益生菌对皮肤光老化的修复作用及其机制研究进展

2022-04-24 mirza MedSci原创

皮肤是人体最大的器官，也是人体与外界环境之间的第一道屏障，在保护、调节体温、感觉、分泌、排泄和免疫等多方面发挥作用。

皮肤是人体最大的器官，也是人体与外界环境之间的第一道屏障，在保护、调节体温、感觉、分泌、排泄和免疫等多方面发挥作用。

当皮肤器官功能出现衰老性损伤、难以适应内外环境变化、发生色泽及弹性下降的情况时，被称为皮肤老化(skin aging)。皮肤老化除了与我们常提到的年龄、紫外线等因素有关外，还与在皮肤表面的庞大微生态群落系统息息相关。

皮肤微生态在防御入侵病原体、调整人体的免疫系统和分解代谢产物方面起着至关重要的作用，因此对皮肤乃至全身健康起到重要作用。在机体衰老过程中，皮肤微生态也随之发生动态变化。研究团队通过随访长寿家族成员，发现随着年龄的增长，皮肤微生态多样性急剧下降，芽孢杆菌丰度增多，粪球菌丰度减少；皮肤微生物的辅因子及维生素合成、糖原生成及代谢能力逐渐下降，而致癌微生物逐渐增多。

有很多研究结果表明，在皮肤老化进程中皮肤微生态发挥着重要的作用，所以目前国内外对于抗皮肤光老化功能因子的研究从开发植物源性的多肽类、多糖类和黄酮类物质逐渐转向通过微生物手段维持皮肤健康微生态。

益生菌(probiotics)是一类被世界卫生组织定义为通过摄取适当的量、对食用者的身体健康能发挥有效作用的活菌。某些特定的益生菌能够积极影响机体微生物区系的组成，提升宿主局部器官状态。已有研究证实益生菌补充剂对特应性皮炎的治疗有作用，但在皮肤应用领域中，并没有明确益生菌具体治疗功效。

虽然在中国化妆品行业国标中要求产品的菌落总数小于等于 1000 CFU/g，但在一些欧美国家已经允许含有益生菌活菌成分的产品上架，这也印证了益生菌在日化行业广阔的开发前景。本文将从光老化损伤的病理机制及益生菌在皮肤领域的研究现状，系统综述益生菌抑制皮肤光老化研究取得的最新进展。

01益生菌的抗光老化作用

1.1抗氧化作用

益生菌是一类对人体有益的活性微生物，具有维持肠道菌群结构平衡、调节机体免疫力、提高机体抗氧化水平等功能。其中，益生菌的抗氧化功能与皮肤系统的健康密切相关。益生菌的抗氧化机制可以分为 4 种：清除活性氧和自由基系统、增强抗氧化酶系统、还原调控系统和氧化损伤修复系统。由于益生菌可以通过多种途径协助机体抗氧化，因此不少研究者试图将益生菌应用于皮肤抗光老化的治疗中。部分益生菌菌株可以增加抗氧化酶活性或清除 ROS，减轻皮肤在 UV 辐照后的氧化损伤。

表 1 文献中报道的具有抗光老化特性的益生菌

图 1 益生菌对皮肤光老化的修复通路

不仅益生菌本身可以抗光老化，亦有研究者尝试将益生菌用于植物天然成分的提取中，以增加植物提取物的抗氧化特性。

Lim 等通过比较未发酵和鼠李糖乳杆菌HK-9 发酵的龙舌兰叶提取物的皮肤抗氧化特性，发现采用 HK-9 发酵后的龙舌兰叶提取物能显著抑制角质形成细胞中活性氧如 NO 和iNOS 的产生，证明采用益生菌能提高天然产物的抗光老化活性。

