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Changing our microbiome: probiotics in dermatology [原文来自：www.ii77.com]
Y. Yu¹, S. Dunaway¹, J. Champer², J. Kim³ and A. Alikhan⁴
1.Department of Dermatology, University of Cincinnati, Cincinnati, OH, U.S.A.
2.Department of Computational Biology and Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, U.S.A.
3.Division of Dermatology and Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, U.S.A.
4.Sutter Medical Foundation, Sacramento, CA, U.S.A.
提纲
配景：在人类健康与发病机制中，共生细菌饰演着主要的脚色。人类对共生细菌的乐趣一日千里，且不光仅局限于胃肠道微生物菌群，还包罗皮肤微生物菌群以及其对多种皮肤疾病的影响。
目的：本文综述与肠道和皮肤微生物菌群在皮肤病的应用相关的最新进展，评估口服或外用益生菌对治疗某些皮肤病是否有效的相关临床数据。
方式：采用PubMed和ClinicalTrials.gov数据库完成与根蒂科学、转化研究和临床研究相关的搜刮，说明使用益生菌前后皮肤微生态的差别以及其对特应性皮炎、平常痤疮、银屑病、难愈创面、脂溢性皮炎和皮肤肿瘤的影响。
究竟：除特应性皮炎外，很少有临床试验研究益生菌在皮肤病防治中的应用。且大部门研究都集中在口服益生菌干涉以及局部施用益生菌两方面，在皮肤共生菌方面的研究还较为缺乏。总之，现有的临床试验获得了较为积极的究竟：采用益生菌干涉有助于改善皮肤状况。
结论：口服和局部使用益生菌对于治疗某些炎性皮肤病显露出积极结果，在创面修复和皮肤癌治疗方面也显露潜力，但仍需更多研究来验证。
已知信息：
1. 微生物菌群在人类健康和发病机制中施展着主要的感化。
2. 益生菌有助于调节宿主的微生物菌群，并或者有利于患者的健康。
3. 迄今已开展口服或局部外用益生菌对特定皮肤病疗效的索求。
本研究的立异点：
1. 从根蒂科学与临床试验数据综述了肠道与皮肤微生物菌群在皮肤病学中的感化。
2. 综述益生菌防治包罗特应性皮炎、平常痤疮、银屑病、脂溢性皮炎、难愈创面以及皮肤肿瘤在内的皮肤病最新资料。
3. 提出了将来的益生菌干涉方案。
共生细菌对于维持人类健康的免疫系统至关主要，菌群失调有利于机会致病菌以及致病细菌的定植，导致疾病的发生。已有大量文献报道与胃肠道疾病相关的微生物菌群，以及其对皮肤的影响¹ ²。固然定植于皮肤上的微生物数量显著低于胃肠道菌群，但二者对免疫系统的调节及其致病机理都较为相似³。
微生物菌群在疾病中所饰演的脚色已经被研究得越来越透辟⁴，是以经由微生物调节人体免疫系统来治疗相关疾病这一新方式具有广宽的应用前景。个中一种直接的方式就是包罗活菌在内的微生物制剂（益生菌）的使用⁵，当其达到充沛浓度时，将有利于宿主的健康⁶。本文综述微生物菌群对人类健康的影响，稀奇是口服和局部外用益生菌在皮肤病防治中是若何施展感化的。
方式
以“微生物组”、“微生物菌群”、“共生”、“细菌”、“微生物制剂”、“局部的”、“皮肤”和“皮肤病学”作为要害词，在PubMed和ClinicalTrial.gov数据库搜刮查找相关研究文献。将所有的检索词做分歧组合，并依据文献摘要的相关性进行筛选。经由根蒂科学、体外试验、动物模型研究以及临床试验进行口服和局部外用益生菌干涉的研究（本综述未包罗非英文相关文献）。重点是已经研究发现皮肤微生物组学有差别的皮肤病，包罗特应性皮炎（atopic dermatitis, AD）、平常痤疮、银屑病、脂溢性皮炎、难愈创面及伤口愈合、皮肤肿瘤，以及益生菌在这些患者群体中的影响。
