微生物学报

Strain	Form and dosage	Test sample and quantity	Mechanism	Effect
Lactobacillusrhamnosus HN001	Capsulated probiotic 6×10⁹ CFU/d	157 infants	Shape the immune system and increase IFN-γ level	The prevalence of eczema were significantly reduced^[69]
Lactobacillusplantarum CCFM8610	Lyophilized powder 1×10⁹ CFU/d	109 adult patients	Regulate the gut microbiota; maintain the immune responses and barrier integrity; change in functional genes of the gut microbiota	Improve SCORAD index; increase the expression levels of IL-10; decrease the F/B ratio; increase species evenness and diversity^[70]
Lactobacillusplantarum IS-10506	Microencapsulated probiotic 2×10¹⁰ CFU/d	30 adult patients: 15 controlsvs. 15 interventions	Suppression of the Th2 adaptive immune response and increase in the Th1 adaptive immune response; increase the Treg immune response and decrease Th17 response	The SCORAD score, IL-4, and IL-17 levels were significantly lower; the IFN-γ and Foxp3+ levels were significantly higher^[71]
Lactobacillusrhamnosus IDCC 3201	Tyndallized probiotics 1×10¹⁰ CFU/d	66 children: 33 controlsvs. 33 tests	Decreased production or activity of IL-31 and eosinophils	The SCORAD score, eosinophil count, and the IL-31 levels were decreased^[72]
Lactobacillusparacasei KBL382	Live bacteria 1×10⁹ CFU/d	NC/Nga mice: 7 controlsvs. 7 modelsvs. 7 tests	Increase the immunosuppressive response and change the metabolic functions of gut microbiota	Reduced AD-associated skin lesions, serum levels of IgE, and immune cell infiltration^[73]
Lactobacillusplantarum CJLP55	Lyophilized powder 1×10¹⁰ CFU/d	NC/Nga mice: 8 controlsvs. 8 modelsvs. 8 tests	Alter the balance of Th1/Th2 ratio or induce IL-10 production	Suppressed AD-like skin lesions, high serum IgE levels; diminished the accumulation of eosinophils and mast cells; decreased production of IL-4 and IL-5^[74]
Kazachstaniaturicensis CAU Y1706	Freeze-dried 1×10¹⁰ CFU/d	BALB/c mice: 10 controlsvs. 10 modelsvs. 10 tests	Interactions between gut microbiota, SCFA, and immune modulation between Th1 and Th2	Reduced IgE levels and the number of mast cells and eosinophil; the serum concentrations of Th2 cytokines were significantly lower^[75]
Limosilactobacillusreuteri FN041	Live bacteria 1×10⁹ CFU/d	BALB/c mice: 12 controlsvs. 12 modelsvs. 12 tests	Regulate the ileum microbiota, strengthen the ileal mucosal barrier	The plasma IgE were significantly decreased; the intestinal mucosal barrier was enhanced^[76]
Lactobacillusplantarum LM1004	Lyophilized powder 2×10¹² cells/g 0.01 g/kg-bw	SD rats: 10 controlsvs. 10 modelsvs. 10 tests	Inhibited Th2 cell responses; activated the responses of Treg cell; modulated gut microbiota	Decreased the scratching behaviors; reduced vasodilation and serum histamine; decreased serum IgE contents^[77]
Bifidobacteriumadolescentis	Live bacteria 1×10⁹ CFU/d	C57bl/6 mice: 5 controlsvs. 5 modelsvs. 5 tests	Promote Tregs population in the spleen; restore the balance between Th1- and Th2-type immune responses; regulate the gut microbiota composition	Reduced ear and skin thickness and suppressed eosinophils and mast cells infiltration^[78]
Bifidobacteriumlongum	Cell-free culture supernatant 1×10⁷ CFU/d	Hairless mice: 5 controlsvs. 5 modelsvs. 5 tests	Attenuate skin inflammation and enhance skin barrier function	Attenuated DNCB-induced skin inflammation, abnormal TEWL, AD-like skin, and deficiency of epidermal barrier proteins^[79]
Lactococcuschungangensis CAU 28T	Live bacteria 1×10⁹ CFU/mL	RAW 264.7 cells; human mast cell	Inhibit the release of allergy-associated proteins	Inhibited the production of the proinflammatory mediators; reduced the release of histamine^[80]

