犬特应性皮炎的皮肤屏障、皮肤微生物群和宿主防御肽的最新进展-2 ...

王帆

Update on the skin barrier, cutaneous microbiome and host defence peptides in canine atopic dermatitis

犬特应性皮炎的皮肤屏障、皮肤微生物群和宿主防御肽的最新进展

 

作者：Domenico Santoro | Manolis Saridomichelakis | Melissa Eisenschenk | Chie Tamamoto-Mochizuki | Patrick Hensel | Cherie Pucheu-Haston | for the International Committee on Allergic Diseases of Animals (ICADA)

 

翻译：叶精精

 

Abstract 摘要

Background: Canine atopic dermatitis (AD) is a complex inflammatory skin disease associated with cutaneous microbiome, immunological and skin barrier alterations. This review summarises the current evidence on skin barrier defects and on cutaneous microbiome dysfunction in canine AD.

背景：犬特应性皮炎（AD）是一种复杂的炎症性皮肤病，与皮肤微生物群、免疫学和皮肤屏障的改变有关。本文综述了目前关于AD患犬皮肤屏障缺陷和皮肤微生物群功能障碍的证据。

Objective: To this aim, online citation databases, abstracts and proceedings from international meetings on skin barrier and cutaneous microbiome published between 2015 and 2023 were reviewed.

目的：为此，我们查阅了 2015 年至 2023 年间发表的有关皮肤屏障和皮肤微生物组的在线引文数据库、摘要和国际会议论文集。

Results: Since the last update on the pathogenesis of canine AD, published by the International Committee on Allergic Diseases of Animals in 2015, 49 articles have been published on skin barrier function, cutaneous/aural innate immunity and the cutaneous/aural microbiome in atopic dogs. Skin barrier dysfunction and cutaneous microbial dysbiosis are essential players in the pathogenesis of canine AD. It is still unclear if such alterations are primary or secondary to cutaneous inflammation, although some evidence supports their primary involvement in the pathogenesis of canine AD.

结果：自国际动物过敏性疾病委员会于 2015 年发布关于犬过敏性疾病发病机制的最新进展以来，已发表了 49 篇关于AD患犬皮肤屏障功能、皮肤/耳道先天性免疫和皮肤/耳道微生物组的文章。皮肤屏障功能障碍和皮肤微生物菌群失调是犬过敏性疾病发病机制中的重要因素。尽管有证据表明皮肤屏障功能障碍和皮肤微生物菌群失调在犬过敏性疾病的发病机制中起着主要作用，但目前还不清楚这种改变是原发性的还是继发性的皮肤炎症。

Conclusion and Clinical Relevance: Although many studies have been published since 2015, the understanding of the cutaneous host–microbe interaction is still unclear, as is the role that cutaneous dysbiosis plays in the development and/or worsening of canine AD. More studies are needed aiming to design new therapeutic approaches to restore the skin barrier, to increase and optimise the cutaneous natural defences, and to rebalance the cutaneous microbiome.

结论和临床意义：尽管自2015年以来已经发表了许多研究，但对皮肤宿主-微生物相互作用的了解尚不清楚，因为皮肤菌群失调在犬AD的发展和/或恶化中也有什么作用。需要更多的研究来设计新的治疗方法来恢复皮肤屏障，增加和优化皮肤的自然防御，并重新平衡皮肤微生物群。

KEYWORDS 

ceramides, cutaneous dysbiosis, filaggrin, host defence peptides

关键词 

神经酰胺，皮肤菌群失调，丝聚合蛋白，宿主防御肽

 

INTRODUCTION 
简介

Canine atopic dermatitis (AD) is a hereditary, generally pruritic and predominantly T-cell-driven inflammatory skin disease involving interplay between skin barrier abnormalities, allergen sensitisation and microbial dysbiosis. In 2015, the International Committee on Allergic Diseases of Animals (ICADA) published a series of articles highlighting the most up-to-date information on the pathogenesis of AD. Since then, many articles have been published on the skin barrier structure, innate immunity and cutaneous and aural microbiome alterations in atopic dogs. These publications are reviewed in this article along with a brief review of the previous literature on these topics. For more detailed information on the previous literature, the reader should refer to the ICADA pathogenesis articles published in 2015.

犬特应性皮炎（AD）是一种遗传的、通常是瘙痒的、主要由T细胞驱动的炎症性皮肤病，涉及皮肤屏障异常、过敏原致敏和微生物菌群失调之间的相互作用。2015年，国际动物过敏性疾病委员会（ICADA）发表了一系列文章，强调了有关AD发病机制的最新信息。从那时起，发表了许多关于AD患犬的皮肤屏障结构、先天免疫，皮肤和耳道微生物群改变的文章发表。本文回顾了这些出版物，并简要回顾了以前关于这些主题的文献。有关既往文献的详细信息，请参考2015年发表的ICADA发病机制文章。

 

Alterations of the skin barrier function are attracting significant interest in veterinary and human dermatology. In the previous edition of this review series, published in 2015, it was made clear that skin barrier dysfunction, along with immunological alterations, represent the core of the pathogenesis of canine AD. Whether skin barrier dysfunction is a primary defect and/or appears secondarily to cutaneous inflammation was, and still is, open to debate. Since that publication, more research has been published on the differences between atopic and healthy canine skin suggesting some primary defects of the barrier, at least in some dogs with AD. Unfortunately, very few studies have compared skin barrier function between AD and other inflammatory, nonallergic skin conditions to determine if these alterations are intrinsic to canine AD or instead the result of a nonspecific cutaneous inflammatory response.

皮肤屏障功能的改变正吸引着兽医和人类皮肤学的重大兴趣。在2015年发表的上一期综述系列中，我们明确指出，皮肤屏障功能障碍和免疫学改变是犬AD发病机制的核心。皮肤屏障功能障碍是否是主要缺陷和/或继发于皮肤炎症，过去和现在仍存在争议。自发表以来，更多关于特应性皮肤和健康犬皮肤之间的差异的研究发表，表明一些屏障的主要缺陷，至少在一些AD犬中是这样。不幸的是，很少有研究比较AD和其他炎症性、非过敏性皮肤疾病之间的皮肤屏障功能，以确定这些改变是犬AD固有的，还是非特异性皮肤炎症反应的结果。

 

The aim of this review was to report updates from research published on skin barrier integrity, host–microbe interaction, as well as the cutaneous and aural microbiome in dogs with AD.

