Microbial view of central nervous system autoimmunity

Not much is known about the initial events leading to the development of the central nervous system (CNS)-specific autoimmune disorder Multiple Sclerosis (MS). Environmental factors are suspected to trigger the pathogenic events in people with genetic disease susceptibility. Historically, many infectious microbes were linked to MS, but no infection has ever been demonstrated to be the cause of the disease. Recent emerging evidence from animal models of MS suggests a causal link with resident commensal bacteria. Microbial organisms may trigger the activation of CNS-specific, auto-aggressive lymphocytes either through molecular mimicry or via bystander activation. In addition, several gut microbial metabolites and bacterial products may interact with the immune system to modulate CNS autoimmunity.     

Gut microbiome ADP-ribosyltransferases are widespread phage-encoded fitness factors

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肠道微生物与子宫内膜癌相关危险因素的研究进展

子宫内膜癌（endometrial carcinoma,EC）是一种常见的妇科恶性肿瘤,以雌激素升高、肥胖和胰岛素抵抗等临床表现为主要特征,这些特征影响了EC的进展及预后。肠道菌群是由大量微生物组成的复杂系统,它们维持着人体各系统的稳态并产生一些代谢产物来对机体发挥作用。但因其数量巨大,在菌群失调时可导致宿主生理机能发生紊乱,微生物产生的毒性代谢物参与炎症并增加与肿瘤相关的通路,影响机体的吸收代谢、肿瘤进展和恶化等。随着基因检测技术的发展,越来越多的证据表明肠道微生物与EC的危险因素存在相关性,能促进EC的发生发展。本文主要介绍肠道微生物对EC发生发展的影响,重点探讨肠道微生物与EC相关危险因素间的关系,以期为EC的治疗与预后管理提供新思路。

     

肠道菌群与肿瘤的免疫治疗

肠道菌群是居住于人体肠道内的正常微生物群体。肠道菌群通常与宿主成共生关系,并与宿主的消化、代谢、免疫调节等生理活动息息相关。靶向作用于免疫检查点的免疫检查点抑制剂,作为肿瘤免疫治疗中的新星,有着逆转肿瘤免疫微环境的作用,为肿瘤治疗提供了新的希望。然而研究发现,有部分人群对免疫检查点抑制剂的治疗无响应,而导致其无响应的最主要的原因是肠道菌群的异常。因此,本文对肠道菌群与肿瘤免疫治疗特别是与免疫检查点抑制剂的研究现状进行综述。     

模型动物中的肠道菌群分析及微生物组研究

正肠道菌群与多种疾病密切相关,从消化道疾病(如炎症性肠病)、心脑血管疾病(如动脉粥样硬化)到代谢类疾病(如II型糖尿病)和许多免疫性疾病(如风湿性关节炎),肠道菌群研究为诸多疾病研究和防治开辟了新的方向[1-3]。在肠道菌群研究领域,模型动物应用和实验结果的动物实验验证非常重要,本刊2016年第7期刊登的姬玉娇、孔祥峰等的论文"高、低营养水平饲粮对环江香猪结肠菌群结构及代谢物的影响"[4],通过对高、     

Gut Microbiome Alterations in COVID-19

Since the outset of the coronavirus disease 2019 (COVID-19) pandemic, the gut microbiome in COVID-19 has garnered substantial interest, given its significant roles in human health and pathophysiology. Accumulating evidence is unveiling that the gut microbiome is broadly altered in COVID-19, including the bacterial microbiome, mycobiome, and virome. Overall, the gut microbial ecological network is significantly weakened and becomes sparse in patients with COVID-19, together with a decrease in gut microbiome diversity. Beyond the existence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the gut microbiome of patients with COVID-19 is also characterized by enrichment of opportunistic bacteria, fungi, and eukaryotic viruses, which are also associated with disease severity and presentation. Meanwhile, a multitude of symbiotic bacteria and bacteriophages are decreased in abundance in patients with COVID-19. Such gut microbiome features persist in a significant subset of patients with COVID-19 even after disease resolution, coinciding with ‘long COVID’ (also known as post-acute sequelae of COVID-19). The broadly-altered gut microbiome is largely a consequence of SARS-CoV-2 infection and its downstream detrimental effects on the systemic host immunity and the gut milieu. The impaired host immunity and distorted gut microbial ecology, particularly loss of low-abundance beneficial bacteria and blooms of opportunistic fungi including Candida, may hinder the reassembly of the gut microbiome post COVID-19. Future investigation is necessary to fully understand the role of the gut microbiome in host immunity against SARS-CoV-2 infection, as well as the long-term effect of COVID-19 on the gut microbiome in relation to the host health after the pandemic.     