Strain	Form and dosage	Test sample and quantity	Mechanism	Effect
Lactobacillusrhamnosus HN001	Capsulated probiotic 6×10⁹ CFU/d	157 infants	Shape the immune system and increase IFN-γ level	The prevalence of eczema were significantly reduced^[69]
Lactobacillusplantarum CCFM8610	Lyophilized powder 1×10⁹ CFU/d	109 adult patients	Regulate the gut microbiota; maintain the immune responses and barrier integrity; change in functional genes of the gut microbiota	Improve SCORAD index; increase the expression levels of IL-10; decrease the F/B ratio; increase species evenness and diversity^[70]
Lactobacillusplantarum IS-10506	Microencapsulated probiotic 2×10¹⁰ CFU/d	30 adult patients: 15 controlsvs. 15 interventions	Suppression of the Th2 adaptive immune response and increase in the Th1 adaptive immune response; increase the Treg immune response and decrease Th17 response	The SCORAD score, IL-4, and IL-17 levels were significantly lower; the IFN-γ and Foxp3+ levels were significantly higher^[71]
Lactobacillusrhamnosus IDCC 3201	Tyndallized probiotics 1×10¹⁰ CFU/d	66 children: 33 controlsvs. 33 tests	Decreased production or activity of IL-31 and eosinophils	The SCORAD score, eosinophil count, and the IL-31 levels were decreased^[72]
Lactobacillusparacasei KBL382	Live bacteria 1×10⁹ CFU/d	NC/Nga mice: 7 controlsvs. 7 modelsvs. 7 tests	Increase the immunosuppressive response and change the metabolic functions of gut microbiota	Reduced AD-associated skin lesions, serum levels of IgE, and immune cell infiltration^[73]
Lactobacillusplantarum CJLP55	Lyophilized powder 1×10¹⁰ CFU/d	NC/Nga mice: 8 controlsvs. 8 modelsvs. 8 tests	Alter the balance of Th1/Th2 ratio or induce IL-10 production	Suppressed AD-like skin lesions, high serum IgE levels; diminished the accumulation of eosinophils and mast cells; decreased production of IL-4 and IL-5^[74]
Kazachstaniaturicensis CAU Y1706	Freeze-dried 1×10¹⁰ CFU/d	BALB/c mice: 10 controlsvs. 10 modelsvs. 10 tests	Interactions between gut microbiota, SCFA, and immune modulation between Th1 and Th2	Reduced IgE levels and the number of mast cells and eosinophil; the serum concentrations of Th2 cytokines were significantly lower^[75]
Limosilactobacillusreuteri FN041	Live bacteria 1×10⁹ CFU/d	BALB/c mice: 12 controlsvs. 12 modelsvs. 12 tests	Regulate the ileum microbiota, strengthen the ileal mucosal barrier	The plasma IgE were significantly decreased; the intestinal mucosal barrier was enhanced^[76]
Lactobacillusplantarum LM1004	Lyophilized powder 2×10¹² cells/g 0.01 g/kg-bw	SD rats: 10 controlsvs. 10 modelsvs. 10 tests	Inhibited Th2 cell responses; activated the responses of Treg cell; modulated gut microbiota	Decreased the scratching behaviors; reduced vasodilation and serum histamine; decreased serum IgE contents^[77]
Bifidobacteriumadolescentis	Live bacteria 1×10⁹ CFU/d	C57bl/6 mice: 5 controlsvs. 5 modelsvs. 5 tests	Promote Tregs population in the spleen; restore the balance between Th1- and Th2-type immune responses; regulate the gut microbiota composition	Reduced ear and skin thickness and suppressed eosinophils and mast cells infiltration^[78]
Bifidobacteriumlongum	Cell-free culture supernatant 1×10⁷ CFU/d	Hairless mice: 5 controlsvs. 5 modelsvs. 5 tests	Attenuate skin inflammation and enhance skin barrier function	Attenuated DNCB-induced skin inflammation, abnormal TEWL, AD-like skin, and deficiency of epidermal barrier proteins^[79]
Lactococcuschungangensis CAU 28T	Live bacteria 1×10⁹ CFU/mL	RAW 264.7 cells; human mast cell	Inhibit the release of allergy-associated proteins	Inhibited the production of the proinflammatory mediators; reduced the release of histamine^[80]

益生菌对特应性皮炎的防治及机制研究进展

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王婉妮 ¹^,²^,^# , 李滢 ²^,^# , 曾嘉辉 ² , 谢新强 ² , 吴清平 ²^,^*

微生物学报 | 综述 2024,64(5): 1378-1391

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微生物学报 | 综述 2024, 64(5): 1378-1391

益生菌对特应性皮炎的防治及机制研究进展

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王婉妮¹^,²^,^#, 李滢²^,^#, 曾嘉辉², 谢新强², 吴清平²^,^*

作者信息

1 陕西科技大学食品科学与工程学院, 陕西西安 710021

2 广东省科学院微生物研究所华南应用微生物国家重点实验室广东省微生物安全与健康重点实验室国家卫健委微生物食品营养与安全科技创新平台, 广东广州 510070

Research progress in probiotics for prevention and treatment of atopic dermatitis

Wanni WANG¹^,², Ying LI², Jiahui ZENG², Xinqiang XIE², Qingping WU²^,^*

Affiliations

1 School of Food Science and Engineering, Shaanxi University of Science and Technology, Xi'an 710021, Shaanxi, China

2 State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Safety and Health, National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, Guangdong, China