这篇综述的目的是报道关于AD犬的皮肤屏障完整性、宿主-微生物相互作用以及皮肤和耳道微生物群的最新研究。

 

METHODS AND MATERIALS

方法和材料

A literature search for studies on canine AD published between 2015 and 2023 was conducted using PubMed (pubmed.gov), Web of Science (Thomson Reuters), CAB Abstracts (EBSCOhost Research Databases) and CAB Abstracts Archive (EBSCOhost Research Databases). Restrictions (date or language) were not enforced for the article search. Published abstracts from the annual meetings of the European Society of Veterinary Dermatology/European College of Veterinary Dermatology, American Academy of Veterinary Dermatology/ American College of Veterinary Dermatology and the World Congresses of Veterinary Dermatology between 2015 and 2023 were included. A total of 49 articles were selected and summarised below.

利用PubMed（pubmed.gov）、科学网络（汤森路透）、CAB摘要（EBSCOhost研究数据库）和CAB摘要档案（EBSCOhost研究数据库）对2015-2023年发表的犬AD研究进行了文献检索。对文章搜索没有强制执行限制（日期或语言）。包括2015年至2023年欧洲兽医皮肤病学会/欧洲兽医皮肤病学会、美国兽医皮肤病学会/美国兽医皮肤病学会和世界兽医皮肤病学会年会的发表摘要。共选择了49篇文章并总结如下。

 

UPDATES ON SKIN BARRIER EVALUATION

关于皮肤屏障评估的更新

Most research on skin barrier function in dogs has been performed using indirect measures of skin integrity (e.g. trans epiderma water loss [TEWL]), or assessing the epidermal ceramide content or the presence of filaggrin in atopic skin.1 The TEWL has been the parameter most commonly used to indirectly and atraumatically assess the functionality of the skin barrier. However, this methodology has significant limitations being affected by multiple environmental factors (e.g. room temperature and humidity) as per manufacturers' indications. Recently, it has been demonstrated that some TEWL instruments have high inter- and intraobserver variability (VapoMeter; Delfin Technologies Ltd). Such instruments also may not be able to detect alterations in mildly affected dogs, and the reported values may not correlate with the severity of clinical signs in subsets of dogs with AD.2 Larger studies using accurate and precise instruments are needed to verify the results reported previously.

大多数关于犬的皮肤屏障功能的研究都是通过对皮肤完整性的间接测量（例如，经皮失水率[TEWL]），或评估表皮神经酰胺含量或特应性皮肤中丝聚合蛋白的存在。 TEWL是间接和非创伤性评估皮肤屏障功能最常用的参数。然而，根据制造商的指示，这种方法有显著的限制，但会受到多种环境因素（如室温和湿度）的影响。最近，有研究表明，一些TEWL仪器具有很高的观察者间和观察者内差异性。这种仪器也可能无法检测轻度感染犬的变化，并且报告的值可能与AD犬亚群的临床症状的严重程度无关。需要使用精确精确的仪器进行更大规模的研究来验证以前报道的结果。

 

Since the last series of ICADA updates on the pathogenesis of canine AD, no methodologies able to directly assess the skin barrier integrity have been optimised in either humans or in dogs. TEWL assessment remains the most widely used method. Owing to the variability of this methodology, other techniques have been investigated. A pilot study showed that the use of the Corneometer (Courage+Khazaka electronic GmbH) to assess skin hydration and of the pH meter (Courage+Khazaka electronic GmbH) for the measurement of the cutaneous pH had more reliable results with a lower inter- and intraobserver variability compared to the VapoMeter (Delfin Technologies Ltd).2 In the same study, the authors showed that the Colorimeter (Courage+Khazaka electronic GmbH), to assess the degree of erythema and the pH meter were able to detect significant differences in nonlesional atopic skin when compared to healthy skin. These results may suggest a lower sensitivity for the VapoMeter when compared to the other instruments. Because of increased sensitivity and reliability of newer instruments, the concurrent assessment of cutaneous pH, hydration, erythema and TEWL versus just the evaluation of TEWL alone has been the preferred noninvasive approach to assess skin barrier integrity in dogs. Using these methods, newer studies tried to correlate the degree of skin barrier dysfunction with the clinical severity of AD. A recent study assessed the skin microbiome and cutaneous barrier integrity in atopic dogs during and after a flare. The authors showed that the TEWL (as measured with a TEWA-meter; Courage+Khazaka electronic GmbH) positively correlated with the clinical severity of the disease,3 while there was a negative correlation between pH (via the pH meter) and severity of the clinical signs.

自从上一系列关于犬AD发病机制的ICADA更新以来，没有一种能够直接评估人类或犬类的皮肤屏障完整性的方法得到优化。TEWL评估仍然是应用最广泛的方法。由于这种方法的可变性，人们已经研究了其他技术。一项初步研究表明，使用角膜仪评估皮肤水合作用和pH计测量的皮肤pH。在同一研究中，作者发现色度仪评估皮肤异常发红程度，pH仪能够检测到与健康皮肤相比非病变性特应性皮肤的显著差异。这些结果可能表明，与其他仪器相比，蒸汽计的灵敏度较低。由于新仪器的敏感性和可靠性提高，同时评估皮肤pH、水合、皮肤异常发红和TEWL，而不是单独评估TEWL（一直是评估犬皮肤屏障完整性的首选非侵入性方法）。使用这些方法，较新的研究试图将皮肤屏障功能障碍的程度与AD的临床严重程度联系起来。最近的一项研究评估了AD患犬在疾病爆发期间和之后的皮肤微生物群和皮肤屏障完整性。作者发现，TEWL（用TEWA表记录）与疾病的临床严重程度呈正相关，而pH（通过pH仪）与临床症状的严重程度呈负相关。

 

UPDATES ON STRATUM CORNEUM LIPIDS

角质层脂质的更新

Keratinocytes, representing the major cell type forming the epidermis, are embedded in the cement of a well-organised lipid layer that covers each corneocyte and functions as a seal between cells. As part of the lipid component of the skin barrier, ceramides have been intensively investigated over the years. Their amount, spatial organisation and diversity are essential for the integrity of the skin barrier. Most of the studies on ceramides were done in the first decade of the twenty-first century. These studies showed that, in both humans and dogs, a significant reduction in ceramide amount and/or types is present in lesional and nonlesional skin of atopic patients when compared to healthy skin. Such reduction in ceramide composition has been attributed, in part, to the inflammatory response triggered by allergen exposure in sensitised individuals. The ceramides most frequently found to be altered in AD, when compared to healthy controls, include ceramide 1/CER[EOS], ceramide 9/CER[EOP] and ceramide CER[NP].These findings were demonstrated in both experimentally sensitised and naturally affected5 atopic dogs.

