Ewa Jończyk-Matysiak 1,*
作者： 
Adam Jędrusiak 1 , Wojciech Fortuna 2,3 , 乔安娜-马耶夫斯基 1
, 安杰伊-戈尔斯基 1,3,4 和 Ewa Jończyk-Matysiak 1,*
Bacteriophage Laboratory, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
波兰弗罗茨瓦夫，53-114，波兰科学院赫兹菲尔德免疫学与实验治疗研究所噬菌体实验室
Department of Neurosurgery, Wroclaw Medical University, Borowska 213, 54-427 Wroclaw, Poland
波兰 54-427 弗罗茨瓦夫 Borowska 213 号弗罗茨瓦夫医科大学神经外科系
Phage Therapy Unit, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
波兰弗罗茨瓦夫，53-114，波兰科学院赫兹菲尔德免疫学和实验治疗研究所噬菌体治疗组
Infant Jesus Hospital, The Medical University of Warsaw, 02-006 Warsaw, Poland
波兰华沙 02-006 号华沙医科大学耶稣婴儿医院
Author to whom correspondence should be addressed.
通讯作者
Cells 2023, 12(13), 1720; https://doi.org/10.3390/cells12131720
细胞 2023》，12（13），1720；https://doi.org/10.3390/cells12131720
Abstract 摘要
The central nervous system manages all of our activities (e.g., direct thinking and decision-making processes). It receives information from the environment and responds to environmental stimuli. Bacterial viruses (bacteriophages, phages) are the most numerous structures occurring in the biosphere and are also found in the human organism. Therefore, understanding how phages may influence this system is of great importance and is the purpose of this review. We have focused on the effect of natural bacteriophages in the central nervous system, linking them to those present in the gut microbiota, creating the gut-brain axis network, as well as their interdependence. Importantly, based on the current knowledge in the field of phage application (e.g., intranasal) in the treatment of bacterial diseases associated with the brain and nervous system, bacteriophages may have significant therapeutic potential. Moreover, it was indicated that bacteriophages may influence cognitive processing. In addition, phages (via phage display technology) appear promising as a targeted therapeutic tool in the treatment of, among other things, brain cancers. The information collected and reviewed in this work indicates that phages and their impact on the nervous system is a fascinating and, so far, underexplored field. Therefore, the aim of this review is not only to summarize currently available information on the association of phages with the nervous system, but also to stimulate future studies that could pave the way for novel therapeutic approaches potentially useful in treating bacterial and non-bacterial neural diseases.
中枢神经系统管理着我们的所有活动（如直接思维和决策过程）。它从环境中接收信息，并对环境刺激做出反应。细菌病毒（噬菌体）是生物圈中数量最多的结构，也存在于人类机体中。因此，了解噬菌体如何影响这一系统非常重要，这也是本综述的目的所在。我们重点研究了天然噬菌体对中枢神经系统的影响，将它们与肠道微生物群中的噬菌体联系起来，创建了肠道-大脑轴网络，以及它们之间的相互依存关系。重要的是，根据目前噬菌体在治疗与大脑和神经系统有关的细菌性疾病方面的应用（如鼻内注射），噬菌体可能具有巨大的治疗潜力。此外，有研究表明，噬菌体可能会影响认知过程。此外，噬菌体（通过噬菌体展示技术）似乎有望成为治疗脑癌等疾病的靶向治疗工具。这项工作中收集和回顾的信息表明，噬菌体及其对神经系统的影响是一个令人着迷的领域，但迄今为止尚未得到充分探索。因此，本综述的目的不仅在于总结噬菌体与神经系统相关的现有信息，还在于激励未来的研究，为可能用于治疗细菌和非细菌性神经疾病的新型治疗方法铺平道路。
Keywords:
antibiotic resistance; blood–brain barrier; central nervous system; cerebrospinal fluid; cognitive processing; gut–brain axis; gut phageome; intranasal delivery; therapeutic phages; phage display; phage therapy
关键词： 抗生素耐药性；血脑屏障；中枢神经系统；脑脊液；认知处理；肠脑轴；肠道噬菌体组；鼻内给药；治疗噬菌体；噬菌体展示；噬菌体疗法
1. Introduction 1.导言
Numerous papers have suggested that gut bacteria play a critical role in shaping our health [1,2,3]. It has been demonstrated that a healthy gut microbiota is essential for proper development, immune response, homeostasis, and even learning processes [4,5,6,7,8,9]. Besides the bacterial component of the microbiota, other crucial microorganisms are viruses—more specifically, bacteriophages (phages), which are bacterial viruses, estimated to outnumber bacteria in the gut by one order of magnitude (1015 phages and 1014 bacteria) [10,11,12]. Interestingly, it is probable that 31 billion phage particles pass across the human gut epithelial cell layers each day [13]. The influence of bacteriophages on human health and their role in shaping the overall homeostasis have yet to be fully understood, but it is acknowledged that phages may have a huge impact on the composition of gut microbiota and the function it serves [14,15,16].
