2022, Vol. 49扩展功能
文章信息
- 张雪珥, 王栩芮, 杨峥茹, 刘娥, 王彦瑾, 姚业静, 杨思敏, 曾进浩, 郭静
- ZHANG Xueer, WANG Xurui, YANG Zhengru, LIU E, WANG Yanjin, YAO Yejing, YANG Simin, ZENG Jinhao, GUO Jing
- 基于微生物视角的“皮-肠”轴与特应性皮炎
- Skin-gut axis and atopic dermatitis from the microbial perspective
- 微生物学通报, 2022, 49(11): 4893-4908
- Microbiology China, 2022, 49(11): 4893-4908
- DOI: 10.13344/j.microbiol.china.220529
-
文章历史
- 收稿日期: 2022-05-28
- 接受日期: 2022-07-20
- 网络首发日期: 2022-08-30
2. 成都中医药大学附属医院, 四川 成都 610072;
3. 四川省人民医院, 四川 成都 610031
2. Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan, China;
3. Sichuan Provincial People՚s Hospital, Chengdu 610031, Sichuan, China
特应性皮炎(atopic dermatitis，AD)是一种慢性、复发性和难治性的炎症性皮肤疾病。AD临床表现以皮肤剧烈瘙痒为主，常好发于婴幼儿和青少年，也可延续至成人或老年时期发作。据统计，AD在全球儿童中的发病率为15%−20%，在成人中为1%−3%，且近几十年来呈现上升趋势[1]。AD发病机制复杂，目前认为与皮肤屏障破坏、丝氨酸蛋白酶破坏、角化桥粒、炎症因子表达增加及CD4+ T细胞激活相关。其中，T细胞介导的免疫应答(Th1/Th2失衡，Thl7/Treg失衡)可能起主导作用[2]。AD的西医治疗多为局部应用糖皮质激素、钙调神经磷酸酶抑制剂，或全身应用抗组胺药、免疫抑制剂和免疫调节剂等[3]。中医治疗AD历史悠久，效果突出，是临床上可选的补充替代治疗方法[4]。然而上述疗法难以根治AD，严重影响了患者的学习状况和生活质量。
近年来，随着元转录组学、宏基因组学和代谢组学等多种技术的应用，证实了局部微生物能影响远端部位的免疫功能。例如，肠道微生物组可能通过免疫调节作用改变皮肤表型，这促成了“皮-肠”轴和“微生物-皮-肠”轴等术语的产生。本文从皮肤和肠道两个微生物簇角度出发，综述了“微生物-皮-肠”轴与AD的关系，及其可能交流的信号分子和潜在途径，并试图阐明这些途径在AD病理机制中的重要作用。此外，本文还重点关注了涉及益生菌、菌群移植和抗菌肽等微生物相关治疗缓解AD的潜在机制。
1 AD与“微生物-皮-肠”轴 1.1 AD患者皮肤菌群特征皮肤微生物群由数百万细菌、真菌和病毒构成，在保护皮肤免受病原体侵袭中发挥重要作用。皮肤上的细菌种群(包括常驻菌与暂驻菌)通常会根据皮肤表面独特的理化性质(温度、年龄、皮脂量和汗液等)来适应它们在皮肤中占据的生态位[5-7]。这一特性使皮脂丰富的部位以脂类角质菌属(丙酸菌)和真菌马拉色菌属为主；腋窝等湿润的部位以棒状杆菌、葡萄球菌为主；四肢屈侧等干燥的部位以β-变形杆菌、黄细菌和马拉色素菌的混合种群为主[8]。皮肤微生物通过角质形成细胞(keratinocytes，KC)、抗菌肽(antimicrobial peptides，AMPs)、脂质抗菌剂和细胞因子等调节宿主免疫反应，促进内环境稳定，从而改善皮肤屏障功能[9]。
内环境稳定性的破坏会造成皮肤微生物生态紊乱，主要包括微生物菌群多样性、数量、组成和代谢的显著变化[7, 9]。出生方式、压力、饮食和环境污染等因素均会影响AD患者的皮肤微生物菌群。这一反应可能会介导宿主免疫应答，诱导IgE的产生和Th2细胞的激活，造成AD症状的恶化[10-11]。研究发现，在不同年龄段的AD患者中，发作前后其皮肤微生物多样性均发生了改变(表 1)，该变化通常以丙酸杆菌属、链球菌属、不动杆菌属、棒状杆菌属和普氏杆菌属减少，而表皮葡萄球菌和溶血性葡萄球菌等葡萄球菌属增多为主要特征，其中金黄色葡萄球菌的定殖密度与AD疾病严重程度密切相关[11-13]。
| 部位 Position |
微生物改变 Microbial alterations |
免疫失调 Immune dysregulation |
|
| 皮肤 Skin |
↓丙酸杆菌属 ↓Cutibacterium ↓链球菌属 ↓Streptococcus ↓不动杆菌属 ↓Acinetobacter ↓普氏杆菌属 ↓Prevotella ↓棒状杆菌属 ↓Corynebacterium ↓痤疮丙酸杆菌 ↓Cutbacterium acnes |
↑金黄色葡萄球菌↑Staphylococcus epidermidis ↑表皮葡萄球菌 ↑Staphylococcus epidermidis ↑溶血性葡萄球菌 ↑Staphylococcus haemolyticus |
↓AMPS ↑IL-4, ↑IL-5, ↑IL-13, ↑IL-22, ↑IL-31, ↑IgE, ↑TSLP |
| 肠道 Gut |
↓乳酸杆菌属 ↓Lactobacillus ↓双歧杆菌属 ↓Bifidobacteria |
↑大肠杆菌 ↑Escherichia coli ↑艰难梭菌 ↑Clostridium difficile ↑金黄色葡萄球菌 ↑Staphylococcus epidermidis |
↓Treg, ↓IgA, ↑IL-25, ↑IL-33 |
| 注：↑：升高；↓：降低 Note: ↑: Increase; ↓: Decrease. |
|||
肠道菌群是寄生在人体肠道中微生物的总称，其数量庞大、种群丰度高[14]。目前人类个体共分离出2 172种肠道微生物群，归属12个门，其中93.5%属于拟杆菌门、厚壁菌门、放线菌门和变形菌门[15-16]。最新研究表明，肠道微生物群与肠道炎性疾病、哮喘和特应性皮炎等过敏性疾病的发生息息相关[17]。这可能与肠道微生物群产生的氨基酸代谢物、短链脂肪酸(short chain fatty acids，SCFAs)和低聚糖等代谢物相关。这些代谢物可形成黏膜层，构成肠道屏障，避免微生物群移位进入体循环引发感染，在物质代谢和免疫功能方面发挥至关重要的作用[18]。肠道微生物群与宿主之间的免疫平衡易受到饮食、疾病等因素的影响。如某些食物成分可破坏肠道屏障，加速病原微生物定殖。病原微生物可进入血液循环，激活肠道黏膜免疫，诱发产生多种免疫细胞及炎性细胞因子。
肠道微生物失衡在AD的发病机制中也扮演重要角色。与健康个体相比，AD患者肠道微生物多样性有所下降(表 1)，主要特征是乳酸杆菌、双歧杆菌等有益菌属的相对丰度显著减少，而大肠杆菌、艰难梭菌和金黄色葡萄球菌的相对丰度增加[19-20]。研究发现，重度AD患者肠道微生物多样性较低，产丙酸盐和丁酸的细菌数量较少，而丙酸盐和丁酸作为SCFAs的组成部分具有抗炎和免疫调节的作用，对于缓解AD等慢性炎症疾病至关重要[21-22]。
2 由免疫及神经内分泌系统介导的“皮-肠”轴交流诸多证据显示，肠道与皮肤之间存在双向联系并受饮食、情绪及外界诸多因素影响。有学者认为肠、脑和皮肤细胞来源于同一胚层[23]。研究发现，皮肤和肠道都是免疫和神经内分泌系统发挥作用的关键部位，两者在结构和神经分布上具有高度相似性[24]。因此，免疫及神经内分泌系统可能介导“皮-肠”轴的交流，从而改变肠道与皮肤之间的稳态。
2.1 免疫介导的“皮-肠”轴交流皮肤和肠道屏障的完整性均受到免疫系统的保护，而病原体与免疫细胞炎症受体的相互作用可增加皮肤和肠道屏障的渗透性，从而引起免疫反应。其中免疫调节主要由肠道菌群主导，免疫失衡主要在皮肤中体现。“皮-肠”轴的免疫交流可能涉及3种机制。
(1) Peyer斑
Peyer斑是肠道相关淋巴组织中的一部分，其可合成IL-10并诱导T辅助细胞分化，也被视为黏膜免疫反应的主要诱导部位[23]。研究证实，来自Peyer斑的免疫细胞因子可以通过循环运输到皮肤，从而调节皮肤免疫状态并改善防御功能[25]。
(2) 上皮细胞(epithelial cells，ECs)
ECs是肠道的内表面和皮肤的外表面所覆盖的细胞，在维持机体内外稳态方面发挥重要作用。这归功于ECs可充当机体第一道防线，发挥防止微生物侵入的作用。肠道ECs的完整性被破坏后，会导致肠黏膜通透性增加，形成“肠漏”的病理表现[26]。“肠漏”会造成饮食抗原、细菌毒素和相关免疫原性分子的渗透性增加, 这些免疫原性分子可以进入血液并积聚在皮肤中，干扰表皮屏障，导致皮肤免疫应答，从而引发皮肤炎症[27]。
(3) 血清25 (OH) D
血清25 (OH) D是一种重要的免疫调节剂，常以维生素D的生物非活性形式存在于人体内。巨噬细胞中的维生素D可调节内源性组织蛋白酶抑制素的合成、细胞因子的释放及人体对病原体的防御能力。研究发现，肠道微生物群的α、β多样性与皮肤暴露于紫外线B (ultraviolet B，UVB)后引起的血清25 (OH) D水平升高相关[28]。维生素D能影响先天和适应性免疫细胞，从而抑制促炎反应[29]。这也提示，UVB可能会影响肠道免疫细胞的活化及免疫介质的释放，进而重塑肠道微生物菌群，而其中具体机制有待进一步阐释。
2.2 神经内分泌介导的“皮-肠”轴交流皮肤和肠道两种组织对中枢神经系统的活动具有高度敏感性，而且肠道微生物菌群分泌的激素样化合物可能与皮肤受体相互作用，从而直接或间接影响皮肤。“皮-肠”轴的神经内分泌交流可能涉及2种机制。
(1) 神经肽
从神经内分泌系统上看，脑部认知发育、抑郁焦虑及应激反应等中枢神经系统的活动与肠道菌群相关。精神压力能加速肠道微生物的增长，破坏肠道免疫屏障，增加肠道通透性，促使神经系统释放更多的人血清P物质(human serum substance P，SP)[30]，而SP有诸多作用：增强朗格汉斯细胞(langerhans cells，LCs)的迁移、抗原表现和促敏化[31]；诱导肥大细胞脱粒，释放组胺[32]；刺激角质细胞产生IL-1α、IL-6和IL-8等促炎细胞因子；诱导外周血单核白细胞释放IFN-g、IL-4、TNF-α和IL-10等促炎细胞因子，从而诱导AD、银屑病和酒渣鼻等炎性皮肤病的发生[26]。
(2) 激素样化合物
激素样化合物是由肠道微生物群分泌的多种代谢产物的总称，如SCFAs、皮质醇、γ-氨基丁酸(γ-aminobutyric acid，GABA)、5-羟色胺(5-hydroxytryptamine，5-HT)、多巴胺和色氨酸等。这些激素样化合物可释放到血液中，作用于远处的皮肤产生效应反应[33]。例如，SCFAs (丁酸盐、乙酸盐和丙酸盐等)属于肠道细菌未消化多糖的发酵产物，它们可降低肠道屏障的通透性，释放到血液中并作用于免疫系统。Schwarz等研究证明，SCFA可能通过增加皮肤驻留Treg细胞的数量，从而抑制或终止皮肤炎症[34]。