肠道菌群与肾脏疾病相关性研究进展

人体是一个有机的整体,不同系统之间存在着相互影响。近年来,随着科学的不断发展,肠道菌群与人体健康的关系也逐渐受到重视。肠道菌群虽然居住于肠道,但其作用已经不仅仅局限于消化系统。通过对人体代谢和免疫功能的影响,肠道菌群对人体产生的作用是全身性的。肾脏是体内代谢产物排泄的主要器官,也是免疫复合物沉积的重要部位。因此,肠道菌群在肾脏疾病发展和治疗中都起着至关重要的作用。现如今,两者的关系已经成为科学研究的热点话题。本文总结了近5年的文献,从中西医的角度,针对肠道菌群与肾脏疾病之间的相互关系作一综述。     

Pyridine alkaloids with activity in the central nervous system

This review discusses all pyridine alkaloids with CNS activity, their therapeutic potential, and the interesting array of sources whence they originate.     

Bacterial diversity and community structure of the intestinal microbiome of Channel Catfish (Ictalurus punctatus) during ontogenesis

The acquisition of gut microbes does not occur randomly and is highly dependent on host factors, environmental cues, and self-assembly rules exerted by the microbes themselves. The main objective of this project was to characterize how the gut microbiome develops during the early life stages of Channel Catfish and to identify i) which bacteria are the main constituents of the gut microbiome at different ontogenesis stages, and ii) at which time point(s) the gut microbiome stabilizes. High-throughput Illumina Miseq DNA sequencing of the V4 domain of the 16S rRNA gene was used to assess the microbial community composition during the life stages of Channel Catfish along with water and feed samples. Microbiomes from fertilized eggs, sac fry, swim up fry, pre-fingerlings, and fingerlings were all significantly distinct. OTUs analyses showed that the phylum Proteobacteria, Firmicutes, Fusobacteria and Cyanobacteria dominated the Channel Catfish gut microbiome. During the early stages of ontogenesis, the fish microbiome was dynamic and highly diverse, with significant shifts occurring between fertilized eggs to sac fry (6 dph), and from sac fry to swim up fry (15 dph). The gut microbiome stabilized between the pre-fingerlings and fingerlings stage (≤90 dph) with an observed reduction in species richness. Feed had a more significantly contribution to the microbial colonization of the gut than water. We have identified the period in which the gut microbiome changes rapidly from 15 dph until 21 dph before stabilizing after 90 dph.     

Adenosine in the central nervous system: release mechanisms and extracellular concentrations

Adenosine has several functions within the CNS that involve an inhibitory tone of neurotransmission and neuroprotective actions in pathological conditions. The understanding of adenosine production and release in the brain is therefore of fundamental importance and has been extensively studied. Conflicting results are often obtained regarding the cellular source of adenosine, the stimulus that induces release and the mechanism for release, in relation to different experimental approaches used to study adenosine production and release. A neuronal origin of adenosine has been demonstrated through electrophysiological approaches showing that neurones can release significant quantities of adenosine, sufficient to activate adenosine receptors and to modulate synaptic functions. Specific actions of adenosine are mediated by different receptor subtypes (A(1), A(2A), A(2B) and A(3)), which are activated by various ranges of adenosine concentrations. Another important issue is the measurement of adenosine concentrations in the extracellular fluid under different conditions in order to know the degree of receptor stimulation and understand adenosine central actions. For this purpose, several experimental approaches have been used both in vivo and in vitro, which provide an estimation of basal adenosine levels in the range of 50-200 nM. The purpose of this review is to describe pathways of adenosine production and metabolism, and to summarize characteristics of adenosine release in the brain in response to different stimuli. Finally, studies performed to evaluate adenosine concentrations under physiological and hypoxic/ischemic conditions will be described to evaluate the degree of adenosine receptor activation.     

Physiological and pathological roles of interleukin-6 in the central nervous system

The cytokine interleukin-6 (IL-6) is an important mediator of inflammatory and immune responses in the periphery. IL-6 is produced in the periphery and acts systemically to induce growth and differentiation of cells in the immune and hematopoietic systems and to induce and coordinate the different elements of the acute-phase response. In addition to these peripheral actions, recent studies indicate that IL-6 is also produced within the central nervous system (CNS) and may play an important role in a variety of CNS functions such as cell-to-cell signaling, coordination of neuroimmune responses, protection of neurons from insult, as well as neuronal differentiation, growth, and survival. IL-6 may also contribute to the etiology of neuropathological disorders. Elevated levels of IL-6 in the CNS are found in several neurological disorders including AIDS dementia complex, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma, and viral and bacterial meningitis. Moreover, several studies have shown that chronic overexpression of IL-6 in transgenic mice can lead to significant neuroanatomical and neurophysiological changes in the CNS similar to that commonly observed in various neurological diseases. Thus, it appears that IL-6 may play a role in both physiological and pathophysiological processes in the CNS.     

