这是《肠道产业》第 659 篇文章
人体皮肤上有多种微生物定植，这些微生物与疾病紧密相关。越来越多的研究表明，宿主和微生物组之间的互相作用可能会导致慢性皮肤病。那么是否可以利用皮肤微生物来治疗疾病呢？又该如何利用呢？
今天，我们共同关注生命早期皮肤微生物组的组成及发展，希望本文能够为相关的产业人士和诸位读者带来一些启发和帮助。
居住在屏障组织中的复杂微生物群体被称为微生物组，这些微生物对理解人体健康至关重要，它们支持着人体的许多功能，包括代谢1，维生素的合成2，抵抗病原体的入侵3，免疫发育4,5。
由无菌母体在无菌环境中分娩的无菌动物，表现出多种生理紊乱现象和疾病易感性，而这些问题在具有正常菌群且基因背景相同的动物中并没有发现6-8。因此，在健康宿主中发现的微生物，对双方均有利。
皮肤是人体最大的可与微生物互动的上皮表面9。此表面是一种动态的界面，而非不透水的屏障，微生物组可以延伸至真皮和真皮脂肪10。
皮肤微生物组具有多样、部位特异和稳定的特点。人体皮肤是一个独特的环境，具有与其他灵长类不同的微生物组，表现出某些种属占优势，而整体多样性程度较低的特点11。
尽管如此，健康皮肤依然定植了来自 19 个不同门的超过 200 个属的微生物12-14。身体的不同部分具有不同的皮肤微生物群体15。不同位点之间皮肤微生物共有的特性反映出皮肤生理之间的共性13,16。比如：痤疮丙酸杆菌在皮脂腺发达的皮肤区域上是一种常见菌，而在更艰难的环境中，如干燥的皮肤区域，则是葡萄球菌和链球菌占主导 13,16。
成人皮肤微生物组是高度个体化的，并且菌株构成在长时间内都趋于稳定，因此皮肤微生物更加像是一组指纹 16,17。
与万亿级别的微生物共存并不是没有风险的。共生关系的破坏与皮肤的慢性疾病相关，比如过敏性皮炎18和银屑病19，这与其他器官所发生的慢性病情况类似，比如肺20和肠道21-25。长期存在的问题是：为什么共生微生物有时会引发慢性疾病，以及这是如何发生的。
微生物学家长时间认为，仅凭细菌不足以预测疾病26,27。通过显微镜可以观察到大量的细菌存在于皮肤脓肿27、粉刺28和湿疹等皮肤病中29，这导致了早期的研究者认为疾病是由细菌过度增殖引起的。
Sabouraud 提出，在健康状态下，上皮细胞不断脱落，可防止细菌过度生长30，而后作者将皮肤描述为一种酸性保护层，因为低 pH 31、渗透胁迫32和干燥33等因素对细菌的生长是不利的。
然而，在 20 世纪 70 年代，优化的培养方法证实了痤疮毛囊炎及其对治疗的反应，与细菌无关34-36。这个发现进而导致了一种假说：宿主诱导了痤疮丙酸杆菌向炎症表型发展，也就是定植菌株表现出向炎症转化的可变倾向37。这个猜想的一个关键在于：同一种细菌的不同菌株之间的基因差异可能对宿主产生截然不同且持久的影响。
随着耐药性问题日益严重，以及测序技术的发展，人们重新燃起了对疾病菌株特异性的兴趣38。在过去的十年中，不依赖于培养的研究发现，尽管持续暴露，但是个体微生物组中依然缺乏这些共生和致病菌株39-44。这些发现表明，理解微生物生态的发展，比如宿主和细菌因素如何影响宿主从环境中获取菌株，可能将帮助我们理解许多与菌群失调相关的慢性皮肤疾病。
因此，婴儿获取和选择特定微生物的机制十分重要。本综述将重点阐述在生命早期皮肤微生物的组成和造成细菌特异性发展的宿主-微生物机制。
定植的顺序和时间决定了菌株如何与其它菌株互相作用，其中一个效应叫做优先权45,46。确实，在发生肠道疾病的大鼠模型中，将一个良性菌株先定植于宿主后，可以限制随后同种致病菌株的入侵，从而防止黏膜损伤47。因此，婴儿最早的微生物可能对微生物组的构成和皮肤健康具有长期影响。
刚出生婴儿的无菌性受到了质疑。研究报道，在胎盘、羊膜、胎儿中都发现了细菌 DNA 48-53，包括从妊娠中期胎鼠身上观察和培养出活菌53，然而也有一些团队没有找到在出生前微生物定植的证据，除非有重大感染的发生54,55。有作者报道，母亲的微生物有选择性地被传递到胎盘并在胎儿中定植48,49。在近期的报道中，在剖腹产婴儿的口腔和胎粪中发现了微生物，研究人员推测这些微生物来自于胎盘53。
无论产前环境如何，大规模的微生物定植是从出生开始的。无论分娩方式如何，也不管胎龄大小，微生物自产后立即开始均匀地在人体定植56-59。培养学研究方法发现，在自然分娩后的五分钟内，厚壁菌门中的葡萄球菌就成为了各个部位的可培养微生物中的优势菌种，其余还包括占比较低的类白喉菌（放线菌门，包括表皮细菌和棒状杆菌）59。
然而，与无菌子宫的环境一致，剖腹产婴儿没有检测到细菌59。近期，更多关于新生儿的研究发现，阴道分娩新生儿会优先被阴道中的普雷沃氏菌和乳酸杆菌定植，而剖腹产婴儿的皮肤，则检测到某些丙酸杆菌、棒状杆菌、微球菌，这可能是在手术过程中，受到母体皮肤的污染57,60。
婴儿的第一次洗澡可能改变微生物组成的过程。新生儿皮肤被皮脂覆盖，这是一层分布不均匀的表层，具有由皮脂腺分泌的特殊脂质、神经酰胺和抗菌肽（AMPs）61。由于洗澡会破坏胎儿皮脂层，也会导致体温过低，因此，现在已经不再推荐给出生 24h 内的新生儿洗澡 了62。
培养学研究发现，首次洗澡也与微生物组构成的即时变化相关，关于这点还没有完全得到阐述63,64。这个效应可能与胎龄相关，由于早产儿、足月儿和晚产儿的皮脂分布都不相同65。进入新生儿加护病房的早产儿一般会用抗菌香皂进行清洗66。
这些初期扰动造成的长期影响尚不清楚。早期的微生物组正在经受频繁的菌株更换67-69。因此，出生环境和微生物组之间的联系在数周到数月之间减弱56,70,71。
在没有干扰的情况下，住院婴儿的皮肤微生物与病房有很强的相关性72。在不同部位的皮肤微生物群落在出生两天后就开始分化为不同的功能群体，就像在成人中发现的一样73。出生后 6 周，母亲和婴儿的皮肤微生物比肠道和口咽等身体其他部位的微生物更相似，这可能是因为肠道和口咽等部位的微生物分化更快56。
母体和婴儿之间微生物的相近可能是由于母体菌株的垂直转移。母体微生物对皮肤和肠道微生物组的发展十分关键74-76。母体微生物的产后垂直转移可能提供了早期阶段在儿童肠道中定植的菌种，并将影响之后许多年的微生物构成，直到发展出不同的微生物团体77。
事实上，母体菌株比非母体获得菌株更有可能在婴儿肠道中持续存在，这可能是由于共同的环境和遗传及免疫因素造成的78,79。这也解释了为什么在孕期益生菌的供应与儿童中较低的过敏性皮炎发病率相关80，过敏性皮炎是一种与微生物联系显著的疾病18。皮肤中菌株的垂直转移目前还没有直接的证据，并且，尚不清楚与母婴菌株特异性相关的机制。
关于环境中的细菌，以及它们对皮肤微生物的影响和生命早期的转移机制目前正在研究中。最初定植的菌株是那些直接可从环境中接触到的微生物，比如医院的菌株72,81。产房和母体中的微生物可能是决定最初细菌暴露的重要决定因素，因为在室内发现的微生物可在数小时内就与居住者达成一致41,82。
母亲中的微生物组与婴儿中的相似性会在出生一年后下降83，表明了环境中菌株的成功定植。这些菌株可能通过与皮肤的密切接触而扩散，正如肠道微生物所显示的那样46。
可能很大一部分的细菌转移是间接的。对 3 周岁左右的儿童及他们家庭、家庭环境的大量研究中发现，频繁的人工清洁可以预防金黄色葡萄球菌在家庭环境中的定植，这种细菌在住户中的转移与家庭负担过重，共用卧室、化妆品和浴室毛巾相关44。这项研究表明微生物的转移可以通过改变习惯来控制。
皮肤微生物组的有限组成与正常皮肤的“除菌”过程紧密相关30。细菌生理学的发展引出了皮肤微生物受环境约束的猜想。
表皮的结构成熟在妊娠期的 34 周84。然而，由于更高的水含量、更高的pH、更少的脂质和更迅速的表皮循环，生命早期皮肤与成人的皮肤存在差异85。3 月龄内的婴儿皮肤水含量高于成人86，随着汗腺成熟而产生相应变化87。此变化可能对微生物的定植产生重要影响，因为表皮细菌定植受到水含量的限制33。
人类比其他哺乳动物有更多的皮脂，这也在一定程度上解释了痤疮棒状杆菌含量更高的原因88。生命早期，皮脂分泌是受限的89，这可能解释了为什么儿童中含有较少的棒状杆菌和丙酸杆菌90。脱屑（desquamation）最初是作为皮肤主要的除菌机制所提出来的30，皮脂的产生和表皮的循环成反比，而婴儿的脱屑率较高85,86。
由于阳光暴露，黑色素的产生也同样随着年龄而变化91。黑色素的利用在细菌中是很普遍的92，但是在皮肤生态中的功能还未知。
近期的研究热点转移到了宿主通过免疫系统的特定活动，来选择细菌，包括角质形成细胞。在健康皮肤中，角质形成细胞是 AMPs 的主要来源93；每一种 AMP 都有其独特的抗菌特性，包括 cathelicidins、beta 防御素和 S100A 肽94。AMP 在表皮和真皮中的积累限制了微生物的扩张，并在生命早期达到顶峰95。角质形成细胞会表达微生物模型识别受体，并在微生物配体形成后，上调 AMP 分泌96，以此来平衡微生物密度和 AMP 分泌。
令人惊讶的是，近期在大鼠中，发现 AMP 分泌角质形成细胞表达抗原呈递复合物主要组织相容性复合物 Ⅱ，以此响应屏障保护性细胞因子白细胞介素-22 的应答97。这些特化细胞在生理上与用同源抗原刺激后表达干扰素 γ（IFN-γ）的皮肤 CD4+T 细胞相关97。由共生微生物诱导的 IFN-γ 在小鼠肠道中表现出对病原菌沙门氏菌菌株定植的抑制作用98。