角质形成细胞是形成表皮的主要细胞类型，嵌在脂质层中，起着细胞之间的密封作用。神经酰胺作为皮肤屏障的脂质成分的一部分，多年来一直被深入研究。它们的数量、空间组织性和多样性对皮肤屏障的完整性至关重要。大多数关于神经酰胺的研究都是在21世纪的头十年里完成的。这些研究表明，与健康皮肤相比，在人类和犬中，特应性疾病患者的病变和非病变皮肤中神经酰胺的数量和/或类型显著减少。神经酰胺成分的减少归因于个体暴露于过敏原致敏引发的炎症反应。与健康对照组相比，AD中最常发生改变的神经酰胺包括神经酰胺1/CER[EOS]、神经酰胺9/CER[EOP]和神经酰胺CER[NP]。这些发现在实验致敏和自然感染的AD患犬中都得到了证实。

 

A recent small study in 2018 which investigated the relative abundance of each ceramide, the total lipid content and the stratum corneum (SC) organisation in healthy and atopic dogs challenged previous results. In particular, the authors showed that the SC of atopic dogs is characterised by a hexagonal lipid packing instead of the classic orthorhombic packing characterising the lamellar organisation of lipids in healthy skin. This alteration was accompanied by a decrease in the relative abundance of free fatty acids (and not of ceramides or cholesterol) in atopic compared to healthy skin. Neither relative abundance of several ceramide subclasses nor total ceramide content differed between atopic and healthy skin. However, a decreased ratio of CER[NS] C44/C34 was seen in atopic skin. The ratio of CER[NS] C44/C34 showed a nonlinear negative correlation with the clinical severity of AD.

2018年的一项小型研究调查了健康和AD患犬中每种神经酰胺的相对丰度、总脂质含量和角质层（SC）组织，对之前的结果提出了质疑。特别是，作者指出，AD患犬的SC的特征是六角形脂质堆积，而不是健康皮肤的脂质层状组织经典的正交晶体堆积。与健康皮肤相比，特应性皮肤中这种改变伴随着游离脂肪酸（而不是神经酰胺或胆固醇）的相对丰度的下降。在特应性皮肤和健康皮肤之间，几种神经酰胺亚类的相对丰度和总神经酰胺含量都没有差异。然而，在特应性皮肤中，CER[NS] C44/C34的比例下降。CER[NS] C44/C34的比值与AD的临床严重程度呈非线性负相关。

 

In summary, not many new studies have been published evaluating the ceramide composition in the SC of atopic dogs. However, although small in size (only three healthy and five atopic dogs were included), the study by Chermprapai et al. opened a new perspective on the potential involvement of lipid disturbances in the pathogenesis of canine AD. The importance of this study resides in the concept that the spatial organisation and carbon atom composition of ceramide may be as important as the amount of ceramides present in the SC of atopic skin.

综上所述，关于AD患犬SC中神经酰胺组成的研究和神经酰胺组成尚未发表。然而，尽管体量很小（只有3只健康犬和5只AD患犬），Chermprapai等人的研究为脂质紊乱可能参与犬AD的发病机制开辟了一个新的视角。这项研究的重要性在于，神经酰胺的空间组织和碳原子组成可能与特应性皮肤SC中神经酰胺的数量一样重要。

 

UPDATES ON STRATUM CORNEUM STRUCTURAL PROTEINS

角质层结构蛋白的最新进展

Along with lipids, structural proteins such as filaggrin, filaggrin 2, involucrin and corneodesmosin are essential for the formation of the cornified envelope. Filaggrin has attracted much attention in the past two decades for its role in human AD. In people, while not present in all patients, filaggrin gene mutations have been recognised as one of the most reliable genetic factors predisposing to the development of AD. In a subset of dogs with AD, a decrease in or an undetectable expression of epidermal filaggrin has been demonstrated via immunofluorescence. Mutations of the filaggrin gene have not been associated with canine AD in most of the breeds in which this gene has been evaluated. However, a single-nucleotide polymorphism in the filaggrin gene was strongly associated with AD in Labrador retrievers from the UK, suggesting the potential role of filaggrin in specific breeds and geographical locations. Such findings may help explain breed-specific phenotypes in canine AD. Because of these contrasting data, although filaggrin is recognised as an important component of the skin barrier, its involvement in the pathogenesis of AD remains unknown.

与脂质一样，结构蛋白如丝聚合蛋白、丝聚合蛋白2、外皮蛋白和角桥粒是角化包膜的形成所必需的。在过去的二十年里，丝聚合蛋白因其在人类AD中的作用而引起了人们的广泛关注。在人群中，虽然不是所有患者，但丝聚合蛋白基因突变被认为是诱发AD发展的最可靠的遗传因素之一。在一部分患有AD的犬中，通过免疫荧光证实了表皮丝聚合蛋白的表达减少或检测不到。在该基因已被评估的大多数品种中，丝聚合蛋白基因的突变尚未与犬AD相关。然而，在来自英国的拉布拉多猎犬中，丝聚合蛋白基因的单核苷酸多态性与AD密切相关，提示丝聚合蛋白可能在特定品种和地理位置发挥作用。这些发现可能有助于解释犬AD的品种特异性表型。由于这些对比性的数据，尽管丝聚合蛋白被认为是皮肤屏障的重要组成部分，但其在AD发病机制中的作用尚不清楚。

 

In recent years, investigation of the canine filaggrin structure has resulted in the identification of a very similar S100 fused-type protein, called filaggrin 2. Filaggrin 2, like filaggrin, is involved in the production of natural moisturising factors (NMFs), and also is an integral component of the cornified envelope. Because of the poor characterisation of canine filaggrin, it is likely that some of the older studies suggesting an alteration of filaggrin expression in atopic skin were actually investigating filaggrin 2 rather than filaggrin. Controversial results have been published after 2015 on the expression of the enzymes involved in the degradation of filaggrin in atopic dogs. One immunohistochemical study showed decreased caspase-14 in the nonlesional skin of atopic dogs when compared to healthy dogs, while another study showed increased expression of calpain-1, caspase-14 and matriptase in nonlesional skin of atopic dogs compared to healthy breed-matched dogs.