3 “微生物-皮-肠”轴在AD中的潜在途径 3.1 皮肤屏障途径AD患者皮肤菌群失调与皮肤屏障功能破坏、天然保湿因子含量降低、表面pH值增加及表面脂质成分改变密切相关[35]。最新研究表明，金黄色葡萄球菌定殖与AD发病机制、疾病耀斑和疾病表型相关。金黄色葡萄球菌具有高度进化的多种细胞壁蛋白和分泌因子，可通过物理、化学和炎症机制，黏附在人类皮肤上并干扰皮肤屏障功能。
(1) 皮肤屏障受损
AD患者皮肤表面定殖的金黄色葡萄球菌可表达多种毒素因子和蛋白酶，进而引起浅表和侵袭性皮肤感染。如金黄色葡萄球菌分泌的穿孔α毒素(攻膜毒素)可穿透并溶解宿主细胞膜[36-38]；分泌的大量蛋白酶(丝氨酸蛋白酶、激肽释放酶KLK6、13和14)可溶解角质层，导致皮肤屏障功能受损[39-40]。
(2) 细菌黏附增加
金黄色葡萄球菌可产生结块因子A和B (clumping factor A，ClfA；clumping factor B，ClfB)、纤维素结合蛋白(fibronectin，Fn)和铁调节表面决定剂A (iron responsive surface determinant A，IsdA)等表面分子黏附在人类角质层上[40]。此外，AD患者皮肤脂质的缺乏及IL-4等细胞因子的释放，增加了Fn和纤维蛋白原的表达，这为金黄色葡萄球菌的黏附提供了有利环境[41]。
(3) 细菌清除缺陷
皮肤角质层细胞膜稳定性不足，会增加AD的经皮水分损失(trans epidermal water loss，TEWL)、pH值、血清IgE及嗜酸性粒细胞，最终导致皮肤细菌清除缺陷，加速病原微生物的定殖。研究表明，AD患者皮肤平均pH值的增加会引起角质层中鞘脂类(鞘氨醇)水平降低[41-42]。鞘氨醇作为细胞膜结构的重要组成部分，其水平降低会增加血管通透性及加剧皮肤炎症反应[43]。
3.2 免疫途径皮肤、肠道微生物参与人类免疫的方式相似，均能影响Toll样受体(toll like receptors，TLR)的表达，使机体产生免疫应答反应。皮肤微生物通过产生抗菌肽，增加补体系统活性与IL-1水平，影响TLR和Nod/CARD受体功能性变体的表达，在有效性保护和破坏性保护之间平衡免疫系统[44]。就AD患者皮肤上最常见的金黄色葡萄菌与马拉色菌而言，金黄色葡萄球菌在葡萄球菌肠毒素(staphylococcal enterotoxin，SE)的介导下可释放肠毒素A (staphylococcal enterotoxin A，SEA)、肠毒素B (staphylococcal enterotoxin B，SEB)和中毒性休克综合征毒素-1 (toxic shock syndrome toxin，TSST-1)等毒素因子。它们被称为“超抗原” (superantigens，SAg)[45]。SAg可激活大量的T细胞，触发肥大细胞脱颗粒，导致Th2细胞因子增加[46]；还可与朗格汉斯细胞和巨噬细胞上的HLA-DR结合，刺激产生IL-1、TNF-α和IL-12，从而导致AD病情加重和反复发作[47]。金黄色葡萄球菌还能促进角质形成和细胞凋亡，释放胸腺基质淋巴细胞生成素(thymic stromal lymphopoietin，TSLP)和苯酚溶性霉素(phenol soluble mycophenolate，PSM)[48]。TSLP的释放可激活皮肤树突状细胞，分泌IL-4和IL-13，影响Th2细胞的募集，从而介导瘙痒反应[49]。PSM具有直接促炎驱动作用，在表皮中可刺激IL-36α驱动的γδ T细胞介导的炎症；而在真皮中可刺激IL-1β驱动的TH17炎症反应[48]。马拉色菌可介导树突状细胞成熟，刺激角质形成细胞产生IL-4、IL-6、IL-8和TNF-α等多种炎症细胞因子；还可诱导IgE介导的肥大细胞脱颗粒，继而释放白三烯，使炎症状态持续存在[44]。
肠道微生物群可激活Toll样受体(TLR2、4和6)，并通过经典的核因子激活B细胞的κ-轻链增强(nuclear factor kappa-B，NF-κB)通路引起炎症反应[50]。在AD儿童患者的血浆样本中发现，IL-17A表达的降低与肠道中罗姆布茨菌和多尔氏菌属的减少及厌氧菌和普氏栖粪杆菌的增加有关[51-52]。例如，双歧杆菌可通过刺激Tregs中的IL-10/IL-10Ra信号，从而直接或间接增强Tregs的免疫抑制功能[50]；植物乳杆菌LM1004可降低Th2、Th17细胞转录因子水平及血清IgE水平，并增加Treg、Th1细胞和FLG转录因子水平，减少TSLP表达，同时调节肠道微生物菌群的丁酸盐，从而显著改善AD症状[53]。
3.3 代谢物途径微生物可分泌SCFA、皮质醇、GABA、5-HT、多巴胺和色氨酸等多种代谢产物。这些代谢产物可积聚在皮肤下，或改变肠黏膜通透性进入到血液中，从而下调角蛋白的表达，最后影响角质形成细胞分化、皮肤水合能力和表皮屏障功能。“皮-肠”轴中的微生物代谢产物与AD的发生机制有着密切联系，不同的代谢产物可成为AD分型或疾病复发的独立因素。
(1) 多不饱和脂肪酸(polyunsaturated fatty acids，PUFA)
Lee等发现，AD患者皮肤中定殖的马拉色菌可通过产生脂肪酶和磷脂酶等多种酶，从皮肤脂质中释放PUFA来引发皮肤炎症反应。而且在AD患者的T淋巴细胞膜中可检测到十八碳烯酸和花生四烯酸(arachidonic acid，ARA)异构体[54]。AD的发生与ARA的释放密切相关，ARA会在磷脂酶A2 (phospholipase A2，PLA2)的作用下产生具有促炎作用的类二十烷酸(前列腺素类)与白三烯类，从而导致角质层的炎症和损伤[55]。动物实验发现，过度表达PLA2的小鼠会表现出在组织学上与AD相似的皮肤表型：如角化不全、角化过度、棘层肥厚、糜烂、溃疡和皮脂腺增生[56]。
(2) 色氨酸
色氨酸代谢物的配体能通过芳香烃受体(aryl hydrocarbon receptor，AHR)信号传导，抑制皮肤、肠道中炎性细胞因子的产生，从而减少炎症反应的发生[57-58]。吲哚-3-丙烯酸、吲哚乙酸、吲哚-3-碳醛和吲哚乙醛等吲哚及其衍生物属于色氨酸代谢产物[59]。其中，吲哚-3-碳醛与犬尿喹啉酸分别属于肠道双歧杆菌菌株CCFM1029、LKM512的色氨酸代谢物，可激活AHR介导的免疫信号通路，以减轻AD瘙痒症状并提高患者的生活质量[60-61]。目前，AHR依赖性抗炎活性剂(Tapinarof乳膏)在动物模型中被证明能减少炎症细胞因子的产生并改善皮肤炎症症状，并在随机对照试验中证实了其治疗轻至重度AD的有效性及安全性[62-63]。这也意味着微生物代谢物的局部给药可能会缓解皮肤炎症性疾病，但仍需要更多研究去证实这一关联。
3.4 神经内分泌途径近几年，研究发现肠道微生物介导了情绪和神经状态对皮肤的影响，这也证实了微生物是“皮-肠”轴通讯网络中的一个重要因素[64-65]。微生物可通过神经内分泌途径直接或间接调节“皮-肠”轴。这种影响主要依赖于微生物菌群和中枢神经系统的相互作用及微生物信号分子对宿主的信号传导。中枢神经系统可直接或间接影响肠道微生物群[66]。其中，交感神经和副交感/迷走神经(autonomic nervous system，ANS)可介导肠黏液层的分泌，从而影响肠道微生物群[67]；调节巨噬细胞和肥大细胞等肠道免疫细胞，对含有抗菌肽的细菌产生反应[68]。肠道微生物也可通过信号分子影响迷走神经的功能。其中信号分子主要包括微生物产生的神经活性代谢物、神经递质及微生物在免疫反应中释放的细胞因子等。研究发现，迷走神经切断术可消除由长双歧杆菌引起的焦虑样行为[69]；乳酸杆菌可明显缓解压力性脱发与神经性皮炎[70]。
(1) 神经活性代谢物
SCFAs、皮质醇和色氨酸是常见的肠道微生物产生的代谢产物，它们可通过神经内分泌途径和肠道内局部细胞上的受体向宿主发出信号。AD患者通常存在下丘脑-垂体-肾上腺轴(hypothalamic pituitary adrenal axis，HPA)功能障碍[71]。HPA轴的急性兴奋性降低，会导致皮质醇水平升高。这种应激反应的不平衡会造成Th1/Th2失衡，产生大量促敏细胞因子，影响AD患者的炎症免疫表型[72]。色氨酸可影响中枢血清素浓度及下游神经活性代谢物，直接介导AD非依赖性瘙痒[73]。SCFAs可刺激交感神经系统与神经细胞相互作用，上调神经因子的表达，从而影响AD皮损表型[74-75]。
(2) 神经递质
Valles-Colomer等认为肠道微生物产生的GABA、5-HT等神经递质会影响肠道与大脑的交流[76]。神经递质可能是“皮-肠”轴交流的关键调节器。其中外周5-HT已被确定为强效的瘙痒诱导剂，其可参与免疫和中枢神经系统之间的交流。这可能与特异性5-HT受体(HTR7)的表达有关，HTR7与刺激受体TRPA1的耦合可触发神经元兴奋，并介导瘙痒反应[77]。GABA是主要由乳酸细菌和双歧杆菌产生的抑制性神经递质，其可抑制iNOS、IL-1和TNFα的产生水平，以发挥抗炎活性作用[78]。最新研究表明，皮肤中GABA配体和GABAA受体的表达增加，可能会介导炎症性皮肤疾病中的瘙痒反应[79]。这也提示我们神经递质可能作为一种新的免疫调节剂，用于AD的治疗。
(3) 免疫反应中释放的细胞因子
微生物免疫反应中释放的细胞因子，可通过迷走神经或脊髓神经通路，产生瘙痒信号从而介导AD瘙痒反应[80]。例如，肥大细胞通过色氨酸酶、组胺和神经肽等介质与HPA轴之间进行沟通[81]；同时激活Mrgprs相关GPCR受体，调节TRPA1的表达，介导与组胺无关的瘙痒反应[82-83]。IL-31可直接作用于IL-31RA+/瞬时受体电位(TRPV1)/TRPA1+DRG神经元的亚群[84-85]；激活JAK-STAT通路从而介导瘙痒反应[86]。在一项Ⅱ期临床试验中，抗IL-31RA单克隆抗体——奈莫利珠单抗能显著改善中重度AD患者的瘙痒症状[87]。这也提示我们，针对微生物释放的免疫细胞因子和神经递质进行干预，将会是治疗皮肤疾病的新靶点。
综上所述，“微生物-皮-肠”轴主要通过皮肤屏障途径、免疫途径、代谢途径和神经内分泌途径等特定途径影响和加剧AD (图 1)。主要表现为：微生物通过物理、化学和炎症机制，黏附在人类皮肤上并干扰皮肤屏障功能；释放SAg等毒素因子以及分泌PUAF和多巴胺等代谢产物，引起T细胞的增殖和分化，介导Th1/Th2/Th17的免疫应答，从而参与AD发病机制和影响AD疾病表型；释放GABA、5-HT等神经递质或SCFAs、皮质醇和色氨酸等神经活性代谢物，产生瘙痒信号从而介导AD瘙痒反应。
|
| 图 1 “微生物-皮-肠”轴的交流[35-38, 44-45, 64-66] Figure 1 Communication in the"microbiota-skin-gut" axis[35-38, 44-45, 64-66]. IL: Interleukin; 5-HT: 5-hydroxytryptamine; TNF-α: Tumor necrosis factor-α; IFN-γ: Interferon-γ; SCFAs: Short chain fatty acids; SEA/B: Staphylococcal enterotoxin A/B; TSST: Toxic shock syndrome toxin; GABA: Gamma-amino butyric acid; BAS: Basophils; Trp: Tryptophan; SCFAs: Short chain fatty acids. |
