Combined therapies to treat complex diseases: The role of the gut microbiota in multiple sclerosis

The commensal microbiota has emerged as an environmental risk factor for multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE) models have shown that the commensal microbiota is an essential player in triggering autoimmune demyelination. Likewise, the commensal microbiota modulates the host immune system, alters the integrity and function of biological barriers and has a direct effect on several types of central nervous system (CNS)-resident cells. Moreover, a characteristic gut dysbiosis has been recognized as a consistent feature during the clinical course of MS, and the MS-related microbiota is gradually being elucidated. This review highlights animal studies in which commensal microbiota modulation was tested in EAE, as well as the mechanisms of action and influence of the commensal microbiota not only in the local milieu but also in the innate and adaptive immune system and the CNS. Regarding human research, this review focuses on studies that show how the commensal microbiota might act as a pathogenic environmental risk factor by directing immune responses towards characteristic pathogenic profiles of MS. We speculate how specific microbiome signatures could be obtained and used as potential pathogenic events and biomarkers for the clinical course of MS. Finally, we review recently published and ongoing clinical trials in MS patients regarding the immunomodulatory properties exerted by some microorganisms. Because MS is a complex disease with a large variety of associated environmental risk factors, we suggest that current treatments combined with strategies that modulate the commensal microbiota would constitute a broader immunotherapeutic approach and improve the clinical outcome for MS patients.     

Role of metabolic changes of mucosal layer in the intestinal barrier dysfunction following trauma/hemorrhagic shock

Background

The mucosal layer plays an important role in regulating the intestinal barrier function. However, the underlying mechanisms of intestinal barrier dysfunction caused by trauma-hemorrhagic shock (THS) are still unknown.

淀粉样蛋白前体/早老素1转基因小鼠大脑皮质内kinesin1介导的神经元轴浆运输障碍

目的 探讨轴突运输蛋白,kinesin1和神经丝蛋白（SIM-312）在阿尔茨海默病(AD)发生、发展中的作用。 方法 出生后30～360 d淀粉样蛋白前体（APP）/早老素1（PS1）转基因小鼠（n＝40）和野生型小鼠（n＝40）用于此研究,利用免疫荧光染色和Western blotting技术检测上述两种小鼠大脑皮层内老年斑的沉积及星形胶质细胞的分布以及在大脑皮质发育过程中kinesin1和SIM-312阳性细胞个数及蛋白的表达变化。 结果 APP/PS1转基因小鼠与正常对照组相比,β-淀粉样蛋白（Aβ）斑块增多,星形胶质细胞数目增多,神经元减少;而kinesin1阳性细胞的数量在APP/PS1转基因小鼠生长发育过程中减少,且在出生9月（P9M）之后与野生型小鼠之间差异存在着显著性 (P<0.05);SIM-312标记的神经丝蛋白随着年龄的增长自P6M之后开始出现缠结现象。 结论 Kinesin1和SIM-312的异常改变导致神经元中轴浆运输障碍以及AD的病理变化。     

CNS: Not an immunoprivilaged site anymore but a virtual secondary lymphoid organ

The cardinal dogma of central nervous system (CNS) immunology believed brain is an immune privileged site, but scientific evidences gathered so far have overturned this notion proving that CNS is no longer an immune privileged site, but rather an actively regulated site of immune surveillance. Landmark discovery of lymphatic system surrounding the duramater of the brain, made possible by high resolution live imaging technology has given new dimension to neuro-immunology. Here, we discuss the immune privilege status of CNS in light of the previous and current findings, taking into account the differences between a healthy state and changes that occur during an inflammatory response. Cerebrospinal fluid (CSF) along with interstitial fluid (ISF) drain activated T cells, natural killer cells, macrophages and dendritic cells from brain to regional lymph nodes present in the head and neck region. To keep an eye on inflammation, this system hosts an army of regulatory T cells (CD25+ FoxP3+) that regulate T cell hyper activation, proliferation and cytokine production. This review is an attempt to fill the gaps in our understanding of neuroimmune interactions, role of innate and adaptive immune system in maintaining homeostasis, interplay of different immune cells, immune tolerance, knowledge of communication pathways between the CNS and the peripheral immune system and lastly how interruption of immune surveillance leads to neurodegenerative diseases. We envisage that discoveries should be made not only to decipher underlying cellular and molecular mechanisms of immune trafficking, but should aid in identifying targeted cell populations for therapeutic intervention in neurodegenerative and autoimmune disorders.     

