIDS compared with healthy individuals. Dysbiosis was characterized by decreased α‐diversity, low mean counts of Bacteroidetes, Faecalibacterium, Prevotella, Bacteroides vulgatus, Dialister and Roseburia inulnivorans, and high mean counts of Proteobacteria, Enterococcus, Streptococcus, Lactobacillus, Lachnociostridium, Ruminococcus gnavus and Streptococcus vestibularis. Increased abundance of Bacilli was observed in homosexual patients. Proteobacteria were higher among heterosexual patients with HIV infections. Tenericutes were higher among patients with history of intravenous drug abuse. Restoration of gut microbiota diversity and a significant increase in abundance of Faecalibacterium, Blautia and Bacteroides were found in patients receiving HAART compared to those who did not receive. HIV infection‐associated dysbiosis is characterized by decreased levels of α‐diversity and Bacteroidetes, increased levels of Proteobacteria and the alterations of gut microbiota correlate with the route of HIV transmission. The imbalanced faecal microbiota of HIV infection is partially restored after therapy.