Lysophospholipids and their receptors in the central nervous system

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), two of the best-studied lysophospholipids, are known to influence diverse biological events, including organismal development as well as function and pathogenesis within multiple organ systems. These functional roles are due to a family of at least 11 G protein-coupled receptors (GPCRs), named LPA_1–6 and S1P_1–5, which are widely distributed throughout the body and that activate multiple effector pathways initiated by a range of heterotrimeric G proteins including G_i/o, G_12/13, G_q and G_s, with actual activation dependent on receptor subtypes. In the central nervous system (CNS), a major locus for these signaling pathways, LPA and S1P have been shown to influence myriad responses in neurons and glial cell types through their cognate receptors. These receptor-mediated activities can contribute to disease pathogenesis and have therapeutic relevance to human CNS disorders as demonstrated for multiple sclerosis (MS) and possibly others that include congenital hydrocephalus, ischemic stroke, neurotrauma, neuropsychiatric disorders, developmental disorders, seizures, hearing loss, and Sandhoff disease, based upon the experimental literature. In particular, FTY720 (fingolimod, Gilenya, Novartis Pharma, AG) that becomes an analog of S1P upon phosphorylation, was approved by the FDA in 2010 as a first oral treatment for MS, validating this class of receptors as medicinal targets. This review will provide an overview and update on the biological functions of LPA and S1P signaling in the CNS, with a focus on results from studies using genetic null mutants for LPA and S1P receptors. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.     

Racial disparity in colorectal cancer:Gut microbiome and cancer stem cells

Over the past two decades there has been remarkable progress in cancer diagnosis, treatment and screening. The basic mechanisms leading to pathogenesis of various types of cancers are also understood better and some patients, if diagnosed at a particular stage go on to lead a normal pre-diagnosis life. Despite these achievements, racial disparity in some cancers remains a mystery. The higher incidence, aggressiveness and mortality of breast, prostate and colorectal cancers(CRCs) in AfricanAmericans as compared to Caucasian-Americans are now well documented. The polyp-carcinoma sequence in CRC and easy access to colonic epithelia or colonic epithelial cells through colonoscopy/colonic effluent provides the opportunity to study colonic stem cells early in course of natural history of the disease. With the advent of metagenomic sequencing, uncultivable organisms can now be identified in stool and their numbers correlated with the effects on colonic epithelia. It would be expected that these techniques would revolutionize our understanding of the racial disparity in CRC and pave a way for the same in other cancers as well. Unfortunately, this has not happened. Our understanding of the underlying factors responsible in African-Americans for higher incidence and mortality from colorectal carcinoma remains minimal. In this review, we aim to summarize the available data on role of microbiome and cancer stem cells in racial disparity in CRC. This will provide a platform for further research on this topic.     

肠道菌群与中枢神经系统相互作用及相关疾病

肠道菌群参与宿主的多项生理过程,包括营养物质吸收、代谢及免疫系统的发育成熟、抵抗外来病原体入侵等,新的研究显示肠道菌群通过神经、内分泌、代谢和免疫的途径参与了肠道和中枢神经系统的双向调节。肠道菌群的变化与自闭症、多发性硬化、帕金森病、焦虑和抑郁症等一系列神经精神疾病有关,通过改善肠道菌群的微生态疗法有望成为治疗和预防一些神经系统疾病的有效措施。     

Thioredoxin and glutaredoxin system proteins—immunolocalization in the rat central nervous system

Background

The oxidoreductases of the thioredoxin (Trx) family of proteins play a major role in the cellular response to oxidative stress. Redox imbalance is a major feature of brain damage. For instance, neuronal damage and glial reaction induced by a hypoxic–ischemic episode is highly related to glutamate excitotoxicity, oxidative stress and mitochondrial dysfunction. Most animal models of hypoxia–ischemia in the central nervous system (CNS) use rats to study the mechanisms involved in neuronal cell death, however, no comprehensive study on the localization of the redox proteins in the rat CNS was available.

Methods

The aim of this work was to study the distribution of the following proteins of the thioredoxin and glutathione/glutaredoxin (Grx) systems in the rat CNS by immunohistochemistry: Trx1, Trx2, TrxR1, TrxR2, Txnip, Grx1, Grx2, Grx3, Grx5, and γ-GCS, peroxiredoxin 1 (Prx1), Prx2, Prx3, Prx4, Prx5, and Prx6. We have focused on areas most sensitive to a hypoxia–ischemic insult: Cerebellum, striatum, hippocampus, spinal cord, substantia nigra, cortex and retina.