Immune regulation by microbiome metabolites

Commensal microbes and the host immune system have been co‐evolved for mutual regulation. Microbes regulate the host immune system, in part, by producing metabolites. A mounting body of evidence indicates that diverse microbial metabolites profoundly regulate the immune system via host receptors and other target molecules. Immune cells express metabolite‐specific receptors such as P2X₇, GPR41, GPR43, GPR109A, aryl hydrocarbon receptor precursor (AhR), pregnane X receptor (PXR), farnesoid X receptor (FXR), TGR5 and other molecular targets. Microbial metabolites and their receptors form an extensive array of signals to respond to changes in nutrition, health and immunological status. As a consequence, microbial metabolite signals contribute to nutrient harvest from diet, and regulate host metabolism and the immune system. Importantly, microbial metabolites bidirectionally function to promote both tolerance and immunity to effectively fight infection without developing inflammatory diseases. In pathogenic conditions, adverse effects of microbial metabolites have been observed as well. Key immune‐regulatory functions of the metabolites, generated from carbohydrates, proteins and bile acids, are reviewed in this article.     

Functional morphology of the respiratory organs of the air-breathing fish with particular emphasis on the African catfishes, Clarias mossambicus and C. gariepinus

The evolution of air-breathing and transition from water to land were pivotal events that greatly determined the ecological diversification, the advances and the successes of animal life. During their relocation onto land, the so-called bimodal breathers were literally caught at the water-air interface. Among such animals are the diverse air-breathing bony fish. Such taxa, however, strictly do not constitute the so-called ‘bridging animals’, i.e., the inaugural animals that crossed from water to land, nor are they their direct progenitors. The pioneer transitional animals were the Devonian rhipidistian amphibians that possessed a primitive lung which acquired O₂ directly from air and discharged CO₂ back into the same. By having particular morphological and physiological adaptations for terrestrialness, the modern amphibious- and aquatic air-breathers are heuristic analogues of how and why animals relocated from water to land. It has generally been espoused that lack or dearth of O₂ in water, especially in the warm tropical one, was an elemental driver for adoption of air-breathing. There is, however, no direct causal relationship between the evolution of air-breathing and the shift onto land: the move onto land was a direct solution to the existing inimical respiratory conditions in water. This is evinced in the facts that: a) even after attaining capacity of air-breathing, an important preadaptation for life on land, some animals continued living in water while periodically accessing air, b) in the fish species that live in the well-oxygenated waters, e.g., torrential rivers, only few air-breathe and c) air-breathing has still evolved in freshwaters and seawaters, where levels of dissolved O₂ are sufficiently high. Here, the structure and function of the respiratory organs of the air-breathing fish are succinctly outlined. Two African catfishes, Clarias mossambicus and C. gariepinus are highlighted.     

骨膜在骨组织再生中的作用

骨膜是一种高度血管化的成骨器官,有着复杂、精密而又有序的复合结构。骨膜具有良好的成骨特性、屏障膜特性、材料学特性,同时又有来源广泛、不存在免疫原性等诸多优点,在骨缺损修复、骨组织再生、骨组织工程等方面有着理想的应用前景,近年来也得到了骨科、颌面外科、种植科、牙周科等相关领域医生及学者越来越多的关注。研究并利用好骨膜,将在骨组织再生、骨缺损修复等领域中开辟新的天地。