出版时间: 2024-05-04 doi: 10.13343/j.cnki.wsxb.20230682

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摘要

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特应性皮炎(atopic dermatitis, AD)是一种以反复发作和严重瘙痒为特征、发病率最高的过敏性皮肤病。AD的致病机制涉及遗传易感性、表皮屏障功能障碍、微生物组失调、免疫反应失衡以及环境等多个因素，而现有治疗用药副作用大、疗效欠佳。目前研究已发现肠道菌群尤其是益生菌在AD中起着重要作用。益生菌能够通过抑制病原菌、增强屏障功能、改善肠道环境和平衡Th1/Th2免疫应答等机制改善AD症状。本文综述了AD患者皮肤及肠道微生态特征，基于AD发病的致病机制和影响因素，系统阐明益生菌缓解AD的机制，以期为益生菌治疗AD及相关皮肤过敏性疾病提供理论支持。

关键词

特应性皮炎 / 肠道菌群 / 免疫 / 益生菌 / 组胺

Abstract

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Atopic dermatitis (AD) is a highly prevalent allergic skin disease characterised by recurrent attacks and severe itching. The pathogenesis of AD involves a variety of factors including genetic susceptibility, epidermal barrier dysfunction, microbiome dysbiosis, immune imbalance, and the environment, while the available therapeutic drugs have severe side effects and limited efficacy. Studies have demonstrated that gut microbiota, particularly probiotics, play a role in AD. Probiotics can alleviate AD symptoms by inhibiting pathogens, enhancing barriers, improving the intestinal environment, and balancing the Th1/Th2 immune response, among other mechanisms. In this review, we summarized the skin and intestinal microecological characteristics of AD patients and systematically elucidated the mechanisms of probiotics in alleviating AD from the pathogenesis and influencing factors of AD, aiming to provide theoretical support for probiotics in the treatment of AD and related allergic skin diseases.

Key words

atopic dermatitis / gut microbiota / immunity / probiotics / histamine

引用本文

王婉妮, 李滢, 曾嘉辉, 谢新强, 吴清平. 益生菌对特应性皮炎的防治及机制研究进展. 微生物学报, 2024 , 64 (5) : 1378 -1391 . DOI: 10.13343/j.cnki.wsxb.20230682

Wanni WANG, Ying LI, Jiahui ZENG, Xinqiang XIE, Qingping WU. Research progress in probiotics for prevention and treatment of atopic dermatitis[J]. Acta Microbiologica Sinica, 2024 , 64 (5) : 1378 -1391 . DOI: 10.13343/j.cnki.wsxb.20230682

正文

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皮肤(skin)被覆于体表，作为人体抵御外界因素侵扰的第一道防线，具有屏障保护、结构支撑、调节体温以及维持人体内环境稳定等功能^[1]。特应性皮炎(atopic dermatitis, AD)是一种临床上最常见的慢性炎症性皮肤病，以反复发作和严重瘙痒为主要特征，常与食物过敏、哮喘和过敏性鼻炎等其他过敏反应有关^[2]。据统计，全球约20%的儿童和10%的成年人受此影响^[3]。研究指出，社会心理压力、空气温湿度变化、过敏原刺激、皮肤与肠道菌群失调、皮肤屏障减弱和免疫细胞活性增强为诱发AD的主要因素；AD通常影响身体的特定部位，如脸部、颈部、四肢及皮肤皱褶处，以皮肤干燥、红斑、丘疹、苔藓样硬化、渗出和结痂为典型病理特征；尽管AD是以过敏的形式影响皮肤系统，但近年研究发现其与心血管疾病、神经系统疾病、自身免疫性疾病以及肥胖等非过敏性疾病的高发病率也存在联系^[4-7]。除了对患者躯体造成伤害外，AD也因为其持续的瘙痒症状严重影响患者的生活质量以及工作效率，危害患者心理健康^[3]。

为缓解AD患者的临床症状、减少疾病复发及并发症的发生，临床医生根据成人和儿童皮炎的严重程度，制定了包括回避疗法、漂白浴、润肤剂、外用皮质类固醇(topical corticosteroids, TCS)、钙调神经磷酸酶抑制剂(topical calcineurin inhibitor, TCI)和Janus激酶(Janus kinase, JAK)抑制剂等系列方法，但这些治疗具有诸如皮肤萎缩、多毛、色素沉着、应用部位产生灼烧感和瘙痒、生长迟缓、骨质疏松、鼻咽炎、头痛、恶心和腹泻等较严重的副作用^[8]。抗组胺药是治疗AD皮肤瘙痒的主要疗法，但该药具有嗜睡的副作用，且对儿童认知能力存在影响^[9]。因此，亟需研发出一种新的安全、有效、经济的生物制剂用于AD的预防与治疗。

