（精读热心肠上推荐的一篇综述）（上）
Cell子刊：口腔中的微生物组成和分布（综述）
口腔中牙齿、牙龈、上皮细胞、唾液及舌头等部位均有细菌定殖；
口腔微生物群动态平衡取决于多种因素:唾液流动及黏附、生物膜的脱落和再生，以及宿主和微生物的相互作用；
不同个体口腔微生物群总体组成和共同类群的比例不同，并且在特定的成员组成上也存在差异；
口腔微生物群中微米级组合呈多样性，如某些微生物类群易于形成克隆集群，链球菌常在舌头周围形成一层薄层等；
微米级梯度的短期和长期相互作用影响口腔微生物生境。
文章链接：https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(20)30405-4
Oral Microbiome Geography:Micron-Scale Habitatand Niche
The mouth presents a multiplicity of local environments in communication with one another via saliva.（嘴通过唾液展示了大量的不同环境之间的联系） The spatial organization of microbes within the mouth is shaped by opposing forces in dynamic equilibrium（口腔内微生物的空间组织是由动态平衡的相反作用力形成的）—salivary flow and adhesion, shedding and colonization—and by interactions among and between microbes and the host.（唾液流动和粘附，生物膜的脱落和再生以及微生物和宿主之间的相互作用。） Here we review recent evidence confirming that oral microbes are specialized for individual habitats within the mouth and that microbial habitats and niches are defined by micron-scale gradients in combination with short- and long-range interactions. （这里，我们回顾了最近的证据，证明口腔微生物对于口腔内单个生态环境是特殊的并且微生态环境和生态位是由微米梯度的长程和短程的相互作用形成的。）Micron-scale structure illuminates the roles of individual taxa and provides insight into their community ecology and potential pathogenicity.（微米级结构阐释了单个分类单元的角色并且对群落生态学和潜在的致病因子提供了深刻见解。）
INTRODUCTION
The human mouth is a natural laboratory for microbial ecology. （人类口腔是微生态生态学的一个自然的实验室）The mouth presents a range of substrates—such as teeth, tongue, cheeks, and gums—whose differing chemistry, topography, and stability provide differing habitats for microbial communities.（口腔提供了一系列底物，像如牙齿，舌头，脸颊和牙龈，他们不同的化学性质，位置和稳定性为微生物群落提供了不同的栖息地） Each habitat within the mouth supports a complex, distinctive community, and this distinctiveness presents an opportunity to use the oral microbiome to develop an understanding of fundamental principles of microbial community ecology.（口腔内的每个栖息地支持了一个复杂的不同的群落，并且这种独特性提供了一个机会去用口腔微生物去发展微生物生态学的基本原则的理解。）Oral microbiome communities are also o immediate practical importance, because they influence health and disease not only in the mouth but also throughout the body, and they play under-appreciated roles in systemic human physiology.（口腔微生物群落也具有直接的现实的重要性，因为他们不仅影响口腔内的健康与疾病，也影响全身的，他们在系统的人体生理学中也扮演者未被重视的作用。）
A majorgoal of microbiome research, from a clinical perspective, is to be able to modulate the microbiome to improve health and treat disease.（从临床角度看，微生物组研究的主要目标是通过调节微生物组来改善健康状况和治疗疾病） Microbes colonizing the mouth create spatially organized biofilms (Kolenbrander et al., 2006; Zijnge et al., 2010; Mark Welch et al., 2016; Wilbert et al., 2020; Kim et al., 2020). （定植在口腔中的微生物形成空间组织的生物膜）Understanding the forces governing this spatial organization will be key to success in modulating the microbiome. （了解控制控制空间组织的动力将是成功调节微生物的关键）The concept that spatial order is important in microbial ecosystems is not new; it was introduced implicitly by Winogradsky, the founder of microbial ecology, almost 100 years ago and was explicitly addressed 40 years ago by Wimpenny (1981).（空间秩序在微生物生态系统中很重要的概念并不新鲜；它是由微生物生态学的创始人Winogradsky在将近100年前隐含的提到，而Wimpenny在40年前明确的指出了这一点） Wimpenny discussed the concepts of habitat and niche as they apply to microorganisms.