|
|
AD的基本维持治疗包括局部使用保湿剂、皮质类固醇、钙调磷酸酶抑制剂和磷酸二酯酶抑制剂等抗炎剂。光疗法和全身免疫抑制剂(奥马珠单抗IgE抑制剂、非扎奴单抗IL-22抑制剂、司库奇尤单抗IL-17A抑制剂和奈莫利珠单抗IL-31抑制剂)可治疗顽固性及严重AD[88-89]。本文结合“微生物-皮-肠”轴可能的交流途径，探究从微生物角度干预AD “皮-肠”轴的潜在机制，为AD提供潜在的微生物靶向治疗思路。
4.1 摄入益生菌通过摄入益生菌和益生元来修复皮肤屏障的疗法逐渐被认可。益生菌有多种治疗作用：(1) 调节肠道菌群，刺激黏液分泌，维持上皮紧密连接功能，从而修复肠道黏膜屏障完整性；(2) 分泌多种代谢产物及神经递质(SCFAs、酚类、5-HT和色氨酸等)，改变肠黏膜通透性，继而减少有害物质进入循环系统影响皮肤屏障功能；(3) 诱导产生抗炎细胞因子IL-10，并刺激下丘脑激素分泌，从而调节皮肤免疫状态[90-92]。最新研究发现，麸质饮食与皮肤病关系密切。麸质肽是小麦、黑麦和大麦中的一种蛋白质，它会引起腹腔疾病(celiac disease，CD)患者的免疫反应，并诱发草状皮炎(dermatitis herpetiformis，DH)等皮肤表现[93]。Ciacci等发现CD患者中的AD发病率是其他过敏性疾病的3倍[94]。Lionetti等发现麸质敏感性与肠道菌群失调有关，并证明短双歧杆菌、长双歧杆菌、婴儿双歧杆菌、植物乳杆菌、嗜酸乳杆菌和干酪乳杆菌等益生菌能够水解麸质多肽；同时降低TNF-α水平并增加IL-10水平[95]。因此，益生菌的摄入为治疗麸质敏感性相关AD提供了一种新途径，但其中具体机制有待进一步探究。
4.2 添加抗菌肽抗菌肽(antimicrobial peptides，AMPs)是具有抗菌活性的短肽，它可调节宿主天然免疫系统以促进病原体清除。研究发现，与非AD炎症性皮肤病患者相比，AD患者中的AMPs (LL-37、β-防御素-2、β-防御素-3)产量减少，这可能与金黄色葡萄球菌的定殖有关[96]。Omganan (OMN)是一种具有广泛抗菌活性和抗生物膜活性的抗菌肽。在中重度AD的成年患者中使用OMN可有效恢复皮肤生态平衡，减少金黄色葡萄球菌定殖，增加微生物多样性指数[97]。研究表明，OMN可驱动TLR诱导的IRF、NF-κB炎症途径，并促进T细胞分泌II-IFN，从而发挥抗炎和抗病毒作用[98-99]。因此，AMPs治疗可通过调节先天免疫系统来减少皮肤炎症和修复表皮屏障功能。这也进一步证实了AMPs在促炎和抗炎途径中，依赖的是免疫调节特性而非抗菌特性。减少病原微生物定殖的途径不仅依赖于传统抗生素的使用，还可通过减少促炎因子的产生来达到“抗菌效果”。
4.3 菌群移植菌群移植是一种将功能性细菌移植到皮肤和胃肠道黏膜，以重构微生物平衡和恢复宿主功能的治疗方法。目前，常用于治疗AD的菌群移植方法主要包括凝固酶阴性葡萄球菌(coagulase negative staphylococci，CoNS)移植和粪便微生物群移植(fecal microbiota transplantation，FMT)。它们主要通过重塑皮肤和肠道微生物群，以恢复免疫平衡来治疗AD。
(1) 凝固酶阴性葡萄球菌(CoNS)移植
CoNS是葡萄球菌属中常见的皮肤共生菌，包括表皮葡萄球菌、人葡萄球菌、溶血葡萄球菌和头葡萄球菌等。CoNS可通过启动皮肤免疫系统，产生抗菌肽或拮抗竞争入侵病原体；提高补体系统活性以限制病原体定殖，达到“抗定殖”的效果[100]。研究表明，CoNS群落的抗菌能力与金黄色葡萄球菌的定殖密切相关。例如，表皮葡萄球菌表达的酚溶性调节蛋白能够杀灭金黄色葡萄球菌[101-102]；移植健康人的黏液玫瑰单胞菌可通过溶菌磷脂酰胆碱抑制金黄色葡萄球菌，并激活先天免疫系统从而有效缓解AD[103]。因此，我们认为CoNS移植可产生类似抗生素的化合物，从而拮抗竞争病原体以有效缓解AD。相较于传统抗生素疗法，CoNS移植更有助于恢复皮肤微生物的稳态，因为抗生素的非特异性抗菌作用很可能杀灭CoNS等保护性菌株，反而增加金黄色葡萄球菌定殖的可能性。
(2) 粪便微生物群移植(FMT)
FMT是将健康人体粪便中的功能细菌移植到患者的胃肠道中，以重构肠道微生物平衡并治疗与肠道微生物相关疾病的新方法。研究发现，FMT不仅可应用于胃肠道疾病，还可用于帕金森、阿尔茨海默痴呆症等神经系统疾病[104]。最新临床研究对AD成人患者进行FMT治疗后，患者scoring atopic dermatitis (SCORAD)分数显著下降[105]。为了确定FMT治疗AD的机制，Kim等在AD小鼠模型中发现FMT与肠道微生物群丰度、SCFAs水平和Th1/Th2免疫平衡相关[106]。上述研究提示，FMT可能是治疗AD的有效措施，但仍需要进一步阐明其具体作用机制。
5 总结综上所述，微生物群可作为介导“皮-肠”轴的信号分子，从表皮屏障、免疫、代谢和神经内分泌方面影响“皮-肠”轴的整体稳态。此外，与AD常规治疗相比，本文重点关注了益生菌、抗菌肽、CoNS移植和FMT的治疗优势及潜在机制。益生菌与FMT不仅可以调节肠道微生物，还能分泌多种代谢产物及神经递质，诱导产生抗炎因子，从而调节皮肤免疫状态。然而，补充肠道益生菌是否对AD皮肤菌群有所影响，仍值得进一步研究。从血清25 (OH) D及UVB治疗AD的有效性中可以推断，皮肤微生物群的改变可能会影响肠道免疫细胞的活化以及相关免疫因子的释放，进而重塑肠道微生物群，这也为探索“皮-肠”轴可能交流的途径提供了新的研究思路。截至目前，“微生物-皮-肠”轴治疗AD的潜在机制尚不清楚，因此，我们仍需要整合元转录组学、宏基因组学和代谢组学等多组学进行深入研究，为靶向微生物群治疗过敏性皮肤炎症提供一个新的视角。
| [1] |
Nutten S. Atopic dermatitis: global epidemiology and risk factors[J]. Annals of Nutrition & Metabolism, 2015, 66(Suppl 1): 8-16. |
| [2] |
Auriemma M, Vianale G, Amerio P, Reale M. Cytokines and T cells in atopic dermatitis[J]. European Cytokine Network, 2013, 24(1): 37-44. DOI:10.1684/ecn.2013.0333 |
| [3] |
Chinese guideline for diagnosis and treatment of atopic dermatitis (2020)[J]. Chinese Journal of Dermatology, 2020, 53(2): 81-88 (in Chinese) 中华医学会皮肤性病学分会免疫学组、特应性皮炎协作研究中心. 中国特应性皮炎诊疗指南(2020版)[J]. 中华皮肤科杂志, 2020, 53(2): 81-88 |
| [4] |
Guo J, Xiao M, Peng L, Wang XR, Zhou C. Experience of AI Ru-di in treatment of pediatric atopic dermatitis from the spleen and stomach[J]. China Journal of Traditional Chinese Medicine and Pharmacy, 2017, 32(8): 3534-3536. (in Chinese) 郭静, 肖敏, 彭丽, 王栩芮, 周策. 艾儒棣从脾胃论治小儿特应性皮炎经验[J]. 中华中医药杂志, 2017, 32(8): 3534-3536. |
| [5] |
Belkaid Y, Segre JA. Dialogue between skin microbiota and immunity[J]. Science, 2014, 346(6212): 954-959. DOI:10.1126/science.1260144 |
| [6] |
Grice EA, Kong HH, Conlan S, Deming CB, Davis J, Young AC, Program NISCCS, Bouffard GG, Blakesley RW, Murray PR, et al. Topographical and temporal diversity of the human skin microbiome[J]. Science, 2009, 324(5931): 1190-1192. DOI:10.1126/science.1171700 |
| [7] |
Fitz-Gibbon S, Tomida S, Chiu BH, Nguyen L, Du C, Liu M, Elashoff D, Erfe MC, Loncaric A, Kim J, et al. Propionibacterium acnes strain populations in the human skin microbiome associated with acne[J]. The Journal of Investigative Dermatology, 2013, 133(9): 2152-2160. DOI:10.1038/jid.2013.21 |
| [8] |
Findley K, Oh J, Yang J, Conlan S, Deming C, Meyer JA, Schoenfeld D, Nomicos E, Park M, Kong HH, et al. Topographic diversity of fungal and bacterial communities in human skin[J]. Nature, 2013, 498(7454): 367-370. DOI:10.1038/nature12171 |
| [9] |
Grice EA, Segre JA. The skin microbiome[J]. Nature Reviews Microbiology, 2011, 9(4): 244-253. DOI:10.1038/nrmicro2537 |
| [10] |
He JQ, Chan-Yeung M, Becker AB, Dimich-Ward H, Ferguson AC, Manfreda J, Watson WTA, Sandford AJ. Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children[J]. Genes & Immunity, 2003, 4(5): 385-389. |
| [11] |
Ahmad-Nejad P, Mrabet-Dahbi S, Breuer K, Klotz M, Werfel T, Herz U, Heeg K, Neumaier M, Renz H. The toll-like receptor 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe phenotype[J]. The Journal of Allergy and Clinical Immunology, 2004, 113(3): 565-567. DOI:10.1016/j.jaci.2003.12.583 |