1930年，皮肤病学家John H. Stokes提出关于情绪、肠道菌群及皮肤炎症之间相互关系的开创性理论，揭示了肠道-皮肤轴的存在^[10]。随着新一代测序技术的出现，研究发现AD的发生不仅与皮肤微生物组有关，且与肠道微生物组有关^[11]。肠道菌群失调通过促炎细胞因子增加肠道通透性，进而促进免疫失调，导致包括AD、痤疮以及银屑病等皮肤疾病的发生^[12]。益生菌(probiotics)是一种活的微生物，当给予足够数量时将对宿主的健康产生有益作用^[13]。益生菌具有增强上皮屏障的完整性、抑制病原体增殖以及重新恢复机体免疫平衡的作用，是预防和治疗AD在内的各种过敏性疾病的新手段^[14]。作者所在研究团队累积了超过3万株的健康功能微生物，建成了相应的菌种资源及基因组数据库，并对其进行功能挖掘，目前已证明益生微生物能通过调节肠道菌群在降血压^[15]、降糖降脂^[16]、促睡眠^[17]、抗幽门螺杆菌^[18]、抗病毒^[19]、修复皮肤光老化^[20]以及缓解溃疡性结肠炎^[21]等方面有显著的益生功能。肠道-皮肤轴的存在也为益生菌防治AD提供了理论支撑。因此，本文将从AD的皮肤和肠道微生态特征、病理机制及益生菌在AD领域的研究现状，系统综述益生菌在防治AD的研究中取得的最新进展。

1 AD特征性人体微生态

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1.1 AD的皮肤微生态

皮肤和肠道菌群是人体的2个主要微生态系统^[22]。皮肤表面定殖有数百万微生物，主要为丙酸杆菌(Propionibacteria)、链球菌(Streptococcus)、葡萄球菌(Staphylococcus)和棒状杆菌(Corynebacterium)^[23]。皮肤免疫系统的动态平衡很大程度依赖于皮肤菌群的平衡^[24]，皮肤微生态一旦失衡，不仅会增加病原微生物的感染风险，且极易诱发系列慢性皮肤疾病，如AD^[25]。在过去十年里，高通量测序技术的进步为我们提供了关于皮肤健康与微生态组成的新见解：健康人的皮肤微生物群通常是稳定的，但AD患者皮肤表现出显著的失调，表现为微生物多样性减少，且皮损部位被大量金黄色葡萄球菌(Staphylococcusaureus)定殖^[26]；除了S.aureus外，表皮葡萄球菌、溶血葡萄球菌在AD发病部位也有所增加^[27]；此外，真菌及感染在AD患者中也较为常见，马拉色菌及白色念珠菌在AD患者的皮肤中比健康人更多^[28]，而单纯疱疹病毒感染也常在AD儿童中被发现^[29]。

1.2 AD的肠道微生态

既往研究表明，肠道菌群的定殖与免疫系统的发育密切相关，肠道菌群失调与过敏性疾病的发生相关，且常先于疾病发生^[30]。Watanabe等^[31]发现，AD患者肠道中乳杆菌、双歧杆菌的相对丰度显著降低，而葡萄球菌的比例显著高于健康人群；Fieten等^[32]的研究表明，伴有食物过敏的AD患儿粪便微生物中假链双歧杆菌和大肠杆菌相对较多，而青春双歧杆菌、短双歧杆菌、普拉梭菌及嗜黏蛋白阿克曼氏菌较少；除了双歧杆菌数量减少外，AD患儿肠道拟杆菌数量降低，而肠杆菌数量增加^[33]；Fujimura等^[34]的研究表明，在患上AD及哮喘等高过敏性疾病风险的儿童中，阿克曼氏菌、双歧杆菌及粪杆菌的水平较低，而假丝酵母及红酵母含量较高；在其他研究中还发现，艰难梭菌在生命早期的定殖也导致了随后AD的发生^[35]；进一步研究指出，AD儿童肠道共生细菌对肠黏膜的黏附性较差，导致肠道屏障功能出现障碍，肠道中抗炎因子白介素10 (interleukin, IL-10)的产生减少，而促炎细胞因子水平升高^[36]。综上，肠道微生物多样性及组成变化与AD等过敏性疾病的发生发展密切相关，调节肠道菌群或可改善过敏症状的发展，成为预防和治疗AD的靶点。

2 特应性皮炎的发病机制研究

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2.1 AD的病理机制

医学研究指出，AD属于由IgE抗体介导的Ⅰ型超敏反应，涉及到多个过程的免疫反应是AD致病机制的核心。当过敏原入侵皮肤屏障后，被皮肤抗原递呈细胞(antigen-presenting cells, APC)如朗格汉斯细胞和树突细胞摄取，随后APC将过敏原递呈至组织与血液中的初始辅助性T细胞(naive helper T cell, Th0)，并诱导Th0细胞向Th2细胞分化增殖；分化后Th2细胞分泌大量过敏性细胞因子如IL-4、IL-5、IL-13，形成过度的Th2型免疫反应(图1)。一方面，Th2分泌的细胞因子可募集更多Th0细胞并向Th2分化，另一方面，Th2细胞作用于B细胞，诱导其转化为分泌特异性IgE的浆细胞；这些浆细胞来源的IgE将激活皮肤肥大细胞(mast cell, MC)表面的Fc受体，使MC发生脱颗粒，释放大量致敏效应物质组胺(histamine)进入皮肤组织与血液，引起皮肤红肿、瘙痒等系列症状^[37]。组胺是目前研究较为关注的过敏介质，而人体细胞表面已被证实具有4种组胺受体(histamine receptor, HR)，其中H1R和H4R的异常激活是导致AD患者产生瘙痒症状的主要原因^[38]。皮肤肥大细胞释放出的组胺作用于皮肤感觉神经末梢表达的组胺受体，继而激活神经末梢的信号传导，并通过脊髓丘脑束将瘙痒的感觉传递到大脑，导致患者进入瘙痒-抓挠-严重瘙痒的恶性循环^[39]。