皮肤微生态与局部外用益生菌
人体皮肤定植有跨越1000种细菌，每一种都能与特定的情况相适应⁷。遍及来讲，大部门皮肤细菌都是对宿主无害的共生细菌，组成了皮肤微生物菌落的多样性，有助于预防或缓解疾病（图1）⁸⁻¹⁰。共生细菌经由被动占有和致病微生物相似的生态位干扰致病微生物定植，还经由排泄抗菌因子与致病菌自动竞争。共生细菌还能调节免疫系统，指导免疫系统冲击致病微生物或许提高免疫耐受力，从而缓解炎症¹¹ ¹²。
局部外用微生物制剂是改变皮肤微生物菌群以及对多种疾病进行免疫应答的一种直接方式⁸ ⁹。固然现阶段相关研究较少，但一些局部外用益生菌的临床试验已经显现出良性的究竟。
图1 共生细菌按捺疾病的机制。共生细菌平日和致病微生物占有沟通的生态位，直接故障致病菌定植。共生菌也或者直接排泄如细菌素、丙酸、抗菌肽（AMPs）等或间接调节免疫系统来冲击致病菌。
肠道微生物菌群和口服益生菌与皮肤病
肠道微生物菌群诱发和预防疾病的相关机制在皮肤方面有普遍应用。正常肠道菌群失调会促进慢性炎症的发生，甚至导致肿瘤¹³ ¹⁴。肠道共生菌可以自力调节懈弛解胃肠道炎症¹³。是以，共生菌在健康肠道微生物菌群重建过程中有抗氧化感化，诱导肿瘤按捺基因表达¹⁵，激发免疫系统冲击癌细胞，或经由调控T细胞来削减炎症发生¹⁶⁻¹⁸，匡助宿主抵当恶性肿瘤。
同时，肠道微生物可以影响系统性炎症、氧化应激、血糖掌握以及组织脂质含量²。肠道菌群失调与包罗和肠道相关的皮肤病－关节炎综合症² ¹⁹以及玫瑰痤疮²⁰在内的炎症性皮肤病具有相关性：经由重建正常的肠道微生物菌群使得整个疾病获得缓解。是以，口服益生菌能够调节肠道微生物菌群，从而间接影响皮肤病。其相关治疗在特应性皮炎的研究最透辟。
特应性皮炎（Atopic dermatitis, AD）
特应性皮炎（AD）患者的表皮屏障功能障碍和免疫失调，有利于致病细菌在其体内定植。AD型皮肤外观金..葡萄球菌（Staphylococcus aureus）的数量增多，而整体的微生物多样性削减²¹⁻²⁴。最新研究证实无论是AD患者的皮损部位照样非皮损部位菌群多样性都低于健康人，即AD患者全身的皮肤微生物菌群都发生了改变²⁵。同时，AD的严重水平与微生物多样性成负相关。当患者病情严重时，能视察到皮肤微生物菌群的多样性急剧削减，而当对AD皮损部位进行治疗时，微生物菌群多样性又得以重建²¹ ²⁴ ²⁵。稀奇地，葡萄球菌属的种类在AD活跃期有所增加，个中包罗表皮葡萄球菌（Staphylococcus epidermis），这或者是掌握金..葡萄球菌数量的一种代偿机制²¹ ²² ²⁴。切实，一项针对AD活跃期的查询显露：金..葡萄球菌在重型患者中占主导优势，而表皮葡萄球菌在相对不严重患者中占主导²⁶。并且，肠道情况也会影响AD的致病菌。患有与IgE相关湿疹的婴幼儿，体内双歧杆菌的种类削减，且微生物多样性低于健康婴幼儿¹⁹。2月龄时，大肠杆菌（Escherichia coli）在婴儿肠道中定植，有利于婴儿更长久的健康，好比，其能降低6岁儿童AD的发病率²⁷。是以，调节微生物菌群在AD的治疗中是一种前景广宽的新策略。