近年来，对犬丝聚合蛋白结构的研究发现了一种非常相似的S100融合型蛋白，称为丝聚合蛋白2。丝聚合蛋白2和丝聚合蛋白一样，参与天然保湿因子（NMFs）的产生，也是角化包膜的重要组成部分。由于犬丝聚合蛋白的特征较差，一些较早的研究表明特应性皮肤中丝聚合蛋白表达发生改变的研究实际上是在研究丝聚合蛋白2，而不是丝聚合蛋白。2015年以后，在AD患犬中参与丝聚合蛋白降解的酶的表达发表了有争议的结果。一项免疫组化研究显示，与健康犬相比，AD患犬非病变皮肤中半胱天冬酶-14减少，而另一项研究显示，与健康犬相比，AD患犬非病变皮肤中钙蛋白酶-1、半胱天冬酶-14和蛋白裂解酶的表达增加。

 

Thus, current data on the involvement of filaggrin and filaggrin 2 in the pathogenesis of canine AD remain controversial. It is still unknown if the demonstrated alterations of these proteins, enzymes and NMFs represent a primary defect or are secondary to an inflammatory state. A very recent study, using experimentally sensitised atopic dogs, indirectly suggested that some of these alterations may be a result of cutaneous allergic inflammation rather than being a primary defect.

因此，目前关于丝聚合蛋白和丝聚合蛋白2参与犬AD发病机制的数据仍存在争议。目前尚不清楚这些蛋白、酶和NMF的改变是一种原发性缺陷还是继发于炎症状态。最近的一项研究，使用实验性AD患犬，间接表明这些改变可能是皮肤过敏性炎症的结果，而不是原发性缺陷。

 

Along with filaggrins and NMFs, other structural proteins that have been studied in atopic dogs and humans include the tight junction proteins claudin-1 and occludin. Both proteins have been shown to be significantly decreased in the skin of atopic dogs when compared to healthy canine skin, further highlighting the impaired skin barrier in dogs with AD. Recently, using an experimental model of acute canine AD, authors have shown a decrease in protein expression and distribution of corneodesmosin, another structural protein present in the SC, in atopic skin when compared to healthy skin. The authors were able to demonstrate that, of five structural proteins examined (E-cadherin, desmocollin-1, desmoglein-1, corneodesmosin and claudin-1), the immunoreactivity of both corneodesmosin and claudin-1 was heterogenous and of reduced intensity after a single house dust mite (HDM) epicutaneous challenge.

除了丝聚合蛋白和NMF外，已经在AD患犬和人类中研究过的其他结构蛋白包括紧密连接蛋白-1和闭合蛋白。与健康犬皮肤相比，这两种蛋白在AD患犬的皮肤中均显著降低，进一步突出了AD犬的皮肤屏障受损。最近，作者使用犬急性AD的实验模型发现，与健康皮肤相比，特应性皮肤中另一种结构蛋白角桥粒的蛋白表达和分布减少。作者能够证明，在检测的五种结构蛋白（E-钙黏素,桥粒胶蛋白-1, 桥粒芯蛋白-1, 角桥粒和紧密连接蛋白-1）中，角桥粒和紧密连接蛋白-1 的免疫反应性均为异质性，在单个屋尘螨（HDM）表皮刺激后强度降低。

 

In summary, much is still left to learn about the involvement of structural proteins in the pathogenesis of canine AD. Filaggrin is the most extensively studied structural protein associated with both human and canine AD. However, other studies have demonstrated the involvement of additional structural components of the SC (and viable epidermis) in the alteration of the skin barrier in AD. Of particular interest are alterations of the tight junctions and corneodesmosomes. More recently, in human AD, the involvement of other junctional structures, such as the gap and adherens junctions, has been proposed as another cause of disrupted skin barrier in AD. Such studies point to more complex structural changes of the skin barrier in AD that go beyond filaggrin and ceramides and warrant a more in-depth investigation.

综上所述，关于结构蛋白在犬AD发病机制中的作用还有很多研究有待了解。丝聚合蛋白是研究最广泛的与人类和犬AD相关的结构蛋白。然而，其他研究表明，SC（和有活力的表皮）的其他结构成分参与了AD患者皮肤屏障的改变。特别有趣的是紧密连接和角桥粒的改变。最近，在人类AD中，其他连接结构的参与，如间隙和粘附连接，被认为是AD中皮肤屏障破坏的另一个原因。这些研究指出，AD患者皮肤屏障的更复杂的结构变化，超出了丝聚合蛋白和神经酰胺，值得进行更深入的研究。

 

UPDATES ON CUTANEOUS MICROBIOME

皮肤微生物组更新

Mammalian skin is covered by micro-organisms (bacteria, fungi, parasites and archaeans) that play a significant role in the maintenance and integrity of the skin barrier, as well as constantly interacting with the local immune system. As part of the cutaneous barrier, the skin microbiome and its alterations (cutaneous dysbiosis, defined as an imbalance in the composition of microbial population associated with reduction in microbial diversity and in the number of beneficial bacteria) have been of central interest in the past decades. Multiple studies have demonstrated that both dogs and humans with AD suffer from cutaneous dysbiosis.Whether the dysbiosis is a cause or a consequence of the atopic state remains unclear. However, a recent birth cohort study sampling 109 puppies and 34 parent dogs from Switzerland showed that although the development of skin microbiota (bacterial and fungal) is influenced by both age and environmental factors (e.g. level of hygiene), it is not associated with the development of AD. At the time of the previous edition of this article series, very little was known about cutaneous dysbiosis in dogs with AD. The most common finding was that a decrease in bacterial diversity is present in atopic canine skin when compared with healthy skin. This decreased diversity favours the insurgence and relative predominance of Staphylococcus pseudintermedius above other organisms, with the potential for development of skin infections.

哺乳动物皮肤表面覆盖有微生物群（细菌、真菌、寄生虫和古细菌），这些微生物在皮肤屏障的维护和完整性方面发挥着重要作用，并不断与局部免疫系统相互作用。作为皮肤屏障的一部分，皮肤微生物群及其改变（皮肤菌群失调，定义为与微生物多样性和有益细菌数量减少相关的微生物群组成失衡）在过去几十年里受到关注。多项研究表明，患AD的犬和人类都有皮肤菌群失调。这种菌群失调是特应性疾病的原因还是结果尚不清楚。然而，最近一项对瑞士的109只幼犬和34只父母犬出生队列的研究表明，尽管皮肤微生物群（细菌和真菌）的发展受到年龄和环境因素（如卫生水平）的影响，但它与AD的发展无关。在这篇文章的前一版本，对AD犬的皮肤菌群失调知之甚少。最常见的发现是，与健康的皮肤相比，AD患犬皮肤中的细菌多样性有所下降。这种多样性的减少有利于假中间型葡萄球菌的激增和相对优势高于其他微生物，并有发展为皮肤感染的可能性。

 

In the past decade, the cutaneous and gastrointestinal microbiome has been intensively studied; thanks to the widespread availability of technology capable of performing high-throughput sequence analysis. With the advent of next-generation sequencing (NGS) technology, publications on the microbiome (mainly bacterial and fungal) in both dermatological and nondermatological conditions of humans and animals have exponentially increased. In veterinary dermatology, studies have been mainly focused on canine AD.