相似的，近期的研究显示，IL-4Rα 阻断，增强 IFN-γ 信号，与降低成人特应性患者中的金黄色葡萄球菌定植和增加微生物多样性相关99，这可能部分解释其缓解特应性皮炎症状的效果100。然而，关于 Tonic IFN-γ 的活性是否会选择特定的微生物从而改变皮肤生态，以及这种选择是否会保护宿主或更易导致疾病，仍然需要进一步的研究。
皮肤中也存在先天淋巴细胞（ILCs）和具有先天样功能的淋巴细胞，包括 γδT 细胞，自然杀伤 T（NKT）细胞和粘膜相关恒定 T （MAIT）细胞。
皮肤 ILCs, 通过 C-C 趋化因子基序受体 6 被运输到毛皮脂腺单位，通过表达肿瘤坏死因子受体配体，来促进小鼠的革兰氏阳性细菌的共生，该配体下调皮脂细胞中的 Notch 信号，并抑制抗微生物脂肪酸的分泌101。在不同组织层中的 ILCs 表达不同的基因，体现出免疫功能的选择性101。
大部分人的表皮 T 细胞是 γδT 细胞102。这些细胞可能对微生物有应答103，并且可能对调节胰岛素样生长因子-1 诱导角质形成细胞转换具有重要作用104,105。NKT 细胞改变了鼠模型中的肠道微生物106。在皮肤中，NKT 细胞具有促炎症作用107，可能会造成斑秃108。
MAIT 细胞依赖于由皮肤微生物产生的核黄素衍生物，在无菌动物中无法发育109，被认为可控制细菌移位109,110和促进组织修复111-113。由于小鼠中 MAIT 细胞发育仅发生在生命早期111，早期的免疫-微生物紊乱可能会使该个体在后续更容易出现皮肤生态失调的情况。
生命早期是适应性淋巴细胞发展的关键时期之一。在人类和小鼠的新生皮肤中，抗炎调节性 T 细胞（Tregs）的密度较高，这使新生皮肤倾向于抗炎反应114,115。例如，新生无菌小鼠暴露于表皮葡萄球菌会产生抗原特异性的 Tregs，从而在生命后期抑制对这种共生菌的炎症反应115。毛囊定植是表皮葡萄球菌等凝固酶阴性葡萄球菌的重要生态位，通过趋化因子 C-C 趋化因子基序配体 20 刺激 Treg 募集在毛囊中发生116。
在肠道中，招募 Treg 可能会促进 B 细胞向可分泌 Ig A 的类型转化，从而进行细胞定植选择117。事实上，脆弱拟杆菌可以促进黏膜 Treg 分化，并促进 Ig A 与相关的宿主上皮结合更加紧密，排除外源竞争者118-120。
像肠道微生物组一样，皮肤微生物组在婴儿期后会变得更加稳定77,121,122。这很容易让人推测，皮肤共生体逐渐适应了宿主免疫。
在生命早期阶段，微生物之间的竞争可能对形成长期影响皮肤健康的微生物组具有重要作用123。自 19 世纪 Louis Pasteur 后，每一代微生物学家都会讨论细菌间竞争的药用价值124-126。并基于此发明了一些治疗方法。
在 20 世纪的早期，丹麦医生 Schiotz 发现，一位被错误地安置在白喉病房的患有金黄色葡萄球菌咽炎的年轻患者，对这种疾病有抵抗。Schiotz 从一名外科病人身上成功培养了良性金黄色葡萄球菌，并将该菌接种到白喉棒杆菌携带者的喉部，结果发现这位患者可以抵抗白喉病127-128。在广泛使用抗毒素之前，美国的一些医生对儿童白喉采用了这种“压倒一切”的疗法129-132。
接种葡萄球菌以取代白喉棒状杆菌的变数很大，但是目前尚无法解释131。相似的，引入外源性细菌在肠道生态位中成功定植后的不稳定性，也解释了随机试验中口服益生菌治疗的失败原因133,134。
近期，某些研究发现，在特应性皮炎患者中，使用竞争菌株——链球菌、凝固酶阴性葡萄球菌和革兰氏阴性玫瑰单胞菌粘膜，以替代金黄色葡萄球菌，具有一定的有效性135,136。通过益生菌菌株的长期定植来进行生态位替换，可能可以显著地加强治疗效果。
对儿童群体的替代性治疗方法是，利用致病菌在皮肤上扩张前的时机。在 20 世纪 60 年代，一种被称为噬菌体类型 80/81 的金黄色葡萄球菌菌株，对当时的抗生素产生了抗性，并在全世界的医院托儿所流行起来137-139。
此后，Henry Shinefield 与同事鉴定到了一株常见于婴儿的良性金黄色葡萄球菌菌株 502A，发现其对 80/81 菌株具有抗性。他们发现，预先接种 502A 可以减少菌株 80/81 的感染率，并减少葡萄球菌病的风险140-144。然而，这种竞争机制尚不明确，502A 会随着时间受到环境压力的影响145。
对生态失调在慢性疾病中的作用认识的逐渐深入，重新引起了人们对“生态位的竞争是如何形成微生物组”这一问题的兴趣。
最近的研究揭示了革兰氏阴性细菌之间竞争机制，发现该机制涉及可向邻近细菌注射杀菌毒素的 VI 型分泌系统（T6SS） 146,147。效应蛋白与一些免疫蛋白配对以防止自我中毒；目前，已经报道了数十对这样的具有菌株特异性的蛋白对68。
T6SS 是一个大的蛋白复合体，需要强大的代谢支持148。尽管如此，肠道共生菌中似乎存在着强大的进化压力，不断积累中和 T6S 毒素的遗传元件149，表明了这种系统在形成肠道微生物组中的重要作用。
许多位于皮肤上的革兰氏阳性菌都有相似的 VII 型分泌系统（T7SS）。金黄色葡萄球菌通过 T7SS 分泌四种 ESS 蛋白，提高在鼠类宿主中的永久感染150。在一项研究中报道了在金黄色葡萄球菌 T7S 表达和细菌拮抗作用之间的联系151，没有发现与 T6S 类似的抗菌活性152。
近期在中间链球菌中发现一种具有杀菌特性的 LXG 蛋白 T7SS 依赖系统，该系统与一种自我毒性解毒剂一起表达153，就像在肠道中一样，这些蛋白质可以通过阻止竞争菌株的定植来调节单一菌株的稳定性。然而，T7SS 的流行性和效应蛋白在菌株间的特异性尚不清楚。
金黄色葡萄球菌对棒状杆菌如白喉棒状杆菌抑制作用来源于一种抗菌肽。该抗菌肽在 1947 年分离130，属于细菌素中的一种。
细菌素在 20 世纪 20 年代在大肠杆菌中第一次发现154。虽然细菌素在所有原核生物中都有描述155，但是革兰氏阳性细菌中表现出细菌素特异性的调节和编码转运机制，可以防止自我毒性156。细菌素的毒性一般只限于一些革兰氏阳性细菌157，有限的活性常常受限于相同属、种、菌株，然而也存在具有广谱活性的细菌素158。
来自于大肠杆菌的大肠杆菌素被当作一种模型细菌素用于研究微生物群体已经超过 50 年159-161。细菌素是预测生理结构栖息地最重要的因素162,163，并且在皮肤生物的模型中，细菌素的效果依赖于组织环境与结构164。
近期一项对人体皮肤的研究中，发现了多种对痤疮丙酸杆菌、表皮葡萄球菌和金黄色葡萄球菌有效的新型细菌素165。
已有报道称，在成人特应性皮炎患者中，可使用分泌特定的细菌素的表皮葡萄球菌和人链球菌菌株，来减少金黄色葡萄球菌的定植136。
这种拮抗关系具有菌株和微环境的特异性。例如，头状葡萄球菌菌株 E12 分泌的酚溶性调节蛋白，可以选择性地抑制痤疮杆菌在小鼠和猪皮肤表面增殖166。痤疮杆菌表达的一种叫 cutimycin 的细菌素，在个体之间分布较为广泛，可以抵抗人类毛囊中表皮葡萄球菌167。
细菌素在皮肤微生物生态中的重要性与肠道中的 T6SS 基因一致，细菌素通常由可移动的基因元件携带，在同一物种的不同菌株之间组成不同，并显示出频繁的基因转移历史168。这些多样的竞争性互作因素如何在生命早期影响形成长期存在的皮肤微生物组仍不明确。
人体的微生物组是慢性病的治疗的一个有吸引力的治疗靶标。与基因组不同，它是可以调整的。
由剖腹产出生的新生儿被人为地暴露于阴道微生物组会更易于接受母体的微生物组60。然而，人工接种所有的微生物组也会带来大量的风险169。菌株替换是一种较优越的方法，其可识别致病菌株或良性菌株引起的不良免疫反应。
宏基因组和无菌动物的发展已经用来鉴定抵抗肠道病原菌入侵的健康细菌的最小集合170。与这种方法一致的是，可以通过基因工程来获得与疾病相关的细菌的良性变体，从而得到最佳的细菌拮抗作用。将工程菌株移植到皮肤上，可阻止致病性变异的发生，从而获得持久和长期的健康。
不过，我们仍然需要去了解哪些菌株对皮肤是有益的，皮肤微生物是从哪里起源的，成功定植的免疫决定因素有哪些，以及成功定植者排除竞争者的分子机制。一些现存的干扰对皮肤微生物的影响，比如沐浴和配方喂养，对于这些的了解也是不够的。
微生物组的发展过程是动态的，且易受影响，微生物暴露需要保持谨慎。随着了解的加深，生命早期可能会为微生物组的菌株级工程化提供机会。
参考文献：