2.2 AD的影响因素

AD的发病机制是复杂和多因素的，涉及到遗传易感性、肠道和皮肤微生态失调、局部和全身免疫失衡以及环境因素之间的相互作用^[40]。

2.2.1 遗传易感性

AD具有很强的遗传性^[41]，目前已确定的最大遗传风险与由flg基因编码的皮肤屏障蛋白——微丝蛋白的突变有关^[42]。flg基因突变将导致微丝蛋白表达下降甚至完全丧失^[43]，从而使患AD的风险比未突变人群高3−5倍，同时也增加了哮喘和花生过敏的风险^[44]。此外，位于染色体5q31.1上的基因座包含2型免疫细胞因子IL-4、IL-13的基因以及调控细胞因子表达的rad50基因突变也会引起AD患病风险增高。位于染色体11q13.5上的2个候选基因emsy和lrrc32之间的第3个广泛复制的基因与多种特应性表型相关^[45]。在AD中，迄今已识别有34个基因座突变与疾病发病相关，另外还可能存在其他未识别的基因座或可遗传的表观效应导致AD发病。

2.2.2 微生物组失调

如前文所述，AD患者的皮肤存在表皮屏障功能障碍，表现为经皮水分损失(transepidermal water loss, TEWL)增加、pH升高、皮肤通透性增加、水分保留率降低以及脂质成分改变^[46]，因此也更容易受到细菌感染。S.aureus和Malassezia spp.是主要的定殖菌和病原体，可引发或加剧AD的皮肤炎症^[47-48]。另外，与健康人群相比，患者肠道微生物多样性降低，乳杆菌、双歧杆菌等有益微生物的相对丰度显著降低，而大肠杆菌、艰难梭菌和S.aureus的比例增加。特别在生命早期，肠道微生物的定殖与改变早于临床表现，表明肠道菌群失调也是AD发生的一大影响因素。

2.2.3 免疫反应失衡

过敏反应是一种免疫失调性疾病，Th1/Th2平衡破坏导致Th2细胞亚群及其分泌的细胞因子增多也是AD发生的原因^[49]。在始发阶段，皮肤屏障功能出现障碍，增加了外源性微生物和过敏原的经皮渗透，降低了对抗原和刺激物的炎症阈值；受损表皮中的角质形成细胞通过胸腺基质淋巴生成素(thymic stromal lymphopoietin, TSLP)及IL-33等细胞因子发出促炎和瘙痒信号，激活Th2介导的免疫反应，进一步导致组织损伤^[50]。TSLP通过其受体激活未成熟的树突细胞，促进APC的成熟，同时促进嗜酸性粒细胞的活性，增强IL-4、IL-5和IL-13的表达^[51]，而IL-4及IL-13的上调降低了表皮屏障蛋白的产生，从而加重皮肤屏障缺陷；IL-25可诱导多种趋化因子促进Th2细胞募集^[52]；IL-33通过受体激活核因子κB (nuclear factor kappa-B, NF-κB)及丝裂原激活蛋白激酶，从而刺激与Th2反应相关的细胞因子的产生^[53]。另外，先天淋巴样细胞(innate lymphoid cells, ILCs)能够刺激细胞因子的产生，影响局部组织中的免疫和非免疫细胞。ILC2具有分泌IL4、IL-5和IL-13等促过敏细胞因子的能力，通过启动Th2反应而参与AD等各种过敏性疾病^[54]。

2.2.4 环境因素

宿主所处的生活环境以及生活方式也会影响AD的发生发展，其中气候变化^[55]、空气污染物^[56]、心理压力^[57]、日晒不足^[58]及高硬度水^[59]等被认为是AD发病的驱动因素。研究指出，空气中的屋尘螨、花粉，以及牛奶、蛋清、大豆和花生等常见食物过敏源都是诱发儿童AD及加重疾病最常见的环境刺激物，直接引发免疫异常^[37]。另外，长期暴露在低湿度的环境中会加速AD患者皮肤的水分损失，加重皮肤屏障缺陷^[60]。同时，压力引起的糖皮质激素变化会抑制皮肤神经酰胺、胆固醇和游离脂肪酸的合成，进而破坏了皮肤的疏水屏障导致水分丢失，进一步加重AD并诱发其他皮肤炎症^[61]。