大量文献表明，肠道细菌在塑造我们的健康方面起着至关重要的作用[1, 2, 3]。研究表明，健康的肠道微生物群对正常发育、免疫反应、平衡甚至学习过程都至关重要[4, 5, 6, 7, 8, 9]。除了微生物群中的细菌成分外，其他重要的微生物还有病毒–更具体地说是噬菌体（phages），这是一种细菌病毒，估计其数量比肠道中的细菌多一个数量级（10 15 噬菌体和 10 14 细菌）[10, 11, 12]。有趣的是，每天可能有 310 亿个噬菌体颗粒穿过人体肠道上皮细胞层[ 13]。噬菌体对人类健康的影响及其在塑造整体平衡中的作用尚未完全明了，但人们承认噬菌体可能对肠道微生物群的组成及其功能产生巨大影响[ 14, 15, 16]。
Bacteriophages are viruses that invade bacteria. Not only can they eradicate these bacteria, but they also play a significant role in bacterial evolution. This is due to the bacteriophages’ ability to integrate their genetic material with the bacterial genome and facilitate the transfer of genes between bacteria. Phages are ubiquitous, found in both the environment and living organisms [17,18], and may be isolated from different sources, ranging from aquatic samples to soil, or from human specimens [19,20]. Interestingly, they occupy nearly every ecological niche within our bodies, predominantly inhabiting areas such as the urinary tract, lungs, gut, mouth, and skin [21,22], and the composition of each body niche phageome varies significantly [21]. Among different human phageomes, those inhabiting the gut and mouth are probably the most thoroughly characterized because these sites are easily accessible and phages occur there in high concentrations [19,23,24,25].
噬菌体是入侵细菌的病毒。它们不仅能消灭这些细菌，还在细菌进化过程中发挥着重要作用。这是因为噬菌体能够将其遗传物质与细菌基因组整合，促进细菌之间的基因转移。噬菌体无处不在，既存在于环境中，也存在于生物体内[17, 18]，可以从不同的来源分离出来，从水生样本到土壤，或者从人体标本中[19, 20]。有趣的是，它们几乎占据了人体内的每一个生态位，主要栖息于尿道、肺部、肠道、口腔和皮肤等区域[21, 22]，而且每个生态位的噬菌体组成也有很大差异[21]。在不同的人体噬菌体群中，栖息在肠道和口腔中的噬菌体群可能是特征最全面的，因为这些部位很容易进入，而且噬菌体在这些部位出现的浓度很高[19, 23, 24, 25]。
The central nervous system (CNS) is composed of the brain (cerebrum and cerebellum), spinal cord, and optic nerves, as well as the membranes covering them, and can be infected by different pathogens, regardless of difficulties in penetrating the blood–brain barrier (BBB) [26]. The system is well shielded by the BBB, the major site of a blood–CNS exchange. In humans, it is a neurovascular unit composed of brain microvascular endothelial cells (BMECs), pericytes, astrocytic endfeet, microglia, and neurons. All these cells are connected to each other by tight junctions or adherens junctions, making it extremely difficult for any molecule to penetrate [27]. Surprisingly, recent studies have shown that bacteriophages may also be present in the central nervous system. This is in line with a previous report of bacteriophages’ ability to penetrate the BBB, which opens up a new research area, expanding their therapeutic potential in treating CNS-related bacterial infections, but also in brain cancers and other brain-related diseases (including the study of phages as carriers transporting different drugs through the BBB) [28,29,30,31,32,33,34,35,36].
中枢神经系统（CNS）由大脑（小脑和大脑皮层）、脊髓、视神经以及覆盖它们的膜组成，无论是否难以穿透血脑屏障（BBB），都可能受到不同病原体的感染[26]。血脑屏障是血液与中枢神经系统交换的主要场所，对中枢神经系统有很好的保护作用。在人体中，它是一个由脑微血管内皮细胞（BMECs）、周细胞、星形胶质细胞内膜、小胶质细胞和神经元组成的神经血管单元。所有这些细胞都通过紧密连接或粘连连接相互连接，使得任何分子都极难穿透[ 27]。令人惊讶的是，最近的研究表明，噬菌体也可能存在于中枢神经系统中。这与之前关于噬菌体能够穿透 BBB 的报道相吻合，从而开辟了一个新的研究领域，扩大了噬菌体在治疗中枢神经系统相关细菌感染以及脑癌和其他脑相关疾病（包括研究噬菌体作为载体通过 BBB 转运不同药物）方面的治疗潜力[28, 29, 30, 31, 32, 33, 34, 35, 36]。
In this review, we focused on the occurrence of natural bacteriophages in the nervous system, linking their presence in the intestine with the influence they may have on the nervous system. Additionally, we also focused on the current knowledge of phage application and its potential in the treatment of diseases associated with the brain and nervous system (which have presented serious difficulties for treatment).
在这篇综述中，我们重点探讨了天然噬菌体在神经系统中的存在，将它们在肠道中的存在与它们可能对神经系统产生的影响联系起来。此外，我们还关注了噬菌体应用的现有知识及其在治疗与大脑和神经系统有关的疾病（这些疾病在治疗上存在严重困难）方面的潜力。