| [12] |
Hugon P, Dufour JC, Colson P, Fournier PE, Sallah K, Raoult D. A comprehensive repertoire of prokaryotic species identified in human beings[J]. Lancet Infectious Diseases, 2015, 15(10): 1211-1219. DOI:10.1016/S1473-3099(15)00293-5 |
| [13] |
Li JH, Jia HJ, Cai XH, Zhong HZ, Feng Q, Sunagawa S, Arumugam M, Kultima JR, Prifti E, Nielsen T, et al. An integrated catalog of reference genes in the human gut microbiome[J]. Nature Biotechnology, 2014, 32(8): 834-841. DOI:10.1038/nbt.2942 |
| [14] |
Dinan TG, Cryan JF. The microbiome-gut-brain axis in health and disease[J]. Gastroenterology Clinics of North America, 2017, 46(1): 77-89. DOI:10.1016/j.gtc.2016.09.007 |
| [15] |
Gonzalez ME, Schaffer JV, Orlow SJ, Gao Z, Li HL, Alekseyenko AV, Blaser MJ. Cutaneous microbiome effects of fluticasone propionate cream and adjunctive bleach baths in childhood atopic dermatitis[J]. Journal of the American Academy of Dermatology, 2016, 75(3): 481-493.e8. DOI:10.1016/j.jaad.2016.04.066 |
| [16] |
Seite S, Flores GE, Henley JB, Martin R, Zelenkova H, Aguilar L, Fierer N. Microbiome of affected and unaffected skin of patients with atopic dermatitis before and after emollient treatment[J]. Journal of Drugs in Dermatology, 2014, 13(11): 1365-1372. |
| [17] |
Ahluwalia B, Magnusson MK, Öhman L. Mucosal immune system of the gastrointestinal tract: maintaining balance between the good and the bad[J]. Scandinavian Journal of Gastroenterology, 2017, 52(11): 1185-1193. DOI:10.1080/00365521.2017.1349173 |
| [18] |
Iwasaki A, Kelsall BL. Freshly isolated Peyer՚s patch, but not spleen, dendritic cells produce interleukin 10 and induce the differentiation of T helper type 2 cells[J]. The Journal of Experimental Medicine, 1999, 190(2): 229-239. DOI:10.1084/jem.190.2.229 |
| [19] |
Abrahamsson TR, Jakobsson HE, Andersson AF, Björkstén B, Engstrand L, Jenmalm MC. Low gut microbiota diversity in early infancy precedes asthma at school age[J]. Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology, 2014, 44(6): 842-850. DOI:10.1111/cea.12253 |
| [20] |
Song H, Yoo Y, Hwang J, Na YC, Kim HS. Faecalibacterium prausnitzii subspecies-level dysbiosis in the human gut microbiome underlying atopic dermatitis[J]. The Journal of Allergy and Clinical Immunology, 2016, 137(3): 852-860. DOI:10.1016/j.jaci.2015.08.021 |
| [21] |
Miyazaki K, Masuoka N, Kano M, Iizuka R. Bifidobacterium fermented milk and galacto-oligosaccharides lead to improved skin health by decreasing phenols production by gut microbiota[J]. Beneficial Microbes, 2014, 5(2): 121-128. DOI:10.3920/BM2012.0066 |
| [22] |
Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders[J]. Cell, 2013, 155(7): 1451-1463. DOI:10.1016/j.cell.2013.11.024 |
| [23] |
Wang SX, Wu WC. Effects of psychological stress on small intestinal motility and bacteria and mucosa in mice[J]. World Journal of Gastroenterology, 2005, 11(13): 2016-2021. DOI:10.3748/wjg.v11.i13.2016 |
| [24] |
Burbach GJ, Kim KH, Zivony AS, Kim A, Aranda J, Wright S, Naik SM, Caughman SW, Ansel JC, Armstrong CA. The neurosensory tachykinins substance P and neurokinin A directly induce keratinocyte nerve growth factor[J]. The Journal of Investigative Dermatology, 2001, 117(5): 1075-1082. DOI:10.1046/j.0022-202x.2001.01498.x |
| [25] |
Nakano Y. Stress-induced modulation of skin immune function: two types of antigen-presenting cells in the epidermis are differentially regulated by chronic stress[J]. The British Journal of Dermatology, 2004, 151(1): 50-64. DOI:10.1111/j.1365-2133.2004.05980.x |
| [26] |
Peters EMJ, Ericson ME, Hosoi J, Seiffert K, Hordinsky MK, Ansel JC, Paus R, Scholzen TE. Neuropeptide control mechanisms in cutaneous biology: physiological and clinical significance[J]. The Journal of Investigative Dermatology, 2006, 126(9): 1937-1947. DOI:10.1038/sj.jid.5700429 |
| [27] |
Clarke G, Stilling RM, Kennedy PJ, Stanton C, Cryan JF, Dinan TG. Minireview: gut microbiota-the neglected endocrine organ[J]. Molecular Endocrinology: Baltimore, Md, 2014, 28(8): 1221-1238. DOI:10.1210/me.2014-1108 |
| [28] |
Bosman ES, Albert AY, Lui H, Dutz JP, Vallance BA. Skin exposure to narrow band ultraviolet (UVB) light modulates the human intestinal microbiome[J]. Frontiers in Microbiology, 2019, 10: 2410. DOI:10.3389/fmicb.2019.02410 |
| [29] |
Clark A, Mach N. Role of vitamin D in the hygiene hypothesis: the interplay between vitamin D, vitamin D receptors, gut microbiota, and immune response[J]. Frontiers in Immunology, 2016, 7: 627. |
| [30] |
Luthold RV, Fernandes GR, Franco-De-Moraes AC, Folchetti LGD, Ferreira SRG. Gut microbiota interactions with the immunomodulatory role of vitamin D in normal individuals[J]. Metabolism: Clinical and Experimental, 2017, 69: 76-86. DOI:10.1016/j.metabol.2017.01.007 |