Curiel 等发现采用植物乳杆菌 C2 发酵桃金娘浆可明显提高匀浆中的抗氧化物质如总酚、黄酮和花色苷的浓度，增强其对自由基的清除力和抑制亚油酸的过氧化能力。

因此益生菌可通过菌体自身、发酵上清液以及发酵产生的其他天然成分发挥抗氧化作用，在协助机体防御光老化中有良好的应用前景。

1.2减少 UV 对真皮细胞外基质的破坏

真皮 ECM 损伤如胶原蛋白流失和弹性蛋白下降是皮肤光老化过程中一个重要的病理特征。在光老化的皮肤中，UV 辐照后会使皮肤细胞内的 ROS 增多，诱发 MMPs 水平增高，导致皮肤的胶原蛋白和弹性蛋白被降解，皮肤变得粗糙、松弛和起皱。益生菌除了能显著降低紫外辐射诱导的 ROS 水平之外，还能通过影响多个信号通路直接调节皮肤细胞 MMPs 的表达水平，减少UV 辐照后胶原蛋白和弹性蛋白的降解。

Lim 等发现嗜酸乳杆菌 KCCM 12625 可以通过影响皮肤细胞 AP-1 信号通路，减少皮肤衰老过程中产生的 MMP-1、MMP-9 的 mRNA 的表达，同时增加前胶原蛋白的表达，减少真皮层胶原蛋白流失。Kim 等也证明了植物乳酸菌HY7714 通过抑制 JNK/AP-1 信号通路的激活而降低了 UVB 损伤细胞内过高的 MMP-13 转录水平和 MMP-2、MMP-9 活性。

脂磷壁酸(lipoteichoic acid，LTA)是革兰氏阳性菌细胞壁的一种成分，You 发现清酒乳杆菌 LTA可通过阻断 MAPK信号抑制 MMP-1转录因子 AP-1 的表达，增加真皮细胞胶原蛋白的含量，延缓光老化损伤。

Shirzad 等应用干酪乳杆菌 B9-1 的胞外多糖作用于 UV 损伤的皮肤细胞，同样发现其具有下调 MMP-1、MMP-2、MMP-3、MMP-9 和 MMP-10 表达水平、上调TIMPs 的作用，发现干酪乳杆菌 B9-1 可增强皮肤细胞中抗胶原酶、抗弹性蛋白酶活性，有效减少光照后胶原蛋白的降解。

综上所述，益生菌可通过多种途径减少光老化过程中胶原蛋白和弹性蛋白的流失，继而达到延缓光老化的效果。

1.3益生菌抑制炎症因子的表达

除了上述造成光老化组织学差异的因素之外，炎症因子的累积也是光老化过程中皮肤损伤的一个不可忽视的因素，皮肤炎症因子的增多会导致屏障功能受到破坏，表皮水分失衡、皮肤通透性增加，引起更多的过敏原及化学物质的异常吸入，引起或加重皮肤疾病状态，加速皮肤老化。而益生菌在缓解肠道炎症上已有广泛的应用，同样地，益生菌缓解炎症的功能在调控皮肤免疫平衡上也有良好的疗效，如益生菌在特应性皮炎的治疗上已被广泛应用，证明益生菌可有效降低患者皮肤炎症水平，恢复免疫稳态。

在 UV 辐射下，表皮层的角质形成细胞通过释放白细胞介素 IL-1、IL-6、IL-8、IL-10 和 TNF-α等炎症介质，诱发局部的炎症，导致皮肤通透性增加，屏障功能下降。嗜酸乳杆菌 IDCC 3302 可以抑制 MAPK 信号通路介导的促炎细胞因子的产生，减少 UVB 辐射引起的皮肤炎症。因此，益生菌可通过抑制 UV 辐照后皮肤异常免疫作用的形成，减少皮肤的光老化损伤。

02皮肤应用益生菌的潜在形式

随着人们对皮肤微生物区系了解的不断加深，我们相信会有更多针对个体特征定制的皮肤护理方案出现。但是在益生菌的皮肤应用中还存在很多待解决的问题：

1.口服和外涂哪种才是最好的应用方式？

人们通常认为活性益生菌比灭活益生菌更有可能具有生物活性，因为活性益生菌比灭活细胞更容易附着在宿主黏膜和细胞上，并且可对有害微生物产生更好的抗菌活性。因此，最理想的皮肤益生菌治疗方案应该为让有活性的益生菌在皮肤上保持活性，并在皮肤上定居。