在过去的十年里，人们对皮肤和胃肠道微生物进行了深入的研究；由于能够进行高通量序列分析的技术的广泛应用。随着下一代测序（NGS）技术的出现，有关人类和动物的皮肤病和非皮肤病的微生物组（主要是细菌和真菌）的出版物呈指数级增加。在兽医皮肤科中，研究主要集中在犬AD上。

 

Previous studies have shown that the cutaneous microbiome in healthy dogs is highly diverse. In the course of AD, the microbial diversity is significantly reduced in favour of staphylococcal organisms, leading to cutaneous dysbiosis. The significant increase in the relative abundance of S.pseudintermedius in AD associated pyoderma also was shown in a very recent study, in which samples were collected from atopic dogs with active bacterial folliculitis. The microbiome analysis showed a significant reduction in microbial diversity in favour of S.pseudintermedius in both pustules and epidermal collarettes. However, the other bacterial components of the ‘normal’ microbiota were still present, albeit in much reduced numbers.

先前的研究表明，在健康的犬的皮肤微生物群是高度多样化的。在AD的过程中，微生物多样性显著减少，有利于葡萄球菌微生物，导致皮肤菌群失调。最近的一项研究中，从活跃的毛囊炎AD患犬身上采集的样本显示，AD相关脓皮病的病例中假中间型葡萄球菌的相对丰度显著增加。微生物组分析显示，脓疱和表皮环中的微生物多样性显著减少，有利于假中间型葡萄球菌。不过，“正常”微生物群中的其他细菌成分仍然存在，但数量大大减少。

 

The body of literature on canine cutaneous microbiome has significantly increased in the past 5–10years, yet most of the published data in canines are still more descriptive than mechanistic in nature. Efforts to clarify the role of microbiome in AD have used both experimentally and naturally sensitised atopic dogs. Overall, published studies suggest that dogs with AD have lower relative diversity in bacterial and fungal populations than do healthy dogs. An increased relative abundance of S.pseudintermedius and Malassezia pachydermatis has been reported on the skin of atopic dogs when compared to healthy dogs. Similar results were found in a recent study using an experimental model for canine AD. In this study, the authors experimentally sensitised 14-month-old Beagle dogs (n=6) to Dermatophagoides farinae for 12weeks. At the end of the sensitisation period, relative abundances of Firmicutes followed by Proteobacteria, Actinobacteria, Bacteroidetes and Tenericutes were detected. However, because it was outside of the scope of work, the authors did not assess any correlation between bacterial dysbiosis and development of clinical signs or immunological alterations developing in this model.

在过去的5-10年里，关于犬类皮肤微生物组的文献显著增加，但大多数发表的犬类数据在本质上仍然更具描述性，而不是机制性。为了澄清微生物组在AD中的作用，已经使用了实验和自然敏感的AD患犬。总的来说，已发表的研究表明，患有AD的犬在细菌和真菌种群方面的相对多样性低于健康的犬。据报道，与健康犬相比，AD患犬的皮肤上假中间型葡萄球菌和厚皮马拉色菌的相对丰度增加。在最近的一项使用犬AD实验模型的研究中也发现了类似的结果。在这项研究中，作者让14个月大的比格犬（6只）对粉尘螨致敏12周。在敏化期结束时，相对丰度依次为检测到厚壁菌门、变形菌门、放线菌、拟杆菌门和软壁菌门。然而，由于它超出了工作范围，作者没有评估细菌菌群失调与临床症状或免疫改变之间的任何相关性。

 

The temporal changes of the cutaneous bacterial and fungal microbiota of dogs with AD were assessed in two recent studies. Meason-Smith et al. assessed the temporal changes in the cutaneous mycobiota of naturally and allergen-induced AD under certain circumstances (e.g. exposure to HDM). Although a change in Malassezia population was not found in atopic dogs exposed to HDM, a difference in Malassezia spp. was seen between atopic (predominance of M.pachydermatis) and healthy (predominance of M.globosa) dogs. Similar findings were reported in another study, by the same group of researchers, assessing temporal changes of the cutaneous bacterial community using atopic dogs experimentally sensitised and challenged with HDM. The authors showed no changes in bacterial richness or diversity during the challenge; yet, there was an increase in the relative abundance of Corynebacteriaceae and Staphylococcaceae in the lesional skin which persisted for twoweeks after the remission of skin lesions.

最近的两项研究评估了AD犬皮肤细菌和真菌微生物群的时间变化。Meason-Smith等人评估了在某些情况下（如暴露于HDM），自然和过敏原诱导的AD的皮肤真菌菌群的时间变化。虽然在暴露于HDM的AD患犬中没有发现马拉色菌种群的变化，但马拉色菌种群存在差异。在AD患犬（以厚皮马拉色为主）和健康犬（以球形马拉色为主）之间可见。在另一组研究人员进行的另一项研究中也报道了类似的发现，该研究人员使用实验性过敏犬和暴露HDM的AD患犬来评估皮肤细菌群落的时间变化。作者显示在激发期间细菌的丰富度和多样性没有变化；然而，病变皮肤中棒状杆菌科和葡萄球菌科的相对丰度增加，在病变缓解后持续两周。

 

To date, studies have not been able to determine the exact role of the cutaneous microbiome and its dysbiosis in the pathogenesis of AD, yet it is clear that the alterations of bacterial diversity correlate with skin barrier dysfunction, as measured by TEWL and pH. It also is clear that the loss of cutaneous microbiome diversity is strongly associated with the presence of pyoderma in atopic dogs. In fact, another longitudinal study using privately owned atopic dogs showed that the skin microbiome diversity significantly increased immediately after resolution of a flare and/or of a bacterial infection, becoming more like that of healthy skin. However, by 4–6weeks post-treatment, the diversity had slowly decreased to become, once again, significantly lower when compared to healthy skin. This decrease in microbiome diversity strongly correlated with the increase in relative abundance of S.pseudintermedius, which also correlated with the severity of the clinical signs of AD.

