皮肤菌群如何影响皮肤健康？益生菌/元能拯救烂脸吗？

编者按：

皮肤微生物组对皮肤健康和外观具有重要影响。随着微生物组研究的不断深入，我们对皮肤微生物组有了更为深刻的了解，并开展了一系列的临床试验，以探究包括益生菌、益生元在内的微生物疗法对皮肤疾病的治疗作用。

今天，我们共同关注皮肤微生物组。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。

皮肤微生物组与疾病

近几十年来，由于不当或错误的免疫反应，以及免疫调节网络的缺陷造成的慢性炎症性疾病正在快速蔓延。人们普遍认为是由于环境、生活方式和饮食等因素的变化，导致免疫系统没有得到正确的或充分的训练而产生了这样的结果[1,2]。一些研究认为微生物多样性的降低，以及其他影响微生物代谢的因素也会显著影响免疫系统的耐受性[3]。

人体表面定植着多种微生物，这些微生物形成了复杂的群落结构组织，并利用来自于其他微生物或者宿主的分泌物作为营养进行生存。现代生活方式、药物治疗和社交互动的方式发生了翻天覆地的变化，从根本上影响了人类微生物组的群落结构，并导致免疫介导疾病的患病风险增加[4]。

世界各国有许多研究小组正在深入的研究这种联系密切且复杂的联系机制，以维持能够对宿主的生理、代谢和免疫方面产生益处的稳定环境。虽然人体皮肤所暴露的外界环境发生了变化，但人体皮肤正在积极地调节微生物的定植，以及调控微生物进入真皮或皮下组织。

微生物之间以及其与宿主细胞（包括角质形成细胞和免疫细胞）之间相互作用，使得皮肤环境趋于稳定（图1）。皮肤微生物组对宿主免疫功能的影响包括促进宿主防御病原体的网络，炎症的控制和适应性免疫通路的构建[5,6]。共生皮肤微生物还可以直接抑制病原体和机会性细菌的定植或入侵。例如，表皮葡萄球菌（皮肤中最丰富的共生物种之一）可以刺激角质形成细胞抗菌肽的产生，并在伤口愈合过程中抑制炎症细胞因子的释放和炎症的发生[7]。

随着微生物组研究的不断发展，过去十年里，发表了许多评估益生菌和益生元干预对皮肤病的疗效临床实验研究，结果喜忧参半。

图1.皮肤上微生物和微生物之间以及微生物与宿主细胞之间存在着复杂的相互作用：皮肤和毛囊上的各种微生物相互作用，从而抑制病原微生物的增殖。微生物通过分泌死菌素、自身诱导肽（AIPs），酚溶性调节蛋白（PSMs）和环状抗微生物肽（AMPs）来影响其他微生物的生长。

人体临床试验结果不同

益生菌对儿童异位性皮肤炎症（AD）的治疗潜能一直是研究的焦点。许多随机对照试验（RCT）报告称，在给患有异位性皮肤炎症的儿童口服益生菌后，疾病的严重程度和炎症标志物的丰度都有所降低[8-16]。某些大型的研究观察到，在产前和产后给母亲和婴儿口服益生菌补充剂对预防儿童异位性皮肤炎症有着显著的效果[17-19]。

然而，另一些试验得到了相反的结论，口服益生菌和对照安慰剂在预防或改善儿童异位性皮肤炎症的临床表现或炎症标志物方面并没有差异[20-27]。

多项研究评估了益生菌和益生元组合（合生制剂）对患有异位性皮肤炎症人群的联合作用，发现其可以降低疾病的严重程度[25,28]。然而，其他试验报告发现，在异位性皮肤炎症人群中，这些合生制剂明显缺乏协同促进活性[29,30]。

口服益生菌干预成人痤疮的产生同样也获得了极大的关注。一些试验已经证明了单独使用益生菌或将益生菌与标准治疗联合使用的疗法，都可以改善临床症状[31-33]。然而，一项试验报告表明，单独使用益生菌对干预成人痤疮几乎没有用处，但是当与潜在的益生元乳铁蛋白结合使用时，会有显著的临床改善效果[34,35]。

最近的一些研究表明，口服益生菌对斑块状银屑病[36,37]、成人异位性皮肤炎症[38]、手部皮炎[39]、丘疹脓疱性酒渣鼻、脂溢性皮炎[35]以及头皮屑[40]都有潜在的益处。

虽然有许多研究调查了口服益生菌的临床潜力，但是评估局部使用益生菌和益生元对皮肤病的干预影响试验比较少。

据报道，局部采用益生元治疗能够使得成人和儿童的异位性皮肤炎症严重程度有所降低[41-43]。此外，这类干预性研究还观察到金黄色葡萄球菌的定植有所减少。一项研究甚至表明，仅使用一次从人类皮肤共生体中分离得到的抗菌剂乳液后，患者的金黄色葡萄球菌丰度就会降低[44]。

对于成人痤疮，一项 2 期临床试验报告表明，使用局部益生菌喷雾能够显著降低痤疮的严重程度和炎症损伤，虽然这项研究还未被完整发表[45]。还有研究发现，使用水包油包装的益生菌治疗后，人体的红斑和痤疮病变严重性下降，并且皮肤屏障能够得到恢复[46]；另一项研究也报导了痤疮患者使用局部益生菌喷雾带来的皮肤相关改善[47]。此外，一项随机对照试验表明，单一菌株的益生菌乳膏可显著降低皮肤敏感度，并增强敏感肌女性的皮肤对化学和物理损伤的抵抗力[48]。

需要更深入的研究

虽然有证据能够支持将益生菌或益生元疗法用于治疗皮肤病，但研究结果间存在的差异限制了这一疗法的实施。研究结果间的差异可能是由于治疗方案，参与者统计、纳入和排除标准以及使用单菌株或多菌株制剂等因素的不同导致的。事实上，一项研究表明菌株的选择对治疗异位性皮肤炎症的治疗效果有重要影响[15]。

此外，许多研究存在样本量小、随访时间短等限制。许多疾病可能需要长时间的研究才能看到真实的结果。

尽管我们已经知道宿主微生物组多样性和宿主文化与遗传因素背景之间存在紧密的关联，但是只有很少一部分的研究公开了参与者的种族背景或皮肤类型，对于饮食这一因素的公布则更少[49]。

目前，口服益生菌对儿童和成人异位性皮肤炎症的影响和局部使用益生菌对痤疮以及儿童异位性皮肤炎症的影响的研究正在进行或处于招募中[50]。这些研究有望进一步阐明益生菌干预措施在皮肤病中的有效性。

近年来，我们在描述皮肤微生物组组成和其与皮肤炎症性疾病间的相关性上，取得了重大的进展。然而，我们对皮肤微生物组的理解仍然很有限，特别是对于皮肤微生物-宿主间通讯交流的功能基础的了解。此外，新的益生菌以及传统益生菌都应该进行必要的临床检测。不仅如此，还应该检查其他微生物成分，包括微生物代谢产物，以更好地探索这些新型微生物疗法在病变部位的应用。

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