Results and conclusions

Previous studies implied that these redox proteins may be distributed in most cell types and regions of the CNS. Here, we have observed several remarkable differences in both abundance and regional distribution that point to a complex interplay and crosstalk between the proteins of this family.

General significance

We think that these data might be helpful to reveal new insights into the role of thiol redox pathways in the pathogenesis of hypoxia–ischemia insults and other disorders of the CNS.This article is part of a Special Issue entitled Human and Murine Redox Protein Atlases.     

早期使用抗生素对小儿肠道微生态及生长发育的影响

肠道微生态与人体健康关系密切,婴儿期是肠道菌群定植成熟的关键时期,直接影响人体免疫系统的发育成熟,2岁之前肠道微生态失调导致的免疫功能缺陷将影响孩子终身。抗生素在我国存在过度使用现象,在婴儿及儿童中尤为严重。过度使用抗生素不仅存在多种副作用,导致细菌耐药性,还从多个方面破坏肠道微生态平衡,进而影响孩子的生长发育,并与远期多种疾病发生相关。因此,2岁之前的小儿应谨慎使用抗生素。     

Regeneration in the central nervous system of a pulmonate mollusc,Melampus

Summary The left cerebral ganglion was ablated from 72 anesthetized, adult Melampus bidentatus (Mollusca: Pulmonata). Skin incisions were well healed and normal feeding and locomotion observed four days after surgery. Dissections of animals sacrificed weekly showed that most nerves and connectives regrew within 30 days, attaching to the swollen end of the major labial nerve. The enlarged end of this nerve later developed into a distinctive bud; some of these buds contained cell bodies as soon as 42 days after surgery. As the first known report of central nervous tissue regeneration in molluscs, this study points to the need for controls in experiments involving section or ablation of nervous tissue in molluscs.I am grateful to Dr. W.D. Russell-Hunter for his guidance in the course of this work. Support was principally provided by a grant from the National Science Foundation to Dr. Russell-Hunter (Research Grant No. GB-36757 continued as BMS-72-02511-A01)and by two successive grants to the author from the Theodore Roosevelt Memorial Fund of the American Museum of Natural History, New York     

Development and sensitivity to serotonin of Drosophila serotonergic varicosities in the central nervous system

Serotonin is a classical small-molecule neurotransmitter with known effects on developmental processes. Previous studies have shown a developmental role for serotonin in the fly peripheral nervous system. In this study, we show that serotonin can modulate the development of serotonergic varicosities within the fly central nervous system. We have developed a system to examine the development of serotonergic varicosities in the larval CNS. We use this method to describe the normal serotonergic development in the A7 abdominal ganglion. From first to third instar larvae, the volume of the neuropil and number of serotonergic varicosities increase substantially while the varicosity density remains relatively constant. We hypothesize that serotonin is an autoregulator for serotonergic varicosity density. We tested the sensitivity of serotonergic varicosities to serotonin by adding neurotransmitter at various stages to isolated larval ventral nerve cords. Addition of excess exogenous serotonin decreases native varicosity density in older larvae, and these acute effects are reversible. The effects of serotonin appear to be selective for serotonergic varicosities, as dopaminergic and corazonergic varicosities remain qualitatively intact following serotonin application.     

Glycomics of pediatric and adulthood diseases of the central nervous system

Glycosylation consists in the covalent linkage of a carbohydrate structure to membrane bound and secreted glycoconjugates. It is a common post-translational modification that serves multiple functions in cell differentiation, signaling and intercellular communication. Unlike DNA/RNA/protein, the addition of complex carbohydrates is not-template driven and it is conceivable that both genetics and environmental factors might interact to influence glycosylation machinery in several pathological processes. Over the last few decades, the recognition of Congenital Disorders of Glycosylation (CDG) as an increasing number of genetic diseases of glycosylation with almost constant nervous system involvement, dramatically illustrated the consequences of abnormal glycosylation as improper CNS development and function. In addition, CDG recognition contributed to postulate that aberrant glycosylation processes might play a role in multifactorial, complex CNS diseases. On this context, CNS glycomics explores the effects of possible aberrant glycosylation to identify potential glyco-biomarkers useful for the diagnosis and ultimately for potential intervention strategies in neurological diseases. Up to date, CNS glycomics is an emerging, still uncharted area because of the specificity of CNS glycosylation, the complexity of the neurological disorders and for the inaccessibility and invasiveness of disease relevant samples. Here we review current knowledge on clinical glycomics of nervous system diseases, starting with CDG to include those pediatric and adulthood neuropsychiatric diseases where some evidences suggest that multifactor determinants converge to dysregulate glycosylation. Conventional and mass spectrometry-based high throughput technology for glyco-biomarker detection in CNS diseases is reported.