迄今为止，研究还不能确定皮肤微生物群及其失调在AD发病机制中的确切作用，但根据TEWL和pH的测量，细菌多样性的改变与皮肤屏障功能障碍相关。也很明显，皮肤微生物群多样性的丧失与AD患犬中脓皮病的存在密切相关。事实上，另一项使用家养AD患犬的纵向研究表明，在病情发作和/或细菌感染消失后，皮肤微生物群落的多样性立即显著增加，变得更像健康的皮肤。然而，在治疗后4-6周，与健康皮肤相比，多样性已经缓慢下降，再次显著降低。这种微生物群多样性的减少与假中间型葡萄球菌相对丰度密切相关，这也与AD临床症状的严重程度相关。

 

UPDATES ON AURAL MICROBIOME

关于耳道微生物组的更新

Recently, greater interest has been devoted to aural microbiome and how its dysbiosis relates to canine AD. The results of these studies showed that, in a similar way to the skin, a dysbiosis characterised by a lower species diversity also is present in the external ear canals of dogs with AD. However, as for the skin, is not known if such dysbiosis predisposes atopic dogs to develop otitis. In a recent comparative study, a significant difference was found in the microbiome of the external ear canal in healthy (n = 9) and atopic (n = 11) dogs without signs of otitis externa. The latter had a significantly higher relative abundance of Staphylococcus spp. (Firmicutes) and of Ralstonia spp. (Proteobacteria) organisms. By contrast, a higher relative abundance of Escherichia spp. organisms was found in healthy compared to atopic ears. Although the relative abundance of Firmicutes has been repeatedly found to be altered, this is the first study showing an alteration in the proteobacterium Ralstonia spp. Ralstonia is widely recognised to be an environmental organism, and for this reason, more studies are needed confirming its relevance in canine AD.

近年来，人们对耳道微生物群及其菌群失调与犬AD之间的关系产生了更广泛的关注。这些研究结果表明，与皮肤类似，AD犬的外耳道也存在以物种多样性较低为特征的菌群失调。然而，至于皮肤，目前尚不清楚这种菌群失调是否容易使AD患犬发展为耳炎。在最近的一项比较研究中，发现无外耳炎症状的健康（9只）犬和特应性（11只）犬的外耳道微生物群存在显著差异。后者的葡萄球菌属（厚壁菌门）和罗尔斯顿菌属（变形菌门）微生物的相对丰度显著较高。相比之下，与特应性疾病患耳相比，在健康犬耳中发现的埃希氏菌属微生物的相对丰度更高。虽然厚壁菌门的相对丰度已被反复发现发生改变，但这是第一个研究显示变形菌门罗罗尔斯顿菌的改变。罗尔斯顿菌属被广泛认为是一种环境生物，因此，需要更多的研究来证实其在犬AD中的相关性。

 

A second study from Europe confirmed the results reported by Ngo et al., by simultaneously assessing the aural and cutaneous microbiome of atopic without skin infection (n=12) and healthy (n=12) German shepherd dogs. In this study, Apostolopoulos et al. sampled multiple body regions (left axilla, left front dorsal interdigital region, left side of the groin and left external ear canal). After performing NGS, the authors were able to show no difference in bacterial diversity among the different body sites of healthy dogs. In these dogs, the most abundant bacterial phyla, in descending order, included Actinobacteria, Proteobacteria, Firmicutes and Bacteroidetes. In atopic dogs, there also was no difference in bacterial diversity among body sites with the most abundant organisms belonging to the phyla Proteobacteria and Actinobacteria, followed by Firmicutes and Bacteroides. Finally, when the microbiome of atopic dogs was compared to the microbiome of healthy dogs, there was no difference in bacterial diversity, although bacterial community richness of the former was lower in the axillary region. The authors concluded that atopic German shepherd dogs have a different bacterial community composition and a lower diversity when compared to healthy dogs of the same breed.

来自欧洲的另一项研究同时评估无皮肤感染的AD患犬（12只）和健康（12只）的德国牧羊犬的耳道和皮肤微生物群，证实了Ngo等人报道的结果。在这项研究中，Apostolopoulos等人研究了多个机体区域（左腋窝、左前背指间区、左侧腹股沟和左侧外耳道）。在进行NGS后，作者发现健康犬不同机体部位的细菌多样性没有差异。在这些犬中，最丰富的细菌门，按降序排列，包括放线菌门、变形菌门、厚壁菌门和拟杆菌门。在AD患犬中，不同部位的细菌多样性也无差异，微生物数量最多的变形菌门和放线菌门，其次是厚壁菌门和拟杆菌门。最后，将AD患犬的微生物群与健康犬的微生物群进行比较，虽然前者的腋窝区细菌群落丰富度较低，但发现细菌多样性无差异。作者得出结论，与同品种的健康犬相比，特应性德国牧羊犬具有不同的细菌群落组成和较低的多样性。

 

In 2020, Tang et al. confirmed the results previously reported for both skin and ear microbiome, using a cohort of 172 healthy and 160 ‘clinically affected’ dogs. In that study, the authors defined as ‘clinically affected’ dogs with AD, with ‘skin allergies’, with nonhealing wounds, with wounds with and without biofilm formation, with pustules/ulcers/erosions or with other not precisely defined skin infections. At the end of the study, the researchers showed a significantly different bacterial microbiome on the skin of ‘clinically affected’ dogs with 16 bacterial species being relatively more abundant compared with healthy skin. The most abundant bacteria and fungi present on the skin of healthy dogs included Cutibacterium acnes, S.pseudintermedius, Porphyromonas cangingivalis, Capnodiales, unclassified fungal species and Alternaria sp. The most abundant species present on the skin of ‘clinically affected’ dogs included S.pseudintermedius and S.schleiferi. Bacteroides pyogenes and Peptoniphilus grossensis also were significantly more abundant in ‘clinically affected’ dogs than healthy dogs. As far the aural microbiome, 19 bacterial species and M.pachydermatis were relatively more abundant in the ears of ‘clinically affected’ dogs than healthy dogs. The top three most dominant bacteria in healthy ear samples included C. acnes, S.pseudintermedius, Streptococcus sp. and the top three most dominant fungi included M.pachydermatis, Capnodiales and Pleosporales. The most common organisms isolated from the ears of ‘clinically affected’ dogs included M.pachydermatis, S.pseudintermedius, S. schleiferi and a few anaerobic bacteria such as Finegoldia magna, Peptostreptococcus canis and P. cangingivalis.