| [31] |
Joachim RA, Handjiski B, Blois SM, Hagen E, Paus R, Arck PC. Stress-induced neurogenic inflammation in murine skin skews dendritic cells towards maturation and migration: key role of intercellular adhesion molecule-1/leukocyte function-associated antigen interactions[J]. The American Journal of Pathology, 2008, 173(5): 1379-1388. DOI:10.2353/ajpath.2008.080105 |
| [32] |
Rosa AC, Fantozzi R. The role of histamine in neurogenic inflammation[J]. British Journal of Pharmacology, 2013, 170(1): 38-45. DOI:10.1111/bph.12266 |
| [33] |
Lyte M. Microbial endocrinology and the microbiota-gut-brain axis[J]. Advances in experimental medicine and biology, 2014, 817: 3-24. |
| [34] |
Schwarz A, Bruhs A, Schwarz T. The short-chain fatty acid sodium butyrate functions as a regulator of the skin immune system[J]. The Journal of Investigative Dermatology, 2017, 137(4): 855-864. DOI:10.1016/j.jid.2016.11.014 |
| [35] |
Nakamizo S, Egawa G, Honda T, Nakajima S, Belkaid Y, Kabashima K. Commensal bacteria and cutaneous immunity[J]. Seminars in Immunopathology, 2015, 37(1): 73-80. DOI:10.1007/s00281-014-0452-6 |
| [36] |
Song L, Hobaugh MR, Shustak C, Cheley S, Bayley H, Gouaux JE. Structure of staphylococcal alpha-hemolysin, a heptameric transmembrane pore[J]. Science, 1996, 274(5294): 1859-1866. DOI:10.1126/science.274.5294.1859 |
| [37] |
Nakatsuji T, Chen TH, Two AM, Chun KA, Narala S, Geha RS, Hata TR, Gallo RL. Staphylococcus aureus exploits epidermal barrier defects in atopic dermatitis to trigger cytokine expression[J]. The Journal of Investigative Dermatology, 2016, 136(11): 2192-2200. DOI:10.1016/j.jid.2016.05.127 |
| [38] |
Williams MR, Nakatsuji T, Sanford JA, Vrbanac AF, Gallo RL. Staphylococcus aureus induces increased serine protease activity in keratinocytes[J]. The Journal of Investigative Dermatology, 2017, 137(2): 377-384. DOI:10.1016/j.jid.2016.10.008 |
| [39] |
Brauweiler AM, Goleva E, Leung DYM. Staphylococcus aureus lipoteichoic acid damages the skin barrier through an IL-1-mediated pathway[J]. The Journal of Investigative Dermatology, 2019, 139(8): 1753-1761.e4. DOI:10.1016/j.jid.2019.02.006 |
| [40] |
Cho SH, Strickland I, Tomkinson A, Fehringer AP, Gelfand EW, Leung DY. Preferential binding of Staphylococcus aureus to skin sites of Th2-mediated inflammation in a murine model[J]. The Journal of Investigative Dermatology, 2001, 116(5): 658-663. DOI:10.1046/j.0022-202x.2001.01331.x |
| [41] |
Rippke F, Schreiner V, Doering T, Maibach HI. Stratum corneum pH in atopic dermatitis: impact on skin barrier function and colonization with Staphylococcus aureus[J]. American Journal of Clinical Dermatology, 2004, 5(4): 217-223. DOI:10.2165/00128071-200405040-00002 |
| [42] |
Arikawa J, Ishibashi M, Kawashima M, Takagi Y, Ichikawa Y, Imokawa G. Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patients with atopic dermatitis to colonization by Staphylococcus aureus[J]. The Journal of Investigative Dermatology, 2002, 119(2): 433-439. DOI:10.1046/j.1523-1747.2002.01846.x |
| [43] |
Christoffersen C, Obinata H, Kumaraswamy SB, Galvani S, Ahnström J, Sevvana M, Egerer-Sieber C, Muller YA, Hla T, Nielsen LB, et al. Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M[J]. PNAS, 2011, 108(23): 9613-9618. DOI:10.1073/pnas.1103187108 |
| [44] |
Meilleur CE, Wardell CM, Mele TS, Dikeakos JD, Bennink JR, Mu HH, McCormick JK, Haeryfar SMM. Bacterial superantigens expand and activate, rather than delete or incapacitate, preexisting antigen-specific memory CD8+ T cells[J]. The Journal of Infectious Diseases, 2019, 219(8): 1307-1317. DOI:10.1093/infdis/jiy647 |
| [45] |
Edslev SM, Agner T, Andersen PS. Skin microbiome in atopic dermatitis[J]. Acta Dermato-Venereologica, 2020, 100(12): adv00164. DOI:10.2340/00015555-3514 |
| [46] |
Wedi B, Wieczorek D, Stünkel T, Breuer K, Kapp A. Staphylococcal exotoxins exert proinflammatory effects through inhibition of eosinophil apoptosis, increased surface antigen expression (CD11b, CD45, CD54, and CD69), and enhanced cytokine-activated oxidative burst, thereby triggering allergic inflammatory reactions[J]. The Journal of Allergy and Clinical Immunology, 2002, 109(3): 477-484. DOI:10.1067/mai.2002.121702 |
| [47] |
Takai T. TSLP expression: cellular sources, triggers, and regulatory mechanisms[J]. Allergology International: Official Journal of the Japanese Society of Allergology, 2012, 61(1): 3-17. DOI:10.2332/allergolint.11-RAI-0395 |
| [48] |
Moran TP, Vickery BP. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch[J]. Pediatrics, 2014, 134(Suppl 3): S160-S161. |
| [49] |
Williams MR, Nakatsuji T, Gallo RL. Staphylococcus aureus: master manipulator of the skin[J]. Cell Host & Microbe, 2017, 22(5): 579-581. |
| [50] |