口服益生菌在防治AD方面的疗效已经进行了大型排队研究和随机对照试验。最新的调集剖析究竟显露，口服发酵乳酸杆菌（Lactobacillus fermentum）、唾液乳酸杆菌（Lactobacillus salivarius）以及分歧菌种的夹杂物后，1070名儿童AD患者的AD积分指数值（SCORAD）显著降低²⁸。早前的调集剖析究竟²⁹也支撑口服益生菌可以防治AD：无论是零丁服用乳酸杆菌照样乳酸杆菌与双歧双歧杆菌（Bifidobacterium bifidum）结合服用，都能阻止AD病情成长，其优势比离别为0.7和0.62³⁰。此外，病情适中的AD患者每日口服双歧杆菌和干酪乳酸杆菌（Lactobacillus casei）的夹杂物，一连服用12周后，与不采用益生菌干涉的对照组比拟，其SCORAD值平均降低19.2分³¹。然而，疗效也与菌种特异性相关，好比患者口服鼠李糖乳酸杆菌（Lactobacillus rhamnosus）和副干酪乳杆菌（Lactobacillus paracasei）后得出了分歧的究竟³²⁻³⁶。
迄今为止，仍很少有研究报道局部施用微生物制剂进行AD治疗。Nakatusji等近期报道下场部外用皮肤共生菌来匹敌致病菌的相关案例³⁷。将皮肤共生菌—凝固酶阴性的葡萄球菌接种至AD患者的皮肤外观，因为该共生菌会排泄高效的抗菌肽，可以选择性地杀死金..葡萄球菌，从而导致其菌落数量削减³⁷。早期数据显露，凝固酶阴性葡萄球菌干涉不光可以按捺金..葡萄球菌的生长，还与临床症状改善以及缓解局部炎症相关³⁸。此外，与使用糖皮质激素比拟，局部接种革兰阴性菌玫瑰单胞菌（Roseomonas mucosa）于成人和儿童AD患者皮肤上后，患者瘙痒症状显着减轻，SCORAD值降低，且无副感化和并发症发生³⁹。
此外，一些关于肠道共生菌的局部使用报道也收获可喜究竟。接种约氏乳酸杆菌（Lactobacillus johnsonii）至AD皮损部位（一天2次，3周）时，金..葡萄球菌载量降低，直接导致SCORAD值降低⁴⁰。另一篇研究报道，在AD患者皮损处局部涂抹2周嗜热链球菌（Streptococcus thermophilus）乳霜，患者皮肤红斑，鳞屑以及瘙痒症状都获得了显着的改善⁴¹。将含有革兰阴性菌线状透亮颤菌（Vitreoscilla filiformis，在温泉水中被发现）裂解物的乳霜涂抹于AD患处时，也可以使AD患者的临床症状获得改善⁴²。固然益生菌疗法在AD治疗的研究才方才起步，但好多研究都呈现出了阳性的究竟。
平常痤疮（Acne vulgaris）
平常痤疮与痤疮丙酸杆菌（Cutibacterium acnes，由Propionibacterium acnes改名而来）直接相关。肠道微生物菌群失调可以经由肠-皮轴影响痤疮的发病²，是以口服益生菌对于治疗痤疮具有潜在疗效。研究表明，嗜酸乳杆菌（Lactobacillus acidophilus）、保加利亚乳杆菌（Lactobacillus delbrueckii bulgaricus）以及双歧双歧杆菌在治疗痤疮方面的结果与使用二甲胺四环素相当，且副感化更小，口服益生菌12周后，痤疮患者皮损削减67%⁴³。二甲胺四环素与益生菌结合使用时，治疗结果更佳⁴³。另一项研究表明，痤疮患者在一连服用保加利亚乳杆菌和嗜热链球菌12周后，患者的炎性皮损削减30%，其皮脂含量和游离脂肪酸含量与对照组比拟降低了50%或更多⁴⁴。近期研究发现，与口服抚慰剂的对照组（胰岛素旌旗基因可以正常表达）比拟，患者一连12周口服鼠李糖乳酸杆菌SP1后，其背部痤疮获得了显着改善⁴⁵。
近期研究发现，痤疮丙酸杆菌的某些特定亚型（IA-2，IB-1，I-C）与痤疮更相关，而其他亚型（II-核酸型6，III）多显现在健康皮肤上⁴⁶⁻⁵⁰。是以，这些与痤疮相关的亚型很或者是导致痤疮发生的身分。一项体外实验究竟显露，与痤疮相关的痤疮丙酸杆菌亚型能诱导T辅助细胞（Th）1和Th17的高响应；但与健康皮肤相关的亚型导致（Th）1和Th17低响应，白介素（IL）-10抗炎症高响应⁵¹。以上究竟解说，与健康皮肤相关的痤疮丙酸杆菌亚型或者用于局部益生菌防治痤疮中，用于替代痤疮相关的细菌亚型以及其他潜在的机会致病细菌亚型⁴⁶ ⁵¹ ⁵²。以上靶向策略就是行使同种的细菌占有统一生态位，是以比选择其他皮肤或肠道共生菌加倍高效，可以快速和持久的改善皮肤微生态。