（Wimpenny讨论了栖息地和生态位的概念因为他们运用到了微生物中） Habitat refers to externalities—the physical space and chemical environment that allow an organism to exist, including contributions from other members of the microbial community. （栖息地指的是外部效应—允许一个组织存在的实际空间和化学环境，包括微生物群落的其他成员的贡献）Niche refers to the activity of an organism and the functional role that each member plays in the community.（生态位指的是一个组织的活动以及在群落中每个成员扮演的功能角色） Interactions of the members both with one another and with the habitat drive the emergent organization of the community as a whole.（成员之间以及与栖息地之间的相互作用推动了整个社区的新型组织）
Recent reviews have highlighted the importance of spatial organization in various aspects of human microbial ecology including extracellular matrix and polymicrobial infections (Stacyet al., 2016; Bowen et al., 2018), the gut microbiome (Tropiniet al., 2017), landscape ecology of the upper respiratory tract and mouth (Proctor and Relman, 2017), and implications for caries and periodontal disease (Valm, 2019; Diaz and Valm, 2020; Proctor et al., 2020).（最近的综述已经强调了在人体微生物生态系不同方面空间组织的重要性，包括细胞外基质和多种微生物感染，肠道微生物，上呼吸道和口腔的生态学，以及龋齿和牙周病的预测）In this Minireview, we will focus on how oral microbes are specialized for individual habitats within the mouth and how microbial habitats and niches are defined by micron-scale gradients in combination with short- and longrange interactions. （在本篇微型综述中，我们重点研究在口腔微生物如何针对口腔内的单个生态环境，以及微生物生态环境和生态位如何通过微米级梯度的短期和长期相互作用影响口腔微生物生境）We will discuss how micron-scale structure illuminates the roles of individual taxa and provides insight into their community ecology and potential pathogenicity.（我们将讨论微米级结构如何解释单个分类单元的角色并且对群落生态学和潜在的致病性提供更深刻的见解。）
MAJOR HABITATS WITHIN THE MOUTH（口腔内主要的栖息地）
The mouth is an open system.（口腔是一个开放的系统） Microbes are inhaled with every breath, ingested with every meal or drink, and introduced by close contact with other humans, animals, or our physical surroundings.（微生物被每一次呼吸吸入，随每一次饮食和饮品咽下，以及由与其他人，动物或者我们周围环境的亲密联系引入） As a warm, moist, and nutrient-rich environment, the mouth presents a welcoming home for microbes. （作为一个温暖，潮湿和营养丰富的环境，口腔提供了一个对微生物来说受欢迎的家）Yet among the millions of bacterial species on the planet, only approximately 760 are primary residents, rather than transients, in the mouth (Dewhirst et al., 2010; https://www.homd.org, v15.2).（然而，在地球上数以万计的细菌物种中，只有大约760种是口腔中的常驻居民，而不是临时的）These species are not evenly represented; several dozen abundant and prevalent species make up most of the biomass at each oral site, whereas many species have low prevalence as well as low abundance in the healthy human mouth (Eren et al., 2014; Mark Welch et al., 2019).（这些物种是不平均的；在每个口腔部位中数十种丰富且普遍的物种构成了大部分生态位，然而在健康人口腔中很多物种有着低普遍性和低丰度） Microbes from other body sites, which are adapted to living on or in the human body and to which there must be fairly continual exposure, are not abundant in the mouth.（来自身体其他部位的微生物，适合生活在人体上或者体内并且必须持续暴露在其中，它们在口腔中并不丰富）What accounts for these unique microbial demographics?（什么可以解释这些独特的微生物统计数据） A major determinant is the interplay between the main habitats in the mouth and the selective forces operating on them.（一个主要的决定性因素是在口腔内的主要栖息地和作用于他们的选择性动力之间的相互作用。）