2020年，Tang等人利用172只健康犬和160名“临床患病”的犬，证实了之前报道的皮肤和耳道微生物群的结果。在该研究中，作者定义了患有“皮肤过敏”、伤口不愈合、伤口有或没有形成生物膜、有脓疱/溃疡/糜烂或其他不精确定义的皮肤感染。在研究结束时，研究人员展示了“临床患病”的犬的皮肤上的细菌微生物组，与健康的皮肤相比，有16种细菌相对更丰富。健康犬皮肤上最常见的细菌和真菌包括痤疮丙酸杆菌、假中间型葡萄球菌、链球菌和前三种真菌包括厚皮马拉色菌、煤炱目和腔菌目。从“临床感染”犬的耳道中分离出的最常见的微生物包括厚皮马拉色菌、假中间型葡萄球菌、施氏葡萄球菌和一些厌氧菌，如如大芬戈尔德菌、犬消化链球菌和沧龈假单胞菌。

 

THERAPY AND CUTANEOUS MICROBIOME

治疗和皮肤微生物组

Finally, two studies evaluated the effect of topical antimicrobial therapy and phototherapy on the cutaneous microbiome of dogs with AD. The first study was a very small pilot study assessing the microbiome in three atopic and three healthy dogs over 11weeks. Dogs were sampled fourweeks before (Day 0), then bathed twice weekly with a chlorhexidine-miconazole containing shampoo (Malaseb shampoo; Dermcarevet Pty Ltd) for threeweeks (weeks 4–7), and finally retested fourweeks after the discontinuation of the shampoo therapy (week 11). The authors reported no difference in bacterial microbiome diversity over time in either group. On the contrary, a decrease diversity in fungal microbiome (particularly organisms of the genus Epicoccum and Blumeria) on healthy and atopic skin was seen after the shampoo therapy (week 7) to then increase at the end of the study (week 11).

最后，两项研究评估了外部抗微生物治疗和光疗对AD犬皮肤微生物群的影响。第一项研究是一项非常小的试点研究，在11周内评估3只AD患犬和3只健康犬的微生物群。犬在4周（第0天）前取样，然后每周用含氯己定-咪康唑的香波洗澡3周（第4-7周），最后在停止香波治疗4周后重新测试（第11周）。作者报告了两组患者的细菌微生物组多样性随时间的推移没有差异。相反，在香波治疗（第7周）后，健康和特应性皮肤上的真菌微生物群（特别是附球菌属和白粉病菌属）的多样性减少，然后在研究结束时（第11周）增加。

 

The second study assessed the effects of a phototherapy protocol, implementing the use of a UVB-light skin therapy system (308nm excimer light) applied weekly for two months, on the cutaneous microbiome of atopic (n=10) dogs. In this study, dogs were allowed to be on other treatments for AD (e.g. lokivetmab, oclacitinib, topical antimicrobials) if initiated at least three months before the study. At the end of the study, phototherapy was associated with a significantly increased relative abundance of Actinobacteria and Cyanobacteria in atopic dogs. In addition, phototherapy resulted in an overall decrease in S.pseudintermedius in atopic dogs.

第二项研究评估了光疗法方案的影响，实施使用UVB光皮肤治疗系统（308nm准分子光），每周应用于两次，对特应性皮炎（10只）犬的皮肤微生物组。在这项研究中，在研究前三个月，犬被允许接受其他治疗（如洛基维特单抗、奥拉替尼、外用抗菌素）。在研究结束时，光疗与AD患犬中放线菌和蓝藻细菌的相对丰度显著增加相关。此外，光疗导致了AD患犬的假中间型葡萄球菌的总量减少。

 

SUMMARY OF CUTANEOUS MICROBIOME

皮肤微生物组总结

In summary, in the past 10years, the amount of literature on the cutaneous and aural microbiome in canine AD has significantly increased. Many studies have reported a significant dysbiosis on the skin and in the external ear canals of atopic dogs with a predominance of staphylococcal organisms compared to healthy dogs. However, as mentioned before, if the dysbiosis is a cause or a consequence of the AD status is undetermined at this time. Additionally, researchers have started to look into the effects of topical therapy (shampoo versus phototherapy) on cutaneous microbiome. These studies include a very small number of dogs and the results should be interpreted cautiously. They are an indication that larger studies are needed to assess the effect of the topical antimicrobial therapy on the microbiome of atopic dogs.

综上所述，在过去的10年里，关于AD患犬皮肤和耳道微生物群的文献数量显著增加。许多研究报道，与健康犬相比，AD患犬的皮肤和外耳道存在明显的葡萄球菌失调。然而，如前所述，菌群失调是AD状态的原因或结果，目前尚不确定。此外，研究人员已经开始研究局部治疗（香波和光疗法）对皮肤微生物群的影响。这些研究包括非常少量的犬，结果应该谨慎解释。这表明，需要进行更大规模的研究来评估局部抗菌治疗对AD患犬微生物群的影响。

 

UPDATE ON HOST DEFENCE PEPTIDES

宿主防御肽的最新进展

Along with the structural changes of the cutaneous barrier described above, alterations of the chemical and immunological barriers also have been investigated in atopic dogs. In particular, the role that host defence peptides (HDPs; also known as antimicrobial peptides) play in AD has been extensively studied in humans and to some extent in dogs as well. Several studies identified altered amounts of HDPs in lesional and nonlesional canine atopic skin. However, studies are needed to assess if these alterations are due to a compromised mechanism of production and secretion or because of structural changes of HDPs in atopic dogs.

随着上述皮肤屏障的结构变化，AD患犬化学和免疫屏障的改变也被研究。特别是，宿主防御肽（HDP；也被称为抗菌肽）在AD中的作用已经在人类和一定程度上在犬中也得到了广泛的研究。一些研究发现了犬特应性皮炎病变皮肤和非病变皮肤中HDP数量的改变。然而，需要进行研究来评估这些改变是由于产生和分泌机制的受损，还是由于AD患犬的HDP的结构改变。

 

HDPs represent one of the most important lines of defence against microbial invasion. Along with their powerful antimicrobial action, HDPs also are potent immunomodulatory molecules acting as a bridge between innate and adaptive immunity. Several HDPs have been identified in the skin of healthy and atopic dogs. As in humans, alterations to the expression and/or structure of HDPs have been hypothesised to increase susceptibility to skin infection in dogs with AD. Over the years, few studies on the expression of HDPs in atopic skin have been published. Such studies have shown increased gene expression of HDPs, mainly of β-defensins and cathelicidin, in the skin of atopic dogs when compared to healthy skin, particularly with active infection. Interestingly, the increased gene expression (mRNA) was not always accompanied by a similar increase at the protein level. These results suggested potential dysregulation in the synthesis of HDPs in atopic skin.