3 益生菌防治AD的机制

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益生菌是一类能够附着在胃肠道黏膜且具有多样化临床及免疫能力的活性微生物^[62]。据报道，目前能减轻Ⅰ型过敏反应的益生菌主要来源于乳杆菌属和双歧杆菌属^[63]。一项使用动物双歧杆菌的随机、双盲安慰剂对照研究发现，8周后益生菌组的受试者瘙痒症状显著改善^[64]。Enomoto等^[65]的研究发现，使用短双歧杆菌后，益生菌组特应性皮炎评分(scoring of atopic dermatitis, SCORAD)指数下降。成人AD患者服用唾液乳杆菌LS01后，益生菌治疗组的SCORD评分显著降低，粪便微生物中葡萄球菌载量减少^[66]。使用副干酪乳杆菌K71后，益生菌组的皮肤严重程度评分降低^[67]。联合使用唾液乳杆菌LS01 DSM 2275和短双歧杆菌BR03 DSM 16604的随机对照试验发现，受试者在临床分数上有显著改善且血浆脂多糖(lipopolysaccharides, LPS)水平有所下降^[68]。此外，孕期及婴儿早期补充鼠李糖乳杆菌HN001似乎可以降低患AD的风险^[69]。本文列举了近年来益生菌防治AD的研究进展(表1)，并对益生菌缓解AD的相关机制进行概述。

3.1 增强屏障功能

AD患者肠道菌群失衡，多样性降低，肠道屏障也出现了类似皮肤的屏障功能受损^[81]。研究指出，益生菌通过上调黏蛋白类糖蛋白(mucin-type glycoprotein, MUC)-1、MUC-2和MUC-3促进杯状细胞的黏蛋白分泌，从而限制病原菌在黏膜中的移动；另外，益生菌分泌的α-防御素、β-防御素等抗菌肽通过上调跨膜紧密连接蛋白和细胞间紧密连接蛋白，增强了紧密连接的稳定性并防止细菌增殖，从而降低上皮对病原体及其产物的通透性^[82]。丁酸等益生菌源短链脂肪酸(short chain fatty acid, SCFA)也有助于调节紧密连接蛋白的表达，增强上皮屏障完整性^[83]。Ma等^[84]发现婴儿双歧杆菌YLGB-1496也表现出良好的抗氧化性能，并能够上调皮肤屏障基因增强皮肤屏障功能。作者所在研究团队也发现发酵乳杆菌XJC60可通过分泌烟酰胺等抗氧化物质，维持皮肤角质层的完整性，具有维系皮肤屏障功能的作用^[85]。

3.2 抑制病原体增殖

多项研究发现，益生菌能够与病原体竞争黏蛋白或上皮细胞的结合位点，防止致病微生物过度生长，纠正AD患者微生态的失调；而益生菌产生的抗菌肽、细菌素及SCFA也具有抑制或杀死病原体的作用(图2)。Fang等^[70]发现植物乳杆菌CCFM8610治疗下调了涉及肠道金黄色葡萄球菌感染的功能基因，通过调节肠道微生物组成以及免疫反应，从而改善AD患者的临床症状。另外，本研究团队也证实人源性长双歧杆菌能分泌新型溶菌酶样蛋白，具有调节机体肠道菌群稳定的生物活性^[86]。此外，益生菌还能够增加胃肠道中IgA的含量，分泌型IgA通过连接病原体的抗原从而保护肠上皮细胞免受定殖或侵袭，诱导抗原向DC的逆向运输，下调促炎反应^[87]。

3.3 调节Th1/Th2免疫应答

益生菌在AD中发挥免疫调节作用，一方面通过分泌不同的细胞因子刺激Th1应答，降低Th2应答来平衡Th1/Th2免疫反应；另一方面在IL-2和TGF-β的作用下能够诱导调节性T细胞分化增殖，下调IgE合成，减少过敏反应，维持免疫稳态^[88]。Won等^[74]发现从泡菜中分离的植物乳杆菌CJLP55能够降低IL-4、IL-5水平，增加IL-10产生，通过平衡Th1/Th2免疫反应缓解小鼠AD样皮损。另外，益生菌还可通过产生SCFA、共轭亚油酸、d-色氨酸和吲哚衍生物发挥免疫调节作用；SCFA诱导肠道树突细胞表达视黄醛脱氢酶，促使维生素A转化为视黄酸从而促进Treg细胞的扩增和分化^[89]。SCFA特别是丁酸能够抑制MC上高亲和力Fc受体与IgE结合所引发的脱颗粒，从而降低组胺等炎症介质的释放，减少过敏反应的发生^[90]。Kim等^[77]的研究发现，植物乳杆菌LM1004能显著降低血清中IgE与组胺水平，增加Th1与Treg细胞转录因子水平以及与丁酸产生相关的菌群丰度，减轻AD模型小鼠的皮肤瘙痒。以上发现均表明，益生菌通过调节宿主免疫系统和肠道菌群对防治AD及相关皮肤过敏性疾病具有很大潜力。