Nine of the distinctive habitats in the mouth were sampled in the Human Microbiome Project (HMP) (Segata et al., 2012).（在人类微生物计划中口腔中9个不同的栖息地被采样）Although any surface within the mouth is potentially available for colonization, the HMP selected sites that reflected the range of habitat diversity (Figure 1).（即使口腔内的任意表面对于定植都是有可能的，人类微生物计划选取的部位反映了栖息地多样性的范围） Surfaces sampled included the tooth surface, both above the gum line (supragingival plaque) and below the gum line (subgingival plaque) (Figure 1A)（被采样的表面包括牙齿表面，龈线以上（龈上菌斑）和龈线以下（龈下菌斑））; flexible non-keratinized epithelia (buccal mucosa and throat)（柔性非角质化上皮细胞（颊粘膜和喉咙））; keratinized epithelia (attached gingiva and the hard palate)（角质化上皮细胞（附着龈和硬腭））; and specialized epithelia (tonsils and the tongue dorsum) （以及特殊的上皮细胞（扁桃体和舌背））(Figures 1B and 1C). Saliva, although not a site in itself, was also sampled（唾液，即使本质上不是一个部位，也被采样）. Each of these sites is not monolithic, because differing environmental conditions even within a single oral site can generate differing micro-habitats. （这些位置中的每一个都不是完全统一的，因为即使在一个单独的口腔部位不同的环境条件也会产生不同的微环境）Different sides or aspects of teeth are sheltered or exposed to different degrees.（牙齿的不同边或者面在不同程度上受到遮挡或者暴露） Oxygen is abundant on the crowns of teeth, but the tooth surface in the gingival crevice is in an anoxic environment bathed in gingival crevicular fluid, a protein-rich exudate from the gingival tissues (Jakubovics, 2015a)（牙冠上的氧气很丰富，但是牙龈缝隙中的牙龈表面浸在牙龈沟液中的缺氧环境中，牙龈沟液是一种来自牙龈组织的富含蛋白质的分泌液）. The film of saliva is thinnest at the roof of the mouth while saliva pools at the floor of the mouth（唾液膜在口腔顶部最薄，而在口腔底部聚集）; precise location relative to salivary glands influences the composition and rate of flow of saliva at different sites in the mouth（相对于唾液腺的精确位置影响口腔中不同位置的唾液组成和流速）(Proctor and Relman, 2017; Proctor et al., 2020). The dorsum of the tongue is populated by abundant filiform papillae and fungiform papillae, and a row of large circumvallate papillae, foliate papillae, and lingual tonsils add topographic complexity to the back of the tongue (Figure 1C)（舌背有丰富的丝状乳头和真菌状乳头，并且一排大的轮廓乳头，叶状乳头，和使舌背变得复杂的舌扁桃体）. Additional diversity of oral habitats may exist that is not fully reflected in these nine site categories, as evidenced by the high abundance in saliva of microbes that were not abundant at any of the other sampled sites, suggesting additional unique micro-habitats elsewhere in the mouth (Segata et al., 2012; Eren et al., 2014). （口腔栖息地可能存在其他的多样性，这没有体现在这9个位置范围内，因为在唾液中含量很高的微生物在任意其它采样位置并不丰富，暗示着口腔中另外的特殊的微环境存在）Thus, the mouth provides a structurally complex environment with a range of differentiated and, as yet, incompletely explored habitats.（因此，口腔提供了结构复杂的环境，并具有一系列分化的，但是尚未完全探索的栖息地。）
SELECTIVE FORCES WITHIN THE MOUTH
The mouth’s unique microbial
demographics indicate clearly that there are selective forces to which a
microbe must be adapted in order to thrive in the mouth and to which the host
must be adapted in order to interact effectively with the colonizing microbes. （口腔专门的微生物统计数据清楚地表明，存在一定的选择力，微生物为了在口腔中茁壮成长必须适应，宿主为了有效地与定居微生物相互作用必须适应）The interaction might be understood as three pairs of opposing
factors (Figure 2) that are in dynamic equilibrium in the healthy state.（相互作用可以被理解为在健康状态下处于动态平衡的三对相对因子）