1.Goodman AL, Gordon JI. Our unindicted coconspirators: human metabolism from a microbial perspective. Cell Metab 2010;12:111–6.2.Degnan PH, Taga ME, Goodman AL. Vitamin B12 as a modulator of gut microbial ecology. Cell Metab 2014;20:769–78.3.Buffie CG, Pamer EG. Microbiota-mediated colonization resistance against intestinal pathogens. Nat Rev Immunol 2013;13:790–801.4.Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature 2011;474:327–36.5.Thaiss CA, Zmora N, Levy M, Elinav E. The microbiome and innate immunity. Nature 2016;535:65–74.6.Belkaid Y, Naik S. Compartmentalized and systemic control of tissue immunity by commensals. Nat Immunol 2013;14:646–53.7.Gordon HA, Pesti L. The gnotobiotic animal as a tool in the study of host microbial relationships. Bacteriol Rev 1971;35:390–429.8.Naik S, et al. Compartmentalized control of skin immunity by resident commensals. Science 2012;337:1115–9.9.Gallo RL. Human Skin Is the Largest Epithelial Surface for Interaction with Microbes. J Invest Dermatol 2017;137:1213–4.10.Nakatsuji T, et al. The microbiome extends to subepidermal compartments of normal skin. Nat Commun 2013;4:1431.11.Ross AA, Müller KM, Weese JS, Neufeld JD. Comprehensive skin microbiome analysis reveals the uniqueness of human skin and evidence for phylosymbiosis within the class Mammalia. Proc Natl Acad Sci U S A 2018;115:E5786–95.12.Grice EA, et al. A diversity profile of the human skin microbiota. Genome Res 2008;18:1043–50.13.Grice EA, et al. Topographical and Temporal Diversity of the Human Skin Microbiome. Science 2009;324:1190–2.14.Kong HH, Segre JA. The Molecular Revolution in Cutaneous Biology: Investigating the Skin Microbiome. J Invest Dermatol 2017;137:e119–22.15.Costello EK, et al. Bacterial community variation in human body habitats across space and time. Science 2009;326:1694–7.16.Oh J, et al. Biogeography and individuality shape function in the human skin metagenome. Nature 2014;514:59–64.17.Oh J, et al. Temporal Stability of the Human Skin Microbiome. Cell 2016;165:854–66.18.Paller AS, et al. The microbiome in patients with atopic dermatitis. J Allergy Clin Immunol 2019;143:26–35.19.Fyhrquist N, et al. Microbe-host interplay in atopic dermatitis and psoriasis. Nat Commun 2019;10:4703.20.Stokholm J, et al. Maturation of the gut microbiome and risk of asthma in childhood. Nat Commun 2018;9:141.21.Morgan XC, et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 2012;13:R79.22.Parekh PJ, Balart LA, Johnson DA. The Influence of the Gut Microbiome on Obesity, Metabolic Syndrome and Gastrointestinal Disease. Clin Transl Gastroenterol 2015;6:e91.23.Kostic AD, et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res 2012;22:292–8.24.Vogtmann E, et al. Colorectal Cancer and the Human Gut Microbiome: Reproducibility with Whole-Genome Shotgun Sequencing. PloS One 2016;11:e0155362.25.Zeller G, et al. Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol Syst Biol 2014;10:766.26.Koch R Ueber den augenblicklichen Stand der bakteriologischen Choleradiagnose. Z Für Hyg Infekt 1893;14:319–38.27.Ogston A Report upon Micro-Organisms in Surgical Diseases. Br Med J 1881;1:369.b2–375.28.Whitfield A, Sabouraud R, MacKenna RW. Discussion On Acne And Seborrhoea, Their Causation And Treatment. Br Med J 1912;2:286–9.29.Sabouraud Dr., et al. A Discussion On The Role Of Cocci In The Pathology Of The Skin. Br Med J 1901;2:794–7.30.Marples RR, Richardson JF, Newton FE. Staphylococci as part of the normal flora of human skin. Soc Appl Bacteriol Symp Ser 1990;19:93S–99S.31.Schade H, Marchionini A. Der Säuremantel der Haut (Nach Gaskettenmessungen). Klin Wochenschr 1928;7:12–4.32.Pillsbury DM, Rebell G. The bacterial flora of the skin; factors influencing the growth of resident and transient organisms. J Invest Dermatol 1952;18:173–86.33.Marples RR. The effect of hydration on the bacterial flora of the skin. In: Maibach HI, Hildick-Smith G, editors. Skin Bacteria and their Role in Infection. New York: McGrawHill; 1965. p. 3341.34.Cunliffe WJ, et al. Tetracycline and acne vulgaris: a clinical and laboratory investigation. Br Med J 1973;4:332–5.35.Holland KT, Cunliffe WJ, Roberts