2.应如何安全和持久地植入益生菌？

对于如何安全和持久地植入益生菌，有研究表明局部使用的益生菌可以在皮肤上增殖、定居，并融入宿主正常皮肤微生物区系的成员。如果采用口服摄入益生菌，则难以保证益生菌的长期定植，停用益生菌后功效将很快消失。因此，如何维持益生菌活菌的持久性将是研究者们关注的新方向。

3.活性微生物应用效果会比灭活微生物要好吗？

至今，大多数皮肤益生菌产品并不真的含有活菌，而是由灭活微生物、菌体成分或益生菌的无细胞代谢物组成。目前国内化妆品行业国标要求对产品的菌落总数进行控制，是因为在皮肤上直接应用活菌菌体存在一定风险，例如在皮肤存在伤口的情况下，应用活菌可能会导致细菌移行到血液中，产生菌血症。

4.活菌存活时间有多久？

另外，由于益生菌的保藏和运输方式比较严格，保持活菌在皮肤上存活及生长仍是难以解决的技术问题。

5.多种益生菌混合物应用是否具有协同作用？

目前的科学研究仅从灭活微生物、菌体成分或益生菌的无细胞代谢物对皮肤疾病(如光老化)的分子作用机制和表型进行探讨，而未进一步探究其与皮肤微生态之间的关系。灭活的益生菌、菌体成分或益生菌的无细胞代谢物依然是目前在皮肤上应用益生菌产品首选的应用模式。

03结语

综上所述，UV 辐射会对皮肤中的 DNA、RNA及蛋白质产生直接损伤，影响细胞存活状态；UV 同时诱导细胞内 ROS 累积，导致脂质过氧化发生，进一步损伤 DNA 和 RNA、导致细胞外基质胶原蛋白和弹性蛋白降解；另外 UV 还诱发皮肤局部炎症，降低皮肤对外界有害物质的防御，这些共同促进了皮肤光老化的发生。

而通过应用具有抗氧化功能的益生菌，可以清除活性氧、调节基质金属蛋白酶表达水平，实现缓解细胞外基质损伤，减轻皮肤炎症。益生菌在保护皮肤免受 UV 损伤方面具有良好的应用前景，随着科学研究的不断深入，研究者们将进一步验证益生菌在维护皮肤健康上的应用价值。

因此，在目前的研究基础上，我们还需要从皮肤微生态、益生菌、益生元及后生元的抗光老化分子机制等多方面深入探索益生菌对皮肤系统的作用机制，开发更多新型微生态策略来保护受 UV 辐射的皮肤，延缓光老化。

参考文献：

[1] Jabłońska-Trypuć A, Krętowski R, Kalinowska M, Świderski G, Cechowska-Pasko M, Lewandowski W. Possible mechanisms of the prevention of doxorubicin toxicity by cichoric acid-antioxidant nutrient. Nutrients, 2018, 10(1): 44.

[2] Blume-Peytavi U, Kottner J, Sterry W, Hodin MW, Griffiths TW, Watson REB, Hay RJ, Griffiths CEM. Age-associated skin conditions and diseases: current perspectives and future options. The Gerontologist, 2016, 56(Suppl 2): S230–S242.

[3] Panich U, Sittithumcharee G, Rathviboon N, Jirawatnotai S. Ultraviolet radiation-induced skin

aging: the role of DNA damage and oxidative stress in epidermal stem cell damage mediated skin aging. Stem Cells International, 2016, 2016: 7370642.

[4] Cavinato M, Jansen-Dürr P. Molecular mechanisms of UVB-induced senescence of dermal fibroblasts and its relevance for photoaging of the human skin. Experimental Gerontology, 2017, 94: 78–82.

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#机制研究#

37 0
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2022-07-17 ms8000000819400399

盒的养乐多行不行

40 0
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2022-06-05 同情心)

外用益生菌调理痤疮、湿疹几千例，效果惊人

38 0
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2022-04-26 赛华佗

#益生菌#

113 0
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2022-04-26 mashirong

#研究进展#

38 0
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2022-04-26 ms5822920152752585

#老化#

31 0
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2022-04-24 ms5000000518166734

学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习学习

58 0
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2022-04-24 西瓜0628

***#学习#

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