Flow and adhesion.（流动性和附着力） Retention in the oral environment is shaped by the interplay between the opposing forces of flow and adhesion (Figure 2A). （滞留在口腔环境中是由流动和附着的相反作用力的相互作用形成的）Salivary flow imposes a selective requirement for adherence in the oral cavity: microbes can persist in exposed locations in the mouth only if they are adhered to an underlying substrate or to other microbes that are adhered to the substrate (Gibbons and Van Houte, 1975). （唾液流动对在口腔中的粘附有选择性的要求：微生物只有在粘附到下面的基质或者粘附在基质上的其他微生物的情况下，才能在口腔中暴露在外）Flow also prevents the buildup of microbial metabolites in the mouth and therefore imposes a requirement that microbes be in close proximity in order to interact with one another (Egland et al., 2004). （流动也阻碍了口腔中微生物代谢物的积累，因此要求微生物必须很靠近，以便相互作用）In response to these selective pressures, oral microbes developed highly specific adhesin-receptor interactions that form the basis of a phenomenon referred to as coadhesion or coaggregation, in which binding occurs between microbes of different genera (Kolenbrander et al., 2006). （为了应对这些选择性压力，口腔微生物形成了高度特异性的粘附素-受体相互作用，形成了被称为共粘附或共聚集现象的基础，在该现象中，不同属的微生物之间发生了结合）The binding interactions are strain specific and, in some cases, also site specific. （这种捆绑式的相互作用是菌株特异性的，在一些情形下，也是位点特异性的）For example, veillonellae and streptococci are common inhabitants of the oral cavity, yet veillonellae from the tongue bind to streptococci from the tongue while veillonellae from dental plaque bind to streptococci from dental plaque. （例如，veillonellae和streptococci是口腔中的居民，然而来自舌头的veillonellae捆绑于来自舌头的streptococci，来自牙菌斑的veillonellae捆绑于来自牙菌斑的streptococci ）Thus, flow applies selective pressure for adherence, both for retention in general and for localization to a precise metabolic environment. （因此，流动对附着力施加选择性压力，既可以保持整体，也可以定位到精确地代谢环境）The microbial response of adhesion to specific targets and partners located in well-defined regions of the mouth suggests that precise spatial positioning is critical for microbial survival.（附着力对于特定目标和在口腔中有明确定义的区域的合作者的微生物反应表明，精确的空间定位对于微生物存活至关重要）
Shedding and colonization. （脱落和定植）The microbial community at each site within the mouth is further shaped by the relative dynamics of shedding of (or removal from) the underlying substrate and re-colonization back to the substrate (Figure 2B). （在口腔内每个部位的微生物群落进一步受到从下面的底物脱落和回到底物重新定植的相对动态的影响而形成）On the permanently exposed enamel surface of teeth, the dynamics of removal are set by oral hygiene or by abrasion caused by chewing of food. （在牙齿永久性暴露的牙釉质表面上，去除的动力是通过口腔卫生或食物咀嚼引起的磨损来确定的）In areas sheltered from abrasion and oral hygiene, the plaque biofilm can persist for long periods. （在不受磨损和口腔卫生的地方，菌斑生物膜可以长期存在）This long residence time permits the development of complex communities via succession and diversification (Listgarten et al., 1975; Kolenbrander et al., 2006; Valm, 2019). （很长的居住时间允许通过演替和多样化发展成复杂的群落）On mucosal surfaces, by contrast, epithelial cells are regularly shed, along with the attached microbiota, and removed from the mouth by swallowing. （相反，在黏膜表面，上皮细胞与附着的微生物有规律的脱落，并且通过吞咽从口腔中去除）The rate of shedding, and the rate and nature of colonization on newly presenting epithelial surfaces, influences the density of the mucosal community as well as its membership and spatial organization (Gibbons and Van Houte, 1975). （脱落的速度，以及在新出现的上表皮细胞上的定植的速度和性质，都会影响黏膜群落的密度及其成员和空间组织）Based on the surface area of the mucosal surfaces in the mouth and the number of epithelial cells in saliva, Dawes (2003) estimated that the surface layer of oral epithelial cells was replaced every 2.7 h—a rate that precludes the formation of thick biofilms, and indeed Dawes reported only monolayers of bacteria on the rapidly shedding epithelial cells of the palate, gums, and tongue dorsum.（根据口腔中粘膜表面的表面积和唾液中上皮细胞的数量，Dawes（2003）估计，口腔上皮细胞的表层每隔2.7小时就被更换一次，该速率可避免形成厚厚的生物膜， 确实，Dawes仅报告了上颚，牙龈和舌背快速脱落的上皮细胞上的单层细菌。）