CD. Acne vulgaris: an investigation into the number of anaerobic diphtheroids and members of the Micrococcaceae in normal and acne skin. Br J Dermatol 1977;96:623–6.36.Puhvel SM, Amirian DA. Bacterial flora of comedones. Br J Dermatol 1979;101:543–8.37.Holland KT, Ingham E, Cunliffe WJ. A review, the microbiology of acne. J Appl Bacteriol 1981;51:195–215.38.Planet PJ, Parker D, Ruff NL, Shinefield HR. Revisiting Bacterial Interference in the Age of Methicillin-resistant Staphylococcus aureus: Insights Into Staphylococcus aureus Carriage, Pathogenicity and Potential Control. Pediatr Infect Dis J 2019;38:958–66.39.Gibbons SM, et al. Ecological succession and viability of human-associated microbiota on restroom surfaces. Appl Environ Microbiol 2015;81:765–73.40.Hogan PG, et al. Interplay of personal, pet, and environmental colonization in households affected by community-associated methicillin-resistant Staphylococcus aureus. J Infect 2019;78:200–7.41.Lax S, et al. Longitudinal analysis of microbial interaction between humans and the indoor environment. Science 2014;345:1048–52.42.Miller M, et al. Staphylococcus aureus in the community: colonization versus infection. PloS One 2009;4:e6708.43.Mork RL, et al. Comprehensive modeling reveals proximity, seasonality, and hygiene practices as key determinants of MRSA colonization in exposed households. Pediatr Res 2018;84:668–76.44.Mork RL, et al. Longitudinal, strain-specific Staphylococcus aureus introduction and transmission events in households of children with community-associated methicillin-resistant S aureus skin and soft tissue infection: a prospective cohort study. Lancet Infect Dis 2019;45.Fukami T Historical Contingency in Community Assembly: Integrating Niches, Species Pools, and Priority Effects. Annu Rev Ecol Evol Syst 2015;46:1–23.46.Sprockett D, Fukami T, Relman DA. Role of priority effects in the early-life assembly of the gut microbiota. Nat Rev Gastroenterol Hepatol 2018;15:197–205.47.Hecht AL, et al. Strain competition restricts colonization of an enteric pathogen and prevents colitis. EMBO Rep 2016;17:1281–91.48.Aagaard K, et al. The placenta harbors a unique microbiome. Sci Transl Med 2014;6:237ra65.49.Collado MC, Rautava S, Aakko J, Isolauri E, Salminen S. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep 2016;6:23129.50.Perez-Muñoz ME, Arrieta M-C, Ramer-Tait AE, Walter J. A critical assessment of the “sterile womb” and “in utero colonization” hypotheses: implications for research on the pioneer infant microbiome. Microbiome 2017;5:48.51.Rodríguez JM, et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis [Internet] 2015. [cited 2018 Sep 2];26. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315782/52.Tapiainen T, et al. Maternal influence on the fetal microbiome in a population-based study of the first-pass meconium. Pediatr Res 2018;53.Younge N, et al. Fetal exposure to the maternal microbiota in humans and mice. JCI Insight 2019;4.54.de Goffau MC, et al. Human placenta has no microbiome but can contain potential pathogens. Nature 2019;572:329–34.55.Theis KR, et al. Does the human placenta delivered at term have a microbiota? Results of cultivation, quantitative real-time PCR, 16S rRNA gene sequencing, and metagenomics. Am J Obstet Gynecol 2019;220:267.e1–267.e39.56.Chu DM, et al. Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery. Nat Med 2017;23:314–26.57.Dominguez-Bello MG, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A 2010;107:11971–5.58.Olm MR, et al. Identical bacterial populations colonize premature infant gut, skin, and oral microbiomes and exhibit different in situ growth rates. Genome Res 2017;27:601–12.59.Sarkany I, Gaylarde CC. Skin flora of the newborn. Lancet Lond Engl 1967;1:589–90.60.Dominguez-Bello MG, et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med 2016;22:250–3.61.Nishijima K, Yoneda M, Hirai T, Takakuwa K, Enomoto T. Biology of the vernix caseosa: A review. J Obstet Gynaecol Res 2019;45:2145–9. -62.Bergström A, Byaruhanga R, Okong P. The impact of newborn bathing on the prevalence of neonatal hypothermia in Uganda: a randomized, controlled trial. Acta Paediatr Oslo Nor 1992 2005;94:1462–7.63.Sarkany I, Gaylarde CC. Bacterial colonisation of the skin of the newborn. J Pathol Bacteriol 1968;95:115–22.64.Medves JM, O’Brien B. Does bathing newborns remove potentially harmful pathogens from the skin? Birth Berkeley Calif 2001;28:161–5.65.Visscher MO, et al. Vernix caseosa in neonatal adaptation. J Perinatol Off J Calif Perinat Assoc 2005;25:440–6.66.Lund C Bathing and Beyond: Current Bathing Controversies for Newborn Infants. Adv Neonatal Care Off J Natl Assoc Neonatal Nurses 2016;16 Suppl 5S:S13–20.67.Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature 2012;489:220–30.68.Verster AJ, et al. The Landscape of Type VI Secretion across Human Gut Microbiomes Reveals Its Role in Community Composition. Cell Host Microbe 2017;22:411–419.e4.69.Yatsunenko T, et al. Human gut microbiome viewed across age and geography. Nature 2012;486:222–7.70.Capone KA, Dowd SE, Stamatas GN, Nikolovski J. Diversity of the human skin microbiome early in life. J Invest Dermatol 2011;131:2026–32.71.Costello EK, Carlisle EM, Bik EM, Morowitz MJ, Relman DA. Microbiome assembly across multiple body sites in low-birthweight infants. mBio 2013;4:e00782–00713.72.Younge NE, Araújo-Pérez F, Brandon D, Seed PC. Early-life skin microbiota in hospitalized preterm and full-term infants. Microbiome 2018;6:98.73.Kennedy EA, et al. Skin microbiome before development of atopic dermatitis: Early colonization with commensal staphylococci at 2 months is associated with a lower risk of atopic dermatitis at 1 year. J Allergy Clin Immunol 2017;139:166–72.74.Asnicar F, et al. Studying Vertical Microbiome Transmission from Mothers to Infants by Strain-Level Metagenomic Profiling. mSystems 2017;2.75.Korpela K, et al. Selective maternal seeding and environment shape the human gut microbiome. Genome Res 2018;28:561–8.76.Zhu T, et al. Age and Mothers: Potent Influences of Children’s Skin Microbiota. J Invest Dermatol 2019;139:2497–2505.e6.77.Faith JJ, et al. The long-term stability of the human gut microbiota. Science 2013;341:1237439.78.Ferretti P, et al. Mother-to-Infant Microbial Transmission from Different Body Sites Shapes the Developing Infant Gut Microbiome. Cell Host Microbe 2018;24:133–145.e5.79.Yassour M, et al. Strain-Level Analysis of Mother-to-Child Bacterial Transmission during the First Few Months of Life. Cell Host Microbe 2018;24:146–154.e4.80.Doege K, et al. Impact of maternal supplementation with probiotics during pregnancy on atopic eczema in childhood--a meta-analysis. Br J Nutr 2012;107:1–6.81.Shin H, et al. The first microbial environment of infants born by C-section: the operating room microbes. Microbiome 2015;3:59.82.Lax S, et al. Colonization and Succession of Hospital-Associated Microbiota. Sci Transl Med 2017. 9(391):eaah6500.83.Gaitanis G, et al. Variation of cultured skin microbiota in mothers and their infants during the first year postpartum. Pediatr Dermatol 2019;36:460–5.84.Evans NJ, Rutter N. Development of the epidermis in the newborn. Biol Neonate 1986;49:74–80.85.Oranges T, Dini V, Romanelli M. Skin Physiology of the Neonate and Infant: Clinical mplications. Adv Wound Care 2015;4:587–95.86.Hoeger PH, Enzmann CC. Skin physiology of the neonate and young infant: a prospective study of functional skin parameters during early infancy. Pediatr Dermatol 2002;19:256–62.87.Saijo S, Tagami H. Dry skin of newborn infants: functional analysis of the stratum corneum. Pediatr Dermatol 1991;8:155–9.88.Webster GF, Ruggieri MR, McGinley KJ. Correlation of Propionibacterium acnes populations with the presence of triglycerides