然而，使用肠道和其他非皮肤益生菌治疗痤疮的相关研究还很有限。痤疮患者在一连使用从粪肠球菌（Enterococcus faecalis）SL-5中提取的促肠菌素冻干粉8周后，其炎性皮损与对照组比拟，下降了60%⁵³。一项针对亚硝化单胞菌（Nitrosomonas eutropha）的新型IIb/III的研究报道显露，与对照组比拟，实验组在评估痤疮严重水平的研究者总体评分（Investigator’s Global Assessment）中下降2点，且呈现出炎性皮损数量削减的趋势（一天2次，一连使用12周）⁵⁴。但这些菌并不是皮肤上天然定植，是以当完结治疗时，就不太或者像皮肤微生物一般，为患者供应持续珍爱。比拟而言，一周2次局部涂抹含有表皮葡萄球菌的凝胶，改变了宿主的皮肤微生物菌群，且表皮葡萄球菌可以很好地定植于皮肤上⁵⁵。是以在痤疮治疗中，选择像表皮葡萄球菌如许的皮肤共生菌比亚硝化单胞菌更合适，尤其是体外试验显露表皮葡萄球菌可以按捺痤疮丙酸杆菌生长⁵⁶。
局部外用益生菌也包含痤疮丙酸杆菌噬菌体（可以裂解宿主细菌的病毒）。两项研究显露，一些痤疮丙酸杆菌噬菌体只裂解与痤疮相关和不相关（但或者是潜在的致病型）的痤疮丙酸杆菌亚型，而对健康皮肤相关的亚型无效⁵⁷⁻⁶⁰。将噬菌体和健康皮肤相关的痤疮杆菌结合使用，在高效特异替代其他痤疮丙酸杆菌方面有伟大潜力（图2）。
图2 菌群特异性替代的局部外用益生菌结合治疗法。包含有利健康的共生菌以及细菌噬菌体的一种新型局部外用益生菌配方可以靶向性的针对致病菌，并成为高度特异性菌种替代的潜在策略。
银屑病（Psoriasis）
报道显露银屑病患者皮肤微生物菌群的改变或者会诱导Th17通路的激活⁶¹ ⁶²。比拟于未受银屑病侵袭的正常皮肤，病变皮肤上的微生物菌群多样性呈现出削减的趋势⁶³⁻⁶⁵。好比：银屑病皮损部位的放线菌含量显着低于健康皮肤⁶⁴ ⁶⁵，金..葡萄球菌和酿脓链球菌（Streptococcus pyogenes）在银屑病皮损区也只是微量甚至不存在⁶⁴ ⁶⁵。然而，因为研究数据的缺乏以及分歧的抽样手艺，银屑病与皮肤微生态之间的关系还有好多未解之谜。
迄今为止，固然有证据显露益生菌或者经由削减炎症来施展有益的免疫调控感化⁶⁶ ⁶⁷，但仍缺乏益生菌在银屑病治疗过程中所起感化的相关研究。银屑病患者在口服婴儿双歧杆菌（Bifidobacterium infantis）8周后，其体内炎症C-回响卵白和肿瘤坏死因子-α的水平显著降低，但这是否陪伴着临床症状改善还并不清楚⁶⁷。而在银屑病老鼠模型中，经由口服戊糖乳杆菌（Lactobacillus pentosus）GMNL-77可以降低肿瘤坏死因子-α和IL-23-IL-17促炎细胞因子的水平，并陪伴着其红斑和鳞屑皮损部位的削减⁶⁶。越来越多的研究聚焦于微生物菌群在银屑病治疗中施展的调控感化，这也将对络续成长的免疫治疗学进行增补。
脂溢性皮炎（Seborrhoeic dermatitis）
脂溢性皮炎被认为是对游离脂肪酸的一种炎性响应，游离脂肪酸是皮肤常驻真菌糠秕马拉色菌（Malassezia furfur）【此处是指马拉色菌属（Malassezia sp.）译者注】发生的代谢产品⁶⁸ ⁶⁹。而脂溢性皮炎是否获得改善与酵母菌数量削减相关，但马拉色菌的绝对量与病情的严重水平无关⁷⁰ ⁷¹。病情严重水平能够经由细菌多样性是否削减来进行展望⁷²⁻⁷⁴。基于此，微生物制剂被用于治疗脂溢性皮炎。在一项双盲实验中（60位患者），局部外用线状透亮颤菌可以改善患者皮肤红疹，鳞屑以及瘙痒等症状⁷⁰。线状透亮颤菌的裂解物经由树突细胞以及增加调节性T细胞活性促进IL-10的发生⁷⁶。口服副干酪乳杆菌的患者，其头皮屑、红疹以及皮脂溢显著削减，临床症状获得显着缓解⁷⁷。与透亮颤菌雷同，副干酪乳杆菌是经由发生IL-10和转化生长因子-β诱导转换为正常免疫状况⁷⁸。以上究竟均支撑将局部外用或口服益生菌应用于脂溢性皮炎的治疗中。