Sun S, Luo LJ, Liang WH, Yin Q, Guo J, Rush AM, Lv ZB, Liang QM, Fischbach MA, Sonnenburg JL, et al. Bifidobacterium alters the gut microbiota and modulates the functional metabolism of T regulatory cells in the context of immune checkpoint blockade[J]. PNAS, 2020, 117(44): 27509-27515. DOI:10.1073/pnas.1921223117 |
| [51] |
Roslund MI, Puhakka R, Grönroos M, Nurminen N, Oikarinen S, Gazali AM, Cinek O, Kramná L, Siter N, Vari HK, et al. Biodiversity intervention enhances immune regulation and health-associated commensal microbiota among daycare children[J]. Science Advances, 2020, 6(42): eaba2578. DOI:10.1126/sciadv.aba2578 |
| [52] |
Fang ZF, Li LZ, Zhang H, Zhao JX, Lu WW, Chen W. Gut microbiota, probiotics, and their interactions in prevention and treatment of atopic dermatitis: a review[J]. Frontiers in Immunology, 2021, 12: 720393. DOI:10.3389/fimmu.2021.720393 |
| [53] |
Selander C, Engblom C, Nilsson G, Scheynius A, Andersson CL. TLR2/MyD88-dependent and-independent activation of mast cell IgE responses by the skin commensal yeast Malassezia sympodialis[J]. Journal of Immunology: Baltimore, Md: 1950, 2009, 182(7): 4208-4216. |
| [54] |
Lee YW, Lee SY, Lee Y, Jung WH. Evaluation of expression of lipases and phospholipases of Malassezia restricta in patients with seborrheic dermatitis[J]. Annals of Dermatology, 2013, 25(3): 310-314. DOI:10.5021/ad.2013.25.3.310 |
| [55] |
Sato H, Taketomi Y, Isogai Y, Masuda S, Kobayashi T, Yamamoto K, Murakami M. Group III secreted phospholipase A2 transgenic mice spontaneously develop inflammation[J]. The Biochemical Journal, 2009, 421(1): 17-27. DOI:10.1042/BJ20082429 |
| [56] |
Cummings JH, MacFarlane GT. Role of intestinal bacteria in nutrient metabolism[J]. JPEN Journal of Parenteral and Enteral Nutrition, 1997, 21(6): 357-365. DOI:10.1177/0148607197021006357 |
| [57] |
Rea K, Dinan TG, Cryan JF. The microbiome: a key regulator of stress and neuroinflammation[J]. Neurobiology of Stress, 2016, 4: 23-33. DOI:10.1016/j.ynstr.2016.03.001 |
| [58] |
Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease[J]. Cell Host & Microbe, 2018, 23(6): 716-724. |
| [59] |
Di Meglio P, Duarte JH, Ahlfors H, Owens NDL, Li Y, Villanova F, Tosi I, Hirota K, Nestle FO, Mrowietz U, et al. Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions[J]. Immunity, 2014, 40(6): 989-1001. DOI:10.1016/j.immuni.2014.04.019 |
| [60] |
Christensen GJM, Brüggemann H. Bacterial skin commensals and their role as host guardians[J]. Beneficial Microbes, 2014, 5(2): 201-215. DOI:10.3920/BM2012.0062 |
| [61] |
Schwarz A, Bruhs A, Schwarz T. The short-chain fatty acid sodium butyrate functions as a regulator of the skin immune system[J]. The Journal of Investigative Dermatology, 2017, 137(4): 855-864. DOI:10.1016/j.jid.2016.11.014 |
| [62] |
Smith SH, Jayawickreme C, Rickard DJ, Nicodeme E, Bui T, Simmons C, Coquery CM, Neil J, Pryor WM, Mayhew D, et al. Tapinarof is a natural AhR agonist that resolves skin inflammation in mice and humans[J]. The Journal of Investigative Dermatology, 2017, 137(10): 2110-2119. DOI:10.1016/j.jid.2017.05.004 |
| [63] |
Bissonnette R, Poulin Y, Zhou Y, Tan J, Hong H. C, Webster J, Ip W, Tang L, Lyle M. Efficacy and safety of topical WBI-1001 in patients with mild to severe atopic dermatitis: results from a 12-week, multicentre, randomized, placebo-controlled double-blind trial[J]. The British Journal of Dermatology, 2012, 166(4): 853-860. DOI:10.1111/j.1365-2133.2011.10775.x |
| [64] |
Macfarlane S, Dillon J. F. Microbial biofilms in the human gastrointestinal tract[J]. Journal of Applied Microbiology, 2007, 102(5): 1187-1196. DOI:10.1111/j.1365-2672.2007.03287.x |
| [65] |
Alonso C, Guilarte M, Vicario M, Ramos L, Ramadan Z, Antolín M, Martínez C, Rezzi S, Saperas E, Kochhar S, et al. Maladaptive intestinal epithelial responses to life stress may predispose healthy women to gut mucosal inflammation[J]. Gastroenterology, 2008, 135(1): 163-172. DOI:10.1053/j.gastro.2008.03.036 |
| [66] |
Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X, Deng Y, Blennerhassett PA, Fahnestock M, Moine D, et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut- brain communication[J]. Neurogastroenterol Motil, 2011, 23(12): 1132-1139. DOI:10.1111/j.1365-2982.2011.01796.x |
| [67] |
Arck P, Handjiski B, Hagen E, Pincus M, Bruenahl C, Bienenstock J, Paus R. Is there a "gut-brain-skin axis"?[J]. Experimental Dermatology, 2010, 19(5): 401-405. DOI:10.1111/j.1600-0625.2009.01060.x |
| [68] |
Lonne-Rahm SB, Rickberg H, El-Nour H, Mårin P, Azmitia EC, Nordlind K. Neuroimmune mechanisms in patients with atopic dermatitis during chronic stress[J]. J Eur Acad Dermatol Venereol, 2008, 22(1): 11-18. |
| [69] |
Hendrix S. Neuroimmune communication in skin: far from peripheral[J]. The Journal of Investigative Dermatology, 2008, 128(2): 260-261. DOI:10.1038/sj.jid.5701171 |