on nonhuman skin. Appl Environ Microbiol 1981;41:1269–70.89.Agache P, Blanc D, Barrand C, Laurent R. Sebum levels during the first year of life. Br J Dermatol 1980;103:643–9.90.Oh J, Conlan S, Polley EC, Segre JA, Kong HH. Shifts in human skin and nares microbiota of healthy children and adults. Genome Med 2012;4:77.91.Mack MC, et al. Development of solar UVR-related pigmentation begins as early as the first summer of life. J Invest Dermatol 2010;130:2335–8.92.Nosanchuk JD, Casadevall A. Impact of Melanin on Microbial Virulence and Clinical Resistance to Antimicrobial Compounds. Antimicrob Agents Chemother 2006;50:3519–28.93.Gallo RL, Nakatsuji T. Microbial symbiosis with the innate immune defense system of the skin. J Invest Dermatol 2011;131:1974–80.94.Lai Y, Gallo RL. AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends Immunol 2009;30:131–41.95.Gläser R, et al. Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection. Nat Immunol 2005;6:57–64.96.Schauber J, et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest 2007;117:803–11.97.Tamoutounour S, et al. Keratinocyte-intrinsic MHCII expression controls microbiota-induced Th1 cell responses. Proc Natl Acad Sci U S A 2019;116:23643–52.98.Thiemann S, et al. Enhancement of IFNγ Production by Distinct Commensals Ameliorates Salmonella-Induced Disease. Cell Host Microbe 2017;21:682–694.e5.99.Callewaert C, et al. IL-4Rα Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis. J Invest Dermatol 2020;140:191–202.e7.100.Simpson EL, et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med 2016;375:2335–48.101.Kobayashi T, et al. Homeostatic Control of Sebaceous Glands by Innate Lymphoid Cells Regulates Commensal Bacteria Equilibrium. Cell 2019;176:982–997.e16.102.Davey MS, et al. Clonal selection in the human Vδ1 T cell repertoire indicates γδ TCR-dependent adaptive immune surveillance. Nat Commun 2017;8:14760.103.Kabelitz D Functio and specificity of human gamma/delta-positive T cells. Crit Rev Immunol 1992;11:281–303.104.Sharp LL, Jameson JM, Cauvi G, Havran WL. Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1. Nat Immunol 2005;6:73–9.105.Toulon A, et al. A role for human skin-resident T cells in wound healing. J Exp Med 2009;206:743–50.106.Selvanantham T, et al. NKT Cell-Deficient Mice Harbor an Altered Microbiota That Fuels Intestinal Inflammation during Chemically Induced Colitis. J Immunol Baltim Md 1950 2016;197:4464–72.107.Doisne J-M, et al. Skin and peripheral lymph node invariant NKT cells are mainly retinoic acid receptor-related orphan receptor (gamma)t+ and respond preferentially under inflammatory conditions. J Immunol Baltim Md 1950 2009;183:2142–9.108.Ito T, et al. Maintenance of hair follicle immune privilege is linked to prevention of NK cell attack. J Invest Dermatol 2008;128:1196–206.109.Gold MC, et al. Human thymic MR1-restricted MAIT cells are innate pathogen-reactive effectors that adapt following thymic egress. Mucosal Immunol 2013;6:35–44.110.Le Bourhis L, et al. Antimicrobial activity of mucosal-associated invariant T cells. Nat Immunol 2010;11:701–8.111.Constantinides MG, et al. MAIT cells are imprinted by the microbiota in early life and promote tissue repair. Science 2019;366.112.Hinks TSC, et al. Activation and In Vivo Evolution of the MAIT Cell Transcriptome in Mice and Humans Reveals Tissue Repair Functionality. Cell Rep 2019;28:3249–3262.e5.113.Leng T, et al. TCR and Inflammatory Signals Tune Human MAIT Cells to Exert Specific Tissue Repair and Effector Functions. Cell Rep 2019;28:3077–3091.e5.114.Cordoro KM, et al. Skin-infiltrating, interleukin-22-producing T cells differentiate pediatric psoriasis from adult psoriasis. J Am Acad Dermatol 2017;77:417–24.115.Scharschmidt TC, et al. A Wave of Regulatory T Cells into Neonatal Skin Mediates Tolerance to Commensal Microbes. Immunity 2015;43:1011–21.116.Scharschmidt TC, et al. Commensal Microbes and Hair Follicle Morphogenesis Coordinately Drive Treg Migration into Neonatal Skin. Cell Host Microbe 2017;21:467–477.e5.117.Russler-Germain EV, Rengarajan S, Hsieh C-S. Antigen-Specific Regulatory T Cell Responses to Intestinal Microbiota. Mucosal Immunol 2017;10:1375–86.118.Donaldson GP, et al. Gut microbiota utilize immunoglobulin A for mucosal colonization. Science 2018;360:795–800.119.Lee SM, et al. Bacterial colonization factors control specificity and stability of the gut microbiota. Nature 2013;501:426–9.120.Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 2005;122:107–18.121.Mehta RS, et al. Stability of the human faecal microbiome in a cohort of adult men. Nat Microbiol 2018;3:347–55.122.Truong DT, Tett A, Pasolli E, Huttenhower C, Segata N. Microbial strain-level population structure and genetic diversity from metagenomes. Genome Res 2017;27:626–38.123.Torow N, Hornef MW. The Neonatal Window of Opportunity: Setting the Stage for LifeLong Host-Microbial Interaction and Immune Homeostasis. J Immunol Baltim Md 1950 2017;198:557–63.124.Florey HW. The use of micro-organisms for therapeutic purposes. Yale J Biol Med 1946;19:101–17.125.Henderson DW. Bacterial interference. Bacteriol Rev 1960;24:167–76.126.Sprunt K, Redman W. Evidence suggesting importance of role of interbacterial inhibition in maintaining balance of normal flora. Ann Intern Med 1968;68:579–90.127.Schiotz A Uskadeliggorelse af infektionsbaerere ved difteri. Ugeskr Læg 1909;71:1382–4.128.Books Received. J Am Med Assoc 1910;LIV:422–422.129.Albert H The treatment of diphtheria carriers. J Am Med Assoc 1913;61:1027–31.130.Jennings MA, Sharp AE. Antibacterial activity of the Staphylococcus. Nature 1947;159:133.131.Lorenz WF, Ravenel MP. The treatment of diphtheria-carriers by overriding with Staphylococcus aureus. J Am Med Assoc 1912;LIX:690–3.132.Womer WA. Results of staphylococcus spray treatment in forty-two cases of diphtheria carriers. J Am Med Assoc 1913;61:2293–4.133.Panigrahi P, et al. Long-term colonization of a Lactobacillus plantarum synbiotic preparation in the neonatal gut. J Pediatr Gastroenterol Nutr 2008;47:45–53.134.Panigrahi P, et al. A randomized synbiotic trial to prevent sepsis among infants in rural India. Nature 2017;548:407–12.135.Myles IA, et al. First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis. JCI Insight 2018;3.136.Nakatsuji T, et al. Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci Transl Med 2017;9.137.Blair JE, Carr M. Staphylococci in hospital-acquired infections; types encountered in the United States. J Am Med Assoc 1958;166:1192–6.138.Blair JE, Carr M. Distribution of Phage Groups of Staphylococcus aureus in the Years 1927 through 1947. Science 1960;132:1247–8.139.Rountree PM, Freeman BM. Infections caused by a particular phage type of Staphylococcus aureus. Med J Aust 1955;42:157–61.140.Boris M, et al. Bacterial interference: its effect on nursery-acquired infection with Staphylococcus aureus. IV. The Louisiana epidemic. Am J Dis Child 1960 1963;105:674–82.141.Shinefield HR, Ribble JC, Boris M, Eichenwald HF. Bacterial interference: its effect on nursery-acquired infection with Staphylococcus aureus. I. Preliminary observations on artificial colonzation of newborns. Am J Dis Child 1960 1963;105:646–54.142.Shinefield HR, Sutherland JM, Ribble JC, Eichenwald HF. Bacterial interference: its effect on nursery-acquired infection with Staphylococcus aureus. II. The Ohio epidemic. Am J Dis Child 1960 1963;105:655–62.143.Shinefield HR, Boris M, Ribble JC, Cale EF, Eichenwald HF. Bacterial interference: its effect on nursery-acquired infection with Staphylococcus aureus. III. The Georgia epidemic. Am J Dis Child 1960 1963;105:663–73.144.Shinefield HR, Ribble JC, Eichenwald HF, Boris M, Sutherland JM. Bacterial interference: its effect on nursery-acquired infection