More recently, by gentle scraping of the tongue dorsum, we detected not only thinly colonized epithelial cells but also much thicker biofilms with complex highly structured organization (Wilbert et al., 2020), suggesting that the epithelia of the tongue dorsum are a mixture of both rapidly shedding, thinly colonized cells and longer-lived structures on which a more substantial biofilm can develop. （最近，通过轻轻刮擦舌背，我们不仅检测到薄薄的定植的上皮细胞，而且还检测到具有复杂的高度结构化组织的厚得多的生物膜（Wilbert等人，2020年），这表明舌背上皮是快速脱落，薄薄的定殖细胞和寿命更长的结构，可在其上形成更坚固的生物膜的混合物）Not only the overall thickness but also the spatial structure of the biofilm are influenced by the rate of shedding.（脱落速率不仅影响生物膜的整体厚度，而且影响其空间结构） Oral biofilms can be analyzed as a mosaic of patches of distinctive microbial composition (Proctor and Relman, 2017).（可以将口腔生物膜分析为具有独特微生物组成的马赛克斑块）One could infer that the rate of shedding would influence the size of such patches. （一个人可以推断出脱落的速度会影响这种斑块的大小。）Thin biofilms on oral surfaces are likely to be well oxygenated throughout, but as the biofilm increases in thickness, anoxic habitats can develop, and the abundance of anaerobes could increase in these micro-habitats (Mark Welch et al., 2016; Wilbert et al., 2020). （在口腔表面的薄生物膜很可能被很好地充氧，但是随着生物膜厚度的增加，缺氧的栖息地就会形成，厌氧菌的丰度可能会在这些微生境中增加。）Thus, the host property of epithelial shedding contributes to structuring the composition and spatial organization of microbial biofilms in the mouth.（因此，上皮脱落的宿主特性有助于构造口腔中微生物生物膜的组成和空间组织。）
The microbial response to shedding, and to the loss of microbes from non-shedding surfaces by abrasion, is colonization of fresh substrates. （微生物对脱落以及由于磨损导致微生物从非脱落表面流失的反应是新基质的定殖）A clean enamel surface in the mouth immediately acquires a salivary pellicle or protein-based covering, to which pioneer colonizing microbes bind with high specificity.（口腔中清洁的牙釉质表面会立即获得唾液薄膜或蛋白质基覆盖物，定植的先锋微生物可以高特异性地与唾液膜结合）For example, cell surface adhesins on pioneer colonizing streptococci bind to cysteine repeat domains within glycoproteins or sialic acid of mucin in the enamel pellicle (Jakubovics, 2015b; Diaz and Valm, 2020). （作为开拓者定植streptococci上的细胞表面黏附素结合到牙釉质膜中的糖蛋白或粘蛋白唾液酸的半胱氨酸重复域）Similarly, newly exposed epithelial cells rapidly acquire a salivary mucosal pellicle (Carpenter, 2020).（同样，新暴露的上皮细胞会迅速获得唾液粘膜薄膜） A set of pioneer colonizers, different from those that colonize enamel, adheres more readily to these mucosal surfaces (Gibbons and Van Houte, 1975).（与开拓者牙釉质不同，一组先锋开拓者更容易粘附在这些粘膜表面） Adherence of specific bacteria to the mucosa could be mediated in part by secretory immunoglobulin A, which attaches both to the mucosal pellicle and to a set of oral commensal bacteria (Carpenter, 2020).（特定细菌对粘膜的粘附可以部分由分泌性免疫球蛋白A中和，该免疫球蛋白A既附着于粘膜的薄膜又附着于一组口腔共生细菌） Thus, colonization is a property of microbes but is dependent on molecules from both host and microbial sources.（因此，定殖是微生物的一种特性，但取决于宿主和微生物来源。）