| [70] |
Desbonnet L, Garrett L, Clarke G, Bienenstock J, Dinan TG. The probiotic bifidobacteria infantis: an assessment of potential antidepressant properties in the rat[J]. Journal of Psychiatric Research, 2008, 43(2): 164-174. DOI:10.1016/j.jpsychires.2008.03.009 |
| [71] |
Varela RB, Valvassori SS, Lopes-Borges J, Mariot E, Dal-Pont GC, Amboni RT, Bianchini G, Quevedo J. Sodium butyrate and mood stabilizers block ouabain-induced hyperlocomotion and increase BDNF, NGF and GDNF levels in brain of Wistar rats[J]. Journal of Psychiatric Research, 2015, 61: 114-121. DOI:10.1016/j.jpsychires.2014.11.003 |
| [72] |
Lee HJ, Son Y, Lee M, Moon C, Kim SH, Shin IS, Yang M, Bae S, Kim JS. Sodium butyrate prevents radiation-induced cognitive impairment by restoring pCREB/BDNF expression[J]. Neural Regeneration Research, 2019, 14(9): 1530-1535. DOI:10.4103/1673-5374.255974 |
| [73] |
Valles-Colomer M, Falony G, Darzi Y, Tigchelaar EF, Wang J, Tito RY, Schiweck C, Kurilshikov A, Joossens M, Wijmenga C, et al. The neuroactive potential of the human gut microbiota in quality of life and depression[J]. Nature Microbiology, 2019, 4(4): 623-632. DOI:10.1038/s41564-018-0337-x |
| [74] |
Rausl A, Nordlind K, Wahlgren CF. Pruritic and vascular responses induced by serotonin in patients with atopic dermatitis and in healthy controls[J]. Acta Dermato-Venereologica, 2013, 93(3): 277-280. DOI:10.2340/00015555-1473 |
| [75] |
Lee HJ, Son Y, Lee M, Moon C, Kim SH, Shin IS, Yang M, Bae S, Kim JS. Sodium butyrate prevents radiation-induced cognitive impairment by restoring pCREB/BDNF expression[J]. Neural Regeneration Research, 2019, 14(9): 1530-1535. DOI:10.4103/1673-5374.255974 |
| [76] |
Valles-Colomer M, Falony G, Darzi Y, Tigchelaar EF, Wang J, Tito RY, Schiweck C, Kurilshikov A, Joossens M, Wijmenga C, et al. The neuroactive potential of the human gut microbiota in quality of life and depression[J]. Nature Microbiology, 2019, 4(4): 623-632. DOI:10.1038/s41564-018-0337-x |
| [77] |
Morita T, McClain SP, Batia LM, Pellegrino M, Wilson SR, Kienzler MA, Lyman K, Olsen AS, Wong JF, Stucky CL, et al. HTR7 mediates serotonergic acute and chronic itch[J]. Neuron, 2015, 87(1): 124-138. DOI:10.1016/j.neuron.2015.05.044 |
| [78] |
Han D, Kim HY, Lee HJ, Shim I, Hahm DH. Wound healing activity of gamma-aminobutyric acid (GABA) in rats[J]. Journal of Microbiology and Biotechnology, 2007, 17(10): 1661-1669. |
| [79] |
Nigam R, El-Nour H, Amatya B, Nordlind K. GABA and GABA (A) receptor expression on immune cells in psoriasis: a pathophysiological role[J]. Archives of Dermatological Research, 2010, 302(7). |
| [80] |
Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG, Lyte M. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation[J]. Brain, Behavior, and Immunity, 2011, 25(3): 397-407. DOI:10.1016/j.bbi.2010.10.023 |
| [81] |
Bautista DM, Wilson SR, Hoon MA. Why we scratch an itch: the molecules, cells and circuits of itch[J]. Nature Neuroscience, 2014, 17(2): 175-182. DOI:10.1038/nn.3619 |
| [82] |
Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN, Dong XZ, Bautista DM. TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch[J]. Nature Neuroscience, 2011, 14(5): 595-602. DOI:10.1038/nn.2789 |
| [83] |
Park HJ, Kim HJ, Lee JH, Lee JY, Cho BK, Kang JS, Kang H, Yang Y, Cho DH. Corticotropin-releasing hormone (CRH) downregulates interleukin-18 expression in human HaCaT keratinocytes by activation of p38 mitogen-activated protein kinase (MAPK) pathway[J]. The Journal of Investigative Dermatology, 2005, 124(4): 751-755. DOI:10.1111/j.0022-202X.2005.23656.x |
| [84] |
Fujii M. Current understanding of pathophysiological mechanisms of atopic dermatitis: interactions among skin barrier dysfunction, immune abnormalities and pruritus[J]. Biological & Pharmaceutical Bulletin, 2020, 43(1): 12-19. |
| [85] |
Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR, Haugen HS, Maurer M, Harder B, Johnston J, et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice[J]. Nature Immunology, 2004, 5(7): 752-760. DOI:10.1038/ni1084 |
| [86] |
Foster EL, Simpson EL, Fredrikson LJ, Lee JJ, Lee NA, Fryer AD, Jacoby DB. Eosinophils increase neuron branching in human and murine skin and in vitro[J]. PLoS One, 2011, 6(7): e22029. DOI:10.1371/journal.pone.0022029 |
| [87] |
Drake MG, Scott GD, Blum ED, Lebold KM, Nie ZY, Lee JJ, Fryer AD, Costello RW, Jacoby DB. Eosinophils increase airway sensory nerve density in mice and in human asthma[J]. Science Translational Medicine, 2018, 10(457): eaar8477. DOI:10.1126/scitranslmed.aar8477 |
| [88] |
Frazier W, Bhardwaj N. Atopic dermatitis: diagnosis and treatment[J]. American Family Physician, 2020, 101(10): 590-598. |
| [89] |