HDP是抵御微生物入侵的最重要的防线之一。除了它们强大的抗菌作用外，HDP也是一种强大的免疫调节分子，作为先天免疫和适应性免疫之间的桥梁。在健康和AD患犬的皮肤中已经发现了几种HDP。与人类一样，HDP的表达和/或结构的所有改变都被认为增加了AD犬对皮肤感染的易感性。多年来，关于HDP在特应性皮肤中的表达的研究很少发表。这些研究表明，与健康皮肤相比，特别是活动性感染皮肤相比，AD患犬皮肤中的HDP基因表达增加，特别是β-防御素和抗菌肽。有趣的是，基因表达（mRNA）的增加并不总是伴随着蛋白质水平上类似的增加。这些结果表明，在特应性皮肤中，HDP的合成可能存在失调。

 

Two recent studies have demonstrated qualitative and quantitative alterations of the secretion of HDPs in the skin of atopic dogs. In particular, one study comparing the skin-surface wash fluid from healthy and atopic dogs showed that, despite a similar amount of HDPs, skin wash fluid from atopic dogs had significantly lower inhibitory activity against S.pseudintermedius. This suggests that HDPs in atopic dogs exhibit poorer antimicrobial activity. More recently, another study analysed HDP expression in skin explants harvested from healthy and atopic dogs via indirect immunofluorescence (intracellular accumulation), enzyme-linked immunosorbent assay (secretion) and immuno-scanning electron microscopy (iSEM; surface expression). Atopic skin had higher levels of HDPs retained inside the keratinocytes and a lower level secreted in the supernatant compared to healthy skin. Using iSEM, it was evident that canine β-defensin was retained on the outermost layer of the SC and the number of bacteria-adhered peptides was higher in atopic when compared to healthy skin.

最近的两项研究表明，AD患犬皮肤中HDP的分泌有定量的改变。特别是，一项比较健康犬和AD患犬的皮肤表面清洗液的研究表明，尽管HDP含量相似，但AD患犬的皮肤清洗液对假中间型葡萄球菌的抑制活性明显较低。这表明，AD患犬的HDP表现出较差的抗菌活性。最近，另一项研究通过间接免疫荧光（细胞内积累）、酶联免疫吸附试验（分泌）和免疫扫描电镜（iSEM；表面表达）分析了健康和AD患犬皮肤外植体中HDP的表达。与健康皮肤相比，特应性皮肤在角质形成细胞内保留的HDP水平较高，而在血清中分泌的水平较低。通过iSEM，可以明显看出，犬β-防御素保留在SC的最外层，与健康皮肤相比，特应性皮炎皮肤中细菌粘附肽的数量更高。

 

As reported above, until recently the amount and function of HDPs has only been investigated in the skin of healthy and atopic dogs. In 2023, Santoro published the first report on the amount and antimicrobial activity of aural HDPs in healthy and atopic dogs. In this report, the author described a decreased amount of cBD3-like and cCath in noninfected ears of atopic dogs when compared with healthy ears. Measurable antimicrobial activity was very variable and considered minimal by the author.

如上所述，直到最近，HDP的数量和功能只在健康和AD患犬的皮肤上进行了研究。2023年，Santoro发表了第一份关于健康和AD患犬耳部HDP的数量和抗菌活性的报告。在本报告中，作者描述，与健康的耳道相比，非感染犬的耳道中cbd3样和cCath的数量减少。可测量的抗菌活性非常多变，作者认为其最小。

 

In summary, these studies suggest that atopic skin shows higher HDP gene expression nonassociated with an increase in protein expression. Additionally, there is dysregulation in the secretion (tendency to be retained in the keratinocytes), dispersion (tendency to remain attached on the skin surface), and probably antimicrobial efficacy (lower antibacterial inhibitory effect) of atopic compared to healthy HDPs. Thus, the involvement of HDPs in the pathogenesis of skin infections in dogs with AD may not be related to their levels, and rather to their functionality and secretion.

总之，这些研究表明，特应性皮炎皮肤显示出更高的HDP基因表达，而与蛋白表达的增加无关。此外，与健康皮肤的HDP相比，特应性皮炎皮肤HDP存在分泌失调（易于保留在角质形成细胞中）、散布（易于附着在皮肤表面），以及可能具有抗菌效果（较低的抗菌抑制作用）。因此，HDP参与AD犬皮肤感染的发病机制可能与其水平无关，而与其功能和分泌无关。

 

CONCLUSIONS

结论

In conclusion, in the past sevenyears, a moderate amount of research has been published on the effect of skin barrier integrity in the pathogenesis of canine AD. Such research has been focused not only on structural and immunological changes in the skin barrier, but also on the alterations occurring in the cutaneous and aural microbiome of atopic dogs. The results of these studies confirm the extremely complex nature of canine AD. Although the nonhomogeneous results among studies makes their interpretation difficult, it also favours the concept of AD being a syndrome with more than a single entity. In particular, it is evident that there are several subsets of this disease and intrinsic alterations of skin barrier may play a significant role in some dogs, while the imbalance of the immune system may play a larger role in others. Such recognition is essential to design an appropriate treatment plan. In fact, dogs with intrinsic alterations of skin barrier may benefit more from topical therapies aimed to restore it. However, dogs with a predominant imbalance of the immune response may benefit more from anti-inflammatory medications.

总之，在过去的七年中，关于皮肤屏障完整性在犬AD发病机制中的影响的适度研究已经发表。这类研究不仅关注皮肤屏障的结构和免疫变化，而且还关注在AD患犬的皮肤和耳道微生物群中发生的改变。这些研究的结果证实了犬AD极其复杂的性质。尽管研究之间的非同质结果使其解释变得困难，但它也倾向于将AD看作是一种具有多个单一实体的综合征的概念。特别是，很明显，这种疾病有多个亚群，皮肤屏障的内在改变可能在一些犬中发挥重要作用，而免疫系统的失衡可能在其他犬中发挥更大的作用。这种认识对于设计一个适当的治疗计划至关重要。事实上，有皮肤屏障内在改变的犬可能从旨在恢复它的外部疗法中获益更多。然而，免疫反应失衡的犬可能从抗炎药物中获益更多。

 

Also, newer studies have investigated the role that cutaneous and aural microbiota play in the development and/or worsening of canine AD. Unfortunately, such studies are mainly descriptive and still not able to elucidate the pathogenetic role of dysbiosis in canine AD. Nevertheless, this information is essential to move forward understanding the pathogenesis of this complex disease and to better guide the development of new therapeutic options.

此外，最新的研究已经调查了皮肤和耳道微生物群在犬AD的发展和/或恶化中发挥的作用。不幸的是，这些研究主要是描述性的，仍然不能阐明犬AD中菌群失调的致病作用。然而，这些信息对于进一步了解这一复杂疾病的发病机制和更好地指导新的治疗方案的开发是至关重要的。

 

南海

！！！！

杨先生