with Staphylococcus aureus. V. An analysis and interpretation. Am J Dis Child 1960 1963;105:683–8.145.Light IJ, Sutherland JM, Schott JE. Control of a Staphylococcal Outbreak in a Nursery: Use of Bacterial Interference. JAMA 1965;193:699–704.146.Russell AB, et al. Type VI secretion delivers bacteriolytic effectors to target cells. Nature 2011;475:343–7.147.Russell AB, et al. A type VI secretion-related pathway in Bacteroidetes mediates interbacterial antagonism. Cell Host Microbe 2014;16:227–36.148.Wexler AG, et al. Human symbionts inject and neutralize antibacterial toxins to persist in the gut. Proc Natl Acad Sci U S A 2016;113:3639–44.149.Ross BD, et al. Human gut bacteria contain acquired interbacterial defence systems. Nature 2019;575:224–8.150.Burts ML, DeDent AC, Missiakas DM. EsaC substrate for the ESAT-6 secretion pathway and its role in persistent infections of Staphylococcus aureus. Mol Microbiol 2008;69:736–46.151.Christensen GJM, et al. Antagonism between Staphylococcus epidermidis and Propionibacterium acnes and its genomic basis. BMC Genomics 2016;17:152.152.Ohr RJ, Anderson M, Shi M, Schneewind O, Missiakas D. EssD, a Nuclease Effector of the Staphylococcus aureus ESS Pathway. J Bacteriol 2017;199.153.Whitney JC, et al. A broadly distributed toxin family mediates contact-dependent antagonism between gram-positive bacteria. eLife 2017;6.154.Gillor O, Etzion A, Riley MA. The dual role of bacteriocins as anti- and probiotics. Appl Microbiol Biotechnol 2008;81:591–606.155.Klaenhammer TR. Bacteriocins of lactic acid bacteria. Biochimie 1988;70:337–49.156.Nes IF, et al. Biosynthesis of bacteriocins in lactic acid bacteria. Antonie Van Leeuwenhoek 1996;70:113–28.157.Riley MA, Wertz JE. Bacteriocin diversity: ecological and evolutionary perspectives. Biochimie 2002;84:357–64.158.Mota-Meira M, LaPointe G, Lacroix C, Lavoie MC. MICs of mutacin B-Ny266, nisin A, vancomycin, and oxacillin against bacterial pathogens. Antimicrob Agents Chemother 2000;44:24–9.159.Ikari NS, Kenton DM, Young VM. Interaction in the germfree mouse intestine of colicinogenic and colicin-sensitive microorganisms. Proc Soc Exp Biol Med Soc Exp Biol Med N Y N 1969;130:1280–4.160.Riley MA, Gordon DM. The ecological role of bacteriocins in bacterial competition. Trends Microbiol 1999;7:129–33.161.Sassone-Corsi M, Nuccio S-P, Liu H, et al. Microcins mediate competition among Enterobacteriaceae in the inflamed gut. Nature 2016;540:280–3.162.Chao L, Levin BR. Structured habitats and the evolution of anticompetitor toxins in bacteria. Proc Natl Acad Sci U S A 1981;78:6324–8.163.Durrett R, Levin S. Allelopathy in Spatially Distributed Populations. J Theor Biol 1997;185:165–71.164.Noble WC, Willie JA. Interactions between antibiotic-producing and non-producing staphylococci in skin surface and sub-surface models. Br J Exp Pathol 1980;61:339–43.165.O’Sullivan JN, Rea MC, O’Connor PM, Hill C, Ross RP. Human skin microbiota is a rich source of bacteriocin-producing staphylococci that kill human pathogens. FEMS Microbiol Ecol 2019;95.166.O’Neill AM, et al. Identification of a Human Skin Commensal Bacterium that Selectively Kills Cutibacterium acnes. J Invest Dermatol 2020;167.Claesen J, et al. Cutibacterium acnes antibiotic production shapes niche competition in the human skin microbiome. bioRxiv 2019;594010.168.Janek D, Zipperer A, Kulik A, Krismer B, Peschel A. High Frequency and Diversity of Antimicrobial Activities Produced by Nasal Staphylococcus Strains against Bacterial Competitors. PLoS Pathog 2016;12:e1005812.169.DeFilipp Z, et al. Drug-Resistant E. coli Bacteremia Transmitted by Fecal Microbiota Transplant. N Engl J Med 2019;381:2043–50.170.Sorbara MT, Pamer EG. Interbacterial mechanisms of colonization resistance and the strategies pathogens use to overcome them. Mucosal Immunol 2019;12:1–9.作者｜Benjamin W. Casterline and Amy S. Paller