4 结语与展望

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综上所述，flg基因功能缺失突变导致的遗传因素，瘙痒-抓挠-严重瘙痒引起的表皮功能障碍，皮肤及肠道菌群失调，Th1/Th2免疫调节失衡，气候变化、空气污染、社会心理压力等环境影响，这些因素共同作用促进了AD的发生。益生菌通过与病原菌竞争黏附位置、产生细菌素等抗菌物质、阻止细菌生物膜的形成和促进Th1型细胞因子分泌，抑制Th2型细胞因子水平，从而抑制病原菌生长，修复受损皮肤及肠道屏障，促进失衡菌群平衡重建，恢复Th1/Th2免疫失调，最终减轻及改善患者皮肤过敏及临床症状。随着研究的深入，益生菌对AD的作用已在许多临床试验中进行了研究，但益生菌缓解AD的有效物质基础仍不明确。为了阐明益生菌、肠道菌群及皮肤之间具体的互作机制，精准补充益生菌来达到防治AD的作用，需要结合基因组学、转录组学和代谢组学以揭示益生菌对功能基因、肠道菌群、代谢途径以及具体代谢物的影响，全面解析益生菌对AD的缓解机制。为使治疗完全有效，在未来的研究中，也可考虑将益生菌补充剂与局部应用含有益生菌的乳膏相结合，以期开发出新型微生态方法来改善与治疗AD及相关皮肤过敏性疾病。

基金

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国家重点研发计划(2022YFD2100700)
广东省自然科学基金(2022A1515010946)
广东省重点领域研发计划(2022B1111070006)

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2024年第64卷第5期

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doi: 10.13343/j.cnki.wsxb.20230682

接收时间：2023-11-06
首发时间：2026-03-19
出版时间：2024-05-04

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收稿日期：2023-11-06
录用日期：2024-02-20

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National Key Research and Development Program of China(2022YFD2100700)

国家重点研发计划(2022YFD2100700)

Natural Science Foundation of Guangdong Province(2022A1515010946)

广东省自然科学基金(2022A1515010946)

Key-Area Research and Development Program of Guangdong Province(2022B1111070006)

广东省重点领域研发计划(2022B1111070006)

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1 陕西科技大学食品科学与工程学院, 陕西西安 710021

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Strain	Form and dosage	Test sample and quantity	Mechanism	Effect
Lactobacillusrhamnosus HN001	Capsulated probiotic 6×10⁹ CFU/d	157 infants	Shape the immune system and increase IFN-γ level	The prevalence of eczema were significantly reduced^[69]
Lactobacillusplantarum CCFM8610	Lyophilized powder 1×10⁹ CFU/d	109 adult patients	Regulate the gut microbiota; maintain the immune responses and barrier integrity; change in functional genes of the gut microbiota	Improve SCORAD index; increase the expression levels of IL-10; decrease the F/B ratio; increase species evenness and diversity^[70]
Lactobacillusplantarum IS-10506	Microencapsulated probiotic 2×10¹⁰ CFU/d	30 adult patients: 15 controlsvs. 15 interventions	Suppression of the Th2 adaptive immune response and increase in the Th1 adaptive immune response; increase the Treg immune response and decrease Th17 response	The SCORAD score, IL-4, and IL-17 levels were significantly lower; the IFN-γ and Foxp3+ levels were significantly higher^[71]
Lactobacillusrhamnosus IDCC 3201	Tyndallized probiotics 1×10¹⁰ CFU/d	66 children: 33 controlsvs. 33 tests	Decreased production or activity of IL-31 and eosinophils	The SCORAD score, eosinophil count, and the IL-31 levels were decreased^[72]
Lactobacillusparacasei KBL382	Live bacteria 1×10⁹ CFU/d	NC/Nga mice: 7 controlsvs. 7 modelsvs. 7 tests	Increase the immunosuppressive response and change the metabolic functions of gut microbiota	Reduced AD-associated skin lesions, serum levels of IgE, and immune cell infiltration^[73]
Lactobacillusplantarum CJLP55	Lyophilized powder 1×10¹⁰ CFU/d	NC/Nga mice: 8 controlsvs. 8 modelsvs. 8 tests	Alter the balance of Th1/Th2 ratio or induce IL-10 production	Suppressed AD-like skin lesions, high serum IgE levels; diminished the accumulation of eosinophils and mast cells; decreased production of IL-4 and IL-5^[74]
Kazachstaniaturicensis CAU Y1706	Freeze-dried 1×10¹⁰ CFU/d	BALB/c mice: 10 controlsvs. 10 modelsvs. 10 tests	Interactions between gut microbiota, SCFA, and immune modulation between Th1 and Th2	Reduced IgE levels and the number of mast cells and eosinophil; the serum concentrations of Th2 cytokines were significantly lower^[75]
Limosilactobacillusreuteri FN041	Live bacteria 1×10⁹ CFU/d	BALB/c mice: 12 controlsvs. 12 modelsvs. 12 tests	Regulate the ileum microbiota, strengthen the ileal mucosal barrier	The plasma IgE were significantly decreased; the intestinal mucosal barrier was enhanced^[76]
Lactobacillusplantarum LM1004	Lyophilized powder 2×10¹² cells/g 0.01 g/kg-bw	SD rats: 10 controlsvs. 10 modelsvs. 10 tests	Inhibited Th2 cell responses; activated the responses of Treg cell; modulated gut microbiota	Decreased the scratching behaviors; reduced vasodilation and serum histamine; decreased serum IgE contents^[77]
Bifidobacteriumadolescentis	Live bacteria 1×10⁹ CFU/d	C57bl/6 mice: 5 controlsvs. 5 modelsvs. 5 tests	Promote Tregs population in the spleen; restore the balance between Th1- and Th2-type immune responses; regulate the gut microbiota composition	Reduced ear and skin thickness and suppressed eosinophils and mast cells infiltration^[78]
Bifidobacteriumlongum	Cell-free culture supernatant 1×10⁷ CFU/d	Hairless mice: 5 controlsvs. 5 modelsvs. 5 tests	Attenuate skin inflammation and enhance skin barrier function	Attenuated DNCB-induced skin inflammation, abnormal TEWL, AD-like skin, and deficiency of epidermal barrier proteins^[79]
Lactococcuschungangensis CAU 28T	Live bacteria 1×10⁹ CFU/mL	RAW 264.7 cells; human mast cell	Inhibit the release of allergy-associated proteins	Inhibited the production of the proinflammatory mediators; reduced the release of histamine^[80]