创面愈合（Wound healing）
皮肤微生物菌群失调以及持续性的炎症都邑导致创面难以愈合⁷⁹。益生菌或者经由调节炎性响应和限制致病菌定植来促进伤口愈合。关于动物实验的最新调集剖析究竟显露，局部外用包含短乳杆菌（Lactobacillus brevis）、植物乳杆菌（Lactobacillus plantarum）和发酵乳酸杆菌的微生物制剂，会导致炎症减轻及加快创面收缩⁸⁰。而人体实验也有报道局部外用益生菌对慢性溃疡有优点：局部外用含有植物乳杆菌的益生菌可以经由调控IL-8和招募吞噬细胞以及成纤维细胞降低菌载量，促进糖尿病溃疡的愈合⁸¹；与此雷同，当非糖尿病患者一连局部外用含植物乳杆菌的微生物制剂30天后，其慢性腿部溃疡有跨越90%的区域获得缓解⁸¹；而口服含乳杆菌的微生物制剂，在治疗慢性糖尿病溃疡方面结果也很显著，其溃疡面积以及炎性标记物的水平均有所降低⁸²。
益生菌的研究究竟也施展在提高烧伤病人的创面愈合能力上⁸³ ⁸⁴，并可以防治皮肤传染。在老鼠模型实验中，局部外用含有植物乳杆菌的微生物制剂可以削减烧伤创面由铜绿假单胞菌（Pseudomonas aeruginosa）引起的皮肤传染⁸⁵。对人类而言，将植物乳杆菌局部用于2度和3度烧伤患者患处，在降低菌载量以及传染风险方面，其能力与磺胺嘧啶银相当，并促进肉芽组织形成和伤口愈合⁸⁴。因为皮肤共生菌对皮肤情况的适应能力强，是以也是局部外用益生菌的优良候选者。好比，皮肤共生菌Propioniferax innocua可以降解形成的生物膜⁸⁶。在老鼠模型中，山羊葡萄球菌（Staphylococcus caprae）对于抗甲氧西林的金..葡萄球菌具有抗菌能力，并能按捺金..葡萄球菌的定植⁸⁷。表皮葡萄球菌发生的抗菌化合物可以选择性的杀伤金..葡萄球菌和酿脓链球菌，同时也能按捺由脂磷壁酸引起的皮肤炎症¹⁰ ¹² ⁸⁸。有两篇文献报道，在具有开放创面的老鼠模型中，痤疮丙酸杆菌可以发生丙酸，以按捺金..葡萄球菌生长⁹⁰。
皮肤癌（Skin cancer）
皮肤微生物菌群失调现象存在于某些皮肤肿瘤中，并促进皮肤癌变。例如，经由葡萄球菌引起的上层抗原的潜在感化，说明了金..葡萄球菌传染与皮肤T细胞淋巴瘤的严重水平之间的关联⁹¹⁻⁹⁴。
相反，健康的皮肤微生物菌群能够经由调节免疫系统以及激活抗肿瘤的免疫监管途径来按捺致癌因子的释放³ ⁹⁵。例如，口服脂磷壁酸（从乳酸杆菌中提取）可以降低皮肤的紫外伤害以及患皮肤癌的风险⁹⁶。比来发现，表皮葡萄球菌发生的碱基分子可以选择性按捺肿瘤细胞的增殖。在老鼠模型中，这些菌的应用也能降低由紫外伤害诱发的肿瘤⁹⁷。健康微生物菌群也能经由调节肿瘤细胞的微生态情况，潜在影响癌症的响应和治疗。研究报道，比拟于无菌或抗菌处理的小鼠模型，在拥有健康肠道微生物菌群的小鼠中应用寡核苷酸免疫疗法和铂化疗手段，肿瘤治疗的结果更佳⁹⁸。是以，我们有来由相信使用益生菌对降低患肿瘤风险以及在皮肤肿瘤的治疗中都是有效的。
结论与瞻望
总之，微生物菌群在皮肤病学中施展着主要的感化，在治疗皮肤病方面也具有伟大潜能。微生物制剂可经由减缓炎症，竖立免疫均衡，阻止致病菌定植来促进健康微生态形成。跟着益生菌的医药用途迅猛增加，其平安性相关的数据还较为缺乏。同时，在免疫低下的人群中，益生菌是否会激发传染或其他严重副感化也值得考虑⁹⁹。是以，在治疗疾病时，需要将微生物菌群作为风险身分做更多的根蒂和风行病学研究。在关于口服和局部外用益生菌的临床试验中，应加大样本量评估其平安性，筛选最佳特定菌种组合、菌种浓度及治疗时间。益生菌与噬菌体或许抗生素连系治疗法或者会成为微生物菌群替代策略的将来成长偏向。
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