Mandlik DS, Mandlik SK. Atopic dermatitis: new insight into the etiology, pathogenesis, diagnosis and novel treatment strategies[J]. Immunopharmacology and Immunotoxicology, 2021, 43(2): 105-125. DOI:10.1080/08923973.2021.1889583 |
| [90] |
Levkovich T, Poutahidis T, Smillie C, Varian BJ, Ibrahim YM, Lakritz JR, Alm EJ, Erdman SE. Probiotic bacteria induce a 'glow of health'[J]. PLoS One, 2013, 8(1): e53867. DOI:10.1371/journal.pone.0053867 |
| [91] |
Seth A, Yan F, Polk DB, Rao RK. Probiotics ameliorate the hydrogen peroxide-induced epithelial barrier disruption by a PKC- and MAP kinase-dependent mechanism[J]. American Journal of Physiology Gastrointestinal and Liver Physiology, 2008, 294(4): G1060-G1069. DOI:10.1152/ajpgi.00202.2007 |
| [92] |
Li X, Wang F, Xu SJ, Lü XF, Li WF. Probiotics in the prevention and treatment of atopic dermatitis[J]. Microbiology China, 2022, 49(1): 283-291. (in Chinese) 李响, 王斐, 徐树杰, 吕寻飞, 李卫芬. 益生菌防治特应性皮炎的研究进展[J]. 微生物学通报, 2022, 49(1): 283-291. DOI:10.13344/j.microbiol.china.210419 |
| [93] |
S M, AM R, KL B N. Gluten and skin disease beyond dermatitis herpetiformis: a review[J]. International journal of dermatology, 2021, 60(3): 281-288. DOI:10.1111/ijd.15098 |
| [94] |
Ciacci C, Cavallaro R, Iovino P, Sabbatini F, Palumbo A, Amoruso D, Tortora R, Mazzacca G. Allergy prevalence in adult celiac disease[J]. The Journal of Allergy and Clinical Immunology, 2004, 113(6): 1199-1203. DOI:10.1016/j.jaci.2004.03.012 |
| [95] |
Lionetti E, Catassi C. New clues in celiac disease epidemiology, pathogenesis, clinical manifestations, and treatment[J]. International Reviews of Immunology, 2011, 30(4): 219-231. DOI:10.3109/08830185.2011.602443 |
| [96] |
Hata TR, Kotol P, Boguniewicz M, Taylor P, Paik A, Jackson M, Nguyen M, Kabigting F, Miller J, Gerber M, et al. History of eczema herpeticum is associated with the inability to induce human β-defensin (HBD)-2, HBD-3 and cathelicidin in the skin of patients with atopic dermatitis[J]. The British Journal of Dermatology, 2010, 163(3): 659-661. DOI:10.1111/j.1365-2133.2010.09892.x |
| [97] |
Niemeyer-Van Der Kolk TNV, Wall H, Hogendoorn GK, Rijneveld R, Luijten S, Alewijk DCJG, Munckhof EHA, Kam ML, Feiss GL, Prens EP, et al. Pharmacodynamic effects of topical omiganan in patients with mild to moderate atopic dermatitis in a randomized, placebo-controlled, phase II trial[J]. Clinical and Translational Science, 2020, cts.12792. DOI:10.1111/cts.12792 |
| [98] |
Niemeyer-Van Der Kolk T, Assil S, Buters TP, Rijsbergen M, Klaassen ES, Feiss G, Florencia E, Prens EP, Burggraaf J, Van Doorn MBA, et al. Omiganan enhances imiquimod-induced inflammatory responses in skin of healthy volunteers[J]. Clinical and Translational Science, 2020, 13(3): 573-579. DOI:10.1111/cts.12741 |
| [99] |
Smits JPH, Ederveen THA, Rikken G, Van Den Brink NJM, Van Vlijmen-Willems IMJJ, Boekhorst J, Kamsteeg M, Schalkwijk J, Van Hijum SAFT, Zeeuwen PLJM, et al. Targeting the cutaneous microbiota in atopic dermatitis by coal tar via AHR-dependent induction of antimicrobial peptides[J]. The Journal of Investigative Dermatology, 2020, 140(2): 415-424.e10. DOI:10.1016/j.jid.2019.06.142 |
| [100] |
Kim S, Covington A, Pamer EG. The intestinal microbiota: antibiotics, colonization resistance, and enteric pathogens[J]. Immunological Reviews, 2017, 279(1): 90-105. DOI:10.1111/imr.12563 |
| [101] |
Nakatsuji T, Chen TH, Narala S, Chun KA, Two AM, Yun T, Shafiq F, Kotol PF, Bouslimani A, Melnik AV, et al. Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis[J]. Science Translational Medicine, 2017, 9(378): eaah4680. DOI:10.1126/scitranslmed.aah4680 |
| [102] |
Zipperer A, Konnerth MC, Laux C, Berscheid A, Janek D, Weidenmaier C, Burian M, Schilling NA, Slavetinsky C, Marschal M, et al. Human commensals producing a novel antibiotic impair pathogen colonization[J]. Nature, 2016, 535(7613): 511-516. DOI:10.1038/nature18634 |
| [103] |
Myles IA, Williams KW, Reckhow JD, Jammeh ML, Pincus NB, Sastalla I, Saleem D, Stone KD, Datta SK. Transplantation of human skin microbiota in models of atopic dermatitis[J]. JCI Insight, 2016, 1(10): 86955. |
| [104] |
Vendrik KEW, Ooijevaar RE, De Jong PRC, Laman JD, Van Oosten BW, Van Hilten JJ, Ducarmon QR, Keller JJ, Kuijper EJ, Contarino MF. Fecal microbiota transplantation in neurological disorders[J]. Frontiers in Cellular and Infection Microbiology, 2020, 10: 98. DOI:10.3389/fcimb.2020.00098 |
| [105] |
Mashiah J, Karady T, Fliss-Isakov N, Sprecher E, Slodownik D, Artzi O, Samuelov L, Ellenbogen E, Godneva A, Segal E, et al. Clinical efficacy of fecal microbial transplantation treatment in adults with moderate-to-severe atopic dermatitis[J]. Immunity, Inflammation and Disease, 2022, 10(3): e570. |
| [106] |
Kim JH, Kim K, Kim W. Gut microbiota restoration through fecal microbiota transplantation: a new atopic dermatitis therapy[J]. Experimental & Molecular Medicine, 2021, 53(5): 907-916. |