Strain

Form and dosage

Test sample and quantity

Mechanism

Effect

Lactobacillusrhamnosus HN001

Capsulated probiotic
6×10⁹ CFU/d

157 infants

Shape the immune system and increase IFN-γ level

The prevalence of eczema were significantly reduced^[69]

Lactobacillusplantarum CCFM8610

Lyophilized powder
1×10⁹ CFU/d

109 adult patients

Regulate the gut microbiota; maintain the immune responses and barrier integrity; change in functional genes of the gut microbiota

Improve SCORAD index; increase the expression levels of IL-10; decrease the F/B ratio; increase species evenness and diversity^[70]

Lactobacillusplantarum
IS-10506

Microencapsulated probiotic
2×10¹⁰ CFU/d

30 adult patients:
15 controlsvs.
15 interventions

Suppression of the Th2 adaptive immune response and increase in the Th1 adaptive immune response; increase the Treg immune response and decrease Th17 response

The SCORAD score, IL-4, and IL-17 levels were significantly lower; the IFN-γ and Foxp3+
levels were significantly higher^[71]

Lactobacillusrhamnosus
IDCC 3201

Tyndallized probiotics
1×10¹⁰ CFU/d

66 children:
33 controlsvs.
33 tests

Decreased production or activity of IL-31 and eosinophils

The SCORAD score, eosinophil count, and the IL-31 levels were decreased^[72]

Lactobacillusparacasei
KBL382

Live bacteria
1×10⁹ CFU/d

NC/Nga mice:
7 controlsvs.
7 modelsvs.
7 tests

Increase the immunosuppressive response and change the metabolic functions of gut microbiota

Reduced AD-associated skin lesions, serum levels of IgE, and immune cell infiltration^[73]

Lactobacillusplantarum
CJLP55

Lyophilized
powder
1×10¹⁰ CFU/d

NC/Nga mice:
8 controlsvs.
8 modelsvs.
8 tests

Alter the balance of Th1/Th2 ratio or induce IL-10 production

Suppressed AD-like skin lesions, high serum IgE levels; diminished the accumulation of eosinophils and mast cells; decreased production of IL-4 and IL-5^[74]

Kazachstaniaturicensis
CAU Y1706

Freeze-dried
1×10¹⁰ CFU/d

BALB/c mice:
10 controlsvs.
10 modelsvs.
10 tests

Interactions between gut microbiota, SCFA, and immune modulation between Th1 and Th2

Reduced IgE levels and the number of mast cells and eosinophil; the serum concentrations of Th2 cytokines were significantly lower^[75]

Limosilactobacillusreuteri FN041

Live bacteria
1×10⁹ CFU/d

BALB/c mice:
12 controlsvs.
12 modelsvs.
12 tests

Regulate the ileum microbiota, strengthen the ileal mucosal
barrier

The plasma IgE were significantly decreased; the intestinal mucosal barrier was enhanced^[76]

Lactobacillusplantarum
LM1004

Lyophilized
powder
2×10¹² cells/g
0.01 g/kg-bw

SD rats:
10 controlsvs.
10 modelsvs.
10 tests

Inhibited Th2 cell responses; activated the responses of Treg cell; modulated gut microbiota

Decreased the scratching behaviors;
reduced vasodilation and serum histamine; decreased serum IgE contents^[77]

Bifidobacteriumadolescentis

Live bacteria
1×10⁹ CFU/d

C57bl/6 mice:
5 controlsvs.
5 modelsvs.
5 tests

Promote Tregs population in the spleen; restore the balance between Th1- and Th2-type immune responses; regulate the gut microbiota composition

Reduced ear and skin thickness and suppressed eosinophils and mast cells infiltration^[78]

Bifidobacteriumlongum

Cell-free culture supernatant
1×10⁷ CFU/d

Hairless mice:
5 controlsvs.
5 modelsvs.
5 tests

Attenuate skin inflammation and enhance skin barrier function

Attenuated DNCB-induced skin inflammation, abnormal TEWL, AD-like skin, and deficiency of epidermal barrier proteins^[79]

Lactococcuschungangensis CAU 28T

Live bacteria
1×10⁹ CFU/mL

RAW 264.7
cells; human mast cell

Inhibit the release of allergy-associated proteins

Inhibited the production of the proinflammatory mediators; reduced the release of histamine^[80]