Host and microbe. （宿主和微生物）Host and microbe act as selective forces on one another, each shaping the other through sustained interaction and adaptation (Figure 2C). （宿主和微生物彼此作用，通过持续的相互作用和适应相互影响）Salivary flow and immune surveillance are properties of the host that reduce the microbial load. （唾液流量和免疫监测是宿主的可降低微生物负荷的性质。）However, saliva is also a vehicle for positive selection of microbes in the mouth, because mucins and nutrients such as lactate, bicarbonate, nitrate, and vitamins are actively secreted into saliva (Carpenter, 2020). （但是，唾液还是口腔中微生物积极选择的工具，因为粘蛋白和营养物质（例如乳酸，碳酸氢盐，硝酸盐和维生素）会主动分泌到唾液中）Salivary mucins support the growth of microbes that possess the glycosidases capable of releasing oligosaccharides from these complex host substrates, as well as mixed syntrophic communities that can benefit from their digestion (Jakubovics, 2015a; Carpenter, 2020). （唾液粘蛋白支持具有能够从这些复杂宿主底物中释放寡糖的糖苷酶的微生物的生长，以及可以从其消化中受益的混合营养族）The complexity and refractory nature of mucins could therefore encourage the growth of structured microbial communities and discourage overgrowth of single taxa.（因此，粘蛋白的复杂性和难治性可能促进结构化微生物群落的生长，并阻止单一类群的过度生长） Synergistic interactions among oral bacteria involve food webs in which one bacterium produces a waste product, such as lactate, that serves as an important nutrient for other lactate-consuming bacteria (Jakubovics 2015b). （口腔细菌之间的协同相互作用涉及食物网，在这种食物网中，一种细菌会产生废物，例如乳酸，它是其他消耗乳酸的细菌的重要营养素。）Such metabolic cooperation occurs when cells are in close proximity and thus selects for coaggregation and spatial mixing rather than segregation of the interacting taxa (Jakubovics 2015b; Stacy et al., 2016).（当细胞紧邻时发生这种代谢合作，因此相互作用的分类单元选择共聚集和空间混合而不是分离） The secretion of lactate, and possibly also bicarbonate, by the host could selectively promote growth of the bacteria participating in these food webs (Carpenter, 2020) and be a mechanism by which the host influences the spatial organization of the microbiota.（宿主分泌的乳酸（可能还有碳酸氢盐）可以选择性地促进参与这些食物网的细菌的生长（Carpenter，2020年），并且是宿主影响微生物群落空间组织的一种机制。）
Host secretion of nitrate into saliva could promote the growth of facultatively anaerobic oral bacteria that use nitrate as an electron acceptor for respiration; the microbial conversion of nitrate to nitrite in turn permits the efficient generation of nitric oxide from dietary nitrate which helps maintain nitric oxide homeostasis (Hezel and Weitzberg, 2015). （宿主向唾液中分泌硝酸盐可以促进兼性厌氧口腔细菌的生长，这些细菌利用硝酸盐作为呼吸的电子受体。 硝酸盐向亚硝酸盐的微生物转化反过来又可以从膳食硝酸盐中高效生成一氧化氮，从而有助于维持一氧化氮的稳态）Nitric oxide provides important benefits to the host including lowering of blood pressure, improved endothelial function, reversal of metabolic syndrome, and reduction of oxidative stress (Lundberg et al., 2018). （一氧化氮为宿主带来重要好处，包括降低血压，改善内皮功能，逆转代谢综合症和减少氧化应激）Other potentially beneficial functions of the oral microbiota include restricting access of non-commensal microbes to the host epithelium by physically blocking the epithelium and by secreting antimicrobials (Valm, 2019).（口腔微生物群的其他潜在有益功能包括：通过物理阻断上皮和分泌抗菌素，限制非共生微生物进入宿主上皮。） Thus, the interaction between host and microbiota is a dynamic equilibrium in which both sides benefit, and each modulates the metabolism of the other.（因此，宿主与微生物群之间的相互作用是一种动态平衡，双方都从中受益，并且相